Materiały źródłowe

• #1 Pathogenesis of Kawasaki disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3095860/

  Kawasaki disease (KD) most frequently affects infants and young children under 5 years of age. This disease is considered a kind of systemic vasculitis syndrome, and primarily invades the medium-sized muscular arteries, including coronary arteries. […] Even though the aetiology of KD is unknown, epidemiological data suggest that some kinds of infectious agents are involved in the onset of KD. In addition, the data indicate that host genetics underlie the disease’s pathogenesis. Histologically, coronary arteritis begins 68 days after the onset of KD, and leads immediately to inflammation of all layers of the artery. The inflammation spreads completely around the artery; as a result, structural components of the artery undergo intense damage; the artery then begins to dilate. Inflammatory cell infiltration continues until about the 25th day of the disease, after which the inflammatory cells gradually decrease in number. KD arteritis is characterized by granulomatous inflammation that consists of severe accumulation of monocytes/macrophages. Aberrant activation of monocytes/macrophages is thought to be involved in the formation of vascular lesions. […] The pathogenesis of KD might be clarified by analysing the mechanism of actions of these therapies in detail.

• #2 Pathogenesis and management of Kawasaki disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2845298/

  Kawasaki disease (KD) is an acute systemic inflammatory illness of young children that can result in coronary artery aneurysms, myocardial infarction and sudden death in previously healthy children. […] The etiology of KD remains a major pediatric enigma, despite efforts to identify the cause over the last four decades. […] The scope of this article is to review the unique immunopathology of KD and to describe current treatment, which is primarily aimed at blocking or reducing inflammation in the coronary arteries. […] We detail the evidence in support of an infectious cause of KD, and we describe exciting new research that has led to discovery of viral-like cytoplasmic inclusion bodies in acute KD tissues; it is hoped that this finding will lead to the identification of the causative agent and to improved diagnostic and treatment modalities.

• #3 Pathogenesis and management of Kawasaki disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2845298/

  Kawasaki disease (KD) is an acute systemic inflammatory illness of young children that can result in coronary artery aneurysms, myocardial infarction and sudden death in previously healthy children. […] The etiology of KD remains a major pediatric enigma, despite efforts to identify the cause over the last four decades. […] The scope of this article is to review the unique immunopathology of KD and to describe current treatment, which is primarily aimed at blocking or reducing inflammation in the coronary arteries. […] We detail the evidence in support of an infectious cause of KD, and we describe exciting new research that has led to discovery of viral-like cytoplasmic inclusion bodies in acute KD tissues; it is hoped that this finding will lead to the identification of the causative agent and to improved diagnostic and treatment modalities.

• #4

  https://www.jci.org/articles/view/176938

  Kawasaki disease (KD) is a systemic vasculitis that affects young children and can result in coronary artery aneurysms. The etiology is currently unknown, but new clues from the epidemiology of KD in Japan, the country of highest incidence, are beginning to shed light on what may trigger this acute inflammatory condition. […] The cause of Kawasaki disease (KD), the most common cause of acquired heart disease in children, remains a mystery after 50 years of investigation. […] Timely diagnosis is imperative, as coronary artery damage from the vasculitis begins early in the course of the illness. […] Once the etiology of KD is determined, accurate diagnostic tests will become available, and new, less expensive, and more effective targeted therapies will likely be possible. […] The rich epidemiologic record of KD cases maintained by Nakamura and colleagues at Jichi University documented the three nationwide epidemics that occurred in 1979, 1982, and 1986.

• #5 Kawasaki disease: insights into pathogenesis and approaches to treatment | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2015.54

  Epidemiologic data strongly suggest an infectious aetiology for Kawasaki disease, which is the leading cause of acquired heart disease among children in developed countries […] Necrotizing arteritis, subacute chronic vasculitis, and luminal myofibroblastic proliferation are three linked processes underlying the arteriopathy associated with Kawasaki disease […] Genetic susceptibility is indicated by the strikingly high rate of Kawasaki disease in children of Asian ethnicity and by its increased incidence in first-degree relatives of affected patients […] This Review summarizes recent advances in understanding of the pathologic processes and pathophysiologic mechanisms leading to coronary arteritis in Kawasaki disease […] Genetic factors also increase susceptibility to Kawasaki disease, as indicated by its strikingly high incidence rate in children of Asian ethnicity and by an increased incidence in first-degree family members […] The added value of adjunctive therapy with corticosteroids in patients at particularly high risk of coronary complications has been demonstrated in Japanese populations, but identification of high-risk patients has proven to be difficult in ethnically diverse populations.

• #6 Kawasaki Disease | AAFP

  https://www.aafp.org/pubs/afp/issues/1999/0601/p3093.html

  Kawasaki disease is a leading cause of acquired heart disease among children in the United States and other developed countries. […] A generalized vasculitis of unknown etiology, Kawasaki disease can cause coronary artery abnormalities, including coronary aneurysms. […] The cause of the disease remains unknown, but epidemiologic investigations and the clinical presentation suggest a microbial agent. […] Epidemiologic features and clinical presentation suggest an infectious etiology for Kawasaki disease. […] To date, however, an etiologic agent has not been documented. […] Even though the initiating event has not yet been identified, the immune system is known to be involved during the acute stage of Kawasaki disease. […] It is postulated that the various secreted cytokines target vascular endothelial cells, producing cell-surface neoantigens. […] Antibodies produced against these antigens may then target the vascular endothelium, resulting in a cascade of events leading to vascular damage.

• #7 Kawasaki Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/965367-overview

  Despite the prominent mucocutaneous clinical findings that define the illness, KD is best regarded as a generalized vasculitis that involves medium-sized arteries. Although the vascular inflammation is most pronounced in the coronary vessels, vasculitis can also occur in veins, capillaries, small arterioles, and larger arteries. […] In the earliest stages of the disease, the endothelial cells and the vascular media become edematous, but the internal elastic lamina remains intact. Then, approximately 7-9 days after the onset of fever, an influx of neutrophils occurs, which is quickly followed by a proliferation of CD8+ (cytotoxic) lymphocytes and immunoglobulin A-producing plasma cells. The inflammatory cells secrete various cytokines (tumor necrosis factor, vascular endothelial growth factor, monocyte chemotactic and activating factor), interleukins (IL-1, IL-4, IL-6), and matrix metalloproteinases (primarily MMP3 and MMP9) that target the endothelial cells and result in a cascade of events that lead to fragmentation of the internal elastic lamina and vascular damage.

• #8 Intravenous Immunoglobulin in Kawasaki Disease—Evolution and Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/13/14/2338

  Kawasaki disease (KD) is an acute vasculitis of childhood that affects the medium vessels with a special predilection to the involvement of coronary arteries. The major morbidity of this disease is due to coronary artery aneurysm, which occurs in about 25–30% of untreated cases. For decades now, intravenous immunoglobulin (IVIg) has consistently been shown to reduce the risk of CAAs to less than 5%. However, the mechanism of immunomodulation remains unclear. Several studies on the role of IVIg in the modulation of toll-like receptor pathways, autophagy, and apoptosis of the mononuclear phagocytic system, neutrophil extracellular trap, and dendritic cell modulation suggest a modulatory effect on the innate immune system. […] In this manuscript, we review the evolution and pathogenic mechanisms of IVIg therapy in KD.

