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Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1 −/− B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and -deficient mice. The TRPV1 + neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1-dependent neuropeptides such as substance P In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy.

Autoimmune target tissues in type 1 diabetes include pancreatic β-cells and peri-islet Schwann cells (pSC)--the latter active participants or passive bystanders in pre-diabetic autoimmune progression. To distinguish between these alternatives, we sought to suppress pSC autoimmunity by transgenic expression of the negative costimulatory molecule B7-H1 in NOD pSC. A B7-H1 transgene was placed under control of the glial fibrillary acidic protein (GFAP) promoter. Transgenic and wild-type NOD mice were compared for transgene PD-1 affinities, diabetes development, insulitis, and pSC survival. Mechanistic studies included adoptive type 1 diabetes transfer, B7-H1 blockade, and T-cell autoreactivity and sublineage distribution. Transgenic and endogenous B7-H1 bound PD-1 with equal affinities. Unexpectedly, the transgene generated islet-selective CD8(+) bias with accelerated rather than suppressed diabetes progression. T-cells of diabetic transgenics transferred type 1 diabetes faster. There were no earlier pSC losses due to conceivable transgene toxicity, but transgenic pSC loss was enhanced by 8 weeks, preceded by elevated GFAP autoreactivity, with high-affinity T-cells targeting the major NOD K(d)-GFAP epitope, p253-261. FoxP3(+) regulatory T- and CD11c(+) dendritic cell pools were unaffected. In contrast with transgenic B7-H1 in NOD mouse β-cells, transgenic B7-H1 in pSC promotes rather than protects from type 1 diabetes. Here, ectopic B7-H1 enhanced the pathogenicity of effector T-cells, demonstrating that pSC can actively impact diabetes progression-likely through modification of intraislet T-cell selection. Although pSC cells emerge as a new candidate for therapeutic targets, caution is warranted with regard to the B7-H1-PD1 axis, where B7-H1 overexpression can lead to accelerated autoimmune disease.

Edgar Engleman and his colleagues show that B cell production of pathogenic IgG antibodies is involved in obesity-induced insulin resistance. They also show that B cell depletion in obese mice ameliorates metabolic disease, and that obese, insulin-resistant humans have a unique profile of IgG autoantibodies. These results suggest a possible new therapeutic target to treat insulin resistance. Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell–depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.

Low blood levels of long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) have been reported to be associated with increased risk for cardiovascular disease (CVD) deaths. Systematic studies measuring LC n-3 PUFA blood levels (pre and post-treatment) in defined subjects, and monitoring the correction of nutritional deficiency with a pure LC n-3 PUFA formulation in sufficient doses, while monitoring CVD risk factors are lacking. We tested the efficacy of a novel LC n-3 PUFA Medical Food formulation (VASCAZEN ® , > 90 % pure with a 6:1 eicosapentaenoic acid-(EPA):docosahexaenoic acid-(DHA) ratio; 6:1-OM3), to correct such deficiency and determine the concomitant effects on lipid profiles. Of 655 subjects screened, 89 % were LC n-3 PUFA deficient (Omega-Score, (OS) = blood EPA + DHA + Docosapentaenoic acid < 6.1 %). From these, a study was conducted on 110 ambulatory cardiovascular subjects. Placebo: corn oil. Primary endpoint: change in OS. Secondary endpoint: changes in blood lipid profiles. At 8 weeks of treatment with 6:1-OM3 (4 g/day), placebo-adjusted median OS levels ( n  = 56) significantly improved (132 %, P  < 0.0001) with a decrease in AA (arachidonic acid): EPA ratio (82 %, P  < 0.0001). In hypertriglyceridemic subjects (TG 2.26–5.65 mmol/L), HDL-C improved (9 %, P  = 0.0069), TG-reduced (48 %, P  < 0.0001), and VLDL-C reduced (30 %, P  = 0.0023), without significantly affecting LDL-C levels. This study confirms that LC n-3 PUFA deficiency is prevalent in the US population, and its correction with 6:1-OM3 in CVD subjects improves lipid profiles. The purity, EPA:DHA ratio and dose are determinant factors for optimal efficacy of a formulation in reducing CVD risk factors.

