Materiały źródłowe

• #1 Primary immunodeficiency

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6157160/

  Primary immunodeficiency disorder (PID) refers to a large heterogeneous group of disorders that result from defects in immune system development and/or function. […] PIDs are broadly classified as disorders of adaptive immunity (i.e., T cell, B-cell or combined immunodeficiencies) or of innate immunity (e.g., phagocyte and complement disorders). […] Most PIDs result from inherited defects in immune system development and/or function; however, acquired forms have also been described. […] It is important to note that PIDs are distinct from secondary immunodeficiencies that may result from other causes, such as viral or bacterial infections, malnutrition, immunoglobulin (Ig) loss, malignancy or treatment with drugs that induce immunosuppression. […] The clinical presentation of PIDs is highly variable; however, most disorders involve increased susceptibility to infection.

• #2 Primary immunodeficiency | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0290-5

  Primary immunodeficiency disorder (PID) refers to a large heterogeneous group of disorders that result from defects in immune system development and/or function. […] PIDs are broadly classified as disorders of adaptive immunity (i.e., T cell, B-cell or combined immunodeficiencies) or of innate immunity (e.g., phagocyte and complement disorders). […] Most PIDs result from inherited defects in immune system development and/or function; however, acquired forms have also been described. […] It is important to note that PIDs are distinct from secondary immunodeficiencies that may result from other causes, such as viral or bacterial infections, malnutrition, immunoglobulin (Ig) loss, malignancy or treatment with drugs that induce immunosuppression. […] The clinical presentation of PIDs is highly variable; however, most disorders involve increased susceptibility to infection.

• #3 The Molecular Pathology of Primary Immunodeficiencies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1867474/

  Primary immunodeficiencies are a heterogeneous group of disorders, which affect cellular and humoral immunity or non-specific host defense mechanisms mediated by complement proteins, and cells such as phagocytes and natural killer (NK) cells. These disorders of the immune system cause increased susceptibility to infection, autoimmune disease, and malignancy. There are over 80 primary immunodeficiencies, many of which are very rare, and in most cases associated with inherited genetic defects. […] The advent of molecular genetic analyses now allows for the detection and confirmation of immunodeficiencies that were otherwise not severe enough during childhood to have led to a specific diagnosis. In addition, effective treatment for many disorders has led to increased survival of many children with primary immunodeficiency into adult life.

• #4 The basics – Immunodeficiency UKAccessibilityIncrease TextDecrease TextGrayscaleHigh ContrastNegative ContrastLight BackgroundLinks UnderlineReadable FontReset

  https://www.immunodeficiencyuk.org/immunodeficiency/primary-immunodeficiency/basics/

  PIDs are caused by errors in the genes of the cells that make up the immune system. Most people with PIDs are born with the condition. PIDs are mainly genetic disorders, meaning they are inherited and can be passed on from one generation to the next. […] In PIDs some of the DNA building blocks that make up the genes involved in the workings of the immune system are either not there or altered. This results in either missing or faulty genes, causing essential parts of the body’s defence against infection not to be made or work properly. […] In some types of PID, for example, common variable immune deficiency and other antibody deficiencies, the link to specific faulty genes is not yet so clear-cut, but this is likely to change as the technology for the screening of genes improves and more research is done.

• #5 The basics – Immunodeficiency UKAccessibilityIncrease TextDecrease TextGrayscaleHigh ContrastNegative ContrastLight BackgroundLinks UnderlineReadable FontReset

  https://www.immunodeficiencyuk.org/immunodeficiency/primary-immunodeficiency/basics/

  PIDs are caused by errors in the genes of the cells that make up the immune system. Most people with PIDs are born with the condition. PIDs are mainly genetic disorders, meaning they are inherited and can be passed on from one generation to the next. […] In PIDs some of the DNA building blocks that make up the genes involved in the workings of the immune system are either not there or altered. This results in either missing or faulty genes, causing essential parts of the body’s defence against infection not to be made or work properly. […] In some types of PID, for example, common variable immune deficiency and other antibody deficiencies, the link to specific faulty genes is not yet so clear-cut, but this is likely to change as the technology for the screening of genes improves and more research is done.

• #6 The Molecular Pathology of Primary Immunodeficiencies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1867474/

  Recent advances in molecular techniques have led to the identification and characterization of more than 25 newly recognized immunological disease genes since 1997. The identification of many genes responsible for primary immunodeficiencies has provided insights regarding the spectrum of clinical severity seen in a particular disorder and the phenotypic overlap resulting from mutations of different genes. […] This review focuses on the molecular genetic features of primary immunodeficiencies with emphasis on the molecular pathophysiology of the diseases. […] The International Union of Immunological Societys Scientific Committee on Primary Immunodeficiency Diseases/World Health Organization define several major categories of primary immunodeficiencies including: defects in non-specific host defense (phagocytes, natural killer cells, complement); defects of specific humoral immunity (B lymphocytes, antibodies); combined deficiency of cellular (T cell mediated) and humoral immune defense; immune defects associated with other major defects; and immunodeficiencies associated with or secondary to other diseases. Selected primary immune disorders, their presumed pathogenesis, inheritance pattern, and diagnostic tests are summarized in Table 2.