• #9 Pathogenesis and management of Kawasaki disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2845298/

  Kawasaki disease (KD) is an acute systemic inflammatory illness of young children that can result in coronary artery aneurysms, myocardial infarction and sudden death in previously healthy children. […] The etiology of KD remains a major pediatric enigma, despite efforts to identify the cause over the last four decades. […] The scope of this article is to review the unique immunopathology of KD and to describe current treatment, which is primarily aimed at blocking or reducing inflammation in the coronary arteries. […] We detail the evidence in support of an infectious cause of KD, and we describe exciting new research that has led to discovery of viral-like cytoplasmic inclusion bodies in acute KD tissues; it is hoped that this finding will lead to the identification of the causative agent and to improved diagnostic and treatment modalities.

• #10 Pathogenesis and management of Kawasaki disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2845298/

  Some theories of KD pathogenesis focus upon endothelial cell antigens as the exclusive targets of the disease process, but such models do not explain many of the pathologic findings of KD such as bronchitis, prostatitis and pancreatic ductitis. […] The theory of KD etiology that best fits the available data is that a ubiquitous infectious agent results in asymptomatic infection in most individuals but causes KD in a subset of genetically predisposed individuals. […] The presence of a predominant IgA plasma cell response in a non-lymphoid, non-mucosal tissue such as arterial tissue is distinctly unusual. […] The presence of IgA deposits or IgA immune complexes in the skin or kidney is characteristic of HenochSchnlein purpura and IgA nephropathy, but IgA plasma cells are not observed in these tissues in these diseases.

• #11 Kawasaki disease – Wikipedia

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

  The specific cause of Kawasaki disease is unknown. A plausible explanation is that it may be caused by an infection that triggers an inappropriate immunologic cascade in a small number of genetically predisposed children. The pathogenesis is complex and incompletely understood. Various explanations exist. […] Circumstantial evidence points to an infectious cause. Since recurrences are unusual in Kawasaki disease, it is thought that the trigger is more likely to be represented by a single pathogen, rather than a range of viral or bacterial agents. Various candidates have been implicated, including upper respiratory tract infection by some novel RNA virus. Despite intensive search, no single pathogen has been identified. There has been debate as to whether the infectious agent might be a superantigen (i.e. one commonly associated with excessive immune system activation). Current consensus favors an excessive immunologic response to a conventional antigen which usually provides future protection.

• #12 Kawasaki disease: insights into pathogenesis and approaches to treatment | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2015.54

  Epidemiologic data strongly suggest an infectious aetiology for Kawasaki disease, which is the leading cause of acquired heart disease among children in developed countries […] Necrotizing arteritis, subacute chronic vasculitis, and luminal myofibroblastic proliferation are three linked processes underlying the arteriopathy associated with Kawasaki disease […] Genetic susceptibility is indicated by the strikingly high rate of Kawasaki disease in children of Asian ethnicity and by its increased incidence in first-degree relatives of affected patients […] This Review summarizes recent advances in understanding of the pathologic processes and pathophysiologic mechanisms leading to coronary arteritis in Kawasaki disease […] Genetic factors also increase susceptibility to Kawasaki disease, as indicated by its strikingly high incidence rate in children of Asian ethnicity and by an increased incidence in first-degree family members […] The added value of adjunctive therapy with corticosteroids in patients at particularly high risk of coronary complications has been demonstrated in Japanese populations, but identification of high-risk patients has proven to be difficult in ethnically diverse populations.

• #13 SciELO Brazil – Doença de Kawasaki Doença de Kawasaki

  https://www.scielo.br/j/abd/a/8gwZLwdH3VZtxbXHvv6gP4G/?lang=en

  Kawasaki disease is a systemic acute vasculitis of unknown etiology. […] The development of diagnostic tests, more specific treatment approaches and prevention of this potentially fatal disease in children depends on continuous advances in the determination of its pathogenesis. […] The cause of Kawasaki disease remains unknown despite its clinical characteristics (self-limiting febrile disease) and epidemiological characteristics (seasonality and epidemic character of the disease), favoring the hypothesis of an infectious agent as the determining cause, without any confirmation yet. […] The most acceptable etiopathogenic hypothesis is that KD is caused by an infectious agent, not identified yet, that determines clinical affections in genetically susceptible subjects in case of Asian descendants.

• #14 Pathogenesis and management of Kawasaki disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2845298/

  The pattern of an IgA B lymphocyte and a CD8 T-lymphocyte response is consistent with an adaptive immune response to an intracellular pathogen such as a virus entering at a mucosal site. […] The presence of a marked IgA plasma cell response in acute KD tissues suggested a specific immune response, potentially directed at antigens involved in disease pathogenesis, such as an inciting etiologic agent. […] The presence of an oligoclonal IgA immune response provided us with the opportunity to prepare synthetic versions of the most prevalent IgA antibodies in the KD arterial wall. […] Using light and electron microscopy, we further studied the antigen identified by the synthetic KD antibodies. […] These studies showed that the antigen in acute KD bronchial epithelium is present in cytoplasmic inclusion bodies that are consistent with aggregates of viral proteins and nucleic acids.

• #15 Pathogenesis and management of Kawasaki disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2845298/

  The pattern of an IgA B lymphocyte and a CD8 T-lymphocyte response is consistent with an adaptive immune response to an intracellular pathogen such as a virus entering at a mucosal site. […] The presence of a marked IgA plasma cell response in acute KD tissues suggested a specific immune response, potentially directed at antigens involved in disease pathogenesis, such as an inciting etiologic agent. […] The presence of an oligoclonal IgA immune response provided us with the opportunity to prepare synthetic versions of the most prevalent IgA antibodies in the KD arterial wall. […] Using light and electron microscopy, we further studied the antigen identified by the synthetic KD antibodies. […] These studies showed that the antigen in acute KD bronchial epithelium is present in cytoplasmic inclusion bodies that are consistent with aggregates of viral proteins and nucleic acids.

• #16 Searching for the cause of Kawasaki disease — cytoplasmic inclusion bodies provide new insight | Nature Reviews Microbiology

  https://www.nature.com/articles/nrmicro1853

  Kawasaki disease (KD) has emerged as the most common cause of acquired heart disease in children in the developed world. The cause of KD remains unknown, although an as-yet unidentified infectious agent might be responsible. […] Recently, identification of an antigen-driven IgA response that was directed at cytoplasmic inclusion bodies in KD tissues has provided new insights that could unlock the mysteries of KD. […] Cytoplasmic inclusion bodies are detected by synthetic antibody in ciliated bronchial epithelium during acute Kawasaki disease. […] The absence of evidence of staphylococcal toxin involvement in the pathogenesis of Kawasaki disease. […] The role of anti-endothelial cell antibodies in Kawasaki disease in vitro and in vivo studies. […] General pathology of Kawasaki disease.

• #17 Pathogenesis and management of Kawasaki disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2845298/

  Additional studies indicate that KD cytoplasmic inclusion bodies contain RNA but not DNA, and that they can be identified in 85% of acute and late-stage KD fatalities and 25% of adult controls, suggesting that the KD agent is a previously unidentified, ubiquitous RNA virus that can result in persistent infection. […] Thus, all available data indicate that IgA antibodies in KD are targeting a microbial antigen, not an autoantigen. […] The following model of KD pathogenesis incorporates clinical, epidemiologic, immunologic and pathologic features of KD. KD is probably the result of infection with a ubiquitous infectious agent, most probably a single virus or a group of closely related viruses, which results in asymptomatic infection in most individuals but leads to KD only in a very small subset of genetically predisposed individuals.

• #18 Associations of infection burden with Kawasaki disease in a population-based setting during 30 years | RMD Open

  https://rmdopen.bmj.com/content/11/1/e005160

  Our study suggests that KD may not be dependent on infection by any specific pathogen but results from a wide range of possible infectious triggers. […] The observed relationship between infections and the subsequent development of KD highlights the importance of clinicians remaining vigilant for signs of inflammatory perturbations secondary to infections that may indicate the onset of KD.