Low blood levels of long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) have been reported to be associated with increased risk for cardiovascular disease (CVD) deaths. Systematic studies measuring LC n-3 PUFA blood levels (pre and post-treatment) in defined subjects, and monitoring the correction of nutritional deficiency with a pure LC n-3 PUFA formulation in sufficient doses, while monitoring CVD risk factors are lacking. We tested the efficacy of a novel LC n-3 PUFA Medical Food formulation (VASCAZEN^sup ^, > 90 % pure with a 6:1 eicosapentaenoic acid-(EPA):docosahexaenoic acid-(DHA) ratio; 6:1-OM3), to correct such deficiency and determine the concomitant effects on lipid profiles. Of 655 subjects screened, 89 % were LC n-3 PUFA deficient (Omega-Score, (OS) = blood EPA + DHA + Docosapentaenoic acid < 6.1 %). From these, a study was conducted on 110 ambulatory cardiovascular subjects. Placebo: corn oil. Primary endpoint: change in OS. Secondary endpoint: changes in blood lipid profiles. At 8 weeks of treatment with 6:1-OM3 (4 g/day), placebo-adjusted median OS levels (n = 56) significantly improved (132 %, P < 0.0001) with a decrease in AA (arachidonic acid): EPA ratio (82 %, P < 0.0001). In hypertriglyceridemic subjects (TG 2.26-5.65 mmol/L), HDL-C improved (9 %, P = 0.0069), TG-reduced (48 %, P < 0.0001), and VLDL-C reduced (30 %, P = 0.0023), without significantly affecting LDL-C levels. This study confirms that LC n-3 PUFA deficiency is prevalent in the US population, and its correction with 6:1-OM3 in CVD subjects improves lipid profiles. The purity, EPA:DHA ratio and dose are determinant factors for optimal efficacy of a formulation in reducing CVD risk factors.[PUBLICATION ABSTRACT]

Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity associated insulin resistance and glucose intolerance. Here we demonstrate a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to activation of pro-inflammatory macrophages and T cells, and production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, while transfer of DIO-IgG rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities to manage the disease.

Type 1 Diabetes (T1D) is a disease characterized by the autoimmune destruction of insulin-producing β-cells. Peri-islet Schwann cells (pSC) encapsulate islets and are destroyed but the mode of destruction and role in T1D development is poorly understood. Islets are also highly innervated and neuronal contributions to β-cell stress, islet inflammation and ultimately T1D development have been reported. Here, I show that pSC death involves a T cell contact-dependant requirement for T-cell-mediated destruction and that islet-innervating spinal nerves can be surgically manipulated as a therapeutic approach to prevent and/or treat T1D. B7-H1 is implicated in protection from autoimmunity and has a cognate requirement for function when it binds to its receptor programmed death-1 (PD-1). Here, glial fibrillary acidic protein (GFAP) promoter-driven transgenic expression of B7-H1 in pSC of Non-obese Diabetic (NOD) mice was employed to investigate the mechanism(s) of pSC destruction. Predicted protection inferred by B7-H1 was not observed. Rather, an amplification of T-cell pathogenicity, increased proportions of CD8+ cytotoxic T-lymphocytes (CTL's) in islets and accelerated pSC/islet destruction and T1D development resulted. Diabetes transfer experiments revealed that pathogenic T cells in transgenic mice do not require continued interaction with transgenically-expressed B7-H1 on pSC to maintain highly pathogenic potential and that pSC-expressed B7-H1 can rapidly confer enhanced pathogenicity on wild-type lymphocytes. Transgenic in vitro T-cell proliferative responses to a low-dose pSC antigen, glial fibrillary acidic protein (GFAP) were more pronounced. NOD mice also develop autoimmune encephalitis (AENOD) after treatment with pertussis toxin, Transgenic mice treated for AENOD induction exhibit aggressive disease and thus, a proinflammatory B7-H1 role in autoimmunity is not restricted to T1D. The neuropeptide substance P (sP), released by TRPV1+ primary sensory afferent nerves is important for β-cell survival, setting basal insulin sensitivity and homeostasis. In the NOD mouse, TRPV1 is mutated, rendering the receptor hypofunctional, resulting in very low sP release. In the islet, low sP levels promote T1D development and exogenous intra-aortic pancreatic sP administration to raise sP levels transiently reverses disease. I developed a novel neurosurgical procedure to harness the plasticity of sensory neuron physiology to raise endogenous sP release permanently. This approach bypasses NOD mouse TRPV1 deficiencies and achieves T1D reversal following unilateral sensory axotomy at thoracic segments T9-T12. The surgical procedure generates a phenotypic switch in contralateral dorsal root ganglia, upregulating sP expression and producing elevated sP levels in pancreas tissue for the entire length of our study. T1D reversal can last for months post treatment and can delay T1D onset if mice are treated early. This treatment impedes T cell proliferation in pancreatic lymph nodes and accumulation of lymphocytes in the islets and is sP-dependent as indicated through rescue experiments utilizing a sP receptor (NK-1R) antagonist. These data support a T cell contact-dependent requirement for pSC destruction, a pro-inflammatory role for B7-H1 in autoimmunity and have provided alternate strategies to treatment or prevention of T1D.