Materiały źródłowe

• #1 Pathophysiology of urticaria – PubMed

  https://pubmed.ncbi.nlm.nih.gov/16461989/

  Urticaria is dermal edema resulting from vascular dilatation and leakage of fluid into the skin in response to molecules released from mast cells. The major preformed mediator histamine produces a prototypic, short-lived urticaria. However, the clinical spectrum and pattern of lesions indicate that other molecules, including prostaglandins, leukotrienes, cytokines, and chemokines, produced at different times after mast cell activation contribute to the polymorphism of this symptom and the variable evolution of this disease. […] It is now well established that urticaria may result from the binding of IgG auto-antibodies to IgE and/or to the receptor for IgE molecules on mast cells, thus corresponding to a type II HS reaction. These auto-immune urticarias represent up to 50% of patients with chronic urticaria. Mast cell activation can also result from type III HS through the binding of circulating immune complexes to mast cell-expressing Fc receptors for IgG and IgM. Finally, under certain circumstances, T-cells can induce activation of mast cells, as well as histamine release (type IV HS). Nonimmunological urticarias result from mast cell activation through membrane receptors involved in innate immunity (e.g., complement, Toll-like, cytokine/chemokine, opioid) or by direct toxicity of xenobiotics (haptens, drugs). In conclusion, urticaria may result from different pathophysiological mechanisms that explain the great heterogeneity of clinical symptoms and the variable responses to treatment.

• #2 Urticaria | Nature Reviews Disease Primers

  https://www.nature.com/articles/s41572-022-00389-z

  Urticaria is an inflammatory skin disorder that affects up to 20% of the world population at some point during their life. […] The pathogenesis of CSU consists of several interlinked events involving autoantibodies, complement and coagulation. […] Current urticaria treatment aims at complete response, with a stepwise approach using second-generation H1 antihistamines, omalizumab and cyclosporine. […] Novel treatment approaches centre on targeting mediators, signalling pathways and receptors of mast cells and other immune cells. […] Further research should focus on defining disease endotypes and their biomarkers, identifying new treatment targets and developing improved therapies.

• #3 Hives – Wikipedia

  https://en.wikipedia.org/wiki/Hives

  Hives are caused by the release of histamine and other mediators of inflammation (cytokines) from cells in the skin. This process can be the result of an allergic or nonallergic reaction, differing in the eliciting mechanism of histamine release. […] Over half of all cases of chronic idiopathic hives are the result of an autoimmune trigger. Roughly 50% of people with chronic urticaria spontaneously develop autoantibodies directed at the receptor FcRI located on skin mast cells. Chronic stimulation of this receptor leads to chronic hives. […] Mechanisms other than allergen-antibody interactions are known to cause histamine release from mast cells. Many drugs, for example morphine, can induce direct histamine release not involving any immunoglobulin molecule. Also, a diverse group of signaling substances called neuropeptides, have been found to be involved in emotionally induced hives. […] The skin lesions of urticarial disease are caused by an inflammatory reaction in the skin, causing leakage of capillaries in the dermis, and resulting in an edema which persists until the interstitial fluid is absorbed into the surrounding cells.

• #4 Urticaria: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/762917-overview

  Urticaria (hives) results from the release of histamine, bradykinin, leukotriene C4, prostaglandin D2, and other vasoactive substances from mast cells and basophils in the dermis. These substances cause extravasation of fluid into the dermis, leading to the urticarial lesion. The intense pruritus (itchiness) of urticaria is a result of histamine released into the dermis. Histamine is the ligand for two membrane-bound receptors, the H1 and H2 receptors, which are present on many cell types. The activation of the H1 histamine receptors on endothelial and smooth muscle cells leads to increased capillary permeability. The activation of the H2 histamine receptors leads to arteriolar and venule vasodilation. […] This process is caused by several mechanisms. The type I allergic IgE response is initiated by antigen-mediated IgE immune complexes that bind and cross-link Fc receptors on the surface of mast cells and basophils, thus causing degranulation with histamine release. The type II allergic response is mediated by cytotoxic T cells, causing deposits of immunoglobulins, complement, and fibrin around blood vessels. This leads to urticarial vasculitis. The type III immune-complex disease is associated with systemic lupus erythematosus and other autoimmune diseases that cause urticaria.

• #5 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Hives-Pathophysiology.aspx

  Urticaria or hives is commonly caused by the release of histamine and other chemical messengers in the skin surface. The reaction begins when cutaneous mast cells and basophils release histamine and other inflammatory mediators at the skin’s surface. The mast cells are stimulated to release these chemicals when Immunoglobulin E (IgE) antibodies bind to an allergen and effectively flag it up as a foreign body. […] Histamine triggers the dilation of the blood vessels across the skin leading to its warm and reddish appearance. In addition, the dilated blood vessels can become leaky and release fluids that cause swelling or edema. This often remains until the excess fluid is absorbed back by cells surrounding the swelling.

• #6 Eczema and Hives: Identifying and Managing Them Successfully

  https://www.dexeryl.com/en/your-skin/atopic-dermatitis/different-types-of-eczema/urticaria-eczema

  Urticaria results from a complex reaction involving mast cells, key immune system cells in the skin, and mucous membranes. These cells contain an inflammation molecule: histamine. When mast cells are activated, they release histamine, which causes blood vessel dilation and increased permeability. This reaction leads to fluid and cell infiltration into the surrounding tissues, causing oedema. This mechanism is at the root of urticaria patches. […] Urticaria splits into two categories: – Acute urticaria is marked by an isolated flare lasting hours to days, potentially recurring in different spots, and usually non-allergic. – Chronic urticaria is characterised by persistent or recurrent outbreaks over at least six weeks. It’s a non-allergic skin inflammation, sensitising the skin’s mast cells to a variety of non-allergic stimuli. It might come with abdominal pain, joint discomfort, and fever. Chronic hives’ course can last months or years.

• #7 Hives: The target of itching | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-hives-the-target-itching-S0301054616300593

  The main effector cell in the physiopathology of urticaria is the mast cell, which releases inflammatory mediators (either preformed or de novo), giving rise to tissue responses involving other effector cells such as basophils, Th2 lymphocytes and, to a lesser degree, neutrophils and eosinophils. […] From the immunopathological perspective, urticaria is characterized by the intervention of proinflammatory cells such as mast cells, eosinophils, neutrophils, monocytes, macrophages and T lymphocytes that release different mediators the fundamental representative of which is histamine (beta-imidazole-ethylamine). This mediator binds to the H1 receptors of blood vessels, causing vascular dilatation, decreased blood pressure and increased capillary permeability, with an outflow of exudate, antibodies, macrophages and other components of the complement system into the interstitial fluid compartment, thereby favoring the development of edema.

• #8 Urticaria: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/762917-overview

  Urticaria (hives) results from the release of histamine, bradykinin, leukotriene C4, prostaglandin D2, and other vasoactive substances from mast cells and basophils in the dermis. These substances cause extravasation of fluid into the dermis, leading to the urticarial lesion. The intense pruritus (itchiness) of urticaria is a result of histamine released into the dermis. Histamine is the ligand for two membrane-bound receptors, the H1 and H2 receptors, which are present on many cell types. The activation of the H1 histamine receptors on endothelial and smooth muscle cells leads to increased capillary permeability. The activation of the H2 histamine receptors leads to arteriolar and venule vasodilation. […] This process is caused by several mechanisms. The type I allergic IgE response is initiated by antigen-mediated IgE immune complexes that bind and cross-link Fc receptors on the surface of mast cells and basophils, thus causing degranulation with histamine release. The type II allergic response is mediated by cytotoxic T cells, causing deposits of immunoglobulins, complement, and fibrin around blood vessels. This leads to urticarial vasculitis. The type III immune-complex disease is associated with systemic lupus erythematosus and other autoimmune diseases that cause urticaria.

• #9 Acute Urticaria: Background, Etiology, Pathophysiology

  https://emedicine.medscape.com/article/137362-overview

  Urticaria results from the release of histamine, bradykinin, leukotriene C4, prostaglandin D2, and other vasoactive substances from mast cells and basophils in the dermis. These substances cause extravasation of plasma into the dermis, leading to the urticarial lesion. The intense pruritus of urticaria is a result of histamine released into the dermis. One study showed that D-dimer levels correlate with the severity of acute urticaria and may serve as a marker of disease severity. […] Although urticaria results from transient extravasation of plasma into the dermis, angioedema is the subcutaneous extension of urticaria that results in deep swelling within subcutaneous/submucosal tissues and is associated with pain but not pruritus. […] Histamine is the ligand for two membrane-bound receptors, the H1 and H2 receptors, which are present on many cell types. The activation of the H1 histamine receptors on endothelial and smooth muscle cells leads to increased capillary permeability. The activation of the H2 histamine receptors leads to arteriolar and venule vasodilation. This process is caused by several types of immune hypersensitivity mechanisms as follows:

• #10 Urticaria: Etiology, pathogenesis, diagnosis, and treatment – IJPP

  https://www.ijpp.org.in/html-article/17719

  These causes histamine release from mast cell. […] Due to histamine release swelling and itch take place. […] Urticaria caused by non-immune mechanism is found in physical urticaria such as dermographism, delayed pressure urticaria, cold urticaria, solar urticaria, aquagenic urticaria and vibratory urticaria. […] Along with Mast cells, basophils also act as effector cells in this mechanism. […] These cells release vasoactive substances like histamine, bradykinin, leukotriene C4, prostaglandin D2, release of these substances and vasodilatation takes place and therefore increases vascular permeability. […] This produces erythema and edema dominant to urticaria lesions. […] Itching, an important feature of urticaria is mediated by histamine receptors as erythema and flushing.

• #11 Urticaria: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/762917-overview

  Urticaria (hives) results from the release of histamine, bradykinin, leukotriene C4, prostaglandin D2, and other vasoactive substances from mast cells and basophils in the dermis. These substances cause extravasation of fluid into the dermis, leading to the urticarial lesion. The intense pruritus (itchiness) of urticaria is a result of histamine released into the dermis. Histamine is the ligand for two membrane-bound receptors, the H1 and H2 receptors, which are present on many cell types. The activation of the H1 histamine receptors on endothelial and smooth muscle cells leads to increased capillary permeability. The activation of the H2 histamine receptors leads to arteriolar and venule vasodilation. […] This process is caused by several mechanisms. The type I allergic IgE response is initiated by antigen-mediated IgE immune complexes that bind and cross-link Fc receptors on the surface of mast cells and basophils, thus causing degranulation with histamine release. The type II allergic response is mediated by cytotoxic T cells, causing deposits of immunoglobulins, complement, and fibrin around blood vessels. This leads to urticarial vasculitis. The type III immune-complex disease is associated with systemic lupus erythematosus and other autoimmune diseases that cause urticaria.