• #19 Kawasaki disease – Wikipedia

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

  Research points to an unidentified ubiquitous virus, possibly one that enters through the respiratory tract. […] Seasonal trends in the appearance of new cases of Kawasaki disease have been linked to tropospheric wind patterns, which suggests wind-borne transport of something capable of triggering an immunologic cascade when inhaled by genetically susceptible children. Winds blowing from central Asia correlate with numbers of new cases of Kawasaki disease in Japan, Hawaii, and San Diego. These associations are themselves modulated by seasonal and interannual events in the El Niño-Southern Oscillation in winds and sea surface temperatures over the tropical eastern Pacific Ocean. […] Debate has occurred about whether Kawasaki disease should be viewed as a characteristic immune response to some infectious pathogen, as an autoimmune process, or as an autoinflammatory disease (i.e. involving innate rather than adaptive immune pathways). Overall, immunological research suggests that Kawasaki disease is associated with a response to a conventional antigen (rather than a superantigen) that involves both activation of the innate immune system and also features of an adaptive immune response.

• #20 On the interpretation of the atmospheric mechanism transporting the environmental trigger of Kawasaki Disease | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226402

  Recent advances on the environmental determinants of Kawasaki Disease have pointed to the important role of the atmospheric transport of a still unknown agent potentially triggering the disease. […] Recent studies have analyzed the potential connections between KD and a diversity of environmental factors and mechanisms, and among them, important advances have pointed to the relevant role of the atmospheric transport of a still unknown agent triggering the disease. […] Rod et al. pointed to possible microbial antigens or toxins in aerosol particles as a possible trigger for KD, which are capable of eliciting an idiosyncratic immune response in susceptible children. […] The air-borne hypothesis was carefully validated by checking the consistency of atmospheric dynamics across temporal scales and through different modelling techniques.

• #21 Kawasaki syndrome: an intriguing disease with numerous unsolved dilemmas | Pediatric Rheumatology | Full Text

  https://ped-rheum.biomedcentral.com/articles/10.1186/1546-0096-9-17

  More than 40 years have passed since Kawasaki syndrome (KS) was first described. Yet KS still remains an enigmatic illness which damages the coronary arteries in a quarter of untreated patients and is the most common cause of childhood-acquired heart disease in developed countries. […] Many gaps exist in our knowledge of the etiology and pathogenesis of KS, making improvements in therapy difficult. […] Though many etiological agents have been proposed, the exact cause of KS continues to be elusive. […] current research appears to indicate that the primum movens of KS might be an infectious agent with superantigenic activity, leading to a massive stimulation of the immune system and to the development of KS in a small subset of genetically predisposed individuals. […] The immune response in KS encompasses both aspects of innate and adaptive immunity with a significant overproduction of different cytokines and activation of endothelial cells.

• #22 Intravenous Immunoglobulin in Kawasaki Disease—Evolution and Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/13/14/2338

  Proposed mechanisms involve the provision of the anti-idiotypic antibodies, clearance of autoantibodies by binding with Fc receptors, blockade of adhesion molecules, and activation of the inhibitory Fc receptor (i.e., FcγRIIB) on macrophages. IVIg has the potential to neutralize the cytokines and superantigens as well as augment the T-cell suppressor activity. […] The innate immune system is actively involved in inflammation in the acute phase of KD as observed by predominant neutrophilic leucocytosis, and monocytosis, elevated levels of the damage-associated molecular pattern (DAMPs) such as high mobility group box 1 (HMB1) and S100 proteins in patients with KD. […] Neutrophilic leukocytosis is seen in most children with KD during the acute phase, morphologically characterized by toxic granulations and cytotoxic vacuolations, which tends to be higher in KD patients with concomitant CAAs.

• #23 Intravenous Immunoglobulin in Kawasaki Disease—Evolution and Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/13/14/2338

  Proposed mechanisms involve the provision of the anti-idiotypic antibodies, clearance of autoantibodies by binding with Fc receptors, blockade of adhesion molecules, and activation of the inhibitory Fc receptor (i.e., FcγRIIB) on macrophages. IVIg has the potential to neutralize the cytokines and superantigens as well as augment the T-cell suppressor activity. […] The innate immune system is actively involved in inflammation in the acute phase of KD as observed by predominant neutrophilic leucocytosis, and monocytosis, elevated levels of the damage-associated molecular pattern (DAMPs) such as high mobility group box 1 (HMB1) and S100 proteins in patients with KD. […] Neutrophilic leukocytosis is seen in most children with KD during the acute phase, morphologically characterized by toxic granulations and cytotoxic vacuolations, which tends to be higher in KD patients with concomitant CAAs.

• #24 Kawasaki Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/965367-overview

  Despite the prominent mucocutaneous clinical findings that define the illness, KD is best regarded as a generalized vasculitis that involves medium-sized arteries. Although the vascular inflammation is most pronounced in the coronary vessels, vasculitis can also occur in veins, capillaries, small arterioles, and larger arteries. […] In the earliest stages of the disease, the endothelial cells and the vascular media become edematous, but the internal elastic lamina remains intact. Then, approximately 7-9 days after the onset of fever, an influx of neutrophils occurs, which is quickly followed by a proliferation of CD8+ (cytotoxic) lymphocytes and immunoglobulin A-producing plasma cells. The inflammatory cells secrete various cytokines (tumor necrosis factor, vascular endothelial growth factor, monocyte chemotactic and activating factor), interleukins (IL-1, IL-4, IL-6), and matrix metalloproteinases (primarily MMP3 and MMP9) that target the endothelial cells and result in a cascade of events that lead to fragmentation of the internal elastic lamina and vascular damage.

• #25 Kawasaki Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/965367-overview

  Despite the prominent mucocutaneous clinical findings that define the illness, KD is best regarded as a generalized vasculitis that involves medium-sized arteries. Although the vascular inflammation is most pronounced in the coronary vessels, vasculitis can also occur in veins, capillaries, small arterioles, and larger arteries. […] In the earliest stages of the disease, the endothelial cells and the vascular media become edematous, but the internal elastic lamina remains intact. Then, approximately 7-9 days after the onset of fever, an influx of neutrophils occurs, which is quickly followed by a proliferation of CD8+ (cytotoxic) lymphocytes and immunoglobulin A-producing plasma cells. The inflammatory cells secrete various cytokines (tumor necrosis factor, vascular endothelial growth factor, monocyte chemotactic and activating factor), interleukins (IL-1, IL-4, IL-6), and matrix metalloproteinases (primarily MMP3 and MMP9) that target the endothelial cells and result in a cascade of events that lead to fragmentation of the internal elastic lamina and vascular damage.

• #26 Pathogenesis and management of Kawasaki disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2845298/

  Some theories of KD pathogenesis focus upon endothelial cell antigens as the exclusive targets of the disease process, but such models do not explain many of the pathologic findings of KD such as bronchitis, prostatitis and pancreatic ductitis. […] The theory of KD etiology that best fits the available data is that a ubiquitous infectious agent results in asymptomatic infection in most individuals but causes KD in a subset of genetically predisposed individuals. […] The presence of a predominant IgA plasma cell response in a non-lymphoid, non-mucosal tissue such as arterial tissue is distinctly unusual. […] The presence of IgA deposits or IgA immune complexes in the skin or kidney is characteristic of HenochSchnlein purpura and IgA nephropathy, but IgA plasma cells are not observed in these tissues in these diseases.

