Human leukocyte antigen association in idiopathic thrombotic thrombocytopenic purpura: evidence for an immunogenetic link

Abstract

To cite this article: Scully M, Brown J, Patel R, McDonald V, Brown CJ, Machin S. Human leukocyte antigen association in idiopathic thrombotic thrombocytopenic purpura: evidence for an immunogenetic link. J Thromb Haemost 2010; 8: 257-62.Summary. Background: Thrombotic thrombocytopenic purpura (TTP) is a rare, acute, life-threatening disorder, associated with a deficiency in ADAMTS 13. The majority of acute, idiopathic, adult TTP cases are associated with anti-ADAM-TS 13 IgG antibodies. However, the factor(s) precipitating an acute TTP episode are not always obvious; indeed, a multifactorial etiology is likely. Objectives and Methods: DNA was used for human leukocyte antigen (HLA) class II typing, using polymerase chain reaction (PCR)-sequencespecific primer and PCR-sequence-specific oligonucleotide probe to methodology to investigate 50 European acquired idiopathic TTP cases. Results: There was an increase in the frequency of HLA-DQB1*0301 (HLA-DQ7) in patients with TTP as compared with controls [58.0% vs. 34.5% (P = 0.048)]. The frequencies of HLA-DRB1*11 and HLA-DRB3* were also significantly increased in TTP patients as compared with controls [44.0% vs. 12.0% (P = 0.0024) and 84.0% vs. 58.0% (P = 0.024)], although it remains uncertain whether susceptibility is influenced by HLA-DQ or HLA-DR molecules or other genes in this haplotype. The frequencies of HLA-DRB1*04 and HLA-DRB4 (HLA-DR53) were significantly decreased in the patient group as compared with controls [10.0% vs. 35.0% and 26.0% vs. 61.5% (P = 0.0096 and P = 0.0024, respectively)], and may have a protective effect against the development of TTP. Conclusion: Analysis identified HLA class II types associated with susceptibility to and a protective effect against the development of acute acquired TTP in European patients. This provides the first description of a genetic factor predicting the risk of developing acquired antibody-mediated TTP.

The potential role of HLA-DRB1*11 in the development and outcome of haematopoietic stem cell transplantation-associated thrombotic microangiopathy

“…Together with previous reports, our findings suggest that, HLA-DRB1*11 is related to syndromes of thrombotic microangiopathy, including TTP, [22][23][24] haemolytic uraemic syndrome 33 and TA-TMA. The observed association of HLA-DRB1*11 and TA-TMA indicate that the role of HLA-DRB1*11 in the pathogenesis of thrombotic microangiopathies might be complex and extend beyond susceptibility to autoantibody formation against ADAMTS13.…”

“…In recent years, an association of HLA-DRB1*11 and idiopathic TTP has been recognised by independent groups. [22][23][24] Our hypothesis was that in view of the correlations between the two conditions, HLA-DRB1*11 might have a role in the pathogenesis of TA-TMA, as well.…”

A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura

“…In the majority of cases, there is no obvious underlying precipitant, although a genetic link has been identified. 1 Severe deficiency of ADAMTS13 is present in most cases of acquired TTP because of the presence of antibody, primarily IgG, to ADAMTS13. The mainstay of treatment remains plasma exchange (PEX) and steroids.…”

The macrophage mannose receptor promotes uptake of ADAMTS13 by dendritic cells

“…The described association between HLA-DRB1*11 strongly suggests that ADAMTS13-specific CD4 ϩ T cells contribute to the pathogenesis of acquired TTP. 17,18 Based on these findings, we suggest a model in which MR-mediated internalization of ADAMTS13 by DCs results in priming of naive CD4 ϩ T cells, thereby initiating autoimmune responses to ADAMTS13, which results in acquired TTP. …”