• #12 Acute Urticaria: Background, Etiology, Pathophysiology

  https://emedicine.medscape.com/article/137362-overview

  Urticaria results from the release of histamine, bradykinin, leukotriene C4, prostaglandin D2, and other vasoactive substances from mast cells and basophils in the dermis. These substances cause extravasation of plasma into the dermis, leading to the urticarial lesion. The intense pruritus of urticaria is a result of histamine released into the dermis. One study showed that D-dimer levels correlate with the severity of acute urticaria and may serve as a marker of disease severity. […] Although urticaria results from transient extravasation of plasma into the dermis, angioedema is the subcutaneous extension of urticaria that results in deep swelling within subcutaneous/submucosal tissues and is associated with pain but not pruritus. […] Histamine is the ligand for two membrane-bound receptors, the H1 and H2 receptors, which are present on many cell types. The activation of the H1 histamine receptors on endothelial and smooth muscle cells leads to increased capillary permeability. The activation of the H2 histamine receptors leads to arteriolar and venule vasodilation. This process is caused by several types of immune hypersensitivity mechanisms as follows:

• #13 Hives: The target of itching | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-hives-the-target-itching-S0301054616300593

  The main effector cell in the physiopathology of urticaria is the mast cell, which releases inflammatory mediators (either preformed or de novo), giving rise to tissue responses involving other effector cells such as basophils, Th2 lymphocytes and, to a lesser degree, neutrophils and eosinophils. […] From the immunopathological perspective, urticaria is characterized by the intervention of proinflammatory cells such as mast cells, eosinophils, neutrophils, monocytes, macrophages and T lymphocytes that release different mediators the fundamental representative of which is histamine (beta-imidazole-ethylamine). This mediator binds to the H1 receptors of blood vessels, causing vascular dilatation, decreased blood pressure and increased capillary permeability, with an outflow of exudate, antibodies, macrophages and other components of the complement system into the interstitial fluid compartment, thereby favoring the development of edema.

• #14 Urticaria and angioedema | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0288-z

  Mast cells are the primary effector cells in urticaria and in many cases of angioedema. These cells are widely distributed in the skin, mucosa, and other areas of the body, and have high-affinity immunoglobulin E (IgE) receptors. Mast cell degranulation leads to the rapid release of various inflammatory mediators, such as histamine, leukotrienes and prostaglandins, which, in turn, cause vasodilation and leakage of plasma in and below the skin. […] Although the exact pathogenesis of attacks of HAE and AAE remains unclear, excess production of the potent vasodilatory peptide, bradykinin (which is regulated by the C1-INH), appears to play an important role. It is important to note that histamine and other mast cell mediators that are typical of urticaria and associated angioedema are not directly involved in HAE and AAE, which explains patient lack of response to antihistamines and corticosteroids, and distinguishes these forms of isolated angioedema from that associated with urticaria.

• #15 Pathophysiology of urticaria – PubMed

  https://pubmed.ncbi.nlm.nih.gov/16461989/

  Urticaria is dermal edema resulting from vascular dilatation and leakage of fluid into the skin in response to molecules released from mast cells. The major preformed mediator histamine produces a prototypic, short-lived urticaria. However, the clinical spectrum and pattern of lesions indicate that other molecules, including prostaglandins, leukotrienes, cytokines, and chemokines, produced at different times after mast cell activation contribute to the polymorphism of this symptom and the variable evolution of this disease. […] It is now well established that urticaria may result from the binding of IgG auto-antibodies to IgE and/or to the receptor for IgE molecules on mast cells, thus corresponding to a type II HS reaction. These auto-immune urticarias represent up to 50% of patients with chronic urticaria. Mast cell activation can also result from type III HS through the binding of circulating immune complexes to mast cell-expressing Fc receptors for IgG and IgM. Finally, under certain circumstances, T-cells can induce activation of mast cells, as well as histamine release (type IV HS). Nonimmunological urticarias result from mast cell activation through membrane receptors involved in innate immunity (e.g., complement, Toll-like, cytokine/chemokine, opioid) or by direct toxicity of xenobiotics (haptens, drugs). In conclusion, urticaria may result from different pathophysiological mechanisms that explain the great heterogeneity of clinical symptoms and the variable responses to treatment.

• #16 Chronic spontaneous urticaria – Wikipedia

  https://en.wikipedia.org/wiki/Chronic_spontaneous_urticaria

  Chronic spontaneous urticaria, despite its cause being unknown, is linked to a higher prevalence of autoimmune diseases, and is often worsened by triggers like stress, infections, certain foods, or nonsteroidal anti-inflammatory drugs. The hives and angioedema seen in CSU is thought to be linked to the degranulation of skin mast cells. Mast cells release proteases, histamine, cytokines, and arachidonic acid metabolites, causing swelling, redness, and itching. […] The degranulation of skin mast cells in CSU appears to be involved in wheals and angioedema. These cells release proteases, histamine, and cytokines along with platelet-activating factors and other metabolites of arachidonic acid. These mediators cause swelling, redness, and itching by stimulating sensory nerve endings, increasing vascular permeability, and inducing vasodilatation. Edema, mast cell degranulation, and a perivascular infiltrate of cells, including CD4 lymphocytes, monocytes, neutrophils, eosinophils, and basophils, are the hallmarks of a lesion site, also known as a wheal.

• #17 Urticaria: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/762917-overview

  Urticaria (hives) results from the release of histamine, bradykinin, leukotriene C4, prostaglandin D2, and other vasoactive substances from mast cells and basophils in the dermis. These substances cause extravasation of fluid into the dermis, leading to the urticarial lesion. The intense pruritus (itchiness) of urticaria is a result of histamine released into the dermis. Histamine is the ligand for two membrane-bound receptors, the H1 and H2 receptors, which are present on many cell types. The activation of the H1 histamine receptors on endothelial and smooth muscle cells leads to increased capillary permeability. The activation of the H2 histamine receptors leads to arteriolar and venule vasodilation. […] This process is caused by several mechanisms. The type I allergic IgE response is initiated by antigen-mediated IgE immune complexes that bind and cross-link Fc receptors on the surface of mast cells and basophils, thus causing degranulation with histamine release. The type II allergic response is mediated by cytotoxic T cells, causing deposits of immunoglobulins, complement, and fibrin around blood vessels. This leads to urticarial vasculitis. The type III immune-complex disease is associated with systemic lupus erythematosus and other autoimmune diseases that cause urticaria.

• #18 Acute Urticaria: Background, Etiology, Pathophysiology

  https://emedicine.medscape.com/article/137362-overview

  The type I allergic immunoglobulin (Ig) E response is initiated by antigen-mediated IgE immune complexes that bind and cross-link Fc receptors on the surface of mast cells and basophils, thus causing degranulation with histamine release. […] Complement-mediated urticaria includes viral and bacterial infections, serum sickness, and transfusion reactions. Urticarial transfusion reactions occur when allergenic substances in the plasma of the donated blood product react with pre-existing IgE antibodies in the recipient. Certain drugs (opioids, vecuronium, succinylcholine, vancomycin, and others) as well as radiocontrast agents cause urticaria due to mast cell degranulation through a non-IgE-mediated mechanism.

• #19 Urticaria: Etiology, pathogenesis, diagnosis, and treatment – IJPP

  https://www.ijpp.org.in/html-article/17719

  Urticaria is a skin disorder that pathologically produces itchy wheals, surrounded by a red halo or flare. […] The mast cell is the major affected cell in urticaria. […] The first step for formation of wheals is the degranulation of mast cells with release of histamine. […] Activation of the cutaneous mast cells due to vascular changes, which contain a range of mediators mainly histamine. […] Interaction of both H 1 and H 2 histamine receptors produces vascular permeability in skin. […] Due to activation of H 1 receptors in the skin induce flare, erythema, whealing, itching, contraction of smooth muscle in the respiratory and gastro-intestinal tract. […] Activation of H 2 receptors lead to erythema and whealing in the skin. […] Immunological mechanism mediated by IgE antibody.

• #20 Chronic Urticaria—Pathogenesis, Diagnostics, Therapy and Influence of Coexisting Angioedema

  https://www.mdpi.com/2077-0383/12/2/688

  Urticaria is one of the most frequent dermatological diseases and it usually occurs in paroxysmal, recurrent form. The most important role in the pathogenesis of this disease is played by histamine, which is released from mast cells. Immune mechanisms depend on IgE and its complement system. Non-immunological mechanisms, including the direct degranulation of mast cells, play a significant role as well. […] Currently, two endotypes of CSU can be distinguished, which vary in terms of pathogenesis and markers of the disease, as well as clinical course and sensitivity to treatment applied: type I and IIb. Type I CSU is related to the occurrence of IgE antibodies to autoantigens such as TPO (thyroid peroxidase), TG (thyroglobulin), ds-DNA (double-stranded DNA) and Il-24. In type I, it is observed that the occurrence of allergic diseases and the total concentration of IgE are normal or even increased.

• #21 Prevalence of Autoimmune and Autoinflammatory Diseases in Chronic Urticaria: Pathogenetic, Diagnostic and Therapeutic Implications

  https://www.mdpi.com/2227-9059/11/2/410

  Moreover, recently a dysregulation of intracellular signaling pathways in mast cells and basophils leading to defect in cell function and the production of IgG autoantibodies directed against FcεRI or IgE on both mast cells and basophils or IgE autoantibodies against autoantigens like thyroid peroxidase, DNA and IL-24 have been demonstrated to be involved in urticaria pathogenesis. […] Regardless of the mechanism, the release of histamine, platelet-activating factor, tryptase, leukotrienes, and other cytokines lead to sensory nerve activation, vasodilatation, and plasma extravasation, as well as cell recruitment typical of urticarial lesions. […] Each different possible pathway of activation correlates to a different endotype of urticaria that produce different and similar phenotypes. […] Recently, two different endotypes of CSU have been proposed: (1) IgE-mediated CUS, also known as autoallergic CSU and (2) type IIb autoimmune CSU, characterized by the presence of IgG autoantibodies, and probably IgM and IgA that are responsible for direct activation of mast cells with the binding of high-affinity IgE receptors.

• #22 Pathophysiology of urticaria – PubMed

  https://pubmed.ncbi.nlm.nih.gov/16461989/

  Urticaria is dermal edema resulting from vascular dilatation and leakage of fluid into the skin in response to molecules released from mast cells. The major preformed mediator histamine produces a prototypic, short-lived urticaria. However, the clinical spectrum and pattern of lesions indicate that other molecules, including prostaglandins, leukotrienes, cytokines, and chemokines, produced at different times after mast cell activation contribute to the polymorphism of this symptom and the variable evolution of this disease. […] It is now well established that urticaria may result from the binding of IgG auto-antibodies to IgE and/or to the receptor for IgE molecules on mast cells, thus corresponding to a type II HS reaction. These auto-immune urticarias represent up to 50% of patients with chronic urticaria. Mast cell activation can also result from type III HS through the binding of circulating immune complexes to mast cell-expressing Fc receptors for IgG and IgM. Finally, under certain circumstances, T-cells can induce activation of mast cells, as well as histamine release (type IV HS). Nonimmunological urticarias result from mast cell activation through membrane receptors involved in innate immunity (e.g., complement, Toll-like, cytokine/chemokine, opioid) or by direct toxicity of xenobiotics (haptens, drugs). In conclusion, urticaria may result from different pathophysiological mechanisms that explain the great heterogeneity of clinical symptoms and the variable responses to treatment.

• #23 Hives – Wikipedia

  https://en.wikipedia.org/wiki/Hives

  Hives are caused by the release of histamine and other mediators of inflammation (cytokines) from cells in the skin. This process can be the result of an allergic or nonallergic reaction, differing in the eliciting mechanism of histamine release. […] Over half of all cases of chronic idiopathic hives are the result of an autoimmune trigger. Roughly 50% of people with chronic urticaria spontaneously develop autoantibodies directed at the receptor FcRI located on skin mast cells. Chronic stimulation of this receptor leads to chronic hives. […] Mechanisms other than allergen-antibody interactions are known to cause histamine release from mast cells. Many drugs, for example morphine, can induce direct histamine release not involving any immunoglobulin molecule. Also, a diverse group of signaling substances called neuropeptides, have been found to be involved in emotionally induced hives. […] The skin lesions of urticarial disease are caused by an inflammatory reaction in the skin, causing leakage of capillaries in the dermis, and resulting in an edema which persists until the interstitial fluid is absorbed into the surrounding cells.

