Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 50, Issue 4, Pages 581-588Publisher
WILEY
DOI: 10.1002/eji.201948378
Keywords
Autoimmunity; Human; PTPN22; Regulatory T cells; Type 1 diabetes
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Funding
- Academy of Finland [307320, 286765]
- Sigrid Juselius Foundation
- Finnish Diabetes Research Foundation
- Emil Aaltonen Foundation
- JDRF
- Academy of Finland (AKA) [286765, 307320, 307320, 286765] Funding Source: Academy of Finland (AKA)
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Dysfunction of FOXP3-positive regulatory T cells (Tregs) likely plays a major role in the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). Whether genetic polymorphisms associated with the risk of autoimmune diseases affect Treg frequency or function is currently unclear. Here, we analysed the effect of T1D-associated major HLA class II haplotypes and seven single nucleotide polymorphisms in six non-HLA genes [INS (rs689), PTPN22 (rs2476601), IL2RA (rs12722495 and rs2104286), PTPN2 (rs45450798), CTLA4 (rs3087243), and ERBB3 (rs2292239)] on peripheral blood Treg frequencies. These were determined by flow cytometry in 65 subjects who had progressed to T1D, 86 islet autoantibody-positive at-risk subjects, and 215 islet autoantibody-negative healthy controls. The PTPN22 rs2476601 risk allele A was associated with an increase in total (p = 6 x 10(-6)) and naive (p = 4 x 10(-5)) CD4+CD25+CD127lowFOXP3+ Treg frequencies. These findings were validated in a separate cohort comprising ten trios of healthy islet autoantibody-negative children carrying each of the three PTPN22 rs2476601 genotypes AA, AG, and GG (p = 0.005 for total and p = 0.03 for naive Tregs, respectively). In conclusion, our analysis implicates the autoimmune PTPN22 rs2476601 risk allele A in controlling the frequency of Tregs in human peripheral blood.
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