Anti-IL17A Monoclonal antibody, APC

In Wiskott-Aldrich syndrome (WAS), immunodeficiency and autoimmunity often comanifest, yet how WAS mutations misregulate chromatin-signaling in T-helper (T-H) cells favoring development of auto-inflammation over protective immunity is unclear. Previously, we identified an essential promoter-specific, coactivator role of nuclear-WASp in T(H)1 gene transcription. Here we identify small ubiquitin-related modifier (SUMO)ylation as a novel posttranslational modification of WASp, impairment of which converts nuclear-WASp from a transcriptional coactivator to a corepressor of nuclear factor (NF)-kappa B response genes in human (T-H)1-differentiating cells. V75M, one of many disease-causing mutations occurring in SUMO*motif (72-psi psi psi psi KDxxxxSY-83) of WASp, compromises WASp-SUMOylation, associates with COMMD1 to attenuate NF-kappa B signaling, and recruits histone deacetylases-6 (HDAC6) to p300-marked promoters of NF-kappa B response genes that pattern immunity but not inflammation. Consequently, proteins mediating adaptive immunity (IFNG, STAT1, TLR1) are deficient, whereas those mediating auto-inflammation (GM-CSF, TNFAIP2, IL-1 beta) are paradoxically increased in T(H)1 cells expressing SUMOylation-deficient WASp. Moreover, SUMOylation deficient WASp favors ectopic development of the T(H)17-like phenotype (up arrow IL17A, IL21, IL22, IL23R, RORC, and CSF2) under T(H)1-skewing conditions, suggesting a role for WASp in modulating T(H)1/T(H)17 plasticity. Notably, pan-histone deacetylase inhibitors lift promoter-specific repression imposed by SUMOylation-deficient WASp and restore misregulated gene expression. Our findings uncovering a SUMOylation-based mechanism controlling WASp's dichotomous roles in transcription may have implications for personalized therapy for patients carrying mutations that perturb WASp-SUMOylation.

Interleukin 10 receptor (IL10R)-deficient mice develop spontaneous colitis and, similarly, patients with loss-of-function mutations in IL10R develop severe infantonset inflammatory bowel disease. Loss of IL10R signaling in mouse and human macrophages is associated with increased production of interleukin 1 beta. We demonstrated that innate immune production of IL1 beta mediates colitis in IL10R-deficient mice. Transfer of II1r1(-/-) CD4(+) T cells into Rag1(-/-) /II10rb(-/-) mice reduced the severity of their colitis (compared to mice that received CD4(+) T cells that express IL1R), accompanied by decreased production of interferon gamma, tumor necrosis factor-alpha, and IL17A. In macrophages from mice without disruption of IL10R signaling or from healthy humans (controls), incubation with IL10 reduced canonical activation of the inflammasome and production of IL1 beta through transcriptional and post-translational regulation of NLRP3. Lipopolysaccharide and adenosine triphosphate stimulation of macrophages from Il10rb(-/-) mice or IL10R-deficient patients resulted in increased production of IL1 beta. Moreover, in human IL10R-deficient macrophages, lipopolysaccharide stimulation alone triggered IL1 beta secretion via non-canonical, caspase 8-dependent activation of the inflammasome. We treated 2 IL10R-deficient patients with severe and treatment-refractory infant-onset inflammatory bowel disease with the IL1-receptor antagonist anakinra. Both patients had marked clinical, endoscopic, and histologic responses after 4-7 weeks. This treatment served as successful bridge to allogeneic hematopoietic stem cell transplantation in 1 patient. Our findings indicate that loss of IL10 signaling leads to intestinal inflammation, at least in part, through increased production of IL1 by innate immune cells, leading to activation of CD4(+) T cells. Agents that block IL1 signaling might be used to treat patients with inflammatory bowel disease resulting from IL10R deficiency.