• #24 Chronic Urticaria—Pathogenesis, Diagnostics, Therapy and Influence of Coexisting Angioedema

  https://www.mdpi.com/2077-0383/12/2/688

  In type IIb CSU, IgG and IgM antibodies to IgE and high-affinity receptors for IgE (FceRI) are identified. Additionally, in the clinical course of this endotype, greater severity of symptoms and a prolonged duration of the disease, coexistence of autoimmune diseases, presence of ANA (antinuclear antibodies), elevated CRP levels, basopenia and eosinopenia in peripheral blood and reduced levels of total IgE occur. […] Urticaria is a multiform disorder with partially unknown pathophysiology, and therapy effectiveness is still limited, in spite of several options. Recurrent angioedema is a form of chronic urticaria.

• #25 AAIR :: Allergy, Asthma & Immunology Research

  https://e-aair.org/DOIx.php?id=10.4168/aair.2017.9.6.477

  For an extensive discussion of our current knowledge and historical perspectives, review articles can be consulted. I will present a summary of current concepts including some areas that remain controversial. Since there is no exogenous stimulus or cause, neither foods, drugs, food additives, or other chemicals are relevant which is why routine food skin testing or radioallergosorbent test (RAST) is not recommended for evaluation. […] Among the possibilities for the etiology of CSU is that it is an autoimmune skin disease, or at least a subpopulation of patients could be considered as such. Depending on the authors, 35%40% of patients have an IgG antibody to the subunit of the high affinity IgE receptor (IgG anti-FcRI) while an additional 5%10% have IgG anti-IgE. These are functional and can be shown to induce histamine release from blood basophils or cutaneous mast cells.

• #26

  https://www.alliedacademies.org/articles/autoimmune-urticaria-pathogenesis-diagnosis-and-management-31969.html

  Autoimmune urticaria (AIU) is a chronic and often debilitating skin condition characterized by recurrent hives that arise due to an underlying autoimmune mechanism. […] AIU is primarily driven by autoantibodies, particularly immunoglobulin G (IgG) autoantibodies, that target high-affinity IgE receptors (FcRI) on mast cells and basophils. These autoantibodies can directly trigger mast cell degranulation, leading to the release of histamine and other inflammatory mediators responsible for the development of hives. […] Furthermore, AIU has been linked to other autoimmune diseases, such as thyroid disorders (e.g., Hashimotos thyroiditis and Graves disease), systemic lupus erythematosus, and rheumatoid arthritis. This association suggests that dysregulated immune tolerance plays a crucial role in its development. Additionally, complement system activation has been implicated in AIU pathogenesis, further exacerbating mast cell activation and inflammation.

• #27 Chronic Urticaria (Hives) and Autoimmunity

  https://www.skintherapyletter.com/urticaria/autoimmunity/

  Chronic idiopathic urticaria, which has no discernable external cause, comprises the majority of cases of chronic urticaria. Over half of all cases of chronic idiopathic urticaria are thought to occur by an autoimmune mechanism, primarily autoantibodies against the high affinity immunoglobulin E (IgE) receptor (FcεRI). […] Approximately 50% of patients with chronic idiopathic urticaria have IgG antibodies that are specific for the high affinity IgE receptor (FcεRI). These autoantibodies activate mast cells in the skin, circulating basophils, and the complement system. […] It has been hypothesized that thyroid disease may worsen urticaria and angioedema through activation of the complement system. […] Chronic idiopathic urticaria is hypothesized to occur because of a predisposition in the patient to develop autoimmune diseases. […] Autoantibodies to the high affinity IgE receptor are the most commonly identified offender, activating mast cells, basophils, and the complement system, resulting in the wheal and flare reaction.

• #28 Prevalence of Autoimmune and Autoinflammatory Diseases in Chronic Urticaria: Pathogenetic, Diagnostic and Therapeutic Implications

  https://www.mdpi.com/2227-9059/11/2/410

  Moreover, recently a dysregulation of intracellular signaling pathways in mast cells and basophils leading to defect in cell function and the production of IgG autoantibodies directed against FcεRI or IgE on both mast cells and basophils or IgE autoantibodies against autoantigens like thyroid peroxidase, DNA and IL-24 have been demonstrated to be involved in urticaria pathogenesis. […] Regardless of the mechanism, the release of histamine, platelet-activating factor, tryptase, leukotrienes, and other cytokines lead to sensory nerve activation, vasodilatation, and plasma extravasation, as well as cell recruitment typical of urticarial lesions. […] Each different possible pathway of activation correlates to a different endotype of urticaria that produce different and similar phenotypes. […] Recently, two different endotypes of CSU have been proposed: (1) IgE-mediated CUS, also known as autoallergic CSU and (2) type IIb autoimmune CSU, characterized by the presence of IgG autoantibodies, and probably IgM and IgA that are responsible for direct activation of mast cells with the binding of high-affinity IgE receptors.

• #29 Hives: The target of itching | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-hives-the-target-itching-S0301054616300593

  The pathogenesis of urticaria manifests in the form of hives or wheals produced by immunological and non-immunological stimuli that induce plasma extravasation in the papillary dermis. In IgE-mediated urticaria, the presence of this immunoglobulin on the surface of mast cells and basophils triggers the release of leukotrienes, prostaglandin D2, platelet activating factor, eosinophil chemotactic factor and histamine (the main mediator), which binds to the H1 receptors inducing skin erythema, edema and pruritus. […] An association has been established between high levels of B cell activating factor (BAFF) in patients with chronic urticaria and positive autologous serum skin testing, the presence of antithyroid antibodies, antinuclear antibodies, high total IgE titers, and severity of the disease. Autoimmune chronic urticaria is due to the strong affinity of the anti-FcRI autoantibodies (and to a lesser degree also of anti-IgE autoantibodies) for the IgE receptors.

• #30 Chronic Urticaria—Pathogenesis, Diagnostics, Therapy and Influence of Coexisting Angioedema

  https://www.mdpi.com/2077-0383/12/2/688

  In type IIb CSU, IgG and IgM antibodies to IgE and high-affinity receptors for IgE (FceRI) are identified. Additionally, in the clinical course of this endotype, greater severity of symptoms and a prolonged duration of the disease, coexistence of autoimmune diseases, presence of ANA (antinuclear antibodies), elevated CRP levels, basopenia and eosinopenia in peripheral blood and reduced levels of total IgE occur. […] Urticaria is a multiform disorder with partially unknown pathophysiology, and therapy effectiveness is still limited, in spite of several options. Recurrent angioedema is a form of chronic urticaria.

• #31 Hives: The target of itching | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-hives-the-target-itching-S0301054616300593

  Another released mediator is platelet activating factor (PAF), which in turn would cause other cells to release serotonin one of the factors responsible for chronic urticaria. Eosinophil chemotactic factor would induce such cells to migrate towards the inflammatory site. The activated eosinophils release cationic protein (ECP), peroxidase (EPO) and protein X (EPX). In particular, eosinophils are activated by IL-5, transforming into larger cells which are selectively recruited in late-phase inflammatory reactions. […] Complement activation releases anaphylotoxins (C3a, C4a, C5a), which by directly acting upon the cell surface contribute to release more histamine. In this regard, factor C5a is the factor with the strongest impact upon vascular permeability, since its inhibition mediated by anaphylotoxin inhibiting factor occurs in a later stage, allowing it to not only favor permeability but also to act as a chemotactic factor for eosinophils and neutrophils that arrive at the inflammatory site.

• #32 Urticaria pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Urticaria_pathophysiology

  Activation of mast cells and basophils has been increased in urticaria. There are two known mechanisms that lead to mast cell and basophil activation in the process of urticaria: 1: Defect in intracellular signaling: Improper activation of spleen tyrosine kinase (Syk) or improper inhibition of Src homology 2 (SH2)-containing inositol phosphatases (SHIP). 2: Autoimmune mechanisms: Antibody-mediated mast cell and basophil activation via IgG or IgE mediated pathways. […] Complement system is also responsible in pathogenesis of chronic spontaneous urticaria. In-vitro experiments have been demonstrated the role of C5a in enhancement of IgG-dependent histamine release from basophils and mast cells in chronic urticaria. In a study done on 70 patients with chronic spontaneous urticaria significant elevated levels of C3 and C4 have been detected, compared to the normal population. Increased production of C3 and C4 by liver is probably due to elevation in pro-inflammatory cytokines, such as IL-1, IL-6 or tumor necrosis factor (TNF). C3a itself further stimulates the secretion of other pro-inflammatory cytokines and chemokines and expresses on cells responsible in urticaria formation, such as mast cells, basophils, eosinophils, neutrophils and monocytes. Anaphylatoxin C3a is also able to stimulate histamine release which is capable of causing vasodilatation and consequent increased permeability of small blood vessels.

• #33 Hives: The target of itching | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-hives-the-target-itching-S0301054616300593

  Another released mediator is platelet activating factor (PAF), which in turn would cause other cells to release serotonin one of the factors responsible for chronic urticaria. Eosinophil chemotactic factor would induce such cells to migrate towards the inflammatory site. The activated eosinophils release cationic protein (ECP), peroxidase (EPO) and protein X (EPX). In particular, eosinophils are activated by IL-5, transforming into larger cells which are selectively recruited in late-phase inflammatory reactions. […] Complement activation releases anaphylotoxins (C3a, C4a, C5a), which by directly acting upon the cell surface contribute to release more histamine. In this regard, factor C5a is the factor with the strongest impact upon vascular permeability, since its inhibition mediated by anaphylotoxin inhibiting factor occurs in a later stage, allowing it to not only favor permeability but also to act as a chemotactic factor for eosinophils and neutrophils that arrive at the inflammatory site.

• #34 Urticaria pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Urticaria_pathophysiology

  Activation of mast cells and basophils has been increased in urticaria. There are two known mechanisms that lead to mast cell and basophil activation in the process of urticaria: 1: Defect in intracellular signaling: Improper activation of spleen tyrosine kinase (Syk) or improper inhibition of Src homology 2 (SH2)-containing inositol phosphatases (SHIP). 2: Autoimmune mechanisms: Antibody-mediated mast cell and basophil activation via IgG or IgE mediated pathways. […] Complement system is also responsible in pathogenesis of chronic spontaneous urticaria. In-vitro experiments have been demonstrated the role of C5a in enhancement of IgG-dependent histamine release from basophils and mast cells in chronic urticaria. In a study done on 70 patients with chronic spontaneous urticaria significant elevated levels of C3 and C4 have been detected, compared to the normal population. Increased production of C3 and C4 by liver is probably due to elevation in pro-inflammatory cytokines, such as IL-1, IL-6 or tumor necrosis factor (TNF). C3a itself further stimulates the secretion of other pro-inflammatory cytokines and chemokines and expresses on cells responsible in urticaria formation, such as mast cells, basophils, eosinophils, neutrophils and monocytes. Anaphylatoxin C3a is also able to stimulate histamine release which is capable of causing vasodilatation and consequent increased permeability of small blood vessels.

• #35 Urticaria pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Urticaria_pathophysiology

  Activation of mast cells and basophils has been increased in urticaria. There are two known mechanisms that lead to mast cell and basophil activation in the process of urticaria: 1: Defect in intracellular signaling: Improper activation of spleen tyrosine kinase (Syk) or improper inhibition of Src homology 2 (SH2)-containing inositol phosphatases (SHIP). 2: Autoimmune mechanisms: Antibody-mediated mast cell and basophil activation via IgG or IgE mediated pathways. […] Complement system is also responsible in pathogenesis of chronic spontaneous urticaria. In-vitro experiments have been demonstrated the role of C5a in enhancement of IgG-dependent histamine release from basophils and mast cells in chronic urticaria. In a study done on 70 patients with chronic spontaneous urticaria significant elevated levels of C3 and C4 have been detected, compared to the normal population. Increased production of C3 and C4 by liver is probably due to elevation in pro-inflammatory cytokines, such as IL-1, IL-6 or tumor necrosis factor (TNF). C3a itself further stimulates the secretion of other pro-inflammatory cytokines and chemokines and expresses on cells responsible in urticaria formation, such as mast cells, basophils, eosinophils, neutrophils and monocytes. Anaphylatoxin C3a is also able to stimulate histamine release which is capable of causing vasodilatation and consequent increased permeability of small blood vessels.