• #7 Primary immunodeficiency

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6157160/

  Primary immunodeficiency disorder (PID) refers to a large heterogeneous group of disorders that result from defects in immune system development and/or function. […] PIDs are broadly classified as disorders of adaptive immunity (i.e., T cell, B-cell or combined immunodeficiencies) or of innate immunity (e.g., phagocyte and complement disorders). […] Most PIDs result from inherited defects in immune system development and/or function; however, acquired forms have also been described. […] It is important to note that PIDs are distinct from secondary immunodeficiencies that may result from other causes, such as viral or bacterial infections, malnutrition, immunoglobulin (Ig) loss, malignancy or treatment with drugs that induce immunosuppression. […] The clinical presentation of PIDs is highly variable; however, most disorders involve increased susceptibility to infection.

• #8 Primary immunodeficiency | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0290-5

  Primary immunodeficiency disorder (PID) refers to a large heterogeneous group of disorders that result from defects in immune system development and/or function. […] PIDs are broadly classified as disorders of adaptive immunity (i.e., T cell, B-cell or combined immunodeficiencies) or of innate immunity (e.g., phagocyte and complement disorders). […] Most PIDs result from inherited defects in immune system development and/or function; however, acquired forms have also been described. […] It is important to note that PIDs are distinct from secondary immunodeficiencies that may result from other causes, such as viral or bacterial infections, malnutrition, immunoglobulin (Ig) loss, malignancy or treatment with drugs that induce immunosuppression. […] The clinical presentation of PIDs is highly variable; however, most disorders involve increased susceptibility to infection.

• #9 Primary immunodeficiency – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/primary-immunodeficiency/symptoms-causes/syc-20376905

  Primary immunodeficiency disorders also called primary immune disorders or primary immunodeficiency weaken the immune system, allowing infections and other health problems to occur more easily. […] Many primary immunodeficiency disorders are inherited passed down from one or both parents. Problems in the genetic code that acts as a blueprint for producing the cells of the body (DNA) cause many of these immune system defects. […] There are more than 300 types of primary immunodeficiency disorders, and researchers continue to identify more. They can be broadly classified into six groups based on the part of the immune system that’s affected: B cell (antibody) deficiencies, T cell deficiencies, Combination B and T cell deficiencies, Defective phagocytes, Complement deficiencies, Unknown (idiopathic).

• #10 Primary Immunodeficiencies | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/1115/p2001.html

  The more common primary immunodeficiencies are described in the following sections and summarized in Table 1 and Table 2. Other primary defects of immunity are reviewed elsewhere. […] Disorders of humoral immunity affect B-cell differentiation and antibody production. Collectively, these disorders account for approximately 50 percent of primary immunodeficiencies. Patients with antibody deficiencies often present after six months of age, when maternal antibodies are lost, but they can present in adulthood. Typically, these patients develop infections with encapsulated bacteria. Recurrent bacterial sinus and pulmonary infections are the hallmark of antibody primary immunodeficiencies. […] Patients with humoral primary immunodeficiencies have an intact cellular immune system; thus, they are able to handle most viral and fungal pathogens, a factor that can help to distinguish these disorders clinically.

• #11 The Molecular Pathology of Primary Immunodeficiencies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1867474/

  X-linked agammaglobulinemia was the first immunodeficiency to be characterized at the genetic level. XLA is caused by a block in B cell differentiation due to mutations involving the Bruton kinase gene, Btk, which encodes a tyrosine kinase that regulates the activity of signaling pathways by phosphorylation. BTK is activated by immunoglobulins and other membrane receptors that in turn activate phospholipase C and calcium influx. […] Although the specific defect in the signaling pathway that impairs B-cell development is unknown, it is proposed that BTK is important in mediation of survival signals. […] The severe combined immunodeficiencies (SCIDs) syndrome is characterized by gross impairment of both the humoral and cell-mediated immunity and by susceptibility to overwhelming fungal, bacterial, and viral infections. The syndrome comprises a heterogeneous group of primary immunodeficiencies associated with various defects of the immune system involving T, B, and sometimes natural killer cells. […] The identification of specific gene abnormalities important in lymphocyte biology and their link to these rare diseases has led to significant insights into the complexity of the immune system and provided new insights regarding the spectrum of clinical severity seen in a particular disorder and the phenotypic overlap resulting from mutations of different genes.

