It is generally believed that susceptibility to both organ-specific and systemic autoimmune diseases is under polygenic control. importantly, using 150 pedigrees of MS families from two impartial cohorts and the TRANSMIT software, we found that the P1527allele was preferentially transmitted to unaffected individuals (= 0.002). Similarly, an analysis of 187 SLE families revealed the dinucleotide-deleted allele was preferentially transmitted to unaffected individuals (= 0.002). The mRNA levels for the dinucleotide-deletion allele were 2.5-fold less than that of the wild-type allele. The dinucleotide deletion significantly reduced the stability of mRNA. Our results demonstrate that a destabilizing dinucleotide deletion in the 3 UTR of mRNA conveys significant protection against both MS and SLE. Author Summary When an individual’s immune system attacks self tissues or organs, he/she evolves autoimmune diseases. Although it is usually well established that multiple genes control susceptibility to autoimmune diseases, most of the genes remain unidentified. In addition, although different autoimmune diseases have a common immunological basis, a very small number of genes have been recognized that impact multiple autoimmune diseases. Here we show that a variance in is usually a likely genetic factor for the risk and progression of two types of autoimmune diseases, including multiple sclerosis (MS), an organ-specific autoimmune disease affecting the central nervous system, and systemic lupus erythematosus, a systemic autoimmune disease. Our data indicated that if an individual’s gene has a specific two-nucleotide deletion in 169332-60-9 supplier the noncoding region of mRNA, his/her risk of developing MS or SLE is usually reduced by 2- to 3-fold. As a group, MS patients with the two-nucleotide deletion will likely have a slower disease progression. Biochemical analysis indicated that this deletion prospects to quick decay of mRNA, which should result in reduced synthesis of the CD24 protein. Our data may be useful for the treatment and diagnosis of autoimmune diseases. Introduction Multiple sclerosis (MS) is usually a chronic, inflammatory neurodegenerative disease of the central nervous system of unknown etiology. There is evidence to support the hypothesis that MS is an autoimmune process modulated by both genetic and environmental factors [1C6]. An increased risk of MS among MS relatives has been found in numerous prospective epidemiological studies [2,4,7]. Twin studies from different populations consistently indicate that a monozygotic twin has a 5- to 6-fold higher risk of MS than a dizygotic twin [1,2,8]. Collectively, these findings would implicate that, at least in part, the risk for developing 169332-60-9 supplier this disorder and possibly its progression are mediated by multiple genetic factors. Several whole-genome screens were performed in MS affected families. These studies confirmed the association of MS with the class II haplotype but failed to confirm other major putative loci in MS [9C11]. Systemic lupus erythematosus (SLE) is usually a classic systemic autoimmune disease with diverse clinical symptoms, including fatigue, joint pain and swelling, skin rashes, and chest pain. Severe SLE complications include nephritis, central nervous system vasculitis, pulmonary hypertension, interstitial lung disease, and stroke. Whole-genome scans have revealed multiple chromosomal regions [12C17]. However, the identity of most susceptibility genes are unknown . CD24 is usually a glycosylphosphatidylinositol-anchored cell surface protein with expression in a variety of cell types that can participate in the pathogenesis of MS and 169332-60-9 supplier SLE, including activated T cells [19,20], B cells , macrophages , and dendritic cells ENDOG . as a candidate locus , was shown to be essential for the induction of experimental autoimmune encephalomyelitis (EAE) in mice 169332-60-9 supplier . Interestingly, CD24 controls a checkpoint of EAE pathogenesis after the autoreactive T cells are produced . Recently, we showed that CD24 is essential for local clonal growth and persistence of T cells after their migration into the central nervous system and that expression of CD24 on either hematopoietic cells or nonhematopoietic antigen-presenting cells in the recipient 169332-60-9 supplier is sufficient to confer susceptibility to EAE . These findings suggest that CD24 is essential for susceptibility to EAE. Human (CD24) mRNA has a 0.24-kb ORF and a 1.8-kb 3 UTR. A CT single nucleotide polymorphism (SNP) at.