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Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurring suppurating lesions of the intertriginous areas, resulting in a substantial impact on patients’ QOL. HS pathogenesis remains poorly understood. An autoimmune component has been proposed, but disease-specific autoantibodies, autoantigens, or autoreactive T cells have yet to be described. In this study, we identify a high prevalence of IgM, IgG, and IgA antibodies directed against Nε-carboxyethyl lysine (CEL), a methylglyoxal-induced advanced glycation end-product, in the sera of patients with HS. Titers of anti-CEL IgG and IgA antibodies were highly elevated in HS compared with those in healthy controls and individuals with other inflammatory skin diseases. Strikingly, the majority of anti-CEL IgG was of the IgG2 subclass and correlated independently with both disease severity and duration. Both CEL and anti-CEL‒producing plasmablasts could be isolated directly from HS skin lesions, further confirming the disease relevance of this autoimmune response. Our data point to an aberration of the methylglyoxal pathway in HS and support an autoimmune axis in the pathogenesis of this debilitating disease.

ObjectiveTo examine the role of CD40–CD154 costimulation and effects of therapeutic pathway blockade in the non-obese diabetic (NOD/ShiLtJ) model of Sjögren’s syndrome (SS).MethodsWe assessed leucocyte infiltration in salivary glands (SGs) from NOD/ShiLtJ mice by immunohistochemistry and examined transcriptomics data of SG tissue from these animals for evidence of a CD40 pathway gene signature. Additionally, we dosed MR1 (anti-CD154 antibody) in NOD mice after the onset of SS-like disease and examined the effects of MR1 treatment on sialadenitis, autoantibody production, SG leucocyte infiltration, gene expression downstream of CD40 and acquaporin 5 (AQP5) expression.ResultsWe could detect evidence of CD40 expression and pathway activation in SG tissue from NOD mice. Additionally, therapeutic treatment with MR1 suppressed CD40 pathway genes and sialadenitis, inhibited ectopic lymphoid structure formation and autoantibody production, as well as decreased the frequency of antibody-secreting cells in SGs but had minimal effects on AQP5 expression in NOD/ShiLtJ SGs.ConclusionCD40–CD154 interactions play an important role in key pathological processes in a mouse model of SS, suggesting that blockade of this costimulatory pathway in the clinic may have beneficial therapeutic effects in patients suffering from this autoimmune exocrinopathy.

Background T cell-dependent activation of B lymphocytes is a key effector arm of the adaptive immune system, resulting in protective antibody responses and long-lived humoral immunity. Such B cell responses often occur in germinal centres (GCs); specialized anatomical locations within secondary lymphoid organs. Similar GC-like structures can also be found in involved tissue in various autoimmune diseases, including the salivary glands of primary Sjogren9s syndrome (pSS) patients. Objectives Previous work has implicated CD40-CD154 pathway-dependent processes in regulating B cell survival and function in GCs, and we were wanted to investigate whether this costimulatory pathway might be linked to ELS formation and function in pSS. Methods Histological analysis of minor salivary gland biopsies from pSS patients revealed evidence of CD40 and CD154 expression on ELS-resident B and T cells respectively, co-locating receptor and ligand positive cells in affected tissue. These results suggested that there might be ongoing T-B cell collaboration in these ELS and we therefore wanted to examine whether there was evidence of CD40 pathway activation in situ . To do this we first generated a CD40-pathway gene signature in primary human B cells following recombinant CD154 stimulation in vitro . Results Using a published microarray dataset generated using parotid gland biopsies we could demonstrate upregulation of a portion of the B cell CD40 gene signature in biopsies from pSS patients but not from healthy donors or individuals with Sicca symptoms, suggesting that CD40 pathway activation was occurring within disease-relevant tissue in lymphocytes implicated in disease pathology. To better understand the role of CD40-CD154 interactions in ELS, we examined salivary glands in CD40 knockout NOD mice. Wild-type NOD mice develop sialadenitis, anti-SSA/SSB autoantibodies, and display evidence of ELS in salivary glands. In contrast, there was no evidence of ELS, sialadenitis or autoantibodies in CD40 deficient NOD mice up to one year of age. Further, anti-CD154 treatment resulted in disaggregation in splenic GCs as well as established ELS in NOD mice and resulted in decreased levels of IgG secreting cells in salivary glands. Conclusions Collectively our data indicate that CD40 pathway signalling is essential for formation and maintenance of salivary gland ELS and suggest that CD40 pathway signalling is active in established ELS from pSS patients, supporting the notion that blockade of CD40-CD154 interactions may provide therapeutic benefit in patients suffering from this autoimmune exocrinopathy. Disclosure of Interest G. Wieczorek Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland, M. Bigaud Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland, S. Pfister Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland, S. Hoersch Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland, K. McMichael Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland, C. Afatsawo Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland, M. Hamburger Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland, C. Texier Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland, C. Cojean Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland, M. Henry Employee of: Ex employee of Novartis Institutes for Biomedical Research, Basel, Switzerland, J. Rush Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland

FTY720 (fingolimod) has demonstrated efficacy in multiple sclerosis (MS). We evaluated the effects of FTY720 on progressive disability, viral load, and antibody responses in mice infected with Theiler's murine encephalomyocarditis virus (TMEV). FTY720 and phosphorylated FTY720 (FTY720-P) were detected in the brain after intraperitoneal injection of the drug. Bioactivity of FTY720 was confirmed by reduced numbers of mononuclear cells in the spleen and blood after treatment. No significant differences were found in disability progression, viral load, and serum antibody responses between the FTY720-treated versus the PBS-treated mice. There was less production of IgG within the CNS in the FTY-treated group on some measures.