• #36 Urticaria – Dermatologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/dermatologic-disorders/approach-to-the-dermatologic-patient/urticaria

  Urticaria results from the release of histamine, bradykinin, kallikrein, and other vasoactive substances from mast cells and basophils in the superficial dermis, resulting in intradermal edema caused by capillary and venous vasodilation and occasionally caused by leukocyte infiltration. […] The process can be immune mediated or nonimmune mediated. […] Immune-mediated mast cell activation includes Type I hypersensitivity reactions, in which allergen-bound IgE antibodies bind to high-affinity cell surface receptors on mast cells and basophils. […] Autoimmune disorders, in which antibodies to an IgE receptor functionally cross-link IgE receptors and cause mast cell degranulation. […] Nonimmune-mediated mast cell activation includes direct nonallergic activation of mast cells by certain medications or substances.

• #37 Urticaria: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/762917-overview

  Some evidence suggests vitamin D levels have an inverse correlation with the severity of chronic urticaria. […] Complement-mediated urticarias include viral and bacterial infections, serum sickness, and transfusion reactions. Urticarial transfusion reactions occur when allergenic substances in the plasma of the donated blood product react with preexisting IgE antibodies in the recipient. Certain drugs (opioids, vecuronium, succinylcholine, vancomycin, and others) as well as radiocontrast agents cause urticaria due to mast cell degranulation through a nonIgE-mediated mechanism. Urticaria from nonsteroidal anti-inflammatory drugs may be IgE-mediated or due to mast cell degranulation, and there may be significant cross-reactivity among the nonsteroidal anti-inflammatory drugs (NSAIDs) in causing urticaria and anaphylaxis.

• #38 A Diagnosis of Urticaria, Common Skin Condition | EMJ Reviews

  https://www.emjreviews.com/dermatology/article/urticaria-diagnosis/

  The mechanism that stimulates mast cell degranulation is key to the pathophysiology of urticaria. […] Cross-linking of mast cell receptors bound to specific immunoglobulin (Ig)E by exogenous allergens, also known as a Type I hypersensitivity reaction, may be relevant to acute urticaria but may not be relevant to chronic spontaneous disease. […] Other possible exogenous stimuli are pathogen-associated molecular patterns on microbes, which are able to bind to toll-like receptors on mast cells and trigger degranulation. […] Nonimmunologic stimuli include certain drugs, for example opiates, aspirin, and other nonsteroidal anti-inflammatory drugs; neuromuscular blocking agents, such as atracurium; antibiotics, such as polymyxin and vancomycin; and iodinated radiocontrast dyes. […] In addition, other stimuli, including complements, such as C5a anaphylatoxin, stem cell factor, and some neuropeptides, including substance P, can also trigger mast cell degranulation by binding to their respective receptors available on mast cell surface, independent of the involvement of IgE or IgE receptors.

• #39 Urticaria – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/urticaria/

  Activation of cutaneous mast cells liberates various mediators predominantly histamine which induces increased permeability of capillaries and venules which in turn produces uriticaria. The clini-cal response of urticaria to antihistamines proves this hypothesis. […] Mast cells may be activated by allergic or non-allergic mechanisms. Allergic mast cell acti-vation occurs as a result of linkage of two adjacent a sub – units of high affinity eg. penicillin. As a result of this, preformed histamines, proteases, prostag-landin D2, LT4 and interleukin 4 (IL-4), IL – 8 and tumour necrosis factor (TNF – a) are released. Non allergic mast cell activation occurs with a variety of substances like neuropeptides (substance P), drugs like morphine, codeine, vancomycin, radio contrast media and some foods such as strawberries.

• #40 Hives: The target of itching | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-hives-the-target-itching-S0301054616300593

  Although histamine is the most important mast cell mediator, non-mast cell mediators can also intervene. Mast cell activation moreover can be induced by other stimuli such as cytokines, opiates, heat, pressure and vibration, as well as by stem cell factor (SCF), which constitutes an IgE-independent mechanism.

• #41 Acute Urticaria: Background, Etiology, Pathophysiology

  https://emedicine.medscape.com/article/137362-overview

  The type I allergic immunoglobulin (Ig) E response is initiated by antigen-mediated IgE immune complexes that bind and cross-link Fc receptors on the surface of mast cells and basophils, thus causing degranulation with histamine release. […] Complement-mediated urticaria includes viral and bacterial infections, serum sickness, and transfusion reactions. Urticarial transfusion reactions occur when allergenic substances in the plasma of the donated blood product react with pre-existing IgE antibodies in the recipient. Certain drugs (opioids, vecuronium, succinylcholine, vancomycin, and others) as well as radiocontrast agents cause urticaria due to mast cell degranulation through a non-IgE-mediated mechanism.

• #42 Urticaria: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/762917-overview

  The physical urticarias in which some physical stimulus causes urticaria include immediate pressure urticaria, delayed pressure urticaria, cold urticaria, and cholinergic urticaria. […] For some urticarias, especially chronic urticarias, no cause can be found, despite exhaustive efforts—the so-called idiopathic urticarias, although most of these are chronic autoimmune urticaria as defined by a positive autologous serum skin test (ASST). […] To date, no reliable test exists to identify with certainty if chronic urticaria is autoimmune or nonautoimmune in the specific patient.

• #43 Urticaria in children

  https://dermnetnz.org/topics/urticaria-in-children

  Weals are caused by a number of chemical mediators, such as histamine and cytokines, which are released from inflammatory cells, including mast cells. The mediators cause vasodilation and leakage of fluid into surrounding tissues to produce the redness and swelling of urticarial weals. […] Chronic urticaria is usually caused by autoimmunity or a chronic underlying infection. It is rare in children. […] Inducible urticaria is caused by a direct stimulus, such as dermographism, delayed pressure, cold, heat, sunlight, vibration, or exercise. It is linked with atopy and chronic urticaria, but the pathogenesis is not fully understood.

• #44 Hives (Urticaria) Causes, Fast Treatment, Symptoms, Pictures

  https://www.medicinenet.com/hives/article.htm

  Physical urticaria (for example, heat hives) is a type of chronic urticaria produced by physical stimuli. Common environmental provocations such as sunlight (solar urticaria), water, cold, heat, exercise, and pressure occasionally induce hives. […] In dermatographism, raised, itchy red welts with adjacent flares appear wherever the skin is scratched or where belts and other articles of clothing rub against the skin, causing mast cells to leak histamine. […] Another common form of physically induced hives is called cholinergic urticaria. This produces hundreds of small, itchy bumps. These occur within 15 minutes of exercise or physical exertion and are usually gone before a doctor can examine them. This form of hives happens more often in young people.

• #45 Urticaria: Etiology, pathogenesis, diagnosis, and treatment – IJPP

  https://www.ijpp.org.in/html-article/17719

  These causes histamine release from mast cell. […] Due to histamine release swelling and itch take place. […] Urticaria caused by non-immune mechanism is found in physical urticaria such as dermographism, delayed pressure urticaria, cold urticaria, solar urticaria, aquagenic urticaria and vibratory urticaria. […] Along with Mast cells, basophils also act as effector cells in this mechanism. […] These cells release vasoactive substances like histamine, bradykinin, leukotriene C4, prostaglandin D2, release of these substances and vasodilatation takes place and therefore increases vascular permeability. […] This produces erythema and edema dominant to urticaria lesions. […] Itching, an important feature of urticaria is mediated by histamine receptors as erythema and flushing.

• #46 The urticarias: pathophysiology and management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4954105/

  It is widely accepted that the cutaneous mast cell has a central role in urticaria. […] The stimulus for mast cell degranulation may be immunological or non-immunological. […] Autoantibodies against IgE, FceRI or both on basophils and mast cells cause histamine release in vitro and are thought to underpin autoimmune urticaria. […] How physical stimuli cause inducible urticarias is unclear but some historical evidence from passive transfer experiments suggests that IgE may be involved. […] There is evidence that cutaneous mast cells are generally more releasable in chronic spontaneous urticaria to non-immunological stimulation with compound 48/80. […] Urticaria may present as angio-oedema without wheals in approximately 10% of patients. […] There is increasing recognition that angio-oedema without wheals may be mast cell-dependent or -independent.

• #47 A Diagnosis of Urticaria, Common Skin Condition | EMJ Reviews

  https://www.emjreviews.com/dermatology/article/urticaria-diagnosis/

  Mast cells, which are hypersensitive to physical stimulation, and IgE have been implicated in the pathogenesis of dermographism, cold urticaria, and solar urticaria, without certain mechanisms. […] Localised platelet clumping has been demonstrated in cold urticaria and, as such, platelet mediators, for example platelet-activating factor and factor IV, may be involved in disease pathogenesis. […] For delayed-pressure urticaria, pressure-induced wheals may result from a late-phase reaction, but the initial antigen is still yet to be identified. […] A non-autoantibody mechanism may also be involved because functional autoantibodies have been detected in approximately 60% of chronic urticaria sera. […] Activation of an extrinsic coagulation cascade was found in chronic urticaria. […] Increased plasma levels of prothrombin fragments 1 and 2 and D-dimer, a measure of fibrinolysis, have been demonstrated and relate to disease severity, but the contribution of coagulation abnormalities to the pathogenesis of the disease remains unclear.

• #48

  https://link.springer.com/article/10.1007/s11882-009-0038-x

  Patients with cholinergic urticaria (CU) show a number of small, short-lasting hives when their body core temperature increases, usually during sweating following exercise or bathing. […] The precise mechanism(s) of hive formation in CU has been unclear except for the involvement of acetylcholine. […] We discuss the mechanisms of hive formation in these subtypes. […] We propose two subtypes of CU: 1) a sweat-hypersensitivity type with strong hypersensitivity to autologous sweat, nonfollicular hives, development of satellite wheals, and lack of positive ASST; and 2) a follicular type with follicular hives and positive ASST, but no hypersensitivity to autologous sweat or satellite wheals. […] Cholinergic urticaria shows neutrophilic inflammation. […] Cholinergic urticaria, a new pathogenic concept: hypohidrosis due to interference with the delivery of sweat to the skin surface. […] Release of mast-cell mediators and alterations in lung function in patients with cholinergic urticaria. […] Evaluation of a patient with both aquagenic and cholinergic urticaria. […] Acquired idiopathic generalized anhidrosis: a possible role of mast cell in the pathogenesis.

• #49 A Diagnosis of Urticaria, Common Skin Condition | EMJ Reviews

  https://www.emjreviews.com/dermatology/article/urticaria-diagnosis/

  Mast cells, which are hypersensitive to physical stimulation, and IgE have been implicated in the pathogenesis of dermographism, cold urticaria, and solar urticaria, without certain mechanisms. […] Localised platelet clumping has been demonstrated in cold urticaria and, as such, platelet mediators, for example platelet-activating factor and factor IV, may be involved in disease pathogenesis. […] For delayed-pressure urticaria, pressure-induced wheals may result from a late-phase reaction, but the initial antigen is still yet to be identified. […] A non-autoantibody mechanism may also be involved because functional autoantibodies have been detected in approximately 60% of chronic urticaria sera. […] Activation of an extrinsic coagulation cascade was found in chronic urticaria. […] Increased plasma levels of prothrombin fragments 1 and 2 and D-dimer, a measure of fibrinolysis, have been demonstrated and relate to disease severity, but the contribution of coagulation abnormalities to the pathogenesis of the disease remains unclear.

