<i>PDCD1</i> and <i>CTLA4</i> polymorphisms affect the susceptibility to, and clinical features of, chronic immune thrombocytopenia

Kasamatsu, Tetsuhiro; Ino, Rumi; Takahashi, Noriyuki; Gotoh, Nanami; Minato, Yusuke; Takizawa, Makiko; Yokohama, Akihiko; Handa, Hiroshi; Saitoh, Takayuki; Tsukamoto, Norifumi; Murakami, Hirokazu

doi:10.1111/bjh.15085

Cited by 21 publications

(12 citation statements)

References 30 publications

(34 reference statements)

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“…These results are consistent with the Li's study, which indicated that the rs3087243 is not associated with susceptibility to ITP in a Chinese population [14]. However, in a Japanese population study, the rs3087243 was found to be significantly associated with susceptibility to chronic ITP [22]. The controversial results obtained may be due to the different ethnic population studied.…”

Section: Discussionsupporting

confidence: 88%

Association of cytotoxic T-lymphocyte antigen 4 gene with immune thrombocytopenia in Chinese Han children

et al. 2018

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Objectives: To investigate the association of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) with immune thrombocytopenia (ITP). Methods: A case-control association analysis of 277 Chinese Han children was performed. The tagging variants rs11571315 and rs3087243 in the CTLA4 gene were detected using polymerase chain reaction-restriction fragment length polymorphism method. The expression quantitative trait loci (eQTL) analysis and quantitative real-time polymerase chain reaction were performed to determine the relationship of CTLA4 with ITP. Results: Neither SNP was significantly different between case and control groups in either the genotypic or allelic distribution. The eQTL analysis results indicated that in the spleen, the rs3087243 was significant with the expression of CTLA4. The rs11571315 has similar results. Interestingly, the transcript level of CTLA4 was found to significantly decrease in patients with ITP. Discussion: The autoimmune and gene etiology is implicated in the pathogen of ITP. The CTLA4 is important for negative regulation of T-cell activation, and CTLA-4 gene has been identified as a risk factor for some autoimmune diseases. However, association studies of ITP and CTLA4 gene have obtained conflicting results. This is the first study to systematically investigate the association of CTLA4 with ITP in Chinese Han children. Conclusions: The CTLA4 gene is suggested to correlate with ITP through its abnormal expression level instead of gene site mutation.

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Section: Discussionsupporting

confidence: 88%

Association of cytotoxic T-lymphocyte antigen 4 gene with immune thrombocytopenia in Chinese Han children

et al. 2018

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“…With better epidemiological data, it became clear, that this variant is present in the Caucasian population with a frequency of close to 50%. The CT60/G polymorphism was reported in Grave's disease, AIHA, and chronic ITP; yet, CT60/G had a weak link to T1D in other studies . Thus, the association between the polymorphisms in CTLA4 and the susceptibility to autoimmune diseases remains controversial …”

Section: Ctla‐4 and Other Diseasesmentioning

confidence: 97%

What did we learn from CTLA‐4 insufficiency on the human immune system?

Mitsuiki

Schwab

Grimbacher

2018

Immunological Reviews

123

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Summary Cytotoxic‐T‐lymphocyte‐antigen‐4 (CTLA‐4) is a negative immune regulator constitutively expressed on regulatory T (Treg) cells and upregulated on activated T cells. CTLA‐4 inhibits T cell activation by various suppressive functions including competition with CD28, regulation of the inhibitory function of Treg cells, such as transendocytosis, and the control of adhesion and motility. Intrinsic CTLA‐4 signaling has been controversially discussed, but so far no distinct signaling pathway has been identified. The CTLA‐4‐mediated Treg suppression plays an important role in the maintenance of peripheral tolerance and the prevention of autoimmune diseases. Human CTLA‐4 insufficiency is caused by heterozygous germline mutations in CTLA4 and characterized by a complex immune dysregulation syndrome. Clinical studies on CTLA4 mutation carriers showed a reduced penetrance and variable expressivity, suggesting modifying factor(s). One hundred and forty‐eight CTLA4 mutation carriers have been reported; patients showed hypogammaglobulinemia, recurrent infectious diseases, various autoimmune diseases, and lymphocytic infiltration into multiple organs. The CTLA‐4 expression level in Treg cells was reduced, while the frequency of Treg cells was increased in CTLA‐4‐insufficient patients. The transendocytosis assay is a specific functional test for the assessment of newly identified CTLA4 gene variants. Immunoglobulin substitution, corticosteroids, immunosuppressive therapy, and targeted therapy such as with CTLA‐4 fusion proteins and mechanistic target of rapamycin (mTOR) inhibitors were applied; patients with life‐threatening, treatment‐resistant symptoms underwent hematopoietic stem cell transplantation. The fact that in humans CTLA‐4 insufficiency causes severe disease taught us that the amount of CTLA‐4 molecules present in/on T cells matters for immune homeostasis. However, whether the pathology‐causing activated T lymphocytes in CTLA‐4‐insufficient patients are antigen‐specific is an unsolved question. CTLA‐4, in addition, has a role in autoimmune diseases and cancer. Anti‐CTLA‐4 drugs are employed as checkpoint inhibitors to target various forms of cancer. Thus, clinical research on human CTLA‐4 insufficiency might provide us a deeper understanding of the mechanism(s) of the CTLA‐4 molecule and immune dysregulation disorders.

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“…Overall, length of ICI therapy, advanced disease, or extensive prior therapy did not appear to correlate with the severity of the thrombocytopenia, which is consistent with the current literature. [29][30][31] As with traditional ITP, ir-TCP is a diagnosis of exclusion. In all the cases, there was a clear temporal relationship between ICI administration and the onset of thrombocytopenia.…”

Section: Discussionmentioning

confidence: 99%