• #12 Primary Immunodeficiencies | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/1115/p2001.html

  The more common primary immunodeficiencies are described in the following sections and summarized in Table 1 and Table 2. Other primary defects of immunity are reviewed elsewhere. […] Disorders of humoral immunity affect B-cell differentiation and antibody production. Collectively, these disorders account for approximately 50 percent of primary immunodeficiencies. Patients with antibody deficiencies often present after six months of age, when maternal antibodies are lost, but they can present in adulthood. Typically, these patients develop infections with encapsulated bacteria. Recurrent bacterial sinus and pulmonary infections are the hallmark of antibody primary immunodeficiencies. […] Patients with humoral primary immunodeficiencies have an intact cellular immune system; thus, they are able to handle most viral and fungal pathogens, a factor that can help to distinguish these disorders clinically.

• #13 The Molecular Pathology of Primary Immunodeficiencies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1867474/

  The primary cause of CVID is not known. In part because CVID comprises a heterogeneous group of disorders, non-random recurrent cytogenetic abnormalities unique to CVID have not been identified. Current evidence suggests that the humoral defect in CVID patients is as a result of insufficient in vivo stimulus for B cell activation rather than an intrinsic inability of the B lymphocytes to undergo terminal differentiation into plasma cells. […] Furthermore, circulating B cells from CVID patients failed to undergo somatic hypermutation in immunoglobulin-variable region genes, similar to cord blood B cells. They were also unable to produce IgA on engagement of the Ig receptor suggesting the presence of severe deficiency of switched memory B cells (CD27+ IgMIgD) in CVID patients. […] The genetic anomaly in X-linked hyper-IgM syndrome has been mapped to Xq26, and resides in mutations of the CD40 ligand gene now known as CD154. CD40L is a member of the tumor necrosis factor family that binds to its receptor (CD40) expressed in B cells. Interactions between the CD40 ligand present on activated T cells and CD40 on B cells is required for productive isotype switching in B cells. The defect in X-linked hyper-IgM syndrome is a failure of isotype switch. […] Failure of this switch results in defective formation of germinal centers and immunoglobulin switching.

• #14 The Molecular Pathology of Primary Immunodeficiencies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1867474/

  The primary cause of CVID is not known. In part because CVID comprises a heterogeneous group of disorders, non-random recurrent cytogenetic abnormalities unique to CVID have not been identified. Current evidence suggests that the humoral defect in CVID patients is as a result of insufficient in vivo stimulus for B cell activation rather than an intrinsic inability of the B lymphocytes to undergo terminal differentiation into plasma cells. […] Furthermore, circulating B cells from CVID patients failed to undergo somatic hypermutation in immunoglobulin-variable region genes, similar to cord blood B cells. They were also unable to produce IgA on engagement of the Ig receptor suggesting the presence of severe deficiency of switched memory B cells (CD27+ IgMIgD) in CVID patients. […] The genetic anomaly in X-linked hyper-IgM syndrome has been mapped to Xq26, and resides in mutations of the CD40 ligand gene now known as CD154. CD40L is a member of the tumor necrosis factor family that binds to its receptor (CD40) expressed in B cells. Interactions between the CD40 ligand present on activated T cells and CD40 on B cells is required for productive isotype switching in B cells. The defect in X-linked hyper-IgM syndrome is a failure of isotype switch. […] Failure of this switch results in defective formation of germinal centers and immunoglobulin switching.

• #15 Common Variable Immunodeficiency: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1051103-overview

  Common variable immunodeficiency (CVID) is a disorder that involves the following: Low levels of most or all of the immunoglobulin (Ig) classes. Lack of B lymphocytes or plasma cells that are capable of producing antibodies. Frequent bacterial infections. A diagnosis of CVID is reserved for persons with an undefined B-cell dysfunction. […] In patients with common variable immunodeficiency (CVID), numerous immune-system abnormalities are reported, the most common of which is defective antibody formation. Consequently, both humoral and cell-mediated lymphocytic responses are affected. Some CVID patients may have a defect in the T-cell ability to help B cells, and/or B-cell response to T-cell help. Innate immunity defects may modify clinical status and findings in these patients. […] The basic pathophysiologic process in CVID is a simple failure in the differentiation of B lymphocytes. However, evidence shows that this defect in the pathway is not common among patients. One study showed that, when B lymphocytes were stimulated with pokeweed mitogen in vitro, plasma cells failed to differentiate, even in the presence of normal T cells. This finding suggests a defect in B-cell expression in surface molecules.