• #50 AAIR :: Allergy, Asthma & Immunology Research

  https://e-aair.org/DOIx.php?id=10.4168/aair.2017.9.6.477

  Additional abnormalities noted are high levels of metalloproteinases in the plasma of patients with CSU as well as increased fibrin split products and prothrombin fragment suggesting activation of the coagulation cascade and fibrinolysis even though there is no clinical abnormality in hemostasis or thrombosis in this disorder.

• #51 Stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-019-0372-z

  The involvement of the coagulation system in CSU is suggested by the clinical improvement in urticaria when patients are commenced on anticoagulation for other apparently unconnected reasons. […] The mechanism by which coagulation contributes to urticaria is unclear although the interaction between inflammatory factors and coagulation proteins is interesting. […] The ability of pseudoallergens, infections and stress to initiate and/or aggravate CSU suggests that a common pathway may be involved. […] However, an increased frequency of autoimmunity has been linked to stress and several viral infections, but especially Epstein Barr, can encourage autoimmunity. […] The mechanisms here involve a combination of impaired T regulatory activity and specific viral proto-oncogenes that give a survival stimulus to low avidity auto-reactive B cells.

• #52 Hives: The target of itching | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-hives-the-target-itching-S0301054616300593

  The main effector cell in the physiopathology of urticaria is the mast cell, which releases inflammatory mediators (either preformed or de novo), giving rise to tissue responses involving other effector cells such as basophils, Th2 lymphocytes and, to a lesser degree, neutrophils and eosinophils. […] From the immunopathological perspective, urticaria is characterized by the intervention of proinflammatory cells such as mast cells, eosinophils, neutrophils, monocytes, macrophages and T lymphocytes that release different mediators the fundamental representative of which is histamine (beta-imidazole-ethylamine). This mediator binds to the H1 receptors of blood vessels, causing vascular dilatation, decreased blood pressure and increased capillary permeability, with an outflow of exudate, antibodies, macrophages and other components of the complement system into the interstitial fluid compartment, thereby favoring the development of edema.

• #53 Chronic spontaneous urticaria – Wikipedia

  https://en.wikipedia.org/wiki/Chronic_spontaneous_urticaria

  Chronic spontaneous urticaria, despite its cause being unknown, is linked to a higher prevalence of autoimmune diseases, and is often worsened by triggers like stress, infections, certain foods, or nonsteroidal anti-inflammatory drugs. The hives and angioedema seen in CSU is thought to be linked to the degranulation of skin mast cells. Mast cells release proteases, histamine, cytokines, and arachidonic acid metabolites, causing swelling, redness, and itching. […] The degranulation of skin mast cells in CSU appears to be involved in wheals and angioedema. These cells release proteases, histamine, and cytokines along with platelet-activating factors and other metabolites of arachidonic acid. These mediators cause swelling, redness, and itching by stimulating sensory nerve endings, increasing vascular permeability, and inducing vasodilatation. Edema, mast cell degranulation, and a perivascular infiltrate of cells, including CD4 lymphocytes, monocytes, neutrophils, eosinophils, and basophils, are the hallmarks of a lesion site, also known as a wheal.

• #54 Hives: The target of itching | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-hives-the-target-itching-S0301054616300593

  Another released mediator is platelet activating factor (PAF), which in turn would cause other cells to release serotonin one of the factors responsible for chronic urticaria. Eosinophil chemotactic factor would induce such cells to migrate towards the inflammatory site. The activated eosinophils release cationic protein (ECP), peroxidase (EPO) and protein X (EPX). In particular, eosinophils are activated by IL-5, transforming into larger cells which are selectively recruited in late-phase inflammatory reactions. […] Complement activation releases anaphylotoxins (C3a, C4a, C5a), which by directly acting upon the cell surface contribute to release more histamine. In this regard, factor C5a is the factor with the strongest impact upon vascular permeability, since its inhibition mediated by anaphylotoxin inhibiting factor occurs in a later stage, allowing it to not only favor permeability but also to act as a chemotactic factor for eosinophils and neutrophils that arrive at the inflammatory site.

• #55 Urticaria – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/urticaria/

  Chronic idiopathic urticaria patients can de-velop Ig G antibodies directed against the sub unit of the FCE RI or against the receptor bound Ig E. […] Histamine can stimulate sensory afferent nerves to release substance P as these are situated close to the mast cells. This stimulates further re-lease of mast cell histamine and also expression of various adhesion molecules like P selectin and E selectin which amplifies wealing reaction. […] Interleukins like IL-4 regulates vascular en-dothelial adhesion molecules whereas, IL – 8 causes neutrophil leukocyte accumulation. IL-4 also stimu-lates T – lymphocyte differentiation and immunoglo-bulin production. However a direct role of these interleukins has not been found. […] Plasma derived mediators such as bradykinin and complement have no role in chronic urticaria. However, bradykinin plays a role in production of angio-oedema. Complement activation occurs in ur-ticarial vasculitis and immune complex urticaria. Lym-phocytes, neutrophils and eosinophils also may re-lease a variety of cytokines which may enhance or perpetuate the weal response. This mechanism is demonstrated by their presence in the venous efflu-ent from physical urticarias like cold, cholinergic and solar urticarias.

• #56 Chronic spontaneous urticaria – Wikipedia

  https://en.wikipedia.org/wiki/Chronic_spontaneous_urticaria

  Chronic spontaneous urticaria, despite its cause being unknown, is linked to a higher prevalence of autoimmune diseases, and is often worsened by triggers like stress, infections, certain foods, or nonsteroidal anti-inflammatory drugs. The hives and angioedema seen in CSU is thought to be linked to the degranulation of skin mast cells. Mast cells release proteases, histamine, cytokines, and arachidonic acid metabolites, causing swelling, redness, and itching. […] The degranulation of skin mast cells in CSU appears to be involved in wheals and angioedema. These cells release proteases, histamine, and cytokines along with platelet-activating factors and other metabolites of arachidonic acid. These mediators cause swelling, redness, and itching by stimulating sensory nerve endings, increasing vascular permeability, and inducing vasodilatation. Edema, mast cell degranulation, and a perivascular infiltrate of cells, including CD4 lymphocytes, monocytes, neutrophils, eosinophils, and basophils, are the hallmarks of a lesion site, also known as a wheal.

• #57 Urticaria – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/urticaria/

  Chronic idiopathic urticaria patients can de-velop Ig G antibodies directed against the sub unit of the FCE RI or against the receptor bound Ig E. […] Histamine can stimulate sensory afferent nerves to release substance P as these are situated close to the mast cells. This stimulates further re-lease of mast cell histamine and also expression of various adhesion molecules like P selectin and E selectin which amplifies wealing reaction. […] Interleukins like IL-4 regulates vascular en-dothelial adhesion molecules whereas, IL – 8 causes neutrophil leukocyte accumulation. IL-4 also stimu-lates T – lymphocyte differentiation and immunoglo-bulin production. However a direct role of these interleukins has not been found. […] Plasma derived mediators such as bradykinin and complement have no role in chronic urticaria. However, bradykinin plays a role in production of angio-oedema. Complement activation occurs in ur-ticarial vasculitis and immune complex urticaria. Lym-phocytes, neutrophils and eosinophils also may re-lease a variety of cytokines which may enhance or perpetuate the weal response. This mechanism is demonstrated by their presence in the venous efflu-ent from physical urticarias like cold, cholinergic and solar urticarias.

• #58

  https://www.aaaai.org/tools-for-the-public/latest-research-summaries/the-journal-of-allergy-and-clinical-immunology/2022/biology

  Chronic spontaneous urticaria (CSU) consists of the daily, or almost daily, appearance of itchy hives with or without angioedema for more than 6 weeks. […] Despite all this, the exact mechanism of the disease remains elusive. […] The authors found that mast cell activation is a key player in CSU, and identified an important role of the high affinity IgE receptor in CSU pathogenesis. […] Targeting the IgE receptor axis, including the cell signaling cascade involving Bruton Tyrosine kinase, seemed the most promising approaches. […] Other strategies aimed towards interleukin signaling (IL-4 and IL-5) or Siglec-8 seemed to show promise depending on the patient profile. […] Computational CSU models could help not only to unveil the pathology of the disease but also to understand the mechanism of action of drugs available and develop personalized treatments depending on each patient profile. […] The model also provides a framework with which to compare the molecular and cellular mechanisms of action of future CSU drugs.

• #59 Hives: The target of itching | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-resumen-hives-the-target-itching-S0301054616300593

  Autoimmune chronic urticaria is due to the strong affinity of the anti-FcRI autoantibodies (and to a lesser degree also of anti-IgE autoantibodies) for the IgE receptors. […] Another purported pathogenic mechanism underlying chronic urticaria involves IL-3, which would activate basophils, inducing an increase in neutrophil presence and in C-reactive protein. […] The main effector cell in the physiopathology of urticaria is the mast cell, which releases inflammatory mediators (either preformed or de novo), giving rise to tissue responses involving other effector cells such as basophils, Th2 lymphocytes and, to a lesser degree, neutrophils and eosinophils. […] From the immunopathological perspective, urticaria is characterized by the intervention of proinflammatory cells such as mast cells, eosinophils, neutrophils, monocytes, macrophages and T lymphocytes that release different mediators the fundamental representative of which is histamine (beta-imidazole-ethylamine).

• #60 Chronic Spontaneous Urticaria Mechanism of Disease Animation

  https://www.adventprogram.com/us/educational-resources/chronic-spontaneous-urticaria-mechanism-disease-animation-0

  Learn about the complex mechanism of disease involving mast cell activation and the release of inflammatory mediators. […] Learn about the mechanism of disease of chronic spontaneous urticaria, including the roles of mast cell activation and type 2 cytokines. […] How type 2 cytokines can amplify inflammatory response in CSU.

• #61 Hives: The target of itching | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-resumen-hives-the-target-itching-S0301054616300593

  The pathogenesis of urticaria manifests in the form of hives or wheals produced by immunological and non-immunological stimuli that induce plasma extravasation in the papillary dermis. […] In IgE-mediated urticaria, the presence of this immunoglobulin on the surface of mast cells and basophils triggers the release of leukotrienes, prostaglandin D2, platelet activating factor, eosinophil chemotactic factor and histamine (the main mediator), which binds to the H1 receptors inducing skin erythema, edema and pruritus. […] An association has been established between high levels of B cell activating factor (BAFF) in patients with chronic urticaria and positive autologous serum skin testing, the presence of antithyroid antibodies, antinuclear antibodies, high total IgE titers, and severity of the disease.

• #62 Stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-019-0372-z

  Recent work suggests that stress induced release of substance P and CGRP by sensory cutaneous nerves leads to itching and mast cell activation via several receptors. […] It is therefore possible that the itch scratch cycle can prolong the cutaneous inflammation that perpetuates CSU and which is also seen in atopic dermatitis. […] Many patients with CSU are observed to have mildly raised levels of C-reactive protein. […] Chronic low grade inflammation associated with high stress scores, raised C-reactive protein and interleukin 18 may explain the increased frequency of metabolic syndrome in CSU. […] Vitamin D3 (cholecalciferol) has a powerful ability to increase T regulatory cell function and reduce Th1 and Th17 type immunity. […] In CSU, reduced vitamin D levels are found more frequently than in healthy controls and replacement therapy has been found to reduce the severity and duration of the urticarial wheals.