• #27 Pathogenesis and management of Kawasaki disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2845298/

  The pattern of an IgA B lymphocyte and a CD8 T-lymphocyte response is consistent with an adaptive immune response to an intracellular pathogen such as a virus entering at a mucosal site. […] The presence of a marked IgA plasma cell response in acute KD tissues suggested a specific immune response, potentially directed at antigens involved in disease pathogenesis, such as an inciting etiologic agent. […] The presence of an oligoclonal IgA immune response provided us with the opportunity to prepare synthetic versions of the most prevalent IgA antibodies in the KD arterial wall. […] Using light and electron microscopy, we further studied the antigen identified by the synthetic KD antibodies. […] These studies showed that the antigen in acute KD bronchial epithelium is present in cytoplasmic inclusion bodies that are consistent with aggregates of viral proteins and nucleic acids.

• #28

  https://www.omim.org/entry/611775

  Wang et al. (2003) assessed CD40 ligand (CD40LG; 300386) expression in 43 patients with Kawasaki disease and in 43 age-matched febrile controls. CD40LG expression on CD4+ and CD8+ T cells and platelets from patients with Kawasaki disease was significantly higher than that of controls (p less than 0.001) and decreased significantly 3 days after treatment with IVIG (p less than 0.001). Serum CD40LG levels were also significantly higher in Kawasaki disease patients but were not affected by IVIG treatment. Expression of CD40LG on CD4+ T cells and platelets, but not on CD8+ T cells or in serum, correlated with the occurrence of coronary artery lesions in Kawasaki disease patients. Wang et al. (2003) concluded that CD40LG might play a role in the immunopathogenesis of Kawasaki disease, and that IVIG therapy might downregulate CD40LG expression, resulting in decrease of CD40LG-mediated vascular damage.

• #29 SciELO Brazil – Doença de Kawasaki Doença de Kawasaki

  https://www.scielo.br/j/abd/a/8gwZLwdH3VZtxbXHvv6gP4G/?lang=en

  There are many studies trying to elucidate in details the pathogenesis and through this knowledge, find more directed therapeutic approaches and preventive measures against heart sequels. […] The increase in frequency of KD among Asian patients and their descendants, as well as the high incidence of affected family members favor the idea of genetic predisposition in KD. […] The polymorphism of interleukin 1 receptor gene (IL-1R) has also been implied in the pathogenesis of KD. […] The studies have shown that high levels of alpha tumor necrosis factors (TNF-) are significant in coronary vessels of the patients with heart lesions, which may imply more specific therapy (anti-TNF alpha) in cases of heart impairment or refractory response to treatment. […] Matrix metalloproteinases (MMP) are zinc-dependent endopeptidases involved in the degradation of extracellular matrix such as collagen and elastic fibers.

• #30 Reappraisal of VEGF in the Pathogenesis of Kawasaki Disease

  https://www.mdpi.com/2227-9067/9/9/1343

  Vascular endothelial growth factor (VEGF) is an important factor in mediating the inflammation of Kawasaki disease (KD). […] Strong immune reactivation and secretion of cytokines have represented the pathogenesis of KD. […] Elevated VEGF levels have been reported to be associated with the risk of developing coronary artery lesions (CALs) in KD patients. […] The findings in the Takeshita et al. study demonstrated that KD patients with a high VEGF/endostatin ratio were at high risk of CALs. […] Despite the evidence for supporting the correlation of VEGF with CALs in KD, further research is needed to elucidate the effect of VEGF on the outcome of KD patients. […] The significant positive correlation of VEGF with CRP as well as platelet in KD patients was found in both pre-IVIG and post-IVIG acute phases.

• #31 Reappraisal of VEGF in the Pathogenesis of Kawasaki Disease

  https://www.mdpi.com/2227-9067/9/9/1343

  Our results confirmed the involvement of VEGF in the systemic vasculitis of KD. […] The results in this series further imply that VEGF might play an important role in the pathogenesis of KD patients with acute CALs. […] Our findings might suggest that high VEGF level is another risk factor for CALs other than IVIG resistance. […] The previous findings may partially explain the significant positive correlation of VEGF and platelet in our KD patients in the acute stage. […] Our data show that VEGF did not decrease after IVIG treatment, and increased significantly after IVIG treatment in KD patients with acute CALs in the acute phase. VEGF might be related to the complications of CALs in KD patients.

• #32 Research Areas | Cedars-Sinai

  https://www.cedars-sinai.edu/health-sciences-university/research/labs/noval-rivas/areas.html

  The NLRP3 inflammasome activation and consecutive interleukin-1 (IL-1) maturation and secretion play a crucial role for the development of both human and murine KD vasculitis. […] Therefore, autophagy and mitophagy may play an important role in the prevention of cardiovascular lesions in KD vasculitis by diminishing/inhibiting NLRP3 activation, its consecutive IL-1 secretion and the resulting tissue damages.

• #33 Research Areas | Cedars-Sinai

  https://www.cedars-sinai.edu/health-sciences-university/research/labs/noval-rivas/areas.html

  The NLRP3 inflammasome activation and consecutive interleukin-1 (IL-1) maturation and secretion play a crucial role for the development of both human and murine KD vasculitis. […] Therefore, autophagy and mitophagy may play an important role in the prevention of cardiovascular lesions in KD vasculitis by diminishing/inhibiting NLRP3 activation, its consecutive IL-1 secretion and the resulting tissue damages.

• #34 Mechanism of HMGB1–RAGE in Kawasaki disease with coronary artery injury | European Journal of Medical Research | Full Text

  https://eurjmedres.biomedcentral.com/articles/10.1186/s40001-020-00406-5

  On the whole, the findings of this study demonstrate that the expression of HMGB1/RAGE/NF-B is altered at different stages of KD, suggesting that the HMGB1/RAGE/NF-B signaling pathway plays an important role in vascular injury in KD. […] The serum levels of HMGB1 have been shown to be significantly increased in the acute phase of KD. […] The receptor for advanced glycation end products (RAGE) is a high-affinity receptor of HMGB1 currently known, while not the only receptor for HMGB1. […] The binding of HMGB1 to RAGE promotes the activation of mitogen, and the phosphorylation of protein kinases (such as p38 kinase, SAPK/JNK, and ERK1/2), and subsequently activates various signaling pathways, such as NF-B and MAPKp38, inducing the production of inflammatory cytokines and chemokines. […] In summary, we hypothesized that HMGB1-RAGE may be associated with the development of KD; particularly, in the acute phase when HMGB1 accumulates in coronary endothelial cells, causing coronary vasculitis and promoting coronary artery dilatation. […] The findings of this study indicate that the expression of HMGB1, RAGE, and NF-B were significantly increased in the acute phase of children with KD, which was of great value for the early diagnosis of KD, and the expression of HMGB1, RAGE, and NF-B in CAL group were significantly higher than that in NCAL group, which indicate that it is involved in the occurrence and development of KD coronary injury.

• #35 Kawasaki disease: insights into pathogenesis and approaches to treatment | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2015.54

  Epidemiologic data strongly suggest an infectious aetiology for Kawasaki disease, which is the leading cause of acquired heart disease among children in developed countries […] Necrotizing arteritis, subacute chronic vasculitis, and luminal myofibroblastic proliferation are three linked processes underlying the arteriopathy associated with Kawasaki disease […] Genetic susceptibility is indicated by the strikingly high rate of Kawasaki disease in children of Asian ethnicity and by its increased incidence in first-degree relatives of affected patients […] This Review summarizes recent advances in understanding of the pathologic processes and pathophysiologic mechanisms leading to coronary arteritis in Kawasaki disease […] Genetic factors also increase susceptibility to Kawasaki disease, as indicated by its strikingly high incidence rate in children of Asian ethnicity and by an increased incidence in first-degree family members […] The added value of adjunctive therapy with corticosteroids in patients at particularly high risk of coronary complications has been demonstrated in Japanese populations, but identification of high-risk patients has proven to be difficult in ethnically diverse populations.

