Page 23 - Haematologica July

Immune TTP: interplay between haplotypes & environment
hemagglutinin ectodomain of the influenza virus35 and in patients with B-cell lymphoma after chronic hepatitis C infection.36 Sequence analysis of anti-ADAMTS13 IgGs revealed unique heavy-chain complementary determining region 3 motifs, of which some were shared by unrelated patients, suggesting that the autoimmune response in iTTP is antigen-driven.37
Several animal models of iTTP have been developed by directly injecting ADAMTS13 inhibiting Abs.38-41 Importantly, some of these models highlight the role of auto-Abs in the pathology of iTTP, as administration of the antibody alone (passive transfer) was enough to trig- ger the hallmarks of iTTP, as described for the baboon model.38
Clinical relevance of anti-ADAMTS13 Abs in iTTP treatment
The identification of anti-ADAMTS13 antibodies as the main mechanism of ADAMTS13 deficiency in iTTP prompted an evaluation of B-cell depleting therapies in the management of the disease. Several studies showed that rituximab at the acute phase of the disease, in association with TPE and steroids, shortens the time to response.2,33 Upon treatment with rituximab, TPE duration usually does not exceed 30 days, whereas before the era of ritux- imab, 25% of patients required TPE for more than one month.2,42 Moreover, the administration of rituximab dur- ing the acute phase results in fewer relapses in the 12-18 months following remission. Beyond this time, however, relapses can reoccur as a consequence of the reappearance of anti-ADAMTS13 Abs along with peripheral B-cell recovery.2,42,43 The persistence of a severe ADAMTS13 deficiency following the acute phase has been associated with a high risk of relapse,3,29,44 and this has led investiga- tors to propose pre-emptive B-cell depleting strategies. Although based on comparative studies, this strategy proved its efficiency in protecting patients from full- blown relapses by maintaining ADAMTS13 activity with- in normal values.3 This strategy implies, therefore, a regu- lar assessment of ADAMTS13 activity during long-term follow up.
Prognostic value of anti-ADAMTS13 Abs
The role of anti-ADAMTS13 Abs in iTTP prognosis has still not been fully defined. Anti-ADAMTS13 Abs with a strong inhibitory activity were typically associated with more plasma volume to achieve remission and with an increased risk of relapse, as well as with a lower survival rate in some studies (but not all).19,27,29,45 Also, the combina- tion of several anti-ADAMTS13 Abs isotypes (IgG, IgM, and IgA), including very high IgA titers, and the presence of high levels of IgG1 combined with undetectable levels of IgG4, has been associated with poor prognosis and an increased risk of mortality.17,28 Recently, higher mortality rates were found in individuals with higher anti- ADAMTS13 Abs and lower ADAMTS13 antigen levels; patients with anti-ADAMTS13 IgG Abs in the upper quar- tile and ADAMTS13 antigen in the lowest quartile had the highest mortality (27.3%).46
Epitope mapping studies have shown that patients typ- ically display auto-Abs against the cysteine-rich/spacer domains of ADAMTS13, while more than 50% of patients have auto-Abs against the CUB domains or the TSP2-8 domains.47 A major antibody epitope in the spacer domain has been resolved at the amino acid level; residues
R568, F592, R659, R660, Y661 and Y665 in the spacer exosite-3 constitute a conformational epitope that is tar- geted by the majority of anti-spacer Abs.30,48-52 Auto-Abs directed toward the terminal TSP2-8 repeats (+/- CUB domains) have been associated with lower platelet counts;53 however, others have found no correlation between these parameters, suggesting that the “specificity profile” of patients’ auto-Abs is not a major determinant of their pathophysiology.13 Furthermore, the “specificity pro- file” of these auto-Abs may change with time (“epitope spreading”), even in patients subjected to immunomodu- latory treatments. Importantly, anti-ADAMTS13 Abs have been shown to persist during iTTP remission, either in free form or within immune complexes, in spite of a detectable ADAMTS13 activity.16
Human leukocyte antigen molecules as predisposing factors to iTTP; from serotype to immunochip
Immune-mediated thrombotic thrombocytopenic pur- pura occurs after the development of a specific adaptive immune response targeting ADAMTS13. The human leukocyte antigen (HLA) system has an important role as a genetic risk factor in autoimmune diseases, and a similar association could thus be assumed for iTTP, especially considering cases of iTTP in siblings.54,55 The presence of class-switched high-affinity anti-ADAMTS13 Abs implies co-operation between T and B lymphocytes. Activation of ADAMTS13-specific CD4+ T cells requires recognition of ADAMTS13 peptides bound to HLA molecules by T-cell receptors, thereby potentially implicating HLA molecules as predisposing factors for iTTP.
In the 90’s, the first possible association between iTTP/the hemolytic-uremic syndrome (HUS) and HLA was reported.56 More specifically, study of the frequency of supertypic antigens DR52 and DR53, which are linked to the HLA-DRB3 and HLA-DRB4 genes respectively, indicated under-representation of DR53 in patients with iTTP compared to healthy individuals. Interestingly, molecular testing did not reveal any association with spe- cific HLA-DRB3 alleles, suggesting the association was not with DR52 but with absence of the DR53 antigen, which could, therefore, be protective against iTTP.56
In 2010, two studies reported for the first time an asso- ciation of HLA class II with iTTP.57,58 In a cohort of European patients, HLA-DRB1*04 and its associated HLA- DRB4-encoded serotype HLA-DR53 were protective against the development of iTTP. The decreased frequen- cy of HLA-DRB4 in iTTP patients as compared to healthy controls appeared to be attributable to the specific reduc- tion in the frequency of the linked HLA-DRB1*04 allele. In addition, the frequencies of HLA-DRB1*11 and HLA- DQB1*0301 were found to be higher in patients with iTTP when compared to healthy controls, suggesting these alleles to be risk factors for the onset of iTTP, although a primary role for HLA-DQB1*0301 could not be excluded.57 Reconstruction of HLA-haplotypes resulted in statistically higher frequency of DQB1*03-DRB1*11 hap- lotype in iTTP when compared to healthy controls. High- resolution typing of HLA-DRB1*11 revealed that both DRB1*1101 and DRB1*1104 were over-represented in iTTP, suggesting that the generic DRB1*11 is the predis- posing factor.58 Other groups reported comparable find- ings,59,60 and provided additional protective haplotypes (DRB1*07-DQB1*02 and DRB1*13-DQB1*06) or haplo- types associated with susceptibility (DRB1*15-DQB1*06)
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