TRPV1+ Sensory Neurons Control β Cell Stress and Islet Inflammation in Autoimmune Diabetes

Razavi, Rozita; Chan, Yin; Afifiyan, F. Nikoo; Liu, Xue Jun; Wan, Xiang; Yantha, Jason; Tsui, Hubert; Tang, Lan; Tsai, Sue; Santamaría, Pere; Driver, John P.; Serreze, David; Salter, Michael W.; Dosch, Hans‐Michael

doi:10.1016/j.cell.2006.10.038

Cited by 306 publications

(324 citation statements)

References 62 publications

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“…NOD mice deficient in B7-2 develop spontaneous peripheral poly-neuropathy, but not diabetes (19). And, the peri-islet Schwann cells have been shown to be an early target in NOD diabetes and, more recently, an important role for pancreatic sensory neurons in islet inflammation has been uncovered (18,22).…”

Section: Discussionmentioning

confidence: 99%

First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

Suri¹,

Walters

Rohrs

et al. 2008

The Journal of Immunology

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The diversity of Ags targeted by T cells in autoimmune diabetes is unknown. In this study, we identify and characterize a limited number of naturally processed peptides from pancreatic islet β-cells selected by diabetogenic I-Ag7 molecules of NOD mice. We used insulinomas transfected with the CIITA transactivator, which resulted in their expression of class II histocompatibility molecules and activation of diabetogenic CD4 T cells. Peptides bound to I-Ag7 were isolated and examined by mass spectrometry: some peptides derived from proteins present in secretory granules of endocrine cells, and a number were shared with cells of neuronal lineage. All proteins to which peptides were identified were expressed in β cells from normal islets. Peptides bound to I-Ag7 molecules contained the favorable binding motif characterized by acidic amino acids at the P9 position. The draining pancreatic lymph nodes of prediabetic NOD mice contained CD4 T cells that recognized three different natural peptides. Furthermore, four different peptides elicited CD4 T cells, substantiating the presence of such self-reactive T cells. The overall strategy of identifying natural peptides from islet β-cells opens up new avenues to evaluate the repertoire of self-reactive T cells and its role in onset of diabetes.

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Section: Discussionmentioning

confidence: 99%

First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

Suri¹,

Walters

Rohrs

et al. 2008

The Journal of Immunology

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“…Trpv1 is a receptor for capsaicin on nociceptive neurons in dorsal root and trigeminal ganglia, and capsaicin engagement of Tprv1 expressed on immature dendritic cells leads to their maturation and induction of antigen-presenting function (66). The diabetes-associated allele of Idd4.1 was identified as a hypofunctional mutant of Tprv1 that influences peripheral neuronal control of ␤ cell stress and islet inflammation in NOD mice via a proinflammatory state (67). Importantly, H 3 R stimulation has been shown to prevent capsaicin-induced substance P release from C-fibers (68,69).…”