• #63 Urticaria – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/urticaria/

  Chronic idiopathic urticaria patients can de-velop Ig G antibodies directed against the sub unit of the FCE RI or against the receptor bound Ig E. […] Histamine can stimulate sensory afferent nerves to release substance P as these are situated close to the mast cells. This stimulates further re-lease of mast cell histamine and also expression of various adhesion molecules like P selectin and E selectin which amplifies wealing reaction. […] Interleukins like IL-4 regulates vascular en-dothelial adhesion molecules whereas, IL – 8 causes neutrophil leukocyte accumulation. IL-4 also stimu-lates T – lymphocyte differentiation and immunoglo-bulin production. However a direct role of these interleukins has not been found. […] Plasma derived mediators such as bradykinin and complement have no role in chronic urticaria. However, bradykinin plays a role in production of angio-oedema. Complement activation occurs in ur-ticarial vasculitis and immune complex urticaria. Lym-phocytes, neutrophils and eosinophils also may re-lease a variety of cytokines which may enhance or perpetuate the weal response. This mechanism is demonstrated by their presence in the venous efflu-ent from physical urticarias like cold, cholinergic and solar urticarias.

• #64 Urticaria – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/urticaria/

  Chronic idiopathic urticaria patients can de-velop Ig G antibodies directed against the sub unit of the FCE RI or against the receptor bound Ig E. […] Histamine can stimulate sensory afferent nerves to release substance P as these are situated close to the mast cells. This stimulates further re-lease of mast cell histamine and also expression of various adhesion molecules like P selectin and E selectin which amplifies wealing reaction. […] Interleukins like IL-4 regulates vascular en-dothelial adhesion molecules whereas, IL – 8 causes neutrophil leukocyte accumulation. IL-4 also stimu-lates T – lymphocyte differentiation and immunoglo-bulin production. However a direct role of these interleukins has not been found. […] Plasma derived mediators such as bradykinin and complement have no role in chronic urticaria. However, bradykinin plays a role in production of angio-oedema. Complement activation occurs in ur-ticarial vasculitis and immune complex urticaria. Lym-phocytes, neutrophils and eosinophils also may re-lease a variety of cytokines which may enhance or perpetuate the weal response. This mechanism is demonstrated by their presence in the venous efflu-ent from physical urticarias like cold, cholinergic and solar urticarias.

• #65 Urticaria – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/urticaria/

  Increased substance P and vasoac-tive intestinal peptide (VIP) have been demonstrated in cold and cholinergic urticarial lesions. Urticarial vasculitis, also called hypocom- plementaemic vas-culitis, resembles systemic lupus erythematosus in its pathogenesis. […] Papular urticaria is due to type I and type IV hypersensitivity reaction but the antigen remains undetermined.

• #66 Chronic Urticaria—Pathogenesis, Diagnostics, Therapy and Influence of Coexisting Angioedema

  https://www.mdpi.com/2077-0383/12/2/688

  Urticaria is one of the most frequent dermatological diseases and it usually occurs in paroxysmal, recurrent form. The most important role in the pathogenesis of this disease is played by histamine, which is released from mast cells. Immune mechanisms depend on IgE and its complement system. Non-immunological mechanisms, including the direct degranulation of mast cells, play a significant role as well. […] Currently, two endotypes of CSU can be distinguished, which vary in terms of pathogenesis and markers of the disease, as well as clinical course and sensitivity to treatment applied: type I and IIb. Type I CSU is related to the occurrence of IgE antibodies to autoantigens such as TPO (thyroid peroxidase), TG (thyroglobulin), ds-DNA (double-stranded DNA) and Il-24. In type I, it is observed that the occurrence of allergic diseases and the total concentration of IgE are normal or even increased.

• #67 Prevalence of Autoimmune and Autoinflammatory Diseases in Chronic Urticaria: Pathogenetic, Diagnostic and Therapeutic Implications

  https://www.mdpi.com/2227-9059/11/2/410

  Moreover, recently a dysregulation of intracellular signaling pathways in mast cells and basophils leading to defect in cell function and the production of IgG autoantibodies directed against FcεRI or IgE on both mast cells and basophils or IgE autoantibodies against autoantigens like thyroid peroxidase, DNA and IL-24 have been demonstrated to be involved in urticaria pathogenesis. […] Regardless of the mechanism, the release of histamine, platelet-activating factor, tryptase, leukotrienes, and other cytokines lead to sensory nerve activation, vasodilatation, and plasma extravasation, as well as cell recruitment typical of urticarial lesions. […] Each different possible pathway of activation correlates to a different endotype of urticaria that produce different and similar phenotypes. […] Recently, two different endotypes of CSU have been proposed: (1) IgE-mediated CUS, also known as autoallergic CSU and (2) type IIb autoimmune CSU, characterized by the presence of IgG autoantibodies, and probably IgM and IgA that are responsible for direct activation of mast cells with the binding of high-affinity IgE receptors.

• #68 Chronic Urticaria—Pathogenesis, Diagnostics, Therapy and Influence of Coexisting Angioedema

  https://www.mdpi.com/2077-0383/12/2/688

  In type IIb CSU, IgG and IgM antibodies to IgE and high-affinity receptors for IgE (FceRI) are identified. Additionally, in the clinical course of this endotype, greater severity of symptoms and a prolonged duration of the disease, coexistence of autoimmune diseases, presence of ANA (antinuclear antibodies), elevated CRP levels, basopenia and eosinopenia in peripheral blood and reduced levels of total IgE occur. […] Urticaria is a multiform disorder with partially unknown pathophysiology, and therapy effectiveness is still limited, in spite of several options. Recurrent angioedema is a form of chronic urticaria.

• #69 Prevalence of Autoimmune and Autoinflammatory Diseases in Chronic Urticaria: Pathogenetic, Diagnostic and Therapeutic Implications

  https://www.mdpi.com/2227-9059/11/2/410

  Moreover, recently a dysregulation of intracellular signaling pathways in mast cells and basophils leading to defect in cell function and the production of IgG autoantibodies directed against FcεRI or IgE on both mast cells and basophils or IgE autoantibodies against autoantigens like thyroid peroxidase, DNA and IL-24 have been demonstrated to be involved in urticaria pathogenesis. […] Regardless of the mechanism, the release of histamine, platelet-activating factor, tryptase, leukotrienes, and other cytokines lead to sensory nerve activation, vasodilatation, and plasma extravasation, as well as cell recruitment typical of urticarial lesions. […] Each different possible pathway of activation correlates to a different endotype of urticaria that produce different and similar phenotypes. […] Recently, two different endotypes of CSU have been proposed: (1) IgE-mediated CUS, also known as autoallergic CSU and (2) type IIb autoimmune CSU, characterized by the presence of IgG autoantibodies, and probably IgM and IgA that are responsible for direct activation of mast cells with the binding of high-affinity IgE receptors.

• #70 Prevalence of Autoimmune and Autoinflammatory Diseases in Chronic Urticaria: Pathogenetic, Diagnostic and Therapeutic Implications

  https://www.mdpi.com/2227-9059/11/2/410

  Moreover, recently a dysregulation of intracellular signaling pathways in mast cells and basophils leading to defect in cell function and the production of IgG autoantibodies directed against FcεRI or IgE on both mast cells and basophils or IgE autoantibodies against autoantigens like thyroid peroxidase, DNA and IL-24 have been demonstrated to be involved in urticaria pathogenesis. […] Regardless of the mechanism, the release of histamine, platelet-activating factor, tryptase, leukotrienes, and other cytokines lead to sensory nerve activation, vasodilatation, and plasma extravasation, as well as cell recruitment typical of urticarial lesions. […] Each different possible pathway of activation correlates to a different endotype of urticaria that produce different and similar phenotypes. […] Recently, two different endotypes of CSU have been proposed: (1) IgE-mediated CUS, also known as autoallergic CSU and (2) type IIb autoimmune CSU, characterized by the presence of IgG autoantibodies, and probably IgM and IgA that are responsible for direct activation of mast cells with the binding of high-affinity IgE receptors.

• #71 Chronic spontaneous urticaria – Wikipedia

  https://en.wikipedia.org/wiki/Chronic_spontaneous_urticaria

  Chronic spontaneous urticaria, despite its cause being unknown, is linked to a higher prevalence of autoimmune diseases, and is often worsened by triggers like stress, infections, certain foods, or nonsteroidal anti-inflammatory drugs. The hives and angioedema seen in CSU is thought to be linked to the degranulation of skin mast cells. Mast cells release proteases, histamine, cytokines, and arachidonic acid metabolites, causing swelling, redness, and itching. […] The degranulation of skin mast cells in CSU appears to be involved in wheals and angioedema. These cells release proteases, histamine, and cytokines along with platelet-activating factors and other metabolites of arachidonic acid. These mediators cause swelling, redness, and itching by stimulating sensory nerve endings, increasing vascular permeability, and inducing vasodilatation. Edema, mast cell degranulation, and a perivascular infiltrate of cells, including CD4 lymphocytes, monocytes, neutrophils, eosinophils, and basophils, are the hallmarks of a lesion site, also known as a wheal.

• #72 Stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-019-0372-z

  Chronic spontaneous urticaria (CSU) is often associated with organ specific autoimmunity but is rarely caused by food allergy. […] Factors that promote inflammation or reduce anti-inflammatory mechanisms may however, predispose susceptible individuals to CSU. […] There is early evidence of dysbiosis within the gastrointestinal tract in people with CSU and reduced levels of vitamin D are also evident. […] It is quite possible that a state of on-going chronic inflammation with reduced anti-oxidant mechanisms may underlie the not infrequent association between CSU and metabolic syndrome. […] Much recent work has focused on other mechanisms leading to mast cell activation which is critical to CSU. […] In particular, this includes autoimmunity type IIb with IgG anti-IgE auto-antibodies and positive autologous serum skin tests.

• #73 Hives: Causes

  https://www.aad.org/public/diseases/a-z/hives-causes

  The often-itchy bumps and raised patches of hives develop when the body releases histamine. […] Sometimes, the immune system releases histamine when there is no real threat. This happens when people develop an allergic reaction. In fact, some people develop hives when they have an allergic reaction. […] When the body mistakenly releases histamine and hives develop, the cause is often one of the following: An allergic reaction. […] When hives are due to an allergic reaction, it’s often an allergy to: A food, Bug bite or sting, Latex, Medication, Pet dander, Plant, Pollen. […] Some people get hives when they develop an infection like strep throat, a urinary tract infection, or COVID-19. […] Others get hives when they have a medical treatment like radiation therapy or a blood transfusion.

• #74 Stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-019-0372-z

  However, IgE antibodies to TPO have also been detected suggesting a possible mode of action for the benefit of anti-IgE therapy in CSU. […] Regardless, IgG antibodies directly binding to the FcRI and in consequence capable of activating mast cells have been and found in almost a quarter of patients with CSU with only 3.2% in healthy controls. […] The mechanism by which infection contributes to the onset, perpetuation or worsening of CSU is unclear. […] It is therefore not inconceivable that infections associated with inflammation may be associated with urticaria. […] Overall, however, it is likely that infection acts as a facilitating factor for the initiation and perpetuation of CSU and additional cofactors such as stress may be required for the CSU phenotype to be expressed. […] The link between the brain and mast cells within the skin via C fibre sensory nerves is likely involved in the worsening of skin diseases such as atopic dermatitis and CSU with stress.

• #75 Urticaria: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/762917-overview

  Some evidence suggests vitamin D levels have an inverse correlation with the severity of chronic urticaria. […] Complement-mediated urticarias include viral and bacterial infections, serum sickness, and transfusion reactions. Urticarial transfusion reactions occur when allergenic substances in the plasma of the donated blood product react with preexisting IgE antibodies in the recipient. Certain drugs (opioids, vecuronium, succinylcholine, vancomycin, and others) as well as radiocontrast agents cause urticaria due to mast cell degranulation through a nonIgE-mediated mechanism. Urticaria from nonsteroidal anti-inflammatory drugs may be IgE-mediated or due to mast cell degranulation, and there may be significant cross-reactivity among the nonsteroidal anti-inflammatory drugs (NSAIDs) in causing urticaria and anaphylaxis.

