Peritoneal autoantibody profiling identifies p53 as an autoantibody target in endometriosis
Sarah Harden1, Tse Yeun Tan2, Chee Wai Ku2
1Critical Analytics for Manufacturing Precision Medicine, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore; Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry, United Kingdom; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
Objective:
To map the peritoneal autoantibody (AAb) landscape in women with endometriosis.
Design:
Case-control laboratory study.
Setting:
Academic medical and research units.
Patient(S):
Women who presented with or without endometriosis.
Intervention(S):
None.
Main Outcome Measure(S):
Using native-conformation and citrullinated modified protein arrays, proteome-wide analysis of AAbs against 1,623 proteins were profiled in peritoneal fluids (PFs) of 25 women with endometriosis and 25 women without endometriosis.
Result(S):
In women with endometriosis, the median number of AAbs detected was 4, including AAbs that targeted autoantigens involved in implantation, B-cell activation/development, and aberrant migration and mitogenicity. Forty-six percent of women with endometriosis have ≥5 peritoneal AAbs. Conversely, in women without endometriosis, the median number of detected AAbs was 1. Autoantibodies recognizing tumor suppressor protein p53 were the most commonly detected AAbs, being present in 35% of women with endometriosis, and p53 AAb was associated with a monocyte/macrophage-like PF cytokine signature. Further investigation of the global reactivity of AAbs against citrullinated PF antigens by peptidylarginine deiminase enzymes 1, 2, and 6 revealed anticitrullinated p53 as the only AAb target elevated and citrullinated by all 3 peptidylarginine deiminase isotypes. Furthermore, unsupervised hierarchical clustering and integrative pathway analysis revealed that 60% of women with endometriosis-associated infertility were positive for AAbs, which are involved in platelet-derived growth factor, transforming growth factor-β, RAC1/PAK1/p38/MMP2 signaling, LAT2/NTAL/LAB-mediated calcium mobilization, and integrin-mediated cell adhesion.
Conclusion(S):
Together, our data identify peritoneal autoimmunity in a significant subset of women with endometriosis, with implications on infertility and disease pathophysiology. In these patients, p53 was identified as the most frequent PF AAb target, which was present in both the native and citrullinated forms.
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