Influence of Vitamin D on Islet Autoimmunity and Beta-Cell Function in Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease leading to immune-mediated destruction of pancreatic beta cells, resulting in the need for insulin therapy. The incidence of T1D is increasing worldwide, thus prompting researchers to investigate novel immunomodulatory strategies to halt autoimmunity and modify disease progression. T1D is considered as a multifactorial disease, in which genetic predisposition and environmental factors interact to promote the triggering of autoimmune responses against beta cells. Over the last decades, it has become clear that vitamin D exerts anti-inflammatory and immunomodulatory effects, apart from its well-established role in the regulation of calcium homeostasis and bone metabolism. Importantly, the global incidence of vitamin D deficiency is also dramatically increasing and epidemiologic evidence suggests an involvement of vitamin D deficiency in T1D pathogenesis. Polymorphisms in genes critical for vitamin D metabolism have also been shown to modulate the risk of T1D. Moreover, several studies have investigated the role of vitamin D (in different doses and formulations) as a potential adjuvant immunomodulatory therapy in patients with new-onset and established T1D. This review aims to present the current knowledge on the immunomodulatory effects of vitamin D and summarize the clinical interventional studies investigating its use for prevention or treatment of T1D.

Omega-3 fatty acids are associated with a lower prevalence of autoantibodies in shared epitope-positive subjects at risk for rheumatoid arthritis.

OBJECTIVES: Previously, we found that omega-3 fatty acids (n-3 FAs) were inversely associated with anti-cyclic citrullinated peptide (anti-CCP) positivity in participants at risk for future rheumatoid arthritis (RA). We investigated whether n-3 FAs were also associated with rheumatoid factor (RF) positivity and whether these associations were modified by shared epitope (SE) positivity. METHODS: The Studies of the Etiology of RA (SERA) cohort includes RA-free participants who are at increased risk for RA. We conducted a nested case-control study (n=136) to determine the association between RF and anti-CCP2 positivity and n-3 FA percentage in erythrocyte membranes (n-3 FA% in red blood cells (RBCs)). Additionally, in the baseline visit of the SERA cohort (n=2166), we evaluated the association between reported n-3 FA supplement use and prevalence of RF and anti-CCP2. We assessed SE positivity as an effect modifier. RESULTS: In the case-control study, increasing n-3 FA% in RBCs was inversely associated with RF positivity in SE-positive participants (OR 0.27, 95% CI 0.10 to 0.79), but not SE-negative participants. Similar associations were seen with anti-CCP positivity in SE-positive participants (OR 0.42, 95% CI 0.20 to 0.89), but not SE-negative participants. In the SERA cohort at baseline, n-3 FA supplement use was associated with a lower prevalence of RF positivity in SE-positive participants (OR 0.32, 95% CI 0.12 to 0.82), but not SE-negative participants; similar but non-significant trends were observed with anti-CCP2. CONCLUSIONS: The potential protective effect of n-3 FAs on RA-related autoimmunity may be most pronounced in those who exhibit HLA class II genetic susceptibility to RA.

Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria.

A new dimeric macrolide xylopyranoside, cocosolide (1), was isolated from the marine cyanobacterium preliminarily identified as Symploca sp. from Guam. The structure was determined by a combination of NMR spectroscopy, HRMS, X-ray diffraction studies and Mosher's analysis of the base hydrolysis product. Its carbon skeleton closely resembles that of clavosolides A-D isolated from the sponge Myriastra clavosa, for which no bioactivity is known. We performed the first total synthesis of cocosolide (1) along with its [α,α]-anomer (26) and macrocyclic core (28), thus leading to the confirmation of the structure of natural 1. The convergent synthesis featured Wadsworth-Emmons cyclopropanation, Sakurai annulation, Yamaguchi macrocyclization/dimerization reaction, α-selective glycosidation and ß-selective glycosidation. Compounds 1 and 26 potently inhibited IL-2 production in both T-cell receptor dependent and independent manners. Full activity requires the presence of the sugar moiety as well as the intact dimeric structure. Cocosolide also suppressed the proliferation of anti-CD3-stimulated T-cells in a dose-dependent manner.

Lower omega-3 fatty acids are associated with the presence of anti-cyclic citrullinated peptide autoantibodies in a population at risk for future rheumatoid arthritis: a nested case-control study.

OBJECTIVE: The aim of this study was to investigate omega-3 fatty acid (FA) supplement use and omega-3 FAs in erythrocyte membranes [omega-3 FA % in erythrocyte membranes (RBC)] and their association with anti-CCP autoantibodies in a population without RA, but who are at genetic risk for RA. METHODS: The multicentre Studies of the Etiology of RA (SERA) cohort includes RA-free subjects who are first-degree relatives of RA probands or are enriched with the HLA-DR4 allele. In a nested case-control study, 30 SERA cases were identified who were anti-CCP2 antibody positive. We further identified 47 autoantibody negative controls, frequency matched to cases on age at study visit, sex, race and study site. Anti-CCP2 status, self-reported omega-3 FA supplement use and omega-3 FA % in RBCs were obtained from a single visit. RESULTS: Anti-CCP2 positive cases were less likely than controls to report omega-3 FA supplement use (odds ratio: 0.14; 95% CI 0.03, 0.68). In addition, the likelihood of anti-CCP2 positivity was inversely associated with total omega-3 FA % in RBCs (odds ratio: 0.47; 95% CI 0.24, 0.92, for a s.d. increase). CONCLUSION: The inverse association between anti-CCP2 positivity and self-reported omega-3 FA supplement use and omega-3 FA % in RBCs suggests that omega-3 FAs may protect against the development of RA-related autoimmunity in pre-clinical RA.