• #36 Pathophysiology of Kawasaki Disease | SpringerLink

  https://link.springer.com/chapter/10.1007/978-4-431-56039-5_6

  Kawasaki Disease (KD) vasculopathy, which most significantly affects the coronary arteries, is characterized by three linked pathological processes: necrotizing arteritis, subacute/chronic (SA/C) vasculitis, and luminal myofibroblastic proliferation (LMP). […] Necrotizing arteritis (NA), initiated at the endothelial luminal surface, leads to giant aneurysms that can rupture or thrombose. […] SA/C vasculitis begins in the adventitia and is closely associated with LMP. […] LMP consists of actively proliferating smooth muscle cell-derived myofibroblasts and their matrix products, and can result in progressive arterial luminal stenosis. […] All three processes begin in the first 2 weeks after fever onset. […] NA subsides in the first 2 weeks, while subacute/chronic vasculitis and LMP can persist for months or years.

• #37 Pathophysiology of Kawasaki Disease | SpringerLink

  https://link.springer.com/chapter/10.1007/978-4-431-56039-5_6

  Kawasaki Disease (KD) vasculopathy, which most significantly affects the coronary arteries, is characterized by three linked pathological processes: necrotizing arteritis, subacute/chronic (SA/C) vasculitis, and luminal myofibroblastic proliferation (LMP). […] Necrotizing arteritis (NA), initiated at the endothelial luminal surface, leads to giant aneurysms that can rupture or thrombose. […] SA/C vasculitis begins in the adventitia and is closely associated with LMP. […] LMP consists of actively proliferating smooth muscle cell-derived myofibroblasts and their matrix products, and can result in progressive arterial luminal stenosis. […] All three processes begin in the first 2 weeks after fever onset. […] NA subsides in the first 2 weeks, while subacute/chronic vasculitis and LMP can persist for months or years.

• #38 Pathophysiology of Kawasaki Disease | SpringerLink

  https://link.springer.com/chapter/10.1007/978-4-431-56039-5_6

  Kawasaki Disease (KD) vasculopathy, which most significantly affects the coronary arteries, is characterized by three linked pathological processes: necrotizing arteritis, subacute/chronic (SA/C) vasculitis, and luminal myofibroblastic proliferation (LMP). […] Necrotizing arteritis (NA), initiated at the endothelial luminal surface, leads to giant aneurysms that can rupture or thrombose. […] SA/C vasculitis begins in the adventitia and is closely associated with LMP. […] LMP consists of actively proliferating smooth muscle cell-derived myofibroblasts and their matrix products, and can result in progressive arterial luminal stenosis. […] All three processes begin in the first 2 weeks after fever onset. […] NA subsides in the first 2 weeks, while subacute/chronic vasculitis and LMP can persist for months or years.

• #39 Kawasaki Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/965367-overview

  In severely affected vessels, the media develops inflammation with necrosis of smooth muscle cells. The internal and external elastic laminae can split, leading to aneurysms. […] Over the next few weeks to months, the active inflammatory cells are replaced by fibroblasts and monocytes, and fibrous connective tissue begins to form within the vessel wall. The intima proliferates and thickens. The vessel wall eventually becomes narrowed or occluded owing to stenosis or a thrombus. […] Cardiovascular death may occur from a myocardial infarction secondary to thrombosis of a coronary aneurysm or from rupture of a large coronary aneurysm. The period during of the greatest vascular damage is when a concomitant progressive increase in the serum platelet count occurs, and this is the point of the illness when the risk of death is most significant.

• #40 Kawasaki Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/965367-overview

  In severely affected vessels, the media develops inflammation with necrosis of smooth muscle cells. The internal and external elastic laminae can split, leading to aneurysms. […] Over the next few weeks to months, the active inflammatory cells are replaced by fibroblasts and monocytes, and fibrous connective tissue begins to form within the vessel wall. The intima proliferates and thickens. The vessel wall eventually becomes narrowed or occluded owing to stenosis or a thrombus. […] Cardiovascular death may occur from a myocardial infarction secondary to thrombosis of a coronary aneurysm or from rupture of a large coronary aneurysm. The period during of the greatest vascular damage is when a concomitant progressive increase in the serum platelet count occurs, and this is the point of the illness when the risk of death is most significant.

• #41 Kawasaki Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/965367-overview

  In severely affected vessels, the media develops inflammation with necrosis of smooth muscle cells. The internal and external elastic laminae can split, leading to aneurysms. […] Over the next few weeks to months, the active inflammatory cells are replaced by fibroblasts and monocytes, and fibrous connective tissue begins to form within the vessel wall. The intima proliferates and thickens. The vessel wall eventually becomes narrowed or occluded owing to stenosis or a thrombus. […] Cardiovascular death may occur from a myocardial infarction secondary to thrombosis of a coronary aneurysm or from rupture of a large coronary aneurysm. The period during of the greatest vascular damage is when a concomitant progressive increase in the serum platelet count occurs, and this is the point of the illness when the risk of death is most significant.

• #42 Pathogenesis of Kawasaki disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3095860/

  Kawasaki disease (KD) most frequently affects infants and young children under 5 years of age. This disease is considered a kind of systemic vasculitis syndrome, and primarily invades the medium-sized muscular arteries, including coronary arteries. […] Even though the aetiology of KD is unknown, epidemiological data suggest that some kinds of infectious agents are involved in the onset of KD. In addition, the data indicate that host genetics underlie the disease’s pathogenesis. Histologically, coronary arteritis begins 68 days after the onset of KD, and leads immediately to inflammation of all layers of the artery. The inflammation spreads completely around the artery; as a result, structural components of the artery undergo intense damage; the artery then begins to dilate. Inflammatory cell infiltration continues until about the 25th day of the disease, after which the inflammatory cells gradually decrease in number. KD arteritis is characterized by granulomatous inflammation that consists of severe accumulation of monocytes/macrophages. Aberrant activation of monocytes/macrophages is thought to be involved in the formation of vascular lesions. […] The pathogenesis of KD might be clarified by analysing the mechanism of actions of these therapies in detail.

• #43 Pathogenesis of Kawasaki disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3095860/

  Kawasaki disease (KD) most frequently affects infants and young children under 5 years of age. This disease is considered a kind of systemic vasculitis syndrome, and primarily invades the medium-sized muscular arteries, including coronary arteries. […] Even though the aetiology of KD is unknown, epidemiological data suggest that some kinds of infectious agents are involved in the onset of KD. In addition, the data indicate that host genetics underlie the disease’s pathogenesis. Histologically, coronary arteritis begins 68 days after the onset of KD, and leads immediately to inflammation of all layers of the artery. The inflammation spreads completely around the artery; as a result, structural components of the artery undergo intense damage; the artery then begins to dilate. Inflammatory cell infiltration continues until about the 25th day of the disease, after which the inflammatory cells gradually decrease in number. KD arteritis is characterized by granulomatous inflammation that consists of severe accumulation of monocytes/macrophages. Aberrant activation of monocytes/macrophages is thought to be involved in the formation of vascular lesions. […] The pathogenesis of KD might be clarified by analysing the mechanism of actions of these therapies in detail.

