Calcitonin gene–related peptide (CGRP) can bias the outcome of Ag presentation to responsive T cells in vitro away from Th1-type immunity and toward the Th2 and Th17 poles through actions on endothelial cells (ECs). To test the in vivo significance of this observation, we engineered a mouse lacking functional CGRP receptors on ECs (EC receptor activity modifying protein 1 [RAMP1] knockout mice). On percutaneous immunization to 1-fluoro-2,4-dinitrobenzene, stimulated CD4+ T cells from draining lymph nodes showed significantly reduced IL-17A expression with significantly increased IFN-γ, IL-4, and IL-22 expression at the protein and mRNA levels compared with control mice. Retinoic acid receptor-related orphan receptor γ t mRNA was significantly reduced, while mRNAs for T-box expressed in T cells and GATA binding protein 3 were significantly increased. In addition, EC RAMP1 knockout mice had significantly reduced contact hypersensitivity responses, and systemic administration of a CGRP receptor antagonist similarly inhibited contact hypersensitivity in wild-type mice. These observations provide compelling evidence that CGRP is a key regulator of cutaneous immunity through effects on ECs and suggest a novel pathway for potential therapeutic manipulation.

Dermal blood vessels and regional lymph nodes are innervated by sympathetic nerves and, under stress, sympathetic nerves release norepinephrine (NE). Exposure of primary murine dermal microvascular endothelial cells (pDMECs) to NE followed by co-culture with Langerhans cells (LCs), responsive CD4 T-cells and antigen resulted in modulation of CD4 T-cell responses. NE-treatment of pDMECs induced increased production of interleukin (IL)-6 and IL-17A while down-regulating interferon (IFN)-γ and IL-22 release. This effect did not require contact between pDMECs and LCs or T-cells and depended upon pDMEC production of IL-6. The presence of NE-treated pDMECs increased the proportion of CD4 T-cells expressing intracellular IL-17A and increased IL-17A mRNA while decreasing the proportion of IFN-γ- or IL-22-expressing CD4 T-cells and mRNA levels for those cytokines. Retinoic acid receptor-related orphan receptor gamma (ROR-γt) mRNA was significantly increased in CD4 T-cells while T-box transcription factor (T-bet) mRNA was decreased. Intradermal administration of NE prior to hapten immunization at the injection site produced a similar bias in draining lymph node CD4 T-cells towards IL-17A and away from IFN-γ and IL-22 production. Under stress, release of NE may have significant regulatory effects on the outcome of antigen presentation through actions on ECs with enhancement of inflammatory skin disorders involving IL-17/T helper type 17 (Th17) cells.

Background: Anti-glutamic acid decarboxylase 65 (anti-GAD65) antibody encephalitis is a rare form of autoimmune encephalitis that can lead to severe neurologic impairment, coma, and death. Case Report: We present the case of a 54-year-old male with severely altered mental status and profound neurologic impairment who rapidly progressed to a comatose state. Because of the patient's rapidly deteriorating status, lack of yield with diagnostic testing, and lack of clinical improvement with broad empiric treatments, the clinical decision was made to treat the patient with high-dose methylprednisolone, and the treatment returned the patient to his baseline mental status. After the patient's discharge, the autoimmune encephalitis panel returned positive for anti-GAD65 antibodies. Conclusion: This case illustrates the importance of considering a diagnosis of autoimmune encephalitis for patients with rapidly deteriorating mental status. Unless contraindicated, treatment with high-dose glucocorticoids can be successful for these patients. This case also shows a potential association between hypothyroidism and anti-GAD65 antibodies.

Tissue-derived factors are critical for the development and persistence of skin-resident memory CD8 + T cells. Regulated activation of TGFb by integrins a v b 6 and a v b 8 expressed on keratinocytes is required for residence of epidermal T RM that are lost in mice lacking these integrins (Itgb6 -/-Itgb8 DKC mice). However, whether skin-derived signals also affect recirculating memory cells that are only transiently in skin have been never noted. Here, we show that after resolution of skin vaccinia virus (VV) infection, antigen-specific circulating memory CD8 + T cells migrate into skin in an antigen-and inflammation-independent manner. In Itgb6 -/-Itgb8 DKC mice, the absence of activated TGFb results in normal expansion and differentiation of CD8 + T cells but a gradual loss of E-or P-selectin binding central and peripheral memory populations from secondary lymphoid organs that results in reduced protection to VV skin challenge. Notably, pertussis toxin inhibition of skin entry of the memory cells rescues the loss of memory cells in Itgb6 -/-Itgb8 DKC mice. These data demonstrate that skin migration can persist after resolution of local skin infection and, surprisingly, the cytokine environment within this nonlymphoid tissue shapes the differentiation state and persistence of the central and peripheral memory T cell pool. 044IFN-g enhances cell-mediated cytotoxicity against keratinocytes via JAK2/STAT1 in lichen planus Lichen planus (LP) is a chronic debilitating inflammatory disease of unknown etiology affecting the skin, nails, and mucosa. LP is histologically characterized by dense infiltration of T cells and epidermal keratinocyte death. However, little is known about the pathogenesis of LP, and there is urgent need for more effective treatments. Here, using global transcriptomic profiling of LP samples(n¼37) and healthy controls (n¼24), we demonstrate that LP is characterized by type II, but not type I, interferon (IFN) inflammatory response. The type II IFN, IFN-g, is demonstrated to prime keratinocytes and increase their susceptibility to cytotoxic responses. We further demonstrate that the promotion of cytotoxic responses to IFN-g-in keratinocytes are MHC class I dependent and reliant upon JAK1/STAT1 but not JAK1 or STAT2 signaling. Thus, JAK2 or STAT1 knock-outs by CRISPR/Cas9 completely inhibit cell-mediated cytotoxic responses to IFN-g primed keratinocytes. Lastly, using drug prediction algorithms on our transcriptomic data JAK inhibitors are identified as promising therapeutic agents in LP, which we confirm using the JAK1/2 inhibitor baricitinib, which fully protects keratinocytes against cell-mediated cytotoxic responses. In summary, this work elucidates the role and mechanisms of IFN-g in LP pathogenesis and provides evidence for the therapeutic use of JAK-inhibitors in patients with LP. 045B cell cytokine analysis by single cell analysis reveals therapeutic reactivity of systemic sclerosis-associated interstitial lung disease Purpose: Systemic sclerosis (SSc) is an autoimmune disease characterized...

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