Key Points
The complement system plays a pathophysiologic role in the synovium of early RA.
Correlations were found between DAS28 and complement genes in the early RA synovium.
Early RA synovium shows complement activation versus regulatory protein imbalance.
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.
Footnotes
This work was supported by National Institutes of Health Grant R01 AR51749 (to V.M.H. and N.K.B.), the Accelerated Medicines Partnership RA/SLE, and by an Institutional Joint Biology Program pilot grant (to N.K.B.).
V.M.H. and N.K.B. conceived the idea for analyzing complement factors in the synovium of early RA patients. V.M.H. supervised the project and reviewed/revised the manuscript in-depth. N.K.B. executed the experimental plan, analyzed data, and wrote the first and revised draft of the manuscript. K.D. identified suitable patients with or without treatment for this study and referred them to the radiologist for obtaining synovial biopsies. K.D. also reviewed the manuscript in-depth. C.S. collected early RA synovial biopsies by using ultrasound. E.B. and K.G. assisted in analyzing all data and applying appropriate statistical methods. K.G. generated three-dimensional cylindrical volcano plots for a Supplemental Fig. 1A. J.S. assisted in collecting synovial biopsies and follow-up care of early RA patients. K.J., through the Human Immune Monitoring Shared Resource at the AMC, assisted in all MIHC and imaging studies. B.P.M. provided anti-CFHR4 protein Abs and analyzed serum samples for CFHR4 and CFH protein levels using ELISA from healthy subjects and arthritis patients. L.W.M. was involved in early RA synovium-related discussions and provided synovial biopsies from the knee joints of OA patients. M.J.L. and C.P. provided histology sections from synovial biopsies from early RA subjects and were involved in all discussion related to this manuscript.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- ACPA
- anti-citrullinated protein Ab
- AP
- alternative pathway
- C3
- complement component 3
- CAIA
- collagen Ab-induced arthritis
- C3c
- complement component c fragment of C3
- CFB
- complement factor B
- CFD
- complement factor D
- CFH
- complement factor H
- CFHR
- CFH-related protein
- CFP
- complement factor properdin
- CP
- classical pathway
- CS
- complement system
- DAB
- diaminobenzidine
- DAS28-ESR
- disease activity score in 28 joints for erythrocyte sedimentation rate
- ERA
- enthesitis-related arthritis
- FCN
- ficolin
- LP
- lectin pathway
- MAC (C5b-9)
- membrane attack complex
- MBL2
- mannose-binding lectin 2
- MCP (CD48)
- membrane cofactor protein
- MIHC
- multiplexed immunohistochemistry
- OA
- osteoarthritis
- p-adj
- adjusted p
- PEAC
- Pathobiology of Early Arthritis Cohort
- RA
- rheumatoid arthritis
- RF
- rheumatoid factor
- Received December 13, 2021.
- Accepted March 17, 2022.
- Copyright © 2022 by The American Association of Immunologists, Inc.
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