Background/Purpose: In rheumatoid arthritis (RA), inappropriate recruitment of T-cells into the joint contributes to disease pathogenesis and joint destruction. We examined the ability of adiponectin to regulate the migration of T-cells.

Methods: Peripheral blood lymphocytes were isolated from healthy donors and from patients with newly presenting RA fulfilling the 1987 ACR criteria at the time of initial assessment. Lymphocyte migration across TNFα+IFNγ stimulated endothelial cells was assessed ex vivo using phase-contrast microscopy. In vivo, lymphocyte migration was assessed in a model of zymosan-driven peritoneal inflammation.

Results: Adiponectin inhibited the migration of human lymphocytes across inflamed endothelium in a dose dependent manner. This effect was lost when B-cells were absent, but could be regained by the addition of supernatants from adiponectin-stimulated B-cells. Mass spectrometry identified the adiponectin induced B-cell-derived agent as a small peptide, subsequently named PEPITEM. In vitro, PEPITEM blocks T-cell migration by stimulating endothelial cells to release sphingosine-1-phosphate, a known regulator of T-cell migration. In zymosan-induced peritonitis, T-cell recruitment was significantly increased in B-cell deficient animals compared to wild-type controls, and this was ameliorated by treatment with synthetic PEPITEM. B-cells isolated from patients with RA expressed lower levels of adiponectin receptors compared to healthy controls and were unable to respond to adiponectin. Consequently, T-cells from patients with RA were released from the inhibitory effects of adiponectin on transmigration. Excitingly the full effect of adiponectin was rescued by the therapeutic use of exogenous PEPITEM.

Conclusion:  We have identified a novel endogenous peptide (PEPITEM) mediated pathway that suppresses T-cell recruitment across inflamed endothelium, which is dysfunctional in patients with RA. Thus, deregulation of the adiponectin-PEPITEM axis during early development and/or progression of disease could directly contribute to pathology in RA. Re-establishing PEPITEM function to “turn off” pathological recruitment of T-cells represents a novel and potentially powerful approach to treating patients with early rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-b-cell-derived-peptide-regulation-of-homeostatic-t-cell-trafficking-is-subverted-in-rheumatoid-arthritis/