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J. Hrdinová et al.
TTP (iTTP), patients develop antibodies (Abs) against ADAMTS13 that enhance its clearance or inhibit its VWF processing activity.1 Therapeutic plasma exchange (TPE) greatly improved the fatal outcome of iTTP leading to survival rates of more than 80%.1 As iTTP is an autoim- mune disease, steroids were used together with TPE.1 Over the last few years, the use of the B-cell depleting agent rituximab (Mabthera®, Roche) as a more targeted immunomodulator led to a reduction in TPE duration and to efficient prevention of 1-year relapses. The pre-emp- tive administration of rituximab is also increasingly used in patients with a persistently severe acquired ADAMTS13 deficiency, and otherwise in remission, to prevent long-term relapses.2-4 However, the efficacy of rit- uximab is only transient, and in up to 50% of cases, addi- tional courses of rituximab are required to maintain a detectable ADAMTS13 activity. Moreover, 10-15% of patients are primarily unresponsive to rituximab, or expe- rience a subsequent refractoriness after an initial response.3 The pathophysiological mechanisms underly- ing these different scenarios in iTTP, as well as the specif- ic B- and T-cell and plasmacytic subpopulations involved in the reoccurrence of anti-ADAMTS13 Abs after ritux- imab, still remain unknown. Besides the increasing use of immunomodulators, a recombinant form of ADAMTS13 has passed through a phase I clinical trial5 and should soon be available for the treatment of the congenital form of TTP. The use of recombinant ADAMTS13 in iTTP to over-ride inhibitory Abs, in combination with the anti- VWF nanobody caplacizumab, probably represents the next breakthrough in the management of this disease.6 However, the use of a recombinant ADAMTS13 in iTTP may involve the potential risk of boosting inhibitor titers by the activation of ADAMTS13 specific memory B and T cells, as suggested previously.7
Taking into consideration these challenges, it is crucial to understand in more detail the mechanisms leading to the loss and re-establishment of self-tolerance of the immune system towards ADAMTS13. In this review, we address the current knowledge on the immunopathogen- esis of iTTP and the potential forthcoming challenges in the field. We also provide evidence that iTTP represents an illustrative model of multistep disease resulting from the combination of genetic risk factors for autoimmunity and environmental precipitating factors.
Anti-ADAMTS13 Abs: physical and functional features, mechanisms of pathogenicity
The presence of anti-ADAMTS13 Abs in plasma of iTTP patients with an inhibitory activity towards the VWF cleavage activity of normal plasma was first demon- strated by isolating IgGs via protein A-Sepharose, as well as on protein G-Sepharose column chromatography.8,9 Isolated IgGs were later shown to bind to ADAMTS13 in ELISA.10 It is now known that anti-ADAMTS13 Abs result in a profound deficiency in ADAMTS13 activity by two main mechanisms: inhibitory (neutralizing) Abs block the proteolytic activity of ADAMTS13 towards VWF, whereas non-inhibitory Abs increase ADAMTS13 clearance from the circulation by forming immune-com- plexes.11-13 ADAMTS13 antigen (Ag) levels are decreased in most patients, suggesting that Ab-mediated ADAMTS13 depletion is an important pathogenic mech- anism underlying severe loss of enzyme activity.11-13 It is
likely that both inhibitory and non-inhibitory Abs pro- mote ADAMTS13 clearance. Inhibitory IgGs that account for the majority of auto-Abs found in patients with iTTP are mainly directed against the spacer domain of ADAMTS13, while those solely targeting the carboxy- terminal domains are in vitro non-inhibitory.14 Whether immune complexes may in addition activate the comple- ment system and bind to cellular Fc receptors, thereby promoting inflammation, endothelial activation with thrombosis, and relapse, represent attractive mechanisms requiring further exploration.15-17
Retrospective studies based on large series of iTTP patients have shown that, during the first acute event, anti-ADAMTS13 Abs of IgG type (detected either by functional or immunological methods) were identified in approximately 75-90% of patients.18-27 Of all subclasses of anti-ADAMTS13 IgG detected in patients with iTTP, IgG4 was the most prevalent (90%) followed by IgG1 (53%), IgG2 (50%), and IgG3 (33%). There was an inverse correlation between the frequency and abun- dance of IgG4 and IgG1 Abs.17,28 Anti-ADAMTS13 Abs of IgM and IgA type are found in only approximately 10% of iTTP patients, mainly in association with IgG.21,29,30
Interestingly, anti-ADAMTS13 IgG have been reported to be present in 5% of healthy individuals, possibly shar- ing some linear epitopes with iTTP patients.21,22,31 Importantly, these Abs in healthy individuals are non- inhibitory against ADAMTS13, which is likely due to a lower affinity towards the protein.31 However, whether individuals with non-pathogenic anti-ADAMTS13 Abs are prone to develop iTTP still has to be established. It is nevertheless tempting to speculate that non-pathogenic anti-ADAMTS13 IgG Abs could precede clinical disease onset in iTTP, as reported for other autoimmune diseases such as systemic lupus erythematosus (SLE).32 In this sce- nario, the mechanisms turning non-pathogenic anti- ADAMTS13 Abs into pathogenic Abs could involve an enhanced frequency of somatic hypermutation of IgG memory B cells, as well as epitope spreading, underlining the need for future studies in this direction. It would also be of interest to assess whether non-pathogenic anti- ADAMTS13 Abs occur more frequently in healthy indi- viduals carrying the HLA susceptibility alleles DRB1*11 and DQB1*03, and if these individuals are more prone to develop inhibitory autoantibodies from non-pathogenic antibodies. In a study including 160 patients with miscel- laneous diseases but no severe ADAMTS13 deficiency,21 anti-ADAMTS13 Abs of IgG type were also found in 20% of patients with a thrombotic microangiopathy (TMA) other than iTTP, in 8% of patients with various causes of thrombocytopenia, in 13% of patients with SLE, and in 5% of patients with the anti-phospholipid syndrome (APS). In addition, anti-ADAMTS13 Abs of IgM type were also detected in 18% of SLE and APS patients.21 Indeed, conventional inhibitor and ELISA assays allow for assess- ment of anti-ADAMTS13 Abs in a significant proportion of patients with various TMAs. Therefore, attribution of the mechanistic role and clinical significance of anti- ADAMTS13 Abs alone remains challenging.21
The Abs directed against ADAMTS13 spacer domain use the heavy chain (VH) gene segment VH1-69 in 75% of cases.14,33,34 The clinical significance of the restricted VH1- 69 germline gene segment has been observed in neutraliz- ing Abs directed toward a highly conserved region in the
haematologica | 2018; 103(7)