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tive complement pathway to promote the generation of terminal complement complexes (C5b-9).94 These obser- vations therefore deserve systematic explorations to unravel the role of the alternative complement pathway and its regulators (CFH, CFI, MCP and thrombomodulin) in iTTP pathophysiology.
Interestingly, HLA-DRB1*11 was reported to be protec- tive against tuberculosis, whereas HLA-DRB1*04 was associated with an increased risk of tuberculosis and severe malaria.95,96 These observations raise the intriguing possibility that autoimmunity against ADAMTS13 lead- ing to iTTP could represent the cost of an efficient ances- tral immune response selected to fight against historically harmful infectious agents.
Perspectives: future directions
Despite the considerable progress made in unravelling the role of ADAMTS13 in primary hemostasis, our under-
standing of the immunopathogenesis of iTTP is still not complete. Future studies will have to reveal a reason for the paradoxically extremely low incidence of the disease considering the frequent occurrence of identified genetic risk factors within the HLA-class II locus in the healthy population. Another field of investigation involves the mechanisms determining the reoccurrence of autoreactive lymphocytes in patients following immunomodulation with B-cell depleting therapies in order to better anticipate relapses. Moreover, a new therapeutic area is being opened in the field with the development of the recombi- nant ADAMTS13; its interactions with the immune sys- tem of iTTP patients will require further investigation.
Acknowledgements
The authors would like to thank the Horizon 2020 Framework program for Research and Innovation of the European Union for funding this work under 675746 (PROFILE).
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