• #44 Searching for the cause of Kawasaki disease — cytoplasmic inclusion bodies provide new insight | Nature Reviews Microbiology

  https://www.nature.com/articles/nrmicro1853

  Systemic production of vascular endothelial growth factor and fms-like tyrosine kinase-1 receptor in acute Kawasaki disease. […] CD8 T lymphocytes and macrophages infiltrate coronary artery aneurysms in acute Kawasaki disease. […] Systemic arterial expression of matrix metalloproteinases 2 and 9 in acute Kawasaki disease. […] Active remodeling of the coronary arterial lesions in the late phase of Kawasaki disease. […] Imbalance among T-cell subsets in patients with coronary arterial aneurysms in Kawasaki disease.

• #45 SciELO Brazil – Doença de Kawasaki Doença de Kawasaki

  https://www.scielo.br/j/abd/a/8gwZLwdH3VZtxbXHvv6gP4G/?lang=en

  The histological abnormalities found in KD consist of generalized systemic vasculitis, affecting predominantly medium-sized vessels, preferably coronary arteries. […] In the initial stages of vasculitis, there is edema of endothelial cells with nuclear degeneration followed by edema and inflammation of adventitia layer. […] As a result of loss of structural integrity, there is formation of aneurysms. […] The progressive course of coronary lesions in KD is temporarily modified. […] Aneurysms may progress unfavorably with persistence leading to stenosis, occlusion or tortuosity.

• #46 Kawasaki disease: insights into pathogenesis and approaches to treatment | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2015.54

  Epidemiologic data strongly suggest an infectious aetiology for Kawasaki disease, which is the leading cause of acquired heart disease among children in developed countries […] Necrotizing arteritis, subacute chronic vasculitis, and luminal myofibroblastic proliferation are three linked processes underlying the arteriopathy associated with Kawasaki disease […] Genetic susceptibility is indicated by the strikingly high rate of Kawasaki disease in children of Asian ethnicity and by its increased incidence in first-degree relatives of affected patients […] This Review summarizes recent advances in understanding of the pathologic processes and pathophysiologic mechanisms leading to coronary arteritis in Kawasaki disease […] Genetic factors also increase susceptibility to Kawasaki disease, as indicated by its strikingly high incidence rate in children of Asian ethnicity and by an increased incidence in first-degree family members […] The added value of adjunctive therapy with corticosteroids in patients at particularly high risk of coronary complications has been demonstrated in Japanese populations, but identification of high-risk patients has proven to be difficult in ethnically diverse populations.

• #47 Management of Kawasaki disease | Archives of Disease in Childhood

  https://adc.bmj.com/content/99/1/74

  Kawasaki disease (KD) is an acute self-limiting inflammatory disorder, associated with vasculitis, affecting predominantly medium-sized arteries, particularly the coronary arteries. […] The aetiology of KD remains unknown, and it is currently believed that one or more as yet unidentified infectious agents induce an intense inflammatory host response in genetically susceptible individuals. […] The debate regarding the infectious cause of KD has centred around the mechanism of immune activation: conventional antigen versus superantigen (SAg). […] Most authorities believe that one or more potentially ubiquitous infectious agents produces a deleterious host response in a genetically susceptible subject. […] A genetic contribution to the risk of KD is suggested by the much higher risk of the disease in Asian children, particularly the Japanese and Koreans, which persists when patients of these ethnicities migrate to other countries.

• #48 Management of Kawasaki disease | Archives of Disease in Childhood

  https://adc.bmj.com/content/99/1/74

  Many candidate genes have previously been suggested, either as susceptibility genes for developing KD; or increasing risk of CAA. […] A number of GWAS of KD have been published so far. […] It is likely that many other genetic factors have yet to be identified, as the GWAS methodology has so far only identified the most significant associations. […] The purpose of this article is to summarise recent advances in our understanding of the pathogenesis and treatment of KD, and to provide an approach to managing KD in the UK in the light of these advances. […] The updated guidelines are based on evidence from meta-analyses and randomised controlled trials (RCTs), and will highlight areas of practice where evidence remains weak. […] The therapeutic uncertainties raised by the recent studies and are highlighted above, can only be answered by further randomised trials and immunopathological studies to address the issues of patient selection, dose, route and safety of corticosteroid and/or other anti-inflammatory agents.

• #49 Kawasaki disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/kawasaki-disease/

  Kawasaki disease is a sudden and time-limited (acute) illness that affects infants and young children. […] The causes of Kawasaki disease are not well understood. The disorder is generally regarded as being the result of an abnormal immune system activation, but the triggers of this abnormal response are unknown. […] A variation in the ITPKC gene has been associated with an increased risk of Kawasaki disease. The ITPKC gene provides instructions for making an enzyme called inositol 1,4,5-trisphosphate 3-kinase C. This enzyme helps limit the activity of immune system cells called T cells. […] Researchers suggest that the ITPKC gene variation may interfere with the body’s ability to reduce T cell activity, leading to inflammation that damages blood vessels and results in the signs and symptoms of Kawasaki disease. […] It appears likely that other factors, including changes in other genes, also influence the development of this complex disorder.

• #50 Kawasaki syndrome: an intriguing disease with numerous unsolved dilemmas | Pediatric Rheumatology | Full Text

  https://ped-rheum.biomedcentral.com/articles/10.1186/1546-0096-9-17

  The exact mechanisms leading from immune activation to localized coronary artery damage are still not elucidated, but considerable evidence has accumulated in the last decade to suggest that T cells play a significant role. […] Genetic variations in the pathway of transforming growth factor-, a crucial peptide with regulatory functions in T-cell activation and cardiovascular remodeling, have been proven to influence KS susceptibility, disease outcome, and response to therapy. […] Abnormal endothelial function might persist for many years after the resolution of the acute phase of KS, even in patients without detectable coronary artery damage. […] Endothelial dysfunction might also be theoretically a key event in the pathogenesis of premature atherosclerosis, coronary stiffness, and hypertension in these patients. […] The degree to which KS is a cardiovascular risk factor for progression to atherosclerosis is under debate and long term evolution and consequences of the disease are still unknown, despite many efforts of researchers worldwide.

• #51 Understanding Kawasaki Disease

  https://www.uspharmacist.com/article/understanding-kawasaki-disease

  Kawasaki disease is a febrile systemic vasculitis that primarily affects the coronary arteries. […] A number of theories regarding the underlying cause of Kawasaki disease have been proposed, including autoimmunity and genetic factors. […] Proinflammatory cytokines also are believed to play a role in disease pathogenesis. […] This theory suggests that Kawasaki disease may be caused by an immune-mediated response in certain individuals who are genetically or immunologically susceptible to a powerful immunostimulant product, the superantigen of an infectious agent. […] There is strong evidence for both theories, and an increased frequency of alleles associated with elevated tumor necrosis factor-alpha (TNF-alpha) levels has been found. […] During the acute phase, endothelial cells swell and undergo necrosis, and the intima and vasa vasorum of the larger arteries are inflamed.

• #52

  https://www.jci.org/articles/view/176938

  The model has been widely adopted by different groups, with the most detailed studies of disease pathogenesis coming from the Arditi lab where an important contribution was made in demonstrating the central role of the IL-1 pathway. […] Evidence is accumulating that environmental factors may influence or modulate susceptibility to KD. […] While there remains debate about potential causative agents and the role of environmental exposures, there is broad consensus that a complex genetic pattern inherited in a non-Mendelian manner shapes susceptibility to KD. […] Identifying the etiology or etiologies of KD will have a clear effect on diagnosis and treatment and may lead to insights into other unsolved conditions such as sarcoidosis and Behcets disease that are suspected to have an environmental component.

• #53

  https://www.jci.org/articles/view/176938

  The model has been widely adopted by different groups, with the most detailed studies of disease pathogenesis coming from the Arditi lab where an important contribution was made in demonstrating the central role of the IL-1 pathway. […] Evidence is accumulating that environmental factors may influence or modulate susceptibility to KD. […] While there remains debate about potential causative agents and the role of environmental exposures, there is broad consensus that a complex genetic pattern inherited in a non-Mendelian manner shapes susceptibility to KD. […] Identifying the etiology or etiologies of KD will have a clear effect on diagnosis and treatment and may lead to insights into other unsolved conditions such as sarcoidosis and Behcets disease that are suspected to have an environmental component.

• #54 Pathogenesis and management of Kawasaki disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2845298/

  Kawasaki disease (KD) is an acute systemic inflammatory illness of young children that can result in coronary artery aneurysms, myocardial infarction and sudden death in previously healthy children. […] The etiology of KD remains a major pediatric enigma, despite efforts to identify the cause over the last four decades. […] The scope of this article is to review the unique immunopathology of KD and to describe current treatment, which is primarily aimed at blocking or reducing inflammation in the coronary arteries. […] We detail the evidence in support of an infectious cause of KD, and we describe exciting new research that has led to discovery of viral-like cytoplasmic inclusion bodies in acute KD tissues; it is hoped that this finding will lead to the identification of the causative agent and to improved diagnostic and treatment modalities.

• #55 Intravenous Immunoglobulin in Kawasaki Disease—Evolution and Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/13/14/2338

  Kawasaki disease (KD) is an acute vasculitis of childhood that affects the medium vessels with a special predilection to the involvement of coronary arteries. The major morbidity of this disease is due to coronary artery aneurysm, which occurs in about 25–30% of untreated cases. For decades now, intravenous immunoglobulin (IVIg) has consistently been shown to reduce the risk of CAAs to less than 5%. However, the mechanism of immunomodulation remains unclear. Several studies on the role of IVIg in the modulation of toll-like receptor pathways, autophagy, and apoptosis of the mononuclear phagocytic system, neutrophil extracellular trap, and dendritic cell modulation suggest a modulatory effect on the innate immune system. […] In this manuscript, we review the evolution and pathogenic mechanisms of IVIg therapy in KD.

• #56 Intravenous Immunoglobulin in Kawasaki Disease—Evolution and Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/13/14/2338

  The mechanisms underlying the effectiveness of a single large dose of IVIg in KD treatment are not fully understood. However, two possible explanations were suggested by Newburger et al.; one possibility is the neutralization of superantigens that bind nonspecifically to receptors on antigen-presenting cells. Another possibility is the binding of gamma globulin to FcγR1, leading to the rapid downregulation of the cytokine storm. […] The study conducted by JC Burns and colleagues investigated the effect of high doses of IVIg on natural killer (NK) cell activity in peripheral blood in patients with KD. The authors demonstrated that IVIg could inhibit the interaction between NK cells and endothelial cells, suggesting a potential mechanism for its therapeutic effects in KD. […] High-dose IVIg has been used in various autoimmune and inflammatory disorders, and it is hypothesized to exert its immunomodulatory role in both Fab-dependent and Fab-independent manners. The immunomodulatory effects of IVIg involve interactions with different components of the immune and vascular systems, leading to the downregulation of inflammation.

• #57 Intravenous Immunoglobulin in Kawasaki Disease—Evolution and Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/13/14/2338

  The mechanisms underlying the effectiveness of a single large dose of IVIg in KD treatment are not fully understood. However, two possible explanations were suggested by Newburger et al.; one possibility is the neutralization of superantigens that bind nonspecifically to receptors on antigen-presenting cells. Another possibility is the binding of gamma globulin to FcγR1, leading to the rapid downregulation of the cytokine storm. […] The study conducted by JC Burns and colleagues investigated the effect of high doses of IVIg on natural killer (NK) cell activity in peripheral blood in patients with KD. The authors demonstrated that IVIg could inhibit the interaction between NK cells and endothelial cells, suggesting a potential mechanism for its therapeutic effects in KD. […] High-dose IVIg has been used in various autoimmune and inflammatory disorders, and it is hypothesized to exert its immunomodulatory role in both Fab-dependent and Fab-independent manners. The immunomodulatory effects of IVIg involve interactions with different components of the immune and vascular systems, leading to the downregulation of inflammation.

• #58 Intravenous Immunoglobulin in Kawasaki Disease—Evolution and Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/13/14/2338

  Proposed mechanisms involve the provision of the anti-idiotypic antibodies, clearance of autoantibodies by binding with Fc receptors, blockade of adhesion molecules, and activation of the inhibitory Fc receptor (i.e., FcγRIIB) on macrophages. IVIg has the potential to neutralize the cytokines and superantigens as well as augment the T-cell suppressor activity. […] The innate immune system is actively involved in inflammation in the acute phase of KD as observed by predominant neutrophilic leucocytosis, and monocytosis, elevated levels of the damage-associated molecular pattern (DAMPs) such as high mobility group box 1 (HMB1) and S100 proteins in patients with KD. […] Neutrophilic leukocytosis is seen in most children with KD during the acute phase, morphologically characterized by toxic granulations and cytotoxic vacuolations, which tends to be higher in KD patients with concomitant CAAs.

• #59 Intravenous Immunoglobulin in Kawasaki Disease—Evolution and Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/13/14/2338

  These studies suggested the possible mechanism of induction of neutrophil apoptosis by high-dose IVIg in patients with KD. […] The role of neutrophil extracellular trap formation (NETosis) has also been investigated in KD. […] These findings suggest that NETosis may play a role in the pathogenesis of KD, potentially contributing to the inflammatory response and vascular damage observed in the disease. IVIg treatment appears to have a suppressive effect on NET formation, which may contribute to its beneficial effects in managing KD. […] IVIg had an inhibiting effect on FcγRs from monocyte-derived macrophages. Post IVIg infusion leads to down-regulation of FcγRIA and FcγR3A, thus repressing monocytes and monocyte-derived macrophages (MDMs). This is one of the plausible mechanisms of action of IVIg in KD.

• #60 Intravenous Immunoglobulin in Kawasaki Disease—Evolution and Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/13/14/2338

  These studies suggested the possible mechanism of induction of neutrophil apoptosis by high-dose IVIg in patients with KD. […] The role of neutrophil extracellular trap formation (NETosis) has also been investigated in KD. […] These findings suggest that NETosis may play a role in the pathogenesis of KD, potentially contributing to the inflammatory response and vascular damage observed in the disease. IVIg treatment appears to have a suppressive effect on NET formation, which may contribute to its beneficial effects in managing KD. […] IVIg had an inhibiting effect on FcγRs from monocyte-derived macrophages. Post IVIg infusion leads to down-regulation of FcγRIA and FcγR3A, thus repressing monocytes and monocyte-derived macrophages (MDMs). This is one of the plausible mechanisms of action of IVIg in KD.

• #61 Understanding Kawasaki Disease

  https://www.uspharmacist.com/article/understanding-kawasaki-disease

  The subacute phase, which lasts approximately 10 to 25 days after the onset of fever, is associated with inflammation of the coronary arteries that leads to the formation of aneurysms. […] Given the role of activated T cells in the pathogenesis of vasculitis in patients with Kawasaki disease, T-cell inhibitors like cyclosporine have been suggested as a treatment option for refractory Kawasaki disease. […] The anti-inflammatory properties of low-dose MTX have led to its use in the treatment of autoimmune diseases, including rheumatoid arthritis. Although the exact mechanism by which low-dose MTX modulates inflammation is unknown, it is likely that different levels of the pathophysiological cascade are affected, similar to those in Kawasaki disease.

