Vitamin D Actions on CD4+ T Cells in Autoimmune Disease

Abstract

This review summarizes and integrates research on vitamin D and CD4+ T-lymphocyte biology to develop new mechanistic insights into the molecular etiology of autoimmune disease. A deep understanding of molecular mechanisms relevant to gene–environment interactions is needed to deliver etiology-based autoimmune disease prevention and treatment strategies. Evidence linking sunlight, vitamin D, and the risk of multiple sclerosis and type 1 diabetes is summarized to develop the thesis that vitamin D is the environmental factor that most strongly influences autoimmune disease development. Evidence for CD4+ T-cell involvement in autoimmune disease pathogenesis and for paracrine calcitriol signaling to CD4+ T lymphocytes is summarized to support the thesis that calcitriol is sunlight’s main protective signal transducer in autoimmune disease risk. Animal modeling and human mechanistic data are summarized to support the view that vitamin D probably influences thymic negative selection, effector Th1 and Th17 pathogenesis and responsiveness to extrinsic cell death signals, FoxP3+CD4+ T-regulatory cell and CD4+ T-regulatory cell type 1 (Tr1) cell functions, and a Th1–Tr1 switch. The proposed Th1–Tr1 switch appears to bridge two stable, self-reinforcing immune states, pro- and anti-inflammatory, each with a characteristic gene regulatory network. The bi-stable switch would enable T cells to integrate signals from pathogens, hormones, cell–cell interactions, and soluble mediators and respond in a biologically appropriate manner. Finally, unanswered questions and potentially informative future research directions are highlighted to speed delivery of etiology-based strategies to reduce autoimmune disease.

Vitamin D status in patients with psoriasis

“…Deficiency and insufficiency of vitamin D were found in many immune-mediated and neoplastic diseases. So, the role of vitamin D in the pathogenesis of psoriasis, as well as in rheumatoid arthritis, multiple sclerosis, systemic lupus, and inflammatory bowel diseases can be speculated (4)(5)(6). The assessment of the blood level of 25-hydroxyvi-Stoyan Pavlov, Irina Ivanova, Daniela Gerova tamin D, 25(OH)D, which is a major circulating metabolite of vitamin D is an accepted test for a vitamin D status (7).…”

Dietary Vitamin D3 Suppresses Pulmonary Immunopathology Associated with Late-Stage Tuberculosis in C3HeB/FeJ Mice

“…Dietary VitD 3 has been repeatedly demonstrated to suppress organ-specific inflammation in autoimmune disease models (44). To determine if dietary VitD 3 limits pro-inflammatory gene expression in Mtb-infected organs, lungs from Mtb-infected VitD LO and VitD HI groups were collected on post-infection days 35 and 92, used for mRNA extraction and cDNA synthesis, and analyzed via real time PCR array for the expression of select genes of interest.…”

Vitamin D and estrogen synergy in Vdr-expressing CD4+ T cells is essential to induce Helios+FoxP3+ T cells and prevent autoimmune demyelinating disease

“…Although rodent EAE shows strong parallels to human MS, especially in the immunological aspects of these diseases, EAE and MS are distinct entities and the parallels are imperfect. If mammalian evolution co-opted the vitamin D system to contribute to the biological mechanism that protects the fetus from a maternal CD4 + T cell-mediated immune attack as we originally proposed (Nashold et al, 2009;Hayes et al, 2015), then a collaboration between E2 and calcitriol to drive activated CD4 + T cells to a regulatory phenotype when pathogen signals are absent may be universal in female mammals. High level CYP27B1 gene expression and calcitriol synthesis in human and rodent maternal decidua and fetal trophoblasts supports this possibility (Fu et al, 1997;Evans et al, 2004;O'Brien et al, 2014).…”

“…Current evidence suggests that D3 strongly influences MS risk and it does so in a female-biased manner through paracrine calcitriol signaling to CD4 + T lymphocytes (Hayes et al, 2015). The rising female MS incidence correlates temporally with declining global population D3 status, possibly reflecting a causal relationship.…”