• #16 Primary Immunodeficiencies | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/1115/p2001.html

  Disruption of the cellular immune response is observed in patients with defects in T cells or both T and B cells. These primary immunodeficiency disorders are generally more severe than antibody deficiencies. Affected patients often present early in life with failure to thrive and disseminated infection. DiGeorge syndrome is one of the most recognized disorders in this category, and severe combined immunodeficiency is the most severe. General features of this class of diseases include overwhelming viral and fungal infections. […] Chronic granulomatous disease, the most frequently diagnosed phagocytic primary immunodeficiency, is more common in males than in females. In this disease, deficiency of nicotinamide adenine dinucleotide phosphate oxidase in phagocytes results in defective elimination of extracellular pathogens such as bacteria and fungi.

• #17 The Molecular Pathology of Primary Immunodeficiencies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1867474/

  X-linked agammaglobulinemia was the first immunodeficiency to be characterized at the genetic level. XLA is caused by a block in B cell differentiation due to mutations involving the Bruton kinase gene, Btk, which encodes a tyrosine kinase that regulates the activity of signaling pathways by phosphorylation. BTK is activated by immunoglobulins and other membrane receptors that in turn activate phospholipase C and calcium influx. […] Although the specific defect in the signaling pathway that impairs B-cell development is unknown, it is proposed that BTK is important in mediation of survival signals. […] The severe combined immunodeficiencies (SCIDs) syndrome is characterized by gross impairment of both the humoral and cell-mediated immunity and by susceptibility to overwhelming fungal, bacterial, and viral infections. The syndrome comprises a heterogeneous group of primary immunodeficiencies associated with various defects of the immune system involving T, B, and sometimes natural killer cells. […] The identification of specific gene abnormalities important in lymphocyte biology and their link to these rare diseases has led to significant insights into the complexity of the immune system and provided new insights regarding the spectrum of clinical severity seen in a particular disorder and the phenotypic overlap resulting from mutations of different genes.

• #18 Severe Combined Immunodeficiency (SCID): Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/210249-overview

  The earlier the defect, the more devastating the effect on lymphopoiesis. Defects occurring at the CLP stage or those affecting processes common to B- and T-cell development result in SCID involving B, T, and NK cells. […] According to the type of defect that leads to a SCID phenotype, Combined B- and T-cell disorders can be divided into specific groups with unique pathophysiologies that invariably result in an absence of nonfunctional B cells and absence of T cells. […] There are 4 characterized pathways that can result in SCID, as follows: […] Defective V(D)J rearrangements of the T-cell and B-cell receptor genes (accounts for 30% of SCID cases). […] Defective cytokine-dependent survival signaling in T-cell precursors and sometimes NK-cell precursors (accounts for more than 50% of SCID cases).

• #19 Severe Combined Immunodeficiency (SCID): Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/210249-overview

  In this condition, mutations in the genes coding for the recombinases (ie, RAG1 and RAG2) cause a defect in the VDJ rearrangement that is needed for mature B-cells and T-cells to develop, resulting in a paradoxical combination of immunodeficiency and immune dysregulation. […] An extensive number of disorders with SCID manifestations belong to this category in which defects in cytokine receptors and/or cytokine signaling are present. […] The absence of the gamma-C chain or the presence of aberrant forms affect signaling events that are mediated via various cytokine receptors, thus explaining the multiple cell types that are affected in X-linked SCID, which include T, NK, and B cells. […] X-linked SCID is characterized by the absence of T and NK cells but a normal number of dysfunctional B cells (T B+ NK SCID).

• #20 Primary Immunodeficiencies | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/1115/p2001.html

  Disruption of the cellular immune response is observed in patients with defects in T cells or both T and B cells. These primary immunodeficiency disorders are generally more severe than antibody deficiencies. Affected patients often present early in life with failure to thrive and disseminated infection. DiGeorge syndrome is one of the most recognized disorders in this category, and severe combined immunodeficiency is the most severe. General features of this class of diseases include overwhelming viral and fungal infections. […] Chronic granulomatous disease, the most frequently diagnosed phagocytic primary immunodeficiency, is more common in males than in females. In this disease, deficiency of nicotinamide adenine dinucleotide phosphate oxidase in phagocytes results in defective elimination of extracellular pathogens such as bacteria and fungi.

• #21 Primary Immune Deficiency Disorders: A Review | EMJ Reviews

  https://www.emjreviews.com/allergy-immunology/article/a-review-of-primary-immune-deficiency-disorders/

  There are several measures of prophylaxis for infants with SCID. […] Genetic testing is important because of preparation for bone marrow transplant or stem cell transplant, especially if the defect is in the DNA repair genes. […] There are now 50 genetic defects associated with SCID. […] If there is a trial open for genetic therapy for the type of SCID identified, the family may opt to apply for that therapy, which may go on to become standard of care in the near future. […] Primary complement deficiencies can lead to increased infections and autoimmune disease. […] Chronic granulomatous disease (CGD) is a disorder of the NADPH oxidase system which usually forms hydrogen peroxide (H2O2) and reactive chloride species. […] The most accurate assay for the diagnosis of CGD involves measurement of hydrogen peroxide in phagocytes by dihydrorhodamine reductase.

