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

Abstract

BackgroundThe 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.ObjectivesTo 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.Patients and MethodsWe 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.ResultsWe 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.ConclusionOur 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.

Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation

“…This result is in accordance with the IgG subclass switch from IgG1, IgG2, and IgG3 to IgG4 observed in renal biopsies during disease progression by Huang et al [25]. A similar IgG subclass switch was observed in other IgG4-mediated autoimmune diseases such as pemphigus vulgaris and idiopathic thrombotic thrombocytopenic purpura [25,37,38].…”

“…Based on our data, we can hypothesize a multistep mechanism of anti-PLA2R1 cytotoxicity: at disease onset, sera containing multiple IgG subclasses (including IgG4) induce cytotoxicity mediated by various complement pathways, then anti-PLA2R1 IgG4 which becomes the predominant subclass leads to the inhibition of PLA2R1 interaction with collagen from the glomerular basement membrane [45][46][47] at this time, complement-mediated cytotoxicity is not the main pathogenic mechanism. A similar scenario has been described in other autoimmune diseases mediated by IgG4, like in idiopathic thrombotic thrombocytopenic purpura, where an IgG4 subclass switching is associated with increased inhibition of ADAMTS13 enzymatic activity by anti-ADAMTS13 IgG4 antibodies [38]. These findings should now be confirmed in vitro with a podocyte model but will be more difficult to confirm in in vivo animal models due to the lack of expression of PLA2R1 in the mouse kidney [48,49].…”

Case of acquired thrombotic thrombocytopenic purpura associated with influenza A (H1N1) virus and literature review

“…According to the pathogenesis, TTP can be classified as hereditary and acquired, and the regulation of ADAMTS13 gene mutation is determined to be the cause of hereditary TTP 5. More commonly, acquired TTP is an autoimmune disease in which the presence of autoantibodies to the enzyme ADAMTS13 is the cause of its deficiency 6. It is knownhat viruses, drugs, tumours, autoimmune diseases, haematopoietic stem cell transplantation and other factors are associated with the disease.…”

Case Report: Severe Complement-Mediated Thrombotic Microangiopathy in IgG4-Related Disease Secondary to Anti-Factor H IgG4 Autoantibodies

“…On the other hand, pathogenic autoreactive IgG4 antibodies have been observed in other autoimmune diseases such as myasthenia gravis, directed against muscle-specific tyrosine kinase (MuSK) receptor subtype, pemphigus vulgaris, directed against desmoglein 1, and idiopathic membranous glomerulonephritis, directed against M-type phospholipase A2 receptor ( 1 ). Moreover, in patients with acquired thrombotic thrombocytopenic purpura (TTP) related to anti-ADAMTS13 autoantibodies, specific IgG subclasses have all been detected but with a clear predominance of IgG4 ( 12 , 13 ). Interestingly, IgG4 pathogenic autoantibodies directed against ADAMTS13 were reported in a patient with IgG4-RD causing acquired TTP ( 14 ).…”