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J. Hrdinová et al.
Figure 5. Presentation of ADAMTS13 peptides on MHC class II. (A) Three-dimensional model structure of HLA-DRB1*11 (graphic representation in gray) with FIN- VAPHAR peptide (stick representation in magenta with cyan surface) from ADAMTS13 CUB2 domain. (B) Three-dimensional model structure of HLA-DQB1*03 (graph- ic representation in gray) with LIRDTHSLR peptide (stick representation in cyan with magenta surface) from ADAMTS13 CUB2 domain.
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These results imply that the major B-cell epitope in the spacer domain is not accessible for binding of auto-Abs when ADAMTS13 circulates in a so-called closed confor- mation. Because the knowledge on conformational state of ADAMTS13 in patient plasma could be of help in the diag- nosis and prognosis of iTTP, Roose et al. designed an assay to monitor this.85 Their results showed that ADAMTS13 adopts an altered (more open) conformation in iTTP patients in the acute phase of the disease while ADAMTS13 was closed in the majority of iTTP patients in remission, in healthy donors, and patients with sepsis or HUS. Hence, acute iTTP is not only characterized by severe thrombocytopenia, hemolytic anemia, ADAMTS13 activi- ty less than 10%, and presence of anti-ADAMTS13 Abs, but also by the presence of an open ADAMTS13 conforma- tion. It now remains to be determined which factors (anti- ADAMTS13 Abs and/or other plasma factors) open ADAMTS13. However, once the conformation of ADAMTS13 is changed during acute iTTP, anti- ADAMTS13 Abs recognizing not only non-cryptic epitopes but also cryptic epitopes in the spacer domain can now bind, leading to the inhibition and/or clearance of ADAMTS13 (Figure 4). Whether the conformational change in ADAMTS13 also leads to an (additional) immune response, remains to be determined.85
The autoimmune response against ADAMTS13: an infection-driven event?
Many studies have suggested a link between infections and the onset of iTTP. First, infectious agents can be pre- cipitating factors in patients with a severe ADAMTS13 deficiency, through endothelial activation. No specific agents could be identified,86 as opposed to HUS, which was typically associated to specific strains of the bacteria Escherichia coli. Endothelial activation in this context may involve nucleosomes that derive at least in part from neu- trophil extracellular traps (NETS), networks made of nuclear DNA, histones, granular and cytoplasmic proteins that are released by neutrophils in response to infections.87 In response to these agonists, endothelial cells release high molecular weight VWF multimers leading to thrombi in the microvasculature of most organs. Human neutrophil peptides released from activated and degranulated neu-
trophils can also alter ADAMTS13 activity.88 This sce- nario, termed the “two-hit model”, was evidenced from animal models and illustrates the interaction between a genetic background (a severe constitutive ADAMTS13 deficiency or a propensity to develop an immune-mediat- ed ADAMTS13 deficiency) and environmental factors, especially infections and inflammation.89 Second, infec- tions may potentially result in the presentation of pathogen-derived peptides that are homologous to ADAMTS13-derived peptides such as the CUB2 domain- derived peptide FINVAPHAR.90,91 CD4+ T cells developing in response to a challenge by pathogens may, therefore, cross-react with ADAMTS13 peptides presented on MHC class II, resulting in their activation and proliferation. This phenomenon has been designated molecular or epitope mimicry.92 As discussed earlier, our group identified CD4+ T cells reactive to ADAMTS13 peptides derived from the CUB2 domain in patients with iTTP.67 These peptides with amino acid sequence FINVAPHAR and ASYILIRD (Figure 5) may share epitope mimicry with microbiome- derived peptides. CD4+ T cells targeting these microbio- me-derived peptides may cross-react with ADAMTS13 peptides presented on risk alleles for iTTP, thereby con- tributing to the onset of iTTP.
Another hypothesis developed from the observed asso- ciation between infections and iTTP is a gene-environ- ment interaction process involving microbial effectors that activate endothelial and polymorphonuclear cells. Therefore, functionally relevant molecules belonging to the innate immune response pathways could be impor- tant modulators of iTTP initiation in the context of infec- tion. Variants of the anti-infectious innate immunity sen- sor Toll-like receptor (TLR)-9 were reported to be more represented in iTTP patients negative for the HLA- DRB1*11 Class II susceptibility allele.86 TLR-9 harboring specific variants could, therefore, be more prone to acti- vate endothelial and polymorphonuclear cells and pro- duce Th1 cytokines in a context of infection, precipitating an iTTP episode.86 Similarly, anecdotal responses in patients with severe iTTP following the administration of the complement blocker eculizumab suggest a role for complement deregulation in iTTP pathophysiology.93 Unusually large VWF multimers may activate the alterna-
haematologica | 2018; 103(7)