• #22 Primary Immunodeficiencies | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/1115/p2001.html

  Complement disorders account for only 2 percent of all primary immunodeficiency disorders. They result from the disruption of one of the proteins involved in the classic or nonclassic activation pathways of the complement response. Defects in the classic pathway account for the more common type of complement deficiency, and patients often have a high number of autoimmunity disorders, including lupus-like syndromes.

• #23 Primary Immunodeficiency (PID) – Australasian Society of Clinical Immunology and Allergy (ASCIA)

  https://www.allergy.org.au/patients/immunodeficiencies/primary-immunodeficiency

  For this reason, most people with T cell problems have combined immunodeficiencies, because both B and T cell functions are affected. […] Severe combined immunodeficiency (SCID) is the most serious of these disorders. SCID is usually diagnosed within the first year of life and requires a haematopoietic stem cell transplant (HSCT) to survive. […] Phagocytes are white blood cells (neutrophils and macrophages), that eat and kill antibody coated foreign invaders. Severe infections can occur if phagocytes are unable to kill germs or move to the site of an infection. […] Chronic granulomatous disease (CGD) is the most serious form of phagocytic cell deficiency. In CGD neutrophils cant capture and kill germs. […] Immune dysregulation includes a broad group of disorders that occur when the bodys immune system is not being controlled normally and may react against its own cells. […] The complement system has an important role in the control of inflammation, killing of germs and clearance of damaged cells. Some complement deficiencies can increase the risk of autoimmune disease, whilst others result in severe infections such as meningitis or septicaemia.

• #24 Autoimmunity in Primary Immunodeficiency Disorders: An Updated Review on Pathogenic and Clinical Implications

  https://www.mdpi.com/2077-0383/10/20/4729

  Different studies suggested that both genetic background and immunological abnormalities play a significant role in explaining the link between CVID and autoimmunity. […] The mechanisms responsible for autoimmunity in HIGM are heterogeneous and depend on the genetic background. […] The pathogenesis of the autoimmune phenotype is not completely elucidated, but defects in central negative selection secondary to reduced AIRE expression and altered peripheral tolerance are implicated. […] The pathogenic mechanism linking complement deficiencies with autoimmunity is mostly dependent on a reduced clearance of apoptotic cells and immune complexes. This causes an enhanced availability of auto-antigens, which are chronically exposed to the immune system, thus triggering a self-reactive immune response.

• #25 Primary immunodeficiency | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0290-5

  PIDs may present at any age, and the accurate and timely diagnosis of these disorders requires a high index of suspicion and specialized testing. […] PIDs are broadly classified according to the component of the immune system that is primarily disrupted: adaptive or innate immunity. […] The current view of PIDs includes an increasing number of syndromes that are associated with autoimmunity and immune dysregulation as predominant features, rather than an overt pathological risk of infections. […] Defects occurring at any stage of T-cell development, differentiation and maturation lead to T-cell (cellular) immunodeficiency disorders, while defects relating to B-cell development and/or maturation result in B-cell (antibody-deficiency) disorders. […] Since B-cell-mediated antibody production requires intact T-cell function, most T-cell defects lead to combined (B- and T-cell) immunodeficiency disorders (CIDs).

• #26 Primary immunodeficiency | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0290-5

  Defects in the development and function of any of these elements of innate immunity may lead to PIDs. […] In many of these disorders, lymphocytes may be present but dysfunctional, allowing for the development of excessive autoreactivity and resultant autoimmune disease and/or other symptoms of immune dysregulation. […] The treatment of PIDs is complex and generally requires both supportive and definitive strategies. […] Ig replacement therapy is the mainstay of therapy for B-cell disorders, and is also an important supportive treatment for many patients with combined immunodeficiency disorders. […] The treatment of innate immunodeficiency disorders varies depending on the type of defect, but may involve antifungal and antibiotic prophylaxis, cytokine replacement, vaccinations and bone marrow transplantation.

• #27 Primary immunodeficiency | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0290-5

  Defects in the development and function of any of these elements of innate immunity may lead to PIDs. […] In many of these disorders, lymphocytes may be present but dysfunctional, allowing for the development of excessive autoreactivity and resultant autoimmune disease and/or other symptoms of immune dysregulation. […] The treatment of PIDs is complex and generally requires both supportive and definitive strategies. […] Ig replacement therapy is the mainstay of therapy for B-cell disorders, and is also an important supportive treatment for many patients with combined immunodeficiency disorders. […] The treatment of innate immunodeficiency disorders varies depending on the type of defect, but may involve antifungal and antibiotic prophylaxis, cytokine replacement, vaccinations and bone marrow transplantation.