• #76 Stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-019-0372-z

  Recent work suggests that stress induced release of substance P and CGRP by sensory cutaneous nerves leads to itching and mast cell activation via several receptors. […] It is therefore possible that the itch scratch cycle can prolong the cutaneous inflammation that perpetuates CSU and which is also seen in atopic dermatitis. […] Many patients with CSU are observed to have mildly raised levels of C-reactive protein. […] Chronic low grade inflammation associated with high stress scores, raised C-reactive protein and interleukin 18 may explain the increased frequency of metabolic syndrome in CSU. […] Vitamin D3 (cholecalciferol) has a powerful ability to increase T regulatory cell function and reduce Th1 and Th17 type immunity. […] In CSU, reduced vitamin D levels are found more frequently than in healthy controls and replacement therapy has been found to reduce the severity and duration of the urticarial wheals.

• #77 Urticaria (Hives): a complete overview — DermNet

  https://dermnetnz.org/topics/urticaria-an-overview

  Weals are due to release of chemical mediators from tissue mast cells and circulating basophils. These chemical mediators include histamine, platelet-activating factor and cytokines. The mediators activate sensory nerves and cause dilation of blood vessels and leakage of fluid into surrounding tissues. Bradykinin release causes angioedema. […] Several hypotheses have been proposed to explain urticaria. The immune, arachidonic acid and coagulation systems are involved, and genetic mutations are under investigation. […] Chronic spontaneous urticaria is mainly idiopathic (cause unknown). An autoimmune cause is likely. About half of investigated patients carry functional IgG autoantibodies to immunoglobulin IgE or high-affinity receptor FcRI. […] Chronic spontaneous urticaria has also been associated with chronic underlying infection, such as Helicobacter pylori (bowel parasites) and chronic autoimmune diseases, such as systemic lupus erythematosus, thyroid disease, coeliac disease, vitiligo, and others. […] Inducible urticaria is a response to a physical stimulus.

• #78 Patient education: Hives (urticaria) (Beyond the Basics) – UpToDate

  https://www.uptodate.com/contents/hives-urticaria-beyond-the-basics/print

  Hives develop when there is a reaction that activates immune cells in the skin called mast cells. When activated, these cells release natural chemicals. One important chemical is histamine, which causes itching, redness, and swelling of the skin in an area: a hive. […] In most cases of chronic hives, the cause is unknown. Researchers suspect that problems in the immune system play a role. […] Hives can be a sign of several other medical or autoimmune conditions, including thyroid or liver diseases, chronic infections, or lupus. Most people with one of these conditions will have other symptoms apart from hives.

• #79 Acute and Chronic Urticaria: Evaluation and Treatment | AAFP

  https://www.aafp.org/pubs/afp/issues/2017/0601/p717.html

  Causes of acute urticaria often can be identified during the patient history, although 80% to 90% of chronic urticaria cases are idiopathic. […] In some patients, physical stimuli, including pressure, cold, heat, and the raising of the core body temperature (cholinergic urticaria), cause urticaria that tends to be chronic. […] Systemic disease is an uncommon cause of urticaria. Illnesses that have been associated with urticaria or angioedema include Hashimoto thyroiditis, mastocytosis, systemic lupus erythematosus, Sjgren syndrome, rheumatoid arthritis, vasculitis, celiac disease, and lymphoma.

• #80

  https://www.alliedacademies.org/articles/autoimmune-urticaria-pathogenesis-diagnosis-and-management-31969.html

  Autoimmune urticaria (AIU) is a chronic and often debilitating skin condition characterized by recurrent hives that arise due to an underlying autoimmune mechanism. […] AIU is primarily driven by autoantibodies, particularly immunoglobulin G (IgG) autoantibodies, that target high-affinity IgE receptors (FcRI) on mast cells and basophils. These autoantibodies can directly trigger mast cell degranulation, leading to the release of histamine and other inflammatory mediators responsible for the development of hives. […] Furthermore, AIU has been linked to other autoimmune diseases, such as thyroid disorders (e.g., Hashimotos thyroiditis and Graves disease), systemic lupus erythematosus, and rheumatoid arthritis. This association suggests that dysregulated immune tolerance plays a crucial role in its development. Additionally, complement system activation has been implicated in AIU pathogenesis, further exacerbating mast cell activation and inflammation.

• #81

  https://www.alliedacademies.org/articles/autoimmune-urticaria-pathogenesis-diagnosis-and-management-31969.html

  Autoimmune urticaria (AIU) is a chronic and often debilitating skin condition characterized by recurrent hives that arise due to an underlying autoimmune mechanism. […] AIU is primarily driven by autoantibodies, particularly immunoglobulin G (IgG) autoantibodies, that target high-affinity IgE receptors (FcRI) on mast cells and basophils. These autoantibodies can directly trigger mast cell degranulation, leading to the release of histamine and other inflammatory mediators responsible for the development of hives. […] Furthermore, AIU has been linked to other autoimmune diseases, such as thyroid disorders (e.g., Hashimotos thyroiditis and Graves disease), systemic lupus erythematosus, and rheumatoid arthritis. This association suggests that dysregulated immune tolerance plays a crucial role in its development. Additionally, complement system activation has been implicated in AIU pathogenesis, further exacerbating mast cell activation and inflammation.

• #82 Stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-019-0372-z

  Recent work suggests that stress induced release of substance P and CGRP by sensory cutaneous nerves leads to itching and mast cell activation via several receptors. […] It is therefore possible that the itch scratch cycle can prolong the cutaneous inflammation that perpetuates CSU and which is also seen in atopic dermatitis. […] Many patients with CSU are observed to have mildly raised levels of C-reactive protein. […] Chronic low grade inflammation associated with high stress scores, raised C-reactive protein and interleukin 18 may explain the increased frequency of metabolic syndrome in CSU. […] Vitamin D3 (cholecalciferol) has a powerful ability to increase T regulatory cell function and reduce Th1 and Th17 type immunity. […] In CSU, reduced vitamin D levels are found more frequently than in healthy controls and replacement therapy has been found to reduce the severity and duration of the urticarial wheals.

• #83 Stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-019-0372-z

  More recent work suggests a central importance of the Mas related G protein coupled X2 receptor (MRGPRX2) that is found on mast cells. […] CSU is associated with several disorders which either predispose to the condition or facilitate mast cell degranulation. […] The presence of a positive autologous serum (AST) or plasma test (APT) in 40% to 60% of patients with CSU has suggested the presence of auto-antibodies capable of stimulating mast cells. […] Importantly, a positive AST has been shown to increase the possibility of acute spontaneous urticaria progressing to CSU and a reduced chance of resolution within 2 years. […] Several types of autoimmune diseases are increased in patients with CSU. […] IgG anti-thyroid antibodies, in particular, are not infrequent in patients with CSU and especially in females.

• #84 Prevalence of Autoimmune and Autoinflammatory Diseases in Chronic Urticaria: Pathogenetic, Diagnostic and Therapeutic Implications

  https://www.mdpi.com/2227-9059/11/2/410

  Chronic spontaneous urticaria (CSU) is defined as the almost daily occurrence of widespread wheals, angioedema, or both, for more than 6 weeks. […] More than half of all cases of chronic idiopathic urticaria are thought to occur due to an autoimmune mechanism, specifically the production of autoantibodies against the high-affinity immunoglobulin E (IgE) receptor (FcεRI). […] New findings in urticaria showed that it is not only a mast cell-driven disease, but also basophil degranulation and other immune cells like eosinophils, T and B lymphocytes, epithelial, and endothelial cells are involved. […] Among the immunological activation of mast cells, there is the well-known crosslinking of allergens recognized by IgE molecules attached to high-affinity receptors (FcεRI) on the membrane, but other mechanisms are also known to be involved, like C5aR for anaphylotoxins C5a, CRTh2 for PGD2, MRGPRX2 for neuropeptides (like substance P), or proteases and cationic proteins (like MBP and ECP).

• #85 Stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-019-0372-z

  The role of the Mas related G protein coupled X2 receptor (MRGPRX2) found on mast cells may be relevant. […] Importantly, these multiple means of mast cell activation open the possibility that simultaneous subthreshold stimulation by several factors may cumulatively leading to mast cell degranulation and CSU.

• #86 Chronic Urticaria in Children: A Review | EMJ Reviews

  https://www.emjreviews.com/dermatology/article/chronic-urticaria-in-children-a-review/

  Chronic urticaria (CU) is characterised by the recurrence of hives/angioedema for 6 weeks. […] Although the precise pathogenesis of CU remains poorly understood, it is known that urticaria is the result of the mast cell/basophil degranulation triggered by a specific agent. Recently, the role of reactive oxygen species (ROS) and matrix metalloproteinase-9 (MMP-9) in the pathogenesis of CU has been investigated, as they are involved in the inflammatory processes. […] Autoimmunity also plays a role in the pathogenesis of urticaria, since it has been found that at least 30-50% of patients with CU have circulating autoantibodies immunoglobulin (Ig)G against the alpha chain of the IgE receptor. […] Infectious agents can also trigger CU. […] Physical and cholinergic urticaria comprise a very particular subgroup of CU known as CIU. It is characterised by the development of hives or angioedema due to a specific physical stimulus such as heat, cold, pressure, vibration, water, ultraviolet light, etc.

• #87 AAIR :: Allergy, Asthma & Immunology Research

  https://e-aair.org/DOIx.php?id=10.4168/aair.2017.9.6.477

  Additional abnormalities noted are high levels of metalloproteinases in the plasma of patients with CSU as well as increased fibrin split products and prothrombin fragment suggesting activation of the coagulation cascade and fibrinolysis even though there is no clinical abnormality in hemostasis or thrombosis in this disorder.

• #88 Stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-019-0372-z

  Chronic spontaneous urticaria (CSU) is often associated with organ specific autoimmunity but is rarely caused by food allergy. […] Factors that promote inflammation or reduce anti-inflammatory mechanisms may however, predispose susceptible individuals to CSU. […] There is early evidence of dysbiosis within the gastrointestinal tract in people with CSU and reduced levels of vitamin D are also evident. […] It is quite possible that a state of on-going chronic inflammation with reduced anti-oxidant mechanisms may underlie the not infrequent association between CSU and metabolic syndrome. […] Much recent work has focused on other mechanisms leading to mast cell activation which is critical to CSU. […] In particular, this includes autoimmunity type IIb with IgG anti-IgE auto-antibodies and positive autologous serum skin tests.

• #89 Stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-019-0372-z

  However, IgE antibodies to TPO have also been detected suggesting a possible mode of action for the benefit of anti-IgE therapy in CSU. […] Regardless, IgG antibodies directly binding to the FcRI and in consequence capable of activating mast cells have been and found in almost a quarter of patients with CSU with only 3.2% in healthy controls. […] The mechanism by which infection contributes to the onset, perpetuation or worsening of CSU is unclear. […] It is therefore not inconceivable that infections associated with inflammation may be associated with urticaria. […] Overall, however, it is likely that infection acts as a facilitating factor for the initiation and perpetuation of CSU and additional cofactors such as stress may be required for the CSU phenotype to be expressed. […] The link between the brain and mast cells within the skin via C fibre sensory nerves is likely involved in the worsening of skin diseases such as atopic dermatitis and CSU with stress.