Section: Discussionmentioning

confidence: 99%

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Teuscher

Subramanian

Noubade

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Histamine (HA), a biogenic amine with a broad spectrum of activities in both physiological and pathological settings, plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. HA exerts its effect through four G protein-coupled receptors designated HA receptor H 1, H2, H3, and H4. We report here that, compared with wild-type animals, mice with a disrupted HA H 3 receptor (H3RKO), the expression of which is normally confined to cells of the nervous system, develop more severe disease and neuroinflammation. We show that this effect is associated with dysregulation of bloodbrain barrier permeability and increased expression of MIP-2, IP-10, and CXCR3 by peripheral T cells. Our data suggest that pharmacological targeting of the H 3R may be useful in preventing the development and formation of new lesions in multiple sclerosis, thereby significantly limiting the progression of the disease.blood-brain barrier ͉ experimental allergic encephalomyelitis ͉ multiple sclerosis H istamine [2-(4-imidazole) ethylamine] (HA) is a ubiquitous mediator of diverse physiological processes including neurotransmission, secretion of pituitary hormones, and regulation of the gastrointestinal and circulatory systems (1). HA is a potent mediator of inflammation and a regulator of innate and adaptive immunity (2). HA exerts its effect through four G proteincoupled receptors [H 1 , H 2 , H 3 , and H 4 receptor, designated according to the chronological order of their discovery (1)].HA is implicated in the pathophysiology of multiple sclerosis (MS) and its animal models, collectively termed experimental allergic encephalomyelitis (EAE). HA and agents causing the release of HA from mast cells, the primary source of HA in the body (3), alter blood-brain barrier (BBB) permeability. Tissue levels of HA correlate with the onset of EAE (4-6). Inhibitors of mast cell degranulation and H 1 R and H 2 R antagonists modify EAE severity (7)(8)(9)(10)(11)(12). Epidemiological data indicate that use of sedating H 1 R antagonists is associated with decreased MS risk (13). In a small pilot study, patients with relapsing-remitting or relapsing-progressive MS given the H 1 R antagonist hydroxyzine remained stable or improved neurologically (14). Microarray analysis revealed that the H 1 R was overexpressed in the chronic plaques of MS patients (15). Moreover, mouse genetic studies have shown that HA, H 1 R, and H 2 R play an important role in regulating encephalitogenic T cell responses and susceptibility to EAE (16-18). The role of H 3 R and H 4 R in EAE and MS has not been studied.H 3 R is not normally expressed by hematopoietic cells; rather, it is expressed presynaptically where it is an inhibitory autoreceptor (inhibits release of HA from histaminergic neurons) and heteroreceptor (inhibits release of other neurotransmitters such as acetylcholine, noradrenaline, dopamine, and 5-HT from nonhistaminergic neurons) (19). Absence of presynaptic inhibition results in failure to limit neurotransmitter rel...

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“…Because autonomic axons are mostly unmyelinated, our results provide evidence that axonal neuropathy in GLD might also occur independent from demyelination. Together, these findings indicate a crucial role for axonal function in the regulation of various visceral functions, including thymus and secondary lymphoid organs and also at the base for other diseases such as diabetes (Razavi et al, 2006). At this time, we cannot exclude that both epigenetic (loss of autonomic innervation of lymphoid organ) and cell autonomous (GALC deficiency in hematopoietic precursors) contribute to disease progression.…”

Section: Autonomic Denervation Of the Gld Thymusmentioning

confidence: 92%

Autonomic Denervation of Lymphoid Organs Leads to Epigenetic Immune Atrophy in a Mouse Model of Krabbe Disease

Galbiati¹,

Basso²,

Cantuti³

et al. 2007

J. Neurosci.

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Lysosomal ␤-galactosylceramidase deficiency results in demyelination and inflammation in the nervous system causing the neurological Krabbe disease. In the Twitcher mouse model of this disease, we found that neurological symptoms parallel progressive and severe lymphopenia. Although lymphopoiesis is normal before disease onset, primary and secondary lymphoid organs progressively degenerate afterward. This occurs despite preserved erythropoiesis and leads to severe peripheral lymphopenia caused by reduced numbers of T cell precursors and mature lymphocytes. Hematopoietic cell replacement experiments support the existence of an epigenetic factor in mutant mice reconcilable with a progressive loss of autonomic axons that hampers thymic functionality. We propose that degeneration of autonomic nerves leads to the irreversible thymic atrophy and loss of immune-competence. Our study describes a new aspect of Krabbe disease, placing patients at risk of immune-related pathologies, and identifies a novel target for therapeutic interventions.

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TRPV1+ Sensory Neurons Control β Cell Stress and Islet Inflammation in Autoimmune Diabetes

Cited by 306 publications

References 62 publications

First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Autonomic Denervation of Lymphoid Organs Leads to Epigenetic Immune Atrophy in a Mouse Model of Krabbe Disease

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TRPV1+ Sensory Neurons Control β Cell Stress and Islet Inflammation in Autoimmune Diabetes

Cited by 306 publications

References 62 publications

First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

Central histamine H3receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Autonomic Denervation of Lymphoid Organs Leads to Epigenetic Immune Atrophy in a Mouse Model of Krabbe Disease

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Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS