Analysis of complement gene expression, clinical associations, and biodistribution of complement proteins in the synovium of early rheumatoid arthritis patients reveals unique pathophysiologic features

Banda, Nirmal K., Deane, Kevin D., Bemis, Elizabeth A., Strickland, Colin, Seifert, Jennifer, Jordan, Kimberly, Goldman, Katriona, Morgan, B. Paul ORCID: https://orcid.org/0000-0003-4075-7676, Moreland, Larry W., Lewis, Myles J., Pitzalis, Costantino and Holers, V. Michael 2022. Analysis of complement gene expression, clinical associations, and biodistribution of complement proteins in the synovium of early rheumatoid arthritis patients reveals unique pathophysiologic features. Journal of Immunology 208 (11) , pp. 2482-2496. 10.4049/jimmunol.2101170

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Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and inflammation. The finding of autoantibodies in seropositive RA suggests that complement system activation might play a pathophysiologic role due to the local presence of immune complexes in the joints. Our first objective was to explore the Pathobiology of Early Arthritis Cohort (PEAC) mRNA sequencing data for correlations between clinical disease severity as measured by DAS28-ESR (disease activity score in 28 joints for erythrocyte sedimentation rate) and complement system gene expression, both in the synovium and in blood. Our second objective was to determine the biodistribution using multiplex immunohistochemical staining of specific complement activation proteins and inhibitors from subjects in the Accelerating Medicines Partnership (AMP) RA/SLE study. In the PEAC study, there were significant positive correlations between specific complement gene mRNA expression levels in the synovium and DAS28-ESR for the following complement genes: C2, FCN1, FCN3, CFB, CFP, C3AR1, C5AR1, and CR1. Additionally, there were significant negative correlations between DAS28-ESR and Colec12, C5, C6, MASP-1, CFH, and MCP. In the synovium there were also significant positive correlations between DAS28-ESR and FcγR1A, FcγR1B, FcγR2A, and FcγR3A. Notably, CFHR4 synovial expression was positively correlated following treatment with the DAS28-ESR at 6 mo, suggesting a role in worse therapeutic responses. The inverse correlation of C5 RNA expression in the synovium may underlie the failure of significant benefit from C5/C5aR inhibitors in clinical trials performed in patients with RA. Multiplex immunohistochemical analyses of early RA synovium reveal significant evidence of regional alterations of activation and inhibitory factors that likely promote local complement activation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Date of First Compliant Deposit:	9 June 2022
Date of Acceptance:	17 March 2022
Last Modified:	10 Nov 2022 11:24
URI:	https://orca.cardiff.ac.uk/id/eprint/150365

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