• #90 Unravelling the mechanism of urticaria from eruption shapes | EurekAlert!

  https://www.eurekalert.org/news-releases/1009793

  A research group led by Professor Sungrim Seirin-Lee at Kyoto University Institute for the Advanced Study of Human Biology (WPI-ASHBi) leveraged hierarchical mathematical modeling to analyze the shapes of skin eruptions and link these morphological features to the in vivo pathological dynamics of chronic spontaneous urticaria CSU. […] Despite CSU having a clear and visible appearance on the skin surface, the mechanism underlying the various shapes of wheals in vivo remains largely obscured. […] Recently, a number of pathophysiological characteristics of urticaria have been investigated, including autoimmune responses, cellular infiltrates, and activation of the coagulation pathway by the complement system. […] By incorporating both the intravascular and extravascular dynamics using in vitro experimental data, they classified the skin eruption patterns into five potential types.

• #91 Unravelling the mechanism of urticaria from eruption shapes | EurekAlert!

  https://www.eurekalert.org/news-releases/1009793

  Using these patterns, the researchers developed the Criteria for Classification of Eruption Geometry (EGe criteria) according to their relations with tissue factor and histamine dynamics of mast cells, which act on blood vessels and induce wheal formation. […] This study was the first to use mathematical models to clarify the pathophysiology of skin eruptions according to their morphology, and can help to pave the way for alternative treatment methods. […] In addition, this study shows the promise of mathematical models in the understanding the mechanisms of human-specific diseases, where animal models are not available. […] Through these efforts, the authors hope to pioneer mathematical dermatology as a new multidisciplinary research field for practical use, integrating mathematical science and clinical dermatology for elucidating the pathophysiology of skin diseases and developing new strategies for managing intractable skin diseases.

• #92 Articles: Unravelling the mechanism of urticaria from eruption shapes Innovation for developing new treatments based on eruption morphology in mathematical dermatology – ASHBi

  https://ashbi.kyoto-u.ac.jp/news/20231205_research-result_seirin-lee/

  Despite CSU having a clear and visible appearance on the skin surface, the mechanism underlying the various shapes of wheals in vivo remains largely obscured. […] Recently, a number of pathophysiological characteristics of urticaria have been investigated, including autoimmune responses, cellular infiltrates, and activation of the coagulation pathway by the complement system. […] This study was the first to use mathematical models to clarify the pathophysiology of skin eruptions according to their morphology, and can help to pave the way for alternative treatment methods. […] In addition, this study shows the promise of mathematical models in the understanding the mechanisms of human-specific diseases, where animal models are not available.

• #93 Urticaria | Nature Reviews Disease Primers

  https://www.nature.com/articles/s41572-022-00389-z

  Urticaria is an inflammatory skin disorder that affects up to 20% of the world population at some point during their life. […] The pathogenesis of CSU consists of several interlinked events involving autoantibodies, complement and coagulation. […] Current urticaria treatment aims at complete response, with a stepwise approach using second-generation H1 antihistamines, omalizumab and cyclosporine. […] Novel treatment approaches centre on targeting mediators, signalling pathways and receptors of mast cells and other immune cells. […] Further research should focus on defining disease endotypes and their biomarkers, identifying new treatment targets and developing improved therapies.

• #94 Urticaria | Nature Reviews Disease Primers

  https://www.nature.com/articles/s41572-022-00389-z

  Urticaria is an inflammatory skin disorder that affects up to 20% of the world population at some point during their life. […] The pathogenesis of CSU consists of several interlinked events involving autoantibodies, complement and coagulation. […] Current urticaria treatment aims at complete response, with a stepwise approach using second-generation H1 antihistamines, omalizumab and cyclosporine. […] Novel treatment approaches centre on targeting mediators, signalling pathways and receptors of mast cells and other immune cells. […] Further research should focus on defining disease endotypes and their biomarkers, identifying new treatment targets and developing improved therapies.

• #95 Hives (Urticaria) and Angioedema Overview

  https://www.aaaai.org/tools-for-the-public/conditions-library/allergies/hives-(urticaria)-and-angioedema-overview

  This is not hereditary or passed to your children. […] Medications will not cure hives but can help to completely resolve them. […] About 50% of chronic spontaneous urticaria (hives over 6 weeks with no identifiable cause) will respond to antihistamine as discussed above. […] For those who do not improve on antihistamines, 65% respond to omalizumab. […] Chronic hives can last for many years but will often go away.

• #96

  https://link.springer.com/article/10.1007/s12016-017-8628-1

  Urticaria is a common, mast cell-driven disease presenting with wheals or angioedema or both. […] However, the pathogenesis is incompletely understood. […] Recent research focused on characterizing the role of cells and mediators involved in the pathogenesis of urticaria, identifying the mechanisms of mast cell activation, and investigating underlying autoimmune processes in chronic spontaneous urticaria. […] Novel therapeutic strategies aim at specifically targeting cells and mediators involved in the pathogenesis of urticaria. […] Mechanisms of action that contribute to efficacy of omalizumab in chronic spontaneous urticaria. […] Pathogenesis of chronic urticaria: an overview.

• #97

  https://www.aaaai.org/tools-for-the-public/latest-research-summaries/the-journal-of-allergy-and-clinical-immunology/2022/biology

  Chronic spontaneous urticaria (CSU) consists of the daily, or almost daily, appearance of itchy hives with or without angioedema for more than 6 weeks. […] Despite all this, the exact mechanism of the disease remains elusive. […] The authors found that mast cell activation is a key player in CSU, and identified an important role of the high affinity IgE receptor in CSU pathogenesis. […] Targeting the IgE receptor axis, including the cell signaling cascade involving Bruton Tyrosine kinase, seemed the most promising approaches. […] Other strategies aimed towards interleukin signaling (IL-4 and IL-5) or Siglec-8 seemed to show promise depending on the patient profile. […] Computational CSU models could help not only to unveil the pathology of the disease but also to understand the mechanism of action of drugs available and develop personalized treatments depending on each patient profile. […] The model also provides a framework with which to compare the molecular and cellular mechanisms of action of future CSU drugs.

• #98 Rilzabrutinib Reduces Itch and Hives in Antihistamine-Resistant Chronic Spontaneous Urticaria

  https://www.ajmc.com/view/rilzabrutinib-reduces-itch-and-hives-in-antihistamine-resistant-chronic-spontaneous-urticaria

  Rilzabrutinib demonstrated significant efficacy and a rapid onset of action in alleviating itch and hives in patients with moderate to severe chronic spontaneous urticaria (CSU) whose condition did not adequately respond to H1-antihistamines, suggesting a promising new treatment option for patients who continue to experience debilitating symptoms, according to a study published in JAMA Dermatology. […] Researchers do not fully understand the pathogenesis of CSU, but they estimate the allergy is an autoimmune mechanism of mast cell activation and a subsequent release of immune mediators like histamine that cause it. […] Further research is needed to determine long-term efficacy and potential harms, study authors concluded.

• #99

  https://www.aaaai.org/tools-for-the-public/latest-research-summaries/the-journal-of-allergy-and-clinical-immunology/2022/biology

  Chronic spontaneous urticaria (CSU) consists of the daily, or almost daily, appearance of itchy hives with or without angioedema for more than 6 weeks. […] Despite all this, the exact mechanism of the disease remains elusive. […] The authors found that mast cell activation is a key player in CSU, and identified an important role of the high affinity IgE receptor in CSU pathogenesis. […] Targeting the IgE receptor axis, including the cell signaling cascade involving Bruton Tyrosine kinase, seemed the most promising approaches. […] Other strategies aimed towards interleukin signaling (IL-4 and IL-5) or Siglec-8 seemed to show promise depending on the patient profile. […] Computational CSU models could help not only to unveil the pathology of the disease but also to understand the mechanism of action of drugs available and develop personalized treatments depending on each patient profile. […] The model also provides a framework with which to compare the molecular and cellular mechanisms of action of future CSU drugs.

• #100 Pathophysiology of urticaria – PubMed

  https://pubmed.ncbi.nlm.nih.gov/16461989/

  Urticaria is dermal edema resulting from vascular dilatation and leakage of fluid into the skin in response to molecules released from mast cells. The major preformed mediator histamine produces a prototypic, short-lived urticaria. However, the clinical spectrum and pattern of lesions indicate that other molecules, including prostaglandins, leukotrienes, cytokines, and chemokines, produced at different times after mast cell activation contribute to the polymorphism of this symptom and the variable evolution of this disease. […] It is now well established that urticaria may result from the binding of IgG auto-antibodies to IgE and/or to the receptor for IgE molecules on mast cells, thus corresponding to a type II HS reaction. These auto-immune urticarias represent up to 50% of patients with chronic urticaria. Mast cell activation can also result from type III HS through the binding of circulating immune complexes to mast cell-expressing Fc receptors for IgG and IgM. Finally, under certain circumstances, T-cells can induce activation of mast cells, as well as histamine release (type IV HS). Nonimmunological urticarias result from mast cell activation through membrane receptors involved in innate immunity (e.g., complement, Toll-like, cytokine/chemokine, opioid) or by direct toxicity of xenobiotics (haptens, drugs). In conclusion, urticaria may result from different pathophysiological mechanisms that explain the great heterogeneity of clinical symptoms and the variable responses to treatment.

• #101 Urticaria – Dermatologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/dermatologic-disorders/approach-to-the-dermatologic-patient/urticaria

  Urticaria results from the release of histamine, bradykinin, kallikrein, and other vasoactive substances from mast cells and basophils in the superficial dermis, resulting in intradermal edema caused by capillary and venous vasodilation and occasionally caused by leukocyte infiltration. […] The process can be immune mediated or nonimmune mediated. […] Immune-mediated mast cell activation includes Type I hypersensitivity reactions, in which allergen-bound IgE antibodies bind to high-affinity cell surface receptors on mast cells and basophils. […] Autoimmune disorders, in which antibodies to an IgE receptor functionally cross-link IgE receptors and cause mast cell degranulation. […] Nonimmune-mediated mast cell activation includes direct nonallergic activation of mast cells by certain medications or substances.

• #102 Pathophysiology of urticaria – PubMed

  https://pubmed.ncbi.nlm.nih.gov/16461989/

  Urticaria is dermal edema resulting from vascular dilatation and leakage of fluid into the skin in response to molecules released from mast cells. The major preformed mediator histamine produces a prototypic, short-lived urticaria. However, the clinical spectrum and pattern of lesions indicate that other molecules, including prostaglandins, leukotrienes, cytokines, and chemokines, produced at different times after mast cell activation contribute to the polymorphism of this symptom and the variable evolution of this disease. […] It is now well established that urticaria may result from the binding of IgG auto-antibodies to IgE and/or to the receptor for IgE molecules on mast cells, thus corresponding to a type II HS reaction. These auto-immune urticarias represent up to 50% of patients with chronic urticaria. Mast cell activation can also result from type III HS through the binding of circulating immune complexes to mast cell-expressing Fc receptors for IgG and IgM. Finally, under certain circumstances, T-cells can induce activation of mast cells, as well as histamine release (type IV HS). Nonimmunological urticarias result from mast cell activation through membrane receptors involved in innate immunity (e.g., complement, Toll-like, cytokine/chemokine, opioid) or by direct toxicity of xenobiotics (haptens, drugs). In conclusion, urticaria may result from different pathophysiological mechanisms that explain the great heterogeneity of clinical symptoms and the variable responses to treatment.

• #103 Urticaria | Nature Reviews Disease Primers

  https://www.nature.com/articles/s41572-022-00389-z

  Urticaria is an inflammatory skin disorder that affects up to 20% of the world population at some point during their life. […] The pathogenesis of CSU consists of several interlinked events involving autoantibodies, complement and coagulation. […] Current urticaria treatment aims at complete response, with a stepwise approach using second-generation H1 antihistamines, omalizumab and cyclosporine. […] Novel treatment approaches centre on targeting mediators, signalling pathways and receptors of mast cells and other immune cells. […] Further research should focus on defining disease endotypes and their biomarkers, identifying new treatment targets and developing improved therapies.

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