Association of Autoimmune Pancreatitis With Cytotoxic T-lymphocyte Antigen 4 Gene Polymorphisms in Japanese Patients

Abstract

Objectives: Autoimmune pancreatitis (AIP) is characterized by high serum IgG4 concentrations, lymphoplasmacytic inflammation, and a favorable response to corticosteroid treatment. Although the HLA DRB1*0405-DQB1*0401 haplotype and Fc receptor-like 3 polymorphisms have been associated with AIP, the role of other genetic factors is largely unknown. As cytotoxic T lymphocyte antigen 4 (CTLA4) polymorphisms have recently been linked with several autoimmune diseases, we sought to determine if CTLA4 polymorphisms and serum sCTLA4 levels were associated with AIP as well. Methods: Five CTLA4 polymorphisms, located at -1722, -658, and -318 in the promoter, +49 in exon 1, and +6230 in the 3' untranslated region, were genotyped in 59 patients with AIP and 102 healthy subjects. Serum sCTLA4 levels were also determined in cohorts of 52 patients and 32 controls. Results: Compared with healthy subjects, we found a significant increase in the +6230 G/G genotype (64% vs. 42%, odds ratio [OR], 2.48; P = 0.011) in AIP patients. Haplotype 2, which had the +6230A, was associated with AIP resistance (OR, 0.49; P = 0.011). The +49A/A and +6230A/A genotypes were associated with an enhanced risk of relapse (OR, 5.45; P = 0.038 and OR, 12.66; P = 0.022). Additionally, median serum sCTLA4 levels were significantly higher in patients with AIP (8.9 ng/mL) compared with healthy subjects (2.9 ng/mL; P < 0.001). The +6230G/A polymorphism did not influence sCTLA4 levels in AIP patients. Conclusions: Our findings suggest that AIP is associated with a genetic polymorphism in CTLA4 and is positively correlated with serum sCTLA4 levels.

The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

“…A possible genetic association between CTLA-4 polymorphism and AIP has been shown [62,64]. In addition, a recent study has shown that serum sCTLA-4 levels are increased in AIP [62].…”

“…Increased serum levels of sCTLA-4 have been reported in patients with several autoimmune diseases significantly more often than in healthy individuals [20, 33, 49-51, 60, 62]. Patients with GD [20,33,49], HT [20,49], MG [50], systemic lupus erythematosus [55], systemic sclerosis (SSc) [54], CD [51], autoimmune pancreatitis (AIP) [62] and spondyloarthropathies and RA [60] have been investigated. The first studies on sCTLA-4 serum levels in autoimmune disease were performed 10 years ago [20] in 17 patients with GD and 3 patients with HT.…”

“…In addition, a recent study has shown that serum sCTLA-4 levels are increased in AIP [62]. The analysis was performed in a group of 52 patients and 32 controls.…”

“…In addition, such a relationship seems in some points contradictory. Indeed, it is difficult to explain why autoimmune disease susceptibility genotypes (+49G/G and CT60G/G) are associated with lower levels of sCTLA-4 transcripts [10,11,35,61,62,[69][70][71][72][73][74]. It may be hypothesized that abnormal translation of both CTLA-4 transcripts (sCTLA-4 and full-length CTLA-4) and/or abnormal intracellular trafficking and release of sCTLA-4 may occur in patients with autoimmune diseases with high levels of sCTLA-4.…”

Long-Term Follow-Up of Autoimmune Pancreatitis: Characteristics of Chronic Disease and Recurrence

“…12 The cytotoxic T-lymphocyte antigen 4 (CTLA4) polymorphism has been reported to be another predictor of AIP recurrence. 13 CTLA4 is an inhibitory receptor expressed on the cell surface of activated-memory T cells and on regulatory T cells; it acts largely as a negative regulator of T-cell responses by modulating positive T-cell costimulatory signals on antigen-presenting cells. Single nucleotide polymorphisms (SNPs) in CTLA4, termed +49A/G, have been specifically associated with susceptibility to autoimmune diseases, including type 1 diabetes, autoimmune thyroid disease, autoimmune hepatitis, and primary biliary cirrhosis.…”