Two Functional Lupus-Associated BLK Promoter Variants Control Cell-Type- and Developmental-Stage-Specific Transcription

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses

Use of short interfering RNA delivered by cationic liposomes to enable efficient down-regulation of ptpn22 gene in human t lymphocytes

Insulin-dependent diabetes mellitus and thyroid disease are the most common autoimmune endocrine disorders; these are due to target cell destruction by autoreactive T lymphocytes. They occur frequently together. The associated condition is named autoimmune polyglandular syndrome Type 3 variant. The substitutive administration of the deficient hormones is the standard treatment that, however, does not halt the autoimmune process. The incidence of these disorders in on the increase worldwide, therefore identification of innovative immunotherapies, especially aimed to preserve the residual hormone producing cells, is of crucial importance for the quality of life in pediatric patients. Recently, particular interest was generated by the potential pathophysiological role played in several autoimmune conditions by the C1858T PTPN22 (protein tyrosine phosphatase N22 gene) mutation encoding for the R620W lymphoid tyrosine phosphatase variant protein. The PTPN22 encoded Lyp protein is a negative regulator of T cell antigen receptor signaling, acting in concert with C-terminal Src kinase. R620W variant leads to a gain of function mutation with paradoxical reduced T cell activation. The variant has effect on both innate and adaptive immune responses. The goal of this study was to develop novel PTPN22 antisense oligomers and optimize their delivery into Jurkat T cells and peripheral blood lymphocytes by using liposomal carriers. We generated lipoplexes allowing T cell specific knockdown by using antisense strand complementary to the mRNA target site of PTPN22. The results of our study open the pathway to future trials for the treatment of autoimmune diseases based on variant PTPN22 allele selective inhibition using lipoplexes of SiRNA antisense oligomers