Efficacy of a unique omega-3 formulation on the correction of nutritional deficiency and its effects on cardiovascular disease risk factors in a randomized controlled VASCAZEN(®) REVEAL Trial.

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.

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' autoimmunity in type 1 diabetes.

Type 1 diabetes (T1D) results from autoimmune-mediated loss of insulin-producing beta-cells. Recent findings suggest that the events controlling T1D development are not only immunological, but also neuronal in nature. In the non-obese diabetic (NOD) mouse model of T1D, a mutant sensory neuron channel, TRPV1, initiates chronic, progressive beta-cell stress, inducing islet cell inflammation. This novel mechanism of organ-specific damage requires a permissive, autoimmune-prone host, but ascribes tissue specificity to the local secretory dysfunction of sensory afferent neurons. In NOD mice, normalizing this neuronal function by administration of the neurotransmitter substance P clears islet cell inflammation, reduces insulin resistance and restores normoglycemia. Here, we discuss this neuro-immuno-endocrine model, its implications and the involvement of sensory neurons in other autoimmune disorders. These developments might provide novel neuronal-based therapeutic interventions, particularly in diabetes.

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.

Unexpected acceleration of type 1 diabetes by transgenic expression of B7-H1 in NOD mouse peri-islet glia.

OBJECTIVE: Autoimmune target tissues in type 1 diabetes include pancreatic ß-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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: In contrast with transgenic B7-H1 in NOD mouse ß-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.

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.

TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes.

In type 1 diabetes, T cell-mediated death of pancreatic beta cells produces insulin deficiency. However, what attracts or restricts broadly autoreactive lymphocyte pools to the pancreas remains unclear. We report that TRPV1(+) pancreatic sensory neurons control islet inflammation and insulin resistance. Eliminating these neurons in diabetes-prone NOD mice prevents insulitis and diabetes, despite systemic persistence of pathogenic T cell pools. Insulin resistance and beta cell stress of prediabetic NOD mice are prevented when TRPV1(+) neurons are eliminated. TRPV1(NOD), localized to the Idd4.1 diabetes-risk locus, is a hypofunctional mutant, mediating depressed neurogenic inflammation. Delivering the neuropeptide substance P by intra-arterial injection into the NOD pancreas reverses abnormal insulin resistance, insulitis, and diabetes for weeks. Concordantly, insulin sensitivity is enhanced in trpv1(-/-) mice, whereas insulitis/diabetes-resistant NODxB6Idd4-congenic mice, carrying wild-type TRPV1, show restored TRPV1 function and insulin sensitivity. Our data uncover a fundamental role for insulin-responsive TRPV1(+) sensory neurons in beta cell function and diabetes pathoetiology.

Processing of serum proteins underlies the mass spectral fingerprinting of myocardial infarction.

The MALDI-TOF spectra of peptides from the sera of normal and myocardial infarction patients produced patterns that provided an accurate diagnostic of MI. In myocardial infarction, the spectral pattern originated from the cleavage of complement C3 alpha chain to release the C3f peptide and cleavage of fibrinogen to release peptide A. The fibrinogen peptide A and complement C3f peptide were in turn progressively truncated by aminopeptidases to produce two families of fragments that formed the characteristic spectral pattern of MI. Time course and inhibitor studies demonstrated that the peptide patterns in the serum reflect the balance of disease-specific-protease and aminopeptidase activity ex vivo.