Previous reports demonstrated that inflammasomes play a role in autoinflammation and autoimmunity diseases. Mechanisms of NLRP3 inflammasome activation, associated diseases and therapeutics have been discussed in Chapter 1, 4.2 and 4.3. In this study, we found that the NLRP3 inflammasome is critical for development of bullous pemphigoid disease. Furthermore we demonstrated caspase-1 activation and IL-1β secretion is expressed BP180 keratinocytes upon pathogenic IgG stimulation; however the caspase-1 activation mechanisms have not been deeply investigated. BP- IgG complex internalization by endocytosis would interact with lysosome in cells.
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Lysosomal rupture releases Capthepsin B, the proteinase that degrades collagen and also is able to activate NLRP3 inflammasome assembly(26).
Also, whether the NLRP3 inflammasome is activated in mast cells or macrophages has not been extensively tested. Mast cells play a very important role in the pathogenesis of bullous pemphigoid by mechanisms that secrete TNF-α et al cytokines via phosphorylation of p38 induction of degranulation(27)(28)(29). TNF-α and cross- linked pathogenic IgG could be the first and second signals for inflammasome activation respectively(29) . Macrophages as a major innate immunity player have been extensively investigated for inflammasome activation. Previous findings also report that macrophages are important for recruitment of neutrophils to form skin blisters in bullous pemphigoid by mast cell independent mechanisms(27). To investigate the function of the inflammasome in macrophages, NLRP3 deficiency and sufficiency in a macrophage mouse model could be used. However, it is hard to demonstrate a direct relationship between pathogenic IgG and macrophages in vitro. Whether keratinocytes, mast cells and macrophages play a synergistic role or inflammasome activation involves a hierarchical sequence would be a very interesting topic to be investigated.
More importantly, in this study, we demonstrated the IL-1R antagonist, Anakinra is able to prevent and treat bullous pemphigoid, which suggests a new treatment for clinical therapy. Current therapy for bullous pemphigoid mainly counts on corticosteroids and immunosuppressive agents. However, high-dose corticosteroids are poorly tolerated in the elderly and long-term treatments may cause numerous dose-related adverse effects, such as immune suppression, severe infection, diabetes mellitus, osteoporosis, hypertension, and renal failure(30). Our elucidated molecular mechanisms provide a
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scientific basis for use of Anakinra treatment for bullous pemphigoid in the clinical setting and advance the knowledge of the pathogenic mechanism for bullous pemphigoid, which would resolve the suffering of patients.
Autoinflammatory diseases are driven by endogenous danger signals, metabolic mediators and cytokines, whereas autoimmunity involves the activation of T and B cells, the latter requiring V-(D)-J recombination of receptor-chain gene segments for maturation. Most of the time, autoinflammatory diseases are driven by IL-1β and IL-18, however, autoimmunity is associated with type I interferon signatures in the blood(31)(32). IL-1β and IL-18 can also shape adaptive immunity. IL-1β could act on lymphocyte IL-2 receptor expression, prolonging T cell survival and enhancing antibody production by B cells and increasing B cell proliferation. Also, Inflammasome activation could drive Th1 and Th17 cell differentiation and amplification. Due to Inflammasome activation, secretion of IL-1β and IL-18 is involved in multiple steps of T or B cell proliferation and differentiation, this will facilitate identification of potentially new therapeutic reagents for autoimmune diseases.
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