Analysis of human factor H-related gene and protein expressed in rheumatoid arthritis synovium identifies a novel mechanism promoting dysregulated complement pathway activation
Abstract Factor H (FH) is a negative regulator of the alternative pathway (AP) of complement however, five human factor H-related (FHR) proteins, can also function ex vivo as positive regulators. We compare bulk FH and FHR mRNA expressions in both the human rheumatoid arthritis (RA) synovium and blo...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-06-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-03589-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849724930553282560 |
|---|---|
| author | Nirmal K. Banda Larry W. Moreland Kevin D. Deane Dmitri Simberg Robert I. Scheinman Rachel M. Frank Jennifer A. Seifert Accelerating Medicines Partnership (AMP) RA/SLE Network Rachel Lau Costantino Pitzalis Myles J. Lewis V. Michael Holers |
| author_facet | Nirmal K. Banda Larry W. Moreland Kevin D. Deane Dmitri Simberg Robert I. Scheinman Rachel M. Frank Jennifer A. Seifert Accelerating Medicines Partnership (AMP) RA/SLE Network Rachel Lau Costantino Pitzalis Myles J. Lewis V. Michael Holers |
| author_sort | Nirmal K. Banda |
| collection | DOAJ |
| description | Abstract Factor H (FH) is a negative regulator of the alternative pathway (AP) of complement however, five human factor H-related (FHR) proteins, can also function ex vivo as positive regulators. We compare bulk FH and FHR mRNA expressions in both the human rheumatoid arthritis (RA) synovium and blood cells from the Pathobiology of Early Arthritis Cohort (PEAC) and the Stratification of biological therapies for Rheumatoid Arthritis by Pathobiology (STRAP) Cohort. FH and FHR proteins were detected using multiplexed immunohistochemistry (MIHC) in synovium. In three pathotypes, in the synovium, no differences were found in the expression of FHR mRNA. In the synovium, a significant negative correlation was observed between FH expression and the disease activity score and X-ray joint space narrowing. In RA patients, there was a significant positive correlation between FHR3 mRNA level, anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor (RF). FHR proteins were co-localized in the synovial lining area along with complement C3 while FH was almost undetectable in the synovial lining but abundant in sub-synovial lining areas. We do not know whether FH and FHR proteins are locally generated and deposited in synovium or come from circulation. In sum, due to the absence of FH but the presence of FHRs, the synovial lining might fail to be protected from complement-mediated attack, and FHR3 may play a particularly important pathogenic role. |
| format | Article |
| id | doaj-art-a6d55546e5a64eff9b26bdab6fc85bdd |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-a6d55546e5a64eff9b26bdab6fc85bdd2025-08-20T03:10:36ZengNature PortfolioScientific Reports2045-23222025-06-0115111810.1038/s41598-025-03589-1Analysis of human factor H-related gene and protein expressed in rheumatoid arthritis synovium identifies a novel mechanism promoting dysregulated complement pathway activationNirmal K. Banda0Larry W. Moreland1Kevin D. Deane2Dmitri Simberg3Robert I. Scheinman4Rachel M. Frank5Jennifer A. Seifert6Accelerating Medicines Partnership (AMP) RA/SLE NetworkRachel Lau7Costantino Pitzalis8Myles J. Lewis9V. Michael Holers10Division of Rheumatology B115, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical CampusDivision of Rheumatology B115, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical CampusDivision of Rheumatology B115, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical CampusDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical CampusDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical CampusDepartment of Orthopedics and the Colorado Program for Musculoskeletal Research, University of Colorado Anschutz Medical CampusDivision of Rheumatology B115, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical CampusCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of LondonDivision of Rheumatology B115, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical CampusAbstract Factor H (FH) is a negative regulator of the alternative pathway (AP) of complement however, five human factor H-related (FHR) proteins, can also function ex vivo as positive regulators. We compare bulk FH and FHR mRNA expressions in both the human rheumatoid arthritis (RA) synovium and blood cells from the Pathobiology of Early Arthritis Cohort (PEAC) and the Stratification of biological therapies for Rheumatoid Arthritis by Pathobiology (STRAP) Cohort. FH and FHR proteins were detected using multiplexed immunohistochemistry (MIHC) in