Tissue destruction in autoimmunity and chronic inflammation

Intro

What comes first, tissue destruction leading to generation of peptide fragments that are new to the immune system and then cause autoimmunity, or autoimmunity against ECM proteins? Tissue destruction ultimately results in loss of organ function and organ failure. To achieve true efficacy, it may be necessary to halt tissue destruction itself.

Synovial stromal cells and joint pain

Dana Orange, Associate Professor of Clinical Investigation at Rockefeller University.

Abstract: Pain in rheumatoid arthritis is poorly explained by conventional measures of inflammation, and discordance between synovial inflammation and patient-reported pain is common. Synovial tissues exhibit marked heterogeneity, including fibroblast-enriched, low-inflammatory states that are less responsive to immunosuppression, suggesting alternative drivers of symptoms. We recently defined a stromal program linking synovial fibroblasts to nociceptor remodeling. Transcriptomic analyses identify pain-associated genes enriched for neurogenesis and axon guidance pathways and expressed predominantly by lining fibroblasts, which localize adjacent to blood vessels and CGRP+ sensory fibers that form dense perivascular networks. Imaging supports a close spatial relationship between fibroblasts, vasculature, and nociceptors. Functionally, fibroblasts from low-inflammatory synovium promote neurite outgrowth of CGRP+ dorsal root ganglion neurons in a concentration-dependent manner. Netrin-4 (NTN4), a fibroblast-derived guidance factor selectively expressed in lining fibroblasts, enhances CGRP+ neurite branching.

In osteoarthritis, synovial neurogenesis signatures correlate with pain severity, while DNA repair pathways are inversely associated. Senescent fibroblasts localize to perivascular niches, co-localize with nerve fibers, and promote nociceptor growth, linking cellular stress responses to pain. Together, these findings support a model in which synovial fibroblasts regulate nociceptor growth through secreted factors and senescence-associated programs, defining a stromal–neuronal axis as a therapeutic target distinct from inflammation.

Pathogenic fibroblasts in refractory rheumatoid arthritis

Kevin Wei, Assistant Professor of Medicine, Harvard Medical School, Attending Rheumatologist at Brigham and Women’s Hospital, USA, Co-Director, BWH Center for Cellular Profiling

Abstract: Treatment-refractory rheumatoid arthritis (RA) is a major unmet need, and the underlying mechanisms are poorly understood. To identify molecular determinants of refractory RA, we performed spatial transcriptomic profiling on synovial tissue biopsies taken 6 months before and after treatment. In the baseline biopsies of non-remitting patients, we identified increased fibrogenic signaling within vascular tissue niches, marked by high fibroblast COMP expression. We uncovered a role of endothelial-derived Notch signaling as an upstream regulator of fibroblast TGFβ signaling via its opposing ability to induce TGFβ isoform expression while suppressing TGFβ receptors, generating a proximal-distal gradient of TGFβ sensitivity that can be altered with the disruption of steady-state Notch signaling. In post-treatment biopsies, we observed significant immune depletion with expansion of fibrogenic niches, a process that can be reversed by inhibition of Notch and TGFβ signaling in RA patient-derived organoids. Collectively, our data implicates targeting of TGFβ signaling to prevent exuberant synovial tissue fibrosis as a potential therapeutic strategy for refractory RA