TRPV1 gates tissue access and sustains pathogenicity in autoimmune encephalitis.

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.

'Sensing' the link between type 1 and type 2 diabetes.

Obesity-associated insulin resistance is a core element of metabolic syndrome and type 2 diabetes (T2D). Notably, insulin resistance is also a feature of type 1 diabetes (T1D), where findings in the non-obese diabetic mouse model have implicated transient receptor potential vanilloid-1 (TRPV1+) sensory neurons in local islet inflammation and glucose metabolism. Here, we briefly review the role of TRPV1 in non-obese diabetic (NOD) T1D pathogenesis, highlighting commonalities that suggest TRPV1 may contribute to obesity and T2D as well. With the recently discovered importance of adipose infiltrating lymphocytes in the metabolic disturbances of obesity and T2D, sensory innervation of fat may thus play an analogous role to sensory neurons in the islet--modulating neuroendocrine homeostasis and inflammation. In such a scenario, TRPV1+ sensory nerves would provide the pathoaetiological link connecting the shared metabolic and immunologic features of type 1 diabetes and T2D.

Interleukin-15 expression affects homeostasis and function of B cells through NK cell-derived interferon-gamma.

Interleukin-15 (IL-15) is a cytokine important for the development, maturation, and function of many cells of the immune system including NK, NKT, gammadeltaT, and CD8(+) T cells. The relationship between IL-15 and B lymphocytes however, is not well characterized and is the focus of our study. Previous in vitro reports have shown that IL-15 increases proliferation of B lymphocytes and increases antibody secretion however, this relationship remains inadequately defined in vivo. The focus of this study was to examine the role of IL-15 in B cell homeostasis and function in vivo using mice that either over express IL-15 (IL-15tg mice) or are deficient in IL-15 (IL-15(-/-) mice) production. Here we report significant differences between the B cell populations of IL-15(-/-), C57BL/6, and IL-15tg mice. In fact, increased expression of IL-15 resulted in a significant decrease in the percentage and absolute number of CD19(+) cells. In vitro B cell co-cultures implicate interferon-gamma (IFN-gamma) as the factor responsible for inhibiting B cell proliferation. We also show that IL-15 expression affects B cell function, as B cells from IL-15 transgenic mice produce greater amounts of IgG and IgA than IL-15 knockout mice in vitro. Interestingly, despite significant differences in B cell numbers in these strains, there were no significant differences in total antibody titers in serum and vaginal washes of these mice. Results from our in vivo and in vitro experiments suggest that altered expression of IL-15 affects B cell homeostasis through the induction of NK cell-derived IFN-gamma.

B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies.

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.

Normalization of obesity-associated insulin resistance through immunotherapy.

Obesity and its associated metabolic syndromes represent a growing global challenge, yet mechanistic understanding of this pathology and current therapeutics are unsatisfactory. We discovered that CD4(+) T lymphocytes, resident in visceral adipose tissue (VAT), control insulin resistance in mice with diet-induced obesity (DIO). Analyses of human tissue suggest that a similar process may also occur in humans. DIO VAT-associated T cells show severely biased T cell receptor V(alpha) repertoires, suggesting antigen-specific expansion. CD4(+) T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon-gamma (IFN-gamma)-secreting T helper type 1 (T(H)1) cells, overwhelming static numbers of T(H)2 (CD4(+)GATA-binding protein-3 (GATA-3)(+)) and regulatory forkhead box P3 (Foxp3)(+) T cells. CD4(+) (but not CD8(+)) T cell transfer into lymphocyte-free Rag1-null DIO mice reversed weight gain and insulin resistance, predominantly through T(H)2 cells. In obese WT and ob/ob (leptin-deficient) mice, brief treatment with CD3-specific antibody or its F(ab')(2) fragment, reduces the predominance of T(H)1 cells over Foxp3(+) cells, reversing insulin resistance for months, despite continuation of a high-fat diet. Our data suggest that the progression of obesity-associated metabolic abnormalities is under the pathophysiological control of CD4(+) T cells. The eventual failure of this control, with expanding adiposity and pathogenic VAT T cells, can successfully be reversed by immunotherapy.

Islet glia, neurons, and beta cells.

Type 1 diabetes (T1D) is caused by autoimmune beta cell destruction. The early events triggering T1D and the forces that keep diabetic autoimmunity pancreas specific have been unclear. Our discovery that autoimmune islet destruction is not beta-cell-exclusive but includes cytotoxic T cell targeting of peri-islet glia, evoked the possibility that T1D pathogenesis may involve neuronal elements beyond beta cell/immune interactions. Recently, we have found that sensory afferent neurons are a critical component in prediabetes initiation, promoting islet inflammation through altered glucose homeostasis and progressive beta cell stress. These factors orchestrate a catastrophic cascade culminating in insulin insufficiency mediated by an autoimmune-prone host. This neuro-immuno-endocrinological triad explains diabetic inflammation as a consequence of local neuropeptide deficiency, leading to an innovative concept of disease pathogenesis with novel therapeutic implications.

Targeting of pancreatic glia in type 1 diabetes.

OBJECTIVE: Type 1 diabetes reflects autoimmune destruction of beta-cells and peri-islet Schwann cells (pSCs), but the mechanisms of pSC death and the T-cell epitopes involved remain unclear. RESEARCH DESIGN AND METHODS: Primary pSC cultures were generated and used as targets in cytotoxic T-lymphocyte (CTL) assays in NOD mice. Cognate interaction between pSC and CD8(+) T-cells was assessed by transgenic restoration of beta2-microglobulin (beta2m) to pSC in NOD.beta2m(-/-) congenics. I-A(g7) and K(d) epitopes in the pSC antigen glial fibrillary acidic protein (GFAP) were identified by peptide mapping or algorithms, respectively, and the latter tested by immunotherapy. RESULTS: pSC cultures did not express major histocompatibility complex (MHC) class II and were lysed by ex vivo CTLs from diabetic NOD mice. In vivo, restoration of MHC class I in GFAP-beta2m transgenics significantly accelerated adoptively transferred diabetes. Target epitopes in the pSC autoantigen GFAP were mapped to residues 79-87 and 253-261 for K(d) and 96-110, 116-130, and 216-230 for I-A(g7). These peptides were recognized spontaneously in NOD spleens as early as 2.5 weeks of age, with proliferative responses peaking around weaning and detectable lifelong. Several were also recognized by T-cells from new-onset type 1 diabetic patients. NOD mouse immunotherapy at 8 weeks with the CD8(+) T-cell epitope, GFAP 79-87 but not 253-261, significantly inhibited type 1 diabetes and was associated with reduced gamma-interferon production to whole protein GFAP. CONCLUSIONS: Collectively, these findings elucidate a role for pSC-specific CD8(+) T-cells in islet inflammation and type 1 diabetes pathogenesis, further supporting neuronal involvement in beta-cell demise.