Abstract
Immune thrombotic thrombocytopenic purpura (iTTP) is an autoimmune disorder of which the etiology is not fully understood. Autoantibodies targeting ADAMTS13 in iTTP patients have extensively been studied, the immunological mechanisms leading to the breach of tolerance remain to be uncovered. This review addresses the current knowledge on genetic factors associated with the development of iTTP and the interplay between the patient’s immune system and environmental factors in the induction of autoimmunity against ADAMTS13. HLA-DRB1*11 has been identified as a risk factor for iTTP in the Caucasian population. Interestingly, HLA-DRB1*08:03 was recently identified as a risk factor in the Japanese population. Combined in vitro and in silico MHC class II peptide presentation approaches suggest that an ADAMTS13-derived peptide may bind to both HLA-DRB1*11 and HLA-DRB1*08:03 through different anchor-residues. It is apparent that iTTP is associated with the presence of infectious microorganisms, viruses being the most widely associated with development of iTTP. Infections may potentially lead to loss of tolerance resulting in the shift from immune homeostasis to autoimmunity. In the model we propose in this review, infections disrupt the epithelial barriers in the gut or lung, promoting exposure of antigen presenting cells in the mucosa-associated lymphoid tissue to the microorganisms. This may result in breach of tolerance through the presentation of microorganism-derived peptides that are homologous to ADAMTS13 on risk alleles for iTTP.
Highlights
Thrombotic thrombocytopenic purpura (TTP) is a rare and severe life-threatening autoimmune disorder which is mostly acquired by adult patients with an annual incidence of approximately 4 cases per million people [1]
von Willebrand factor (VWF) is synthesized in endothelial cells and upon stimulation ultra-large VWF (UL-VWF) polymers are released in the systemic circulation
The aim of this review was to unravel the etiology of immune TTP (iTTP) by addressing both genetic and environmental factors involved in BOX 1 | Self and non-self
Summary
Thrombotic thrombocytopenic purpura (TTP) is a rare and severe life-threatening autoimmune disorder which is mostly acquired by adult patients with an annual incidence of approximately 4 cases per million people [1]. The development of autoimmunity has often been associated with the occurrence of an infection which can be explained by the mechanism of ‘molecular mimicry’, the similarities between pathogen- and self-peptides resulting in the activation of autoreactive T or B cells in genetically susceptible individuals [89,90,91,92]. After antigen processing the microorganism-derived peptides (peptides 1 in table) are loaded onto the HLA-class II molecule (the risk allele HLA-DRB1*11 or HLA-DRB1*08:01, respectively) and presented to the TCR of an autoreactive CD4 T cell. The association with different types of infection and the rarity of disease manifestation under the described conditions suggest that the genetic factors and the specific infection are involved, but that other environmental cues are at play These should affect larger parts of the population and would tilt the balance from immune homeostasis to autoimmunity only in individuals with these predisposing factors, and only within. Influenza Seasonal Vaccine Pneumococcal Vaccine Influenza, Pneumococcal, Triple Diphtheria-Tetanus-Poliomyelitis Vaccines Rabies Vaccine COVID Vaccine
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
