B cells expressing the IgA receptor FcRL4 participate in the autoimmune response in patients with rheumatoid arthritis.
The clinical efficacy of B cell targeting therapies highlights the pathogenic potential of B cells in inflammatory diseases. Expression of Fc Receptor like 4 (FcRL4) identifies a memory B cell subset, which is enriched in the joints of patients with rheumatoid arthritis (RA) and in mucosa-associated lymphoid tissue. The high level of RANKL production by this B cell subset indicates a unique pathogenic role. In addition, recent work has identified a role for FcRL4 as an IgA receptor, suggesting a potential function in mucosal immunity. Here, the contribution of FcRL4+ B cells to the specific autoimmune response in the joints of patients with RA was investigated. Single FcRL4+ and FcRL4- B cells were sorted from synovial fluid and tissue from RA patients and their immunoglobulin genes characterized. Levels of hypermutation in the variable regions in both populations were largely consistent with memory B cells selected by an antigen- and T cell-dependent process. Recombinant antibodies were generated based on the IgH and IgL variable region sequences and investigated for antigen specificity. A significantly larger proportion of the recombinant antibodies generated from individual synovial FcRL4+ B cells showed reactivity towards citrullinated autoantigens. Furthermore, both in analyses based on heavy chain sequences and flow cytometric detection, FcRL4+ B cells have significantly increased usage of the IgA isotype. Their low level of expression of immunoglobulin and plasma cell differentiation genes does not suggest current antibody secretion. We conclude that these activated B cells are a component of the local autoimmune response, and through their RANKL expression, can contribute to joint destruction. Furthermore, their expression of FcRL4 and their enrichment in the IgA isotype points towards a potential role for these cells in the link between mucosal and joint inflammation.
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-17176 Solna, Stockholm, Sweden.
Khaled
K
Amara
Rheumatology Research Group, RACE AR UK Centre of Excellence in RA Pathogenesis, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Elizabeth
E
Clay
Rheumatology Research Group, RACE AR UK Centre of Excellence in RA Pathogenesis, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Lorraine
L
Yeo
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-17176 Solna, Stockholm, Sweden.
Daniel
D
Ramsköld
Rheumatology Research Group, RACE AR UK Centre of Excellence in RA Pathogenesis, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Julia
J
Spengler
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-17176 Solna, Stockholm, Sweden.
Natalie
N
Sippl
Rheumatology Research Group, RACE AR UK Centre of Excellence in RA Pathogenesis, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
James A
JA
Cameron
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-17176 Solna, Stockholm, Sweden.
Lena
L
Israelsson
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-17176 Solna, Stockholm, Sweden.
Philip J
PJ
Titcombe
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-17176 Solna, Stockholm, Sweden.
Caroline
C
Grönwall
Rheumatology Research Group, RACE AR UK Centre of Excellence in RA Pathogenesis, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Ilfita
I
Sahbudin
Rheumatology Research Group, RACE AR UK Centