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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Infliximab (IFX) is effective for treatment of refractory Kawasaki disease (KD). However, the precise mechanisms and biomarkers for IFX efficacy are unknown. We tried to evaluate the effect and response to IFX therapy by measuring serum cytokine levels. Twenty-nine children with KD who had been resistant to two courses of high-dose intravenous immunoglobulin were enrolled and treated with IFX. Plasma samples were analyzed for cytokines before and after IFX administration. Serum levels of interleukin-6, granulocyte colony-stimulating factor (G-CSF), interferon-gamma-induced monokine, interferon-gamma inducible protein 10 (IP-10), monocyte chemotactic protein 1, and soluble tumor necrosis factor-alpha receptor (sTNFR) 1 and 2 were significantly elevated before IFX treatment, but promptly decreased after the administration. The pre-treatment G-CSF and sTNFR1 levels in non-responders to IFX were significantly higher than in responders, who were defined as patients who defervesce (< 37.5 °C). After IFX administration, elevated cytokines declined to normal ranges in responders, but in non-responsive group, G-CSF and sTNFR1 remained elevated without failing to normal levels. IFX treatment significantly reduced the levels of serum cytokines, chemokines, and sTNFRs in refractory KD. G-CSF and sTNFR1 may be indicators predictive of poor response to IFX. [ABSTRACT FROM AUTHOR]

This study examined the pathogenesis of early-onset sarcoidosis (EOS) in a patient with a rare NOD2 mutation and surveyed the literature to identify the hallmark features for early diagnosis. An infant girl suffering from prolonged fever and skin rash of multiple pinkish papules and subsequent erythema nodosum was referred to our institution. Skin biopsy and DNA sequencing were performed along with cytokine profiling of the patient's serum and stimulated mononuclear cells. NF-κB activation was analyzed using transfected cells . Multiple non-caseating granuloma inclusions were recognized in biopsy specimens obtained from the patient's rash. DNA sequencing revealed a very rare heterozygous Met513Thr (M513T) mutation in NOD2. Mononuclear cells produced a low amount of IL-1β upon stimulation as compared with normal control cells. Mutated NOD2 transfection enhanced NF-κB activation. We suspected that the M513T mutation in NOD2 decreased IL-1β production and enhanced NF-κB activation, which was likely responsible for the patient's granuloma involvement. A comprehensive review of the literature on 30 cases of sporadic type of EOS revealed that all patients had cutaneous manifestations, with all but one displaying granulation. A majority of EOS patients have R334W/Q. But about half of sporadic EOS had NOD2 mutations other than R334W/Q, as in the present case. Accordingly, skin rash with granuloma formation and specific NOD2 mutations may represent early diagnostic hallmarks of EOS in infants with persistent inflammation. [ABSTRACT FROM AUTHOR]

During thymic negative selection, autoreactive thymocytes carrying T cell receptor (TCR) with overtly strong affinity to self-MHC/self-peptide are removed by Bim-dependent apoptosis, but how Bim is specifically regulated to link TCR activation and apoptosis induction is unclear. Here we identify a murine T cell-specific genomic enhancer EBAB (Bub1-Acoxl-Bim), whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, EBAB knockout mice have defective negative selection and fail to delete autoreactive thymocytes in various settings, with this defect accompanied by reduced Bim expression and apoptosis induction. By contrast, EBAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate EBAB as an important, developmental stage-specific regulator of Bim expression and apoptosis induction to enforce thymic negative selection and suppress autoimmunity. Our study unravels a part of genomic enhancer codes that underlie complex and context-dependent gene regulation in TCR signaling. Autoreactive T cells are deleted in the thymus via thymic negative selection and Bim-mediated apoptosis. Here the authors identify a cis-acting enhancer, EBAB, that is essential for proper Bim expression and apoptosis induction, and show that EBAB deficiency specifically impairs thymic negative selection without affecting peripheral T cell homeostasis. [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]