Analysis of Complement Gene Expression, Clinical Associations, and Biodistribution of Complement Proteins in the Synovium of Early Rheumatoid Arthritis Patients Reveals Unique Pathophysiologic Features.

Autor:	Banda NK; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO; nirmal.banda@cuanschutz.edu., Deane KD; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO., Bemis EA; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO., Strickland C; Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, CO.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO., Seifert J; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO., Jordan K; Human Immune Monitoring Shared Resource, University of Colorado Anschutz Medical Campus, Aurora, CO., Goldman K; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K.; and., Morgan BP; Systems Immunity URI, Division of Infection and Immunity, and UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff, U.K., Moreland LW; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO., Lewis MJ; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K.; and., Pitzalis C; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K.; and., Holers VM; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2022 Jun 01; Vol. 208 (11), pp. 2482-2496. Date of Electronic Publication: 2022 May 02.
DOI:	10.4049/jimmunol.2101170
Abstrakt:	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 Fc γ R1A , Fc γ R1B , Fc γ R2A , and Fc γ R3A 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. (Copyright © 2022 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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