• #28 Autoimmunity in Primary Immunodeficiency Disorders: An Updated Review on Pathogenic and Clinical Implications

  https://www.mdpi.com/2077-0383/10/20/4729

  During the last years, studies investigating the intriguing association between immunodeficiency and autoimmunity led to the discovery of new monogenic disorders, the improvement in the knowledge of the pathogenesis of autoimmunity, and the introduction of targeted treatments. […] The pathogenesis of autoimmunity in patients with immunodeficiency is far to be fully elucidated. However, altered germ center reactions, impaired central and peripheral lymphocyte negative selection, uncontrolled lymphocyte proliferation, ineffective cytoskeletal function, innate immune defects, and defective clearance of the infectious agents play an important role. […] The molecular mechanisms responsible for the immune dysregulation in patients with PIDs are multiple and not completely elucidated; impaired B cell differentiation and germ-center reactions, altered T cell central or peripheral tolerance, uncontrolled lymphocyte proliferation and differentiation, dysfunctional complement, and innate immune activation can participate in the complex pathogenic process leading to autoimmunity.

• #29 Primary Immunodeficiencies | Immunopaedia

  https://www.immunopaedia.org.za/immunology/special-focus-area/1-primary-immunodeficiencies/

  The immune deficiency conditions are a group of disorders that result from one or more abnormalities of the immune system and that manifest clinically as an increased susceptibility to infection. […] Because most of the primary immunodeficiencies result from abnormalities in cellular maturation emanating from known molecular lesions in signaling pathways, transcription molecules, or cytokine systems, it may be useful to frame these defects according to the normal ontogenetic development of the immune system described in sections 1, 2 and 3. […] One of the most rapidly developing areas of immunologic research that is finding clinical applicability is being directed to the study of genetic mutations involving signaling pathways and pattern recognition receptors (PRRs) involved in innate immune function, e.g., TLRs that are associated with severe innate immunodeficiency phenotypes.

• #30 Primary Immunodeficiencies | Immunopaedia

  https://www.immunopaedia.org.za/immunology/special-focus-area/1-primary-immunodeficiencies/

  These pathways converge at the activation of NF-B, an important transcription factor dependent on the activation of the inhibitor of the NF-B kinase (IKK) complex and its subsequent phosphorylation of the NF-B inhibitor, IB. […] Defects in one of the IKK components, IKK, also called the NF-B essential modulator (NEMO), cause ectodermal dysplasia together with a complex set of immunodeficiencies with dysfunction of the innate (Toll-like receptors, TNF-R, and IL-1R) and adaptive (CD40 and IL-18) immune systems. […] The prototype for the most common form of SCID has been considered to be the X-linked (SCID-XL) form due to mutations in the shared IL-2 common gamma chain receptor (IL-2Rc, Xq13) found in receptors for IL-2, IL-15, IL-4, IL-7, IL-9, and IL-21. […] The major B cell defects can be divided into three major categories of antibody deficiencies: (1) defects in early B cell development, (2) hyper-IgM syndromes (also called class-switch recombination defects), and (3) common variable immunodeficiency (CVID).

• #31 Primary Immunodeficiencies | Immunopaedia

  https://www.immunopaedia.org.za/immunology/special-focus-area/1-primary-immunodeficiencies/

  These pathways converge at the activation of NF-B, an important transcription factor dependent on the activation of the inhibitor of the NF-B kinase (IKK) complex and its subsequent phosphorylation of the NF-B inhibitor, IB. […] Defects in one of the IKK components, IKK, also called the NF-B essential modulator (NEMO), cause ectodermal dysplasia together with a complex set of immunodeficiencies with dysfunction of the innate (Toll-like receptors, TNF-R, and IL-1R) and adaptive (CD40 and IL-18) immune systems. […] The prototype for the most common form of SCID has been considered to be the X-linked (SCID-XL) form due to mutations in the shared IL-2 common gamma chain receptor (IL-2Rc, Xq13) found in receptors for IL-2, IL-15, IL-4, IL-7, IL-9, and IL-21. […] The major B cell defects can be divided into three major categories of antibody deficiencies: (1) defects in early B cell development, (2) hyper-IgM syndromes (also called class-switch recombination defects), and (3) common variable immunodeficiency (CVID).

• #32 JCM | Special Issue : Primary Immunodeficiencies: Pathogenetic Advances, Diagnostic and Management Challenges

  https://www.mdpi.com/journal/jcm/special_issues/Primary_Immunodeficiencies

  In the last decade, the research advances in the field of pediatric immunology brought a dramatic improvement in the diagnosis of primary immunodeficiency disorders. The use of new genetic panels allowed the identification of a considerable number of monogenic causes of primary immunodeficiency, each one featuring a peculiar clinical and immunological phenotype. […] Moreover, the discovery and molecular characterization of the monogenic causes of primary immunodeficiencies helped to better understand the complex pathogenic and clinical overlap between immunodeficiency, immune dysregulation, autoimmunity and autoinflammation. The risk of lymphoproliferation and non-hematologic malignancies in children with primary immunodeficiencies has also been deeply analyzed, providing interesting information for long-term follow-up and clinical management.

