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Programmed necrosis, such as necroptosis and pyroptosis, is a highly pro-inflammatory cellular event that is associated with chronic inflammation. Although there are various triggers of pyroptosis and necroptosis in autoimmune tissue inflammation and subsequent lytic forms of cell death release abundant inflammatory mediators, including damage-associated molecular patterns and IL-1β, capable of amplifying autoimmune Th17 effector functions, it remains largely unclear whether the programs play a crucial role in the pathogenesis of autoimmune arthritis. We herein report that Gasdermin D (Gsdmd) and receptor interacting serine/threonine kinase 3 (Ripk3)-key molecules of pyroptosis and necroptosis, respectively-are upregulated in inflamed synovial tissues, but dispensable for IL-1β production and the development of IL-17-producing T helper (Th17) cell-mediated autoimmune arthritis in SKG mice. Gsdmd -/- , Ripk3 -/- , or Gsdmd -/- Ripk3 -/- SKG mice showed severe arthritis with expansion of arthritogenic Th17 cells in the draining LNs and inflamed joints, which was comparable to that in wild-type SKG mice. Despite the marked reduction of IL-1β secretion from Gsdmd -/- or Ripk3 -/- bone marrow-derived DCs by canonical stimuli, IL-1β levels in the inflamed synovium were not affected in the absence of Gsdmd or Ripk3. Our results revealed that T cell-mediated autoimmune arthritis proceeds independently of the pyroptosis and necroptosis pathways., (© 2021. The Author(s).)

IL-17-producing T helper (Th17) cells have been implicated in the pathogenesis of many inflammatory and autoimmune diseases. Targeting the effector cytokines IL-17 and GM-CSF secreted by autoimmune Th17 cells has been shown to be effective for the treatment of the diseases. Understanding a molecular basis of Th17 differentiation and effector functions is therefore critical for the regulation of the pathogenicity of tissue Th17 cells in chronic inflammation. Here, we discuss the roles of proinflammatory cytokines and environmental stimuli in the control of Th17 differentiation and chronic tissue inflammation by pathogenic Th17 cells in humans and in mouse models of autoimmune diseases. We also highlight recent advances in the regulation of pathogenic Th17 cells by gut microbiota and immunometabolism in autoimmune arthritis.

Tumour necrosis factor inhibitors (TNFi) have led to a paradigm shift in the treatment for various diseases including rheumatoid arthritis (RA). During the course of treatment, however, they sometimes cause adverse autoimmune disorders such as lupus, psoriasis and vasculitis. Here, we report a case in which a patient with RA under etanercept (ETN) treatment developed simultaneous ulcerations and blisters on the extremities. Skin biopsies showed leucocytoclastic vasculitis (LCV) at the ulcerative lesion, and subepidermal blistering with linear deposits of IgG and C3 at the basement membrane zone of the blister suggesting a pemphigoid disease. Such simultaneous development of LCV and pemphigoid in an RA patient has not previously been reported. We reviewed 71 cases of vasculitis and 7 cases of pemphigoid diseases during anti-TNF therapy. The prevalence of pemphigoids in RA patients appeared to be comparable to that in healthy individuals. This case showed that TNFi treatment may be involved in two distinct autoimmune reactions, in which vasculitis is related to the augmentation of pemphigoid. [ABSTRACT FROM AUTHOR]

Unfortunately, an error occurred in the following passus of the article. The word "receptor" was missing in the sentence "Because T cells do not express GM-CSF receptor [41], GM-CSF affects non-T cells." [ABSTRACT FROM AUTHOR]