The role of human leukocyte antigen DRB1-DQB1 haplotypes in the susceptibility to acquired idiopathic thrombotic thrombocytopenic purpura

The acquired form of idiopathic thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease, in which the underlying ADAMTS13-deficiency is caused by inhibitory autoantibodies against the protease. Human leukocyte antigens (HLA), responsible for antigen presentation, play an important role in the development of antibodies. The loci coding HLA DR and DQ molecules are inherited in linkage as haplotypes. The c.1858C>T polymorphism of the PTPN22 gene, which codes a protein tyrosine phosphatase important in lymphocyte activation, predisposes to a number of autoimmune diseases. We determined the HLA-DRB1-DQB1 haplotypes and the PTPN22 c.1858C>T genotypes in 75 patients with acquired idiopathic TTP and in healthy controls, in order to assess the role of these genetic factors and their interactions in the susceptibility to TTP. We found that the carrier frequencies of the DRB1 *11-DQB1 *03 and DRB1 *15-DQB1 *06 haplotypes were higher, while those of the DRB1 *07-DQB1 *02 and DRB1 *13-DQB1 *06 haplotypes were lower in TTP patients. There was no difference in the overall frequency of the PTPN22 c.1858T allele between TTP patients and controls. In conclusion, we identified four HLA-DRB1-DQB1 haplotypes associated with an increased (DRB1 *11-DQB1 *03 and DRB1 *15-DQB1 *06) or a decreased (DRB1 *07-DQB1 *02 and DRB1 *13-DQB1 *06) susceptibility to acquired idiopathic TTP

Data_Sheet_1_Concentration and Subclass Distribution of Anti-ADAMTS13 IgG Autoantibodies in Different Stages of Acquired Idiopathic Thrombotic Thrombocytopenic Purpura.PDF

Background<p>The acquired form of idiopathic thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease, in which the underlying deficiency of the ADAMTS13 protease is caused by autoantibodies, predominantly of the IgG isotype. Certain HLA-DR-DQ haplotypes were associated with the risk of developing TTP.</p>Objectives<p>To investigate the development of the ADAMTS13-specific antibody response during the course of the disease, we analyzed the concentration, subclass distribution, and inhibitory potential of anti-ADAMTS13 IgG autoantibodies in samples of TTP patients drawn during the first acute phase, in remission, and during relapse. Additionally, we compared the anti-ADAMTS13 IgG levels between patients carrying and not carrying risk and protective HLA-DR-DQ haplotypes.</p>Patients and Methods<p>We determined the anti-ADAMTS13 IgG concentration and subclass distribution in 101 antibody-positive samples of 81 acquired TTP patients by ELISA methods. The presence and semi-quantitative amount of anti-ADAMTS13 inhibitors were determined in 97 of 100 deficient samples, and the specific inhibitory potential of anti-ADAMTS13 autoantibodies was determined in 49 selected samples, by mixing ADAMTS13-activity assays. HLA-DR-DQ typing and haplotype prediction were performed in 70 of the above patients.</p>Results<p>We found that IgG1 and IgG4 were the predominant subclasses, present in almost all samples. While IgG1 was the dominant subclass in almost half of the samples taken during the first acute episode, IgG4 was dominant in all samples taken during or following a relapse. The inhibitory potential of the samples correlated with levels of the IgG4 subclass. Anti-ADAMTS13 antibodies of IgG4-dominant samples had higher specific inhibitory potentials than IgG1-dominant samples, independently of disease stage. Interestingly, we found that patients carrying the protective DR7-DQ2 and DR13-DQ6 haplotypes had higher anti-ADAMTS13 IgG levels.</p>Conclusion<p>Our results indicate that IgG4 becomes the dominant subtype at some point of the disease course, apparently before the first relapse, parallel to the increase in inhibitory potential of the anti-ADAMTS13 autoantibodies. Furthermore, we found an association between the genetic background and the antibody response in TTP.</p

Sex-specific survival difference in association with HLA-DRB1 *04 following allogeneic haematopoietic stem cell transplantation for lymphoid malignancies

The role of HLA system in allogeneic haematopoietic stem cell transplantation (allo-HSCT) outcome is unarguable. In this study we investigated association of HLA-A,-B and-DRB1 alleles with overall survival (OS) in 186 patients undergoing allo-HSCT for lymphoid malignancies. Analyses confirmed significantly better OS for HLA-DRB1 *04 carriers compared with non-carriers (p=0.01). Survival benefit was confined to male patients (in multivariate analyses p=0.034, hazard ratio 0.35, 95% confidence interval 0.13-0.92), whereas in females no difference was noted (p=0.82). Furthermore, donor gender also affected outcome and transplantation from female HLA-DRB1 *04 carrier donors resulted in superior survival compared with female non-carrier donors (p=0.01). Combined analyses including recipient/donor gender and HLA-DRB1 *04 showed that survival of male patients varied significantly according to donor gender and HLA-DRB1 *04 carriership (p=0.04) with best survival among HLA-DRB1 *04 carriers transplanted from female donors. Of relevance to our results, HLA-DRB1 *04 has been documented as risk allele group for lymphoid malignancies, and studies described a male-specific risk. We believe that our findings provide further supporting evidence for sex-specific alterations secondary to HLA-DRB1 *04 or related genes. Further studies are warranted to evaluate whether in contrast to general favour of male donors HLA-DRB1 *04 carrier patients with lymphoid malignancies could benefit from transplantation from female donors