• #33 JCM | Special Issue : Primary Immunodeficiencies: Pathogenetic Advances, Diagnostic and Management Challenges

  https://www.mdpi.com/journal/jcm/special_issues/Primary_Immunodeficiencies

  In the last decade, the research advances in the field of pediatric immunology brought a dramatic improvement in the diagnosis of primary immunodeficiency disorders. The use of new genetic panels allowed the identification of a considerable number of monogenic causes of primary immunodeficiency, each one featuring a peculiar clinical and immunological phenotype. […] Moreover, the discovery and molecular characterization of the monogenic causes of primary immunodeficiencies helped to better understand the complex pathogenic and clinical overlap between immunodeficiency, immune dysregulation, autoimmunity and autoinflammation. The risk of lymphoproliferation and non-hematologic malignancies in children with primary immunodeficiencies has also been deeply analyzed, providing interesting information for long-term follow-up and clinical management.

• #34 Primary immunodeficiency disorders – Latest research and news | Nature

  https://www.nature.com/subjects/primary-immunodeficiency-disorders

  Primary immunodeficiency disorders are a set of syndromes that arise from defects in the immune system. Most are diagnosed in young children, and patients are generally characterized by increased susceptibility to infections. […] Common variable immunodeficiency (CVID) is a prevalent primary immunodeficiency characterized by hypogammaglobulinemia, poor antibody responses, and enhanced susceptibility to infection. Here the authors examine CVID patients infected by SARS-CoV-2 and describe broad immune dysregulation, sustained type I IFN responses, altered B/T cell signaling, impaired NK cell differentiation, and persistent inflammasome activation. […] Common variable immunodeficiency (CVID) is an inborn error of immunity, characterized clinically by low immunoglobulin levels, poor vaccine responses and recurrent sinopulmonary infections. Here authors show that the proportion of V1+ T cells in CVID is higher than in healthy controls and these cells respond to persistent cytomegalovirus viremia with expansion and phenotypic alterations.

• #35 Common variable immunodeficiency – Wikipedia

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

  CVID is a lifelong disease. […] The causative factors of CVID are not fully known. Genetic mutations can be identified as the cause of disease in about 10% of people, while familial inheritance accounts for 10-25% of cases. Rather than arising from a single genetic mutation, CVID seems to result from a variety of mutations that all contribute to a failure in antibody production. […] Mutations in the genes encoding ICOS, TACI, CD19, CD20, CD21, CD80, and BAFFR have been identified as causative of CVID. […] Susceptibility to CVID may also be linked to the major histocompatibility complex (MHC) of the genome, particularly to DR-DQ haplotypes. […] Several recent studies have described a potential role of epigenetics factor (including DNA methylation, chromatin and histone modulation and also non-coding RNAs) in pathogenesis of CVID.

• #36 Common variable immunodeficiency – Wikipedia

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

  CVID is a lifelong disease. […] The causative factors of CVID are not fully known. Genetic mutations can be identified as the cause of disease in about 10% of people, while familial inheritance accounts for 10-25% of cases. Rather than arising from a single genetic mutation, CVID seems to result from a variety of mutations that all contribute to a failure in antibody production. […] Mutations in the genes encoding ICOS, TACI, CD19, CD20, CD21, CD80, and BAFFR have been identified as causative of CVID. […] Susceptibility to CVID may also be linked to the major histocompatibility complex (MHC) of the genome, particularly to DR-DQ haplotypes. […] Several recent studies have described a potential role of epigenetics factor (including DNA methylation, chromatin and histone modulation and also non-coding RNAs) in pathogenesis of CVID.

• #37 The Molecular Pathology of Primary Immunodeficiencies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1867474/

  The primary immunodeficiencies characteristically present in childhood with infections that persist for long duration with multiple recurrences that are resistant to antibiotics. Failure to thrive and developmental delay are significant clues to the seriousness of their infections. Many immunodeficient children develop other symptoms such as skin rashes, and many have associated developmental anomalies of the face, skeletal system, heart, and pigmentation. […] The nature of the pathogens and sites of infections can provide insight as to the underlying immunodeficiency. Defects involving B cell function result in recurrent sinopulmonary infections, often with bacterial septicemia. The lack of antibody production may also increase susceptibility to invasive disease with enteroviruses, resulting in chronic viral meningitis, and giardiasis. T cells are essential for the control of viral and fungal disease, however they also provide helper function to B cells for effective antibody responses. Thus, T cell disorders present as combined T and B cell immunodeficiency with susceptibility to both bacterial and chronic, invasive viral, and fungal pathogens.