synovium. In three pathotypes, in the synovium, no differences were found in the expression of FHR mRNA. In the synovium, a significant negative correlation was observed between FH expression and the disease activity score and X-ray joint space narrowing. In RA patients, there was a significant positive correlation between FHR3 mRNA level, anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor (RF). FHR proteins were co-localized in the synovial lining area along with complement C3 while FH was almost undetectable in the synovial lining but abundant in sub-synovial lining areas. We do not know whether FH and FHR proteins are locally generated and deposited in synovium or come from circulation. In sum, due to the absence of FH but the presence of FHRs, the synovial lining might fail to be protected from complement-mediated attack, and FHR3 may play a particularly important pathogenic role.https://doi.org/10.1038/s41598-025-03589-1 |
| spellingShingle | Nirmal K. Banda Larry W. Moreland Kevin D. Deane Dmitri Simberg Robert I. Scheinman Rachel M. Frank Jennifer A. Seifert Accelerating Medicines Partnership (AMP) RA/SLE Network Rachel Lau Costantino Pitzalis Myles J. Lewis V. Michael Holers Analysis of human factor H-related gene and protein expressed in rheumatoid arthritis synovium identifies a novel mechanism promoting dysregulated complement pathway activation Scientific Reports |
| title | Analysis of human factor H-related gene and protein expressed in rheumatoid arthritis synovium identifies a novel mechanism promoting dysregulated complement pathway activation |
| title_full | Analysis of human factor H-related gene and protein expressed in rheumatoid arthritis synovium identifies a novel mechanism promoting dysregulated complement pathway activation |
| title_fullStr | Analysis of human factor H-related gene and protein expressed in rheumatoid arthritis synovium identifies a novel mechanism promoting dysregulated complement pathway activation |
| title_full_unstemmed | Analysis of human factor H-related gene and protein expressed in rheumatoid arthritis synovium identifies a novel mechanism promoting dysregulated complement pathway activation |
| title_short | Analysis of human factor H-related gene and protein expressed in rheumatoid arthritis synovium identifies a novel mechanism promoting dysregulated complement pathway activation |
| title_sort | analysis of human factor h related gene and protein expressed in rheumatoid arthritis synovium identifies a novel mechanism promoting dysregulated complement pathway activation |
| url | https://doi.org/10.1038/s41598-025-03589-1 |
| work_keys_str_mv | AT nirmalkbanda analysisofhumanfactorhrelatedgeneandproteinexpressedinrheumatoidarthritissynoviumidentifiesanovelmechanismpromotingdysregulatedcomplementpathwayactivation AT larrywmoreland analysisofhumanfactorhrelatedgeneandproteinexpressedinrheumatoidarthritissynoviumidentifiesanovelmechanismpromotingdysregulatedcomplementpathwayactivation AT kevinddeane analysisofhumanfactorhrelatedgeneandproteinexpressedinrheumatoidarthritissynoviumidentifiesanovelmechanismpromotingdysregulatedcomplementpathwayactivation AT dmitrisimberg analysisofhumanfactorhrelatedgeneandproteinexpressedinrheumatoidarthritissynoviumidentifiesanovelmechanismpromotingdysregulatedcomplementpathwayactivation AT robertischeinman analysisofhumanfactorhrelatedgeneandproteinexpressedinrheumatoidarthritissynoviumidentifiesanovelmechanismpromotingdysregulatedcomplementpathwayactivation AT rachelmfrank analysisofhumanfactorhrelatedgeneandproteinexpressedinrheumatoidarthritissynoviumidentifiesanovelmechanismpromotingdysregulatedcomplementpathwayactivation AT jenniferaseifert analysisofhumanfactorhrelatedgeneandproteinexpressedinrheumatoidarthritissynoviumidentifiesanovelmechanismpromotingdysregulatedcomplementpathwayactivation AT acceleratingmedicinespartnershipampraslenetwork analysisofhumanfactorhrelatedgeneandproteinexpressedinrheumatoidarthritissynoviumidentifiesanovelmechanismpromotingdysregulatedcomplementpathwayactivation AT rachellau analysisofhumanfactorhrelatedgeneandproteinexpressedinrheumatoidarthritissynoviumidentifiesanovelmechanismpromotingdysregulatedcomplementpathwayactivation AT costantinopitzalis analysisofhumanfactorhrelatedgeneandproteinexpressedinrheumatoidarthritissynoviumidentifiesanovelmechanismpromotingdysregulatedcomplementpathwayactivation AT mylesjlewis analysisofhumanfactorhrelatedgeneandproteinexpressedinrheumatoidarthritissynoviumidentifiesanovelmechanismpromotingdysregulatedcomplementpathwayactivation AT vmichaelholers analysisofhumanfactorhrelatedgeneandproteinexpressedinrheumatoidarthritissynoviumidentifiesanovelmechanismpromotingdysregulatedcomplementpathwayactivation |