The advancement of genetic and preclinical studies has uncovered the mechanisms involved in the pathogenesis of alopecia areata (AA). The development of targeted therapies using small molecules blocking specific pathways for the treatment of AA is underway. By repurposing Food and Drug Administration-approved small molecule JAK inhibitors as treatments for AA, it has been demonstrated that JAK inhibitors can effectively reverse hair loss in patients with moderate to severe AA. In this review, we summarize and discuss the current preclinical and clinical studies on JAK inhibitors, as well as the prospects of using JAK inhibitors for the treatment of AA.
Purpose: Variants in the gene encoding Programmed Cell Death-1 (PDCD1) have been associated with susceptibility to Systemic Lupus Erythematosus and other autoimmune diseases. Giv-en that clinically distinct autoimmune phenotypes share common genetic susceptibility factors, vari-ants in PDCD-1 were tested for a possible association with Juvenile Idiopathic Arthritis (JIA).Methods: Four Single Nucleotide Polymorphisms (SNPS) in the PDCD1 gene were genotyped and analyzed: rs7421861, rs11568821, rs10204525, and rs7568402 in 834 cases and 855 controls of Northern European ancestry. Each variant was examined for possible associations with JIA and then analyzed for association with JIA categories.Results:PDCD1 variants showed no association with JIA in the cohort overall (rs7421861 p=0.63, rs11568821 p=0.13, rs10204525 p=0.31, and rs7568402 p=0.45). Stratification by JIA categories indicated a significant association between systemic JIA and PDCD1 rs7568402 (OR=0.53, p=0.0027), which remained significant after 10,000 permutations, but was not replicated in an inde-pendent multi-ethnic systemic JIA cohort. A nominal association between enthesitis-related arthritis and rs115668821 was also observed (OR=0.22, p=0.012).Conclusion: Unlike other multiple autoimmune disease associated genetic variants, there was no as-sociation between PDCD1 variants and JIA or JIA categories.
Alopecia areata (AA) is an autoimmune form of hair loss involving infiltration of CD8+ T cells in the hair follicles (HFs) in conjunction with the upregulated antigen presentation processes. The growing (anagen) HFs are preferentially attacked in AA, leading to the hypothesis that epitopes derived from anagen-specific proteins are targeted by the T cells. Melanogenesis is a highly active process during anagen and clinical observations reported preferential loss of pigmented hairs during the initial onset of AA and regrowth of unpigmented hair during recovery. However, whether melanogenesis antigens are an inciting factor for AA has not been determined. We utilized a computer-assisted epitope prediction algorithm to design a panel of candidate CD8 T cell-specific epitope sequences in the C3H/HeJ mouse model, which we derived from several sources including our previous GWAS studies, published data, and known melanogenesis proteins. In addition, we isolated protein homogenates from the skin of AA-affected and normal-haired C3H/HeJ mice at either anagen or telogen stages of hair cycle. The epitope peptides and protein homogenates were used to stimulate skin-draining lymph node cells (LNCs) of C3H/HeJ mice with chronic AA or normal-haired mice and assessed the number of activated IFNg-producing CD8 T cells via ELISpot assays. We found that anagen stage protein homogenates induced a higher level of CD8 T cell activation, especially those with higher molecular weight, supporting the hypothesis that AA is an anagen-specific disease. Interestingly, epitopes derived from melanosomal membrane glycoprotein OA1 and transport protein SLC24A5 and SLC45A2 induced significantly higher frequency of CD8 T cell activation. Some of the antigens that showed higher antigenicity were suggested in previous studies to display molecular mimicry with peptides from the HBV vaccine. Further finemapping of epitopes will help define AA-associated antigens and the development of potential antigen-specific tolerogenic therapies. DNA immunization has theoretical and practical advantages over conventional protein-based immunization strategies. Though studies in animal models demonstrate the promise of nonviral DNA vaccines, clinical translation has thus far been disappointing. Here we develop a unique approach to increase the immunogenicity of non-viral DNA vaccines by combining "skin targeting" with a novel keratinocyte targeted approach to create a pro-immunogenic cutaneous microenvironment. Specifically, we co-delivered antigen with the transcription factor x-box binding protein 1 (XBP1) to the skin. XBP1 is an endoplasmic reticulum (ER) stress-associated factor that regulates ER function, promotes the production and secretion of proteins, regulates survival and function of antigen presenting cells, and has been shown to induce innate immunity under some conditions. In mouse models, we find that compared to delivery of antigen encoding plasmid alone, co-delivery with K14 promoter driven XBP1 plasmid DNA results in improved antigen-specific humor...
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