Historically, vitamin D has been associated with the regulation of bone metabolism. However, increasing evidence demonstrates a strong association between vitamin D signaling and many biological processes that regulate immune responses. The discovery of the vitamin D receptor in multiple immune cell lineages, such as monocytes, dendritic cells, and activated T cells credits vitamin D with a novel role in modulating immunological functions and its subsequent role in the development or prevention of autoimmune diseases. In this review we, discuss five major areas in vitamin D biology of high immunological significance: (1) the metabolism of vitamin D; (2) the significance of vitamin D receptor polymorphisms in autoimmune diseases, such as multiple sclerosis, type 1 diabetes mellitus, and systemic lupus erythematosus; (3) vitamin D receptor transcriptional regulation of immune cell lineages, including Th1, Th17, Th2, regulatory T, and natural killer T cells; (4) the prevalence of vitamin D insufficiency/deficiency in patients with multiple sclerosis, type 1 diabetes mellitus, and systemic lupus erythematosus; and finally, (5) the therapeutic effects of vitamin D supplementation on disease severity and progression.

Highlights d Beige fat progenitors are marked by cell surface proteins, PDGFRa, Sca1, and CD81 d Beige APC proliferation is regulated by temperature, genetic background, and aging d CD81 mediates integrin-FAK signaling in response to irisin d CD81 loss causes obesity, insulin resistance, and adipose tissue inflammation

The interleukin (IL)-12/IL-23 mediated Th1/Th17 signaling pathway has been associated with the etiopathogenesis of primary biliary cirrhosis (PBC). To address the cytokine microenvironment specifically in the liver, we examined the localized expression of cytokine subunits and their corresponding receptors using previously optimized immunohistochemistry with an extensive panel of antibodies directed at IL-12p70, IL-12p35, IFN-γ, IL-12RB2, IL-23p40, IL-23p19, IL-17 and IL-23R using liver from PBC (n=51) and non-PBC (n=80) control liver disease patients. Multiple portal tracts in each patient were blindly evaluated and individually scored. We report herein that although IL-12/Th1 and IL-23/Th17 staining were detected in all of the liver sections, they were primarily localized around the damaged interlobular bile ducts in PBC. Most importantly, Th17 skewing was prominent in advanced PBC patients with intensive secretion of IL-23p19 by inflamed hepatocytes around IL-23R, IL-12RB2, and IFN-γ expressing degenerated cholangiocytes. Our novel finding on the direct association of Th17 skewing and disease severity illustrates the significance of the IL-23/Th17 pathway in the perpetuation of IL-12/Th1-mediated immunopathology in PBC. Furthermore, localized IL-23p19 production by hepatocytes may enhance pro-fibrotic Th17 signaling and pro-inflammatory IFN-γ production that contribute to PBC pathology. In conclusion, our data emphasize the pathogenic relevance of IL-12/Th1 and IL-23/Th17 in the evolution of PBC. Of significance, however, the shift from a Th1 to a Th17 imbalance at advanced stages of the disease suggests the necessity to consider modulation of the IL-23/Th17 pathway as a potential target for therapeutic intervention.

Background Using high-density human recombinant protein microarrays, we identified two potential biomarkers, kelch-like 12 (KLHL12) and hexokinase-1 (HK1), in primary biliary cirrhosis (PBC). The objective of this study was to determine the diagnostic value of anti-KLHL12/HK1 autoantibodies in PBC. Aims Initial discovery used sera from 22 patients with PBC and 62 non-PBC controls. KLHL12 and HK1 proteins were then analyzed for immunoglobulin reactivity by immunoblot and enzyme-linked immunosorbent assay (ELISA) in two independent cohorts of PBC and disease/healthy control patients. Methods Serum samples from 100 patients with PBC and 165 non-PBC disease controls were analyzed by immunoblot and samples from 366 patients with PBC, 174 disease controls, and 80 healthy donors were tested by ELISA. Results Anti-KLHL12 and anti-HK1 antibodies were each detected more frequently in PBC compared with non-PBC disease controls (p < 0.001). Not only are both markers highly specific for PBC (≥ 95%), but they also yielded higher sensitivity than anti-gp210 and anti-sp100 antibodies. Combining anti-HK1 and anti-KLHL12 with available markers (MIT3, gp210 and sp100) increased the diagnostic sensitivity for PBC. Most importantly, anti-KLHL12 and anti-HK1 antibodies were present in 10~35% of AMA-negative PBC patients and adding these two biomarkers to conventional PBC assays dramatically improved the serological sensitivity in AMA-negative PBC from 55% to 75% in immunoblot and 48.3% to 68.5% in ELISA. Conclusions The addition of tests for highly specific anti-KLHL12 and anti-HK1 antibodies to AMA and ANA serological assays significantly improves efficacy in the clinical detection and diagnosis of PBC, especially for AMA-negative subjects.

No abstract