• #62 Understanding Kawasaki Disease

  https://www.uspharmacist.com/article/understanding-kawasaki-disease

  The subacute phase, which lasts approximately 10 to 25 days after the onset of fever, is associated with inflammation of the coronary arteries that leads to the formation of aneurysms. […] Given the role of activated T cells in the pathogenesis of vasculitis in patients with Kawasaki disease, T-cell inhibitors like cyclosporine have been suggested as a treatment option for refractory Kawasaki disease. […] The anti-inflammatory properties of low-dose MTX have led to its use in the treatment of autoimmune diseases, including rheumatoid arthritis. Although the exact mechanism by which low-dose MTX modulates inflammation is unknown, it is likely that different levels of the pathophysiological cascade are affected, similar to those in Kawasaki disease.

• #63 Kawasaki disease: insights into pathogenesis and approaches to treatment | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2015.54

  Epidemiologic data strongly suggest an infectious aetiology for Kawasaki disease, which is the leading cause of acquired heart disease among children in developed countries […] Necrotizing arteritis, subacute chronic vasculitis, and luminal myofibroblastic proliferation are three linked processes underlying the arteriopathy associated with Kawasaki disease […] Genetic susceptibility is indicated by the strikingly high rate of Kawasaki disease in children of Asian ethnicity and by its increased incidence in first-degree relatives of affected patients […] This Review summarizes recent advances in understanding of the pathologic processes and pathophysiologic mechanisms leading to coronary arteritis in Kawasaki disease […] Genetic factors also increase susceptibility to Kawasaki disease, as indicated by its strikingly high incidence rate in children of Asian ethnicity and by an increased incidence in first-degree family members […] The added value of adjunctive therapy with corticosteroids in patients at particularly high risk of coronary complications has been demonstrated in Japanese populations, but identification of high-risk patients has proven to be difficult in ethnically diverse populations.

• #64 Kawasaki Disease Shock Syndrome: Think Earlier, Treat Intensively – Journal of Pediatric Emergency and Intensive Care Medicine

  https://caybdergi.com/articles/kawasaki-disease-shock-syndrome-think-earlier-treat-intensively/doi/cayd.galenos.2023.44265

  Kawasaki disease shock syndrome (KDSS) is a rare disease characterized by cardiovascular collapse that requires aggressive supportive and immunomodulatory therapy. […] The main pathology of the disease is vasculitis of medium and small-sized arteries associated with increased immune response, often triggered by a viral infection, environment and vaccine associated toxins. […] Kawasaki disease shock syndrome (KDSS) refers to a subgroup of patients with KD who present with cardiovascular dysfunctions and other organ system dysfunctions. […] KDSS is severe and acutely life-threatening form of KD and should be suspected in children who do not meet all the criteria of classical KD but have severe inflammation findings and significant coronary artery involvement. Early administration of immunomodulatory treatment is crucial when KDSS is suspected. Steroid treatment and plasmapheresis seem to be effective for controlling disease progress and should not be delayed in patients unresponsive to the initial immunomodulatory treatment.

• #65 SciELO Brazil – Doença de Kawasaki Doença de Kawasaki

  https://www.scielo.br/j/abd/a/8gwZLwdH3VZtxbXHvv6gP4G/?lang=en

  There are many studies trying to elucidate in details the pathogenesis and through this knowledge, find more directed therapeutic approaches and preventive measures against heart sequels. […] The increase in frequency of KD among Asian patients and their descendants, as well as the high incidence of affected family members favor the idea of genetic predisposition in KD. […] The polymorphism of interleukin 1 receptor gene (IL-1R) has also been implied in the pathogenesis of KD. […] The studies have shown that high levels of alpha tumor necrosis factors (TNF-) are significant in coronary vessels of the patients with heart lesions, which may imply more specific therapy (anti-TNF alpha) in cases of heart impairment or refractory response to treatment. […] Matrix metalloproteinases (MMP) are zinc-dependent endopeptidases involved in the degradation of extracellular matrix such as collagen and elastic fibers.

• #66

  https://www.jci.org/articles/view/176938

  The model has been widely adopted by different groups, with the most detailed studies of disease pathogenesis coming from the Arditi lab where an important contribution was made in demonstrating the central role of the IL-1 pathway. […] Evidence is accumulating that environmental factors may influence or modulate susceptibility to KD. […] While there remains debate about potential causative agents and the role of environmental exposures, there is broad consensus that a complex genetic pattern inherited in a non-Mendelian manner shapes susceptibility to KD. […] Identifying the etiology or etiologies of KD will have a clear effect on diagnosis and treatment and may lead to insights into other unsolved conditions such as sarcoidosis and Behcets disease that are suspected to have an environmental component.

• #67

  https://www.jci.org/articles/view/176938

  The model has been widely adopted by different groups, with the most detailed studies of disease pathogenesis coming from the Arditi lab where an important contribution was made in demonstrating the central role of the IL-1 pathway. […] Evidence is accumulating that environmental factors may influence or modulate susceptibility to KD. […] While there remains debate about potential causative agents and the role of environmental exposures, there is broad consensus that a complex genetic pattern inherited in a non-Mendelian manner shapes susceptibility to KD. […] Identifying the etiology or etiologies of KD will have a clear effect on diagnosis and treatment and may lead to insights into other unsolved conditions such as sarcoidosis and Behcets disease that are suspected to have an environmental component.

• #68 Pathophysiology of Kawasaki Disease | SpringerLink

  https://link.springer.com/chapter/10.1007/978-4-431-56039-5_6

  The clinical and epidemiological features of KD are best explained by infection with an as-yet-unidentified ubiquitous agent, likely a virus entering via the respiratory route. […] Recent advances in genomics and RNA sequencing are beginning to reveal specific immune response dysfunction in KD that could lead to new diagnostics and therapeutics for this important childhood illness.

• #69 SciELO Brazil – Doença de Kawasaki Doença de Kawasaki

  https://www.scielo.br/j/abd/a/8gwZLwdH3VZtxbXHvv6gP4G/?lang=en

  There are many studies trying to elucidate in details the pathogenesis and through this knowledge, find more directed therapeutic approaches and preventive measures against heart sequels. […] The increase in frequency of KD among Asian patients and their descendants, as well as the high incidence of affected family members favor the idea of genetic predisposition in KD. […] The polymorphism of interleukin 1 receptor gene (IL-1R) has also been implied in the pathogenesis of KD. […] The studies have shown that high levels of alpha tumor necrosis factors (TNF-) are significant in coronary vessels of the patients with heart lesions, which may imply more specific therapy (anti-TNF alpha) in cases of heart impairment or refractory response to treatment. […] Matrix metalloproteinases (MMP) are zinc-dependent endopeptidases involved in the degradation of extracellular matrix such as collagen and elastic fibers.

• #70 Drop in Kawasaki Disease During COVID-19 Provides Clues to Pathogenesis | tctmd.com

  https://www.tctmd.com/news/drop-kawasaki-disease-during-covid-19-provides-clues-pathogenesis

  Studies from around the world reported a decline in Kawasaki disease numbers after the start of the COVID-19 pandemic. […] Its long been hypothesized, Newburger said, that Kawasaki disease is a postinfectious reaction, much like the multisystem inflammatory syndrome in children (MIS-C) is a response to COVID-19, but a decades-long search has not been able to uncover the pathogen ormore likelypathogens responsible for the hyperimmune response. […] Major remaining research questions revolve around the infectious agents most likely to cause the immune response characteristic of Kawasaki disease; the potential impact of noninfectious environmental triggers; and genetic factors that might explain why some children are more susceptible.

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