• #38 The Molecular Pathology of Primary Immunodeficiencies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1867474/

  The primary immunodeficiencies characteristically present in childhood with infections that persist for long duration with multiple recurrences that are resistant to antibiotics. Failure to thrive and developmental delay are significant clues to the seriousness of their infections. Many immunodeficient children develop other symptoms such as skin rashes, and many have associated developmental anomalies of the face, skeletal system, heart, and pigmentation. […] The nature of the pathogens and sites of infections can provide insight as to the underlying immunodeficiency. Defects involving B cell function result in recurrent sinopulmonary infections, often with bacterial septicemia. The lack of antibody production may also increase susceptibility to invasive disease with enteroviruses, resulting in chronic viral meningitis, and giardiasis. T cells are essential for the control of viral and fungal disease, however they also provide helper function to B cells for effective antibody responses. Thus, T cell disorders present as combined T and B cell immunodeficiency with susceptibility to both bacterial and chronic, invasive viral, and fungal pathogens.

• #39 The Molecular Pathology of Primary Immunodeficiencies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1867474/

  The primary immunodeficiencies characteristically present in childhood with infections that persist for long duration with multiple recurrences that are resistant to antibiotics. Failure to thrive and developmental delay are significant clues to the seriousness of their infections. Many immunodeficient children develop other symptoms such as skin rashes, and many have associated developmental anomalies of the face, skeletal system, heart, and pigmentation. […] The nature of the pathogens and sites of infections can provide insight as to the underlying immunodeficiency. Defects involving B cell function result in recurrent sinopulmonary infections, often with bacterial septicemia. The lack of antibody production may also increase susceptibility to invasive disease with enteroviruses, resulting in chronic viral meningitis, and giardiasis. T cells are essential for the control of viral and fungal disease, however they also provide helper function to B cells for effective antibody responses. Thus, T cell disorders present as combined T and B cell immunodeficiency with susceptibility to both bacterial and chronic, invasive viral, and fungal pathogens.

• #40 Primary immunodeficiency | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0290-5

  Defects in the development and function of any of these elements of innate immunity may lead to PIDs. […] In many of these disorders, lymphocytes may be present but dysfunctional, allowing for the development of excessive autoreactivity and resultant autoimmune disease and/or other symptoms of immune dysregulation. […] The treatment of PIDs is complex and generally requires both supportive and definitive strategies. […] Ig replacement therapy is the mainstay of therapy for B-cell disorders, and is also an important supportive treatment for many patients with combined immunodeficiency disorders. […] The treatment of innate immunodeficiency disorders varies depending on the type of defect, but may involve antifungal and antibiotic prophylaxis, cytokine replacement, vaccinations and bone marrow transplantation.

• #41 Primary immunodeficiency

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6157160/

  Failure of the innate system to identify pathogens delays the induction of the immune response and may worsen outcomes of infection. […] Defects in the development and function of any of these elements of innate immunity may lead to PIDs. […] These PIDs are associated with autoimmune disease due to the dysregulation of the immune system as a whole. […] In many of these disorders, lymphocytes may be present but dysfunctional, allowing for the development of excessive autoreactivity and resultant autoimmune disease and/or other symptoms of immune dysregulation. […] The treatment of PIDs is complex and generally involves both supportive and definitive strategies. […] The mainstay of therapy for most B-cell (antibody-deficiency) disorders is intravenous (IV) or subcutaneous Ig replacement therapy.

• #42 Primary immunodeficiency

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6157160/

  Gene therapy may also be a potential definitive treatment option in the future. […] The prognosis of patients with PIDs varies depending on the etiology of the disorder. […] However, patient outcomes and long-term survival have improved significantly since the 1970s given our improved management of infections and early access to antibiotics, advances in BMT and HSCT techniques, and enhanced intensive care services.

• #43 Primary immunodeficiency

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6157160/

  Gene therapy may also be a potential definitive treatment option in the future. […] The prognosis of patients with PIDs varies depending on the etiology of the disorder. […] However, patient outcomes and long-term survival have improved significantly since the 1970s given our improved management of infections and early access to antibiotics, advances in BMT and HSCT techniques, and enhanced intensive care services.

• #44 JCM | Special Issue : Primary Immunodeficiencies: Pathogenetic Advances, Diagnostic and Management Challenges

  https://www.mdpi.com/journal/jcm/special_issues/Primary_Immunodeficiencies

  Finally, the increasing knowledge on the genetic and immunological background underlying single conditions, together with the collection of data from the literature and international registries, opened up the opportunity to use targeted treatments and genetic therapy and better define the role of hematopoietic stem cell transplantation in pediatric immunodeficiency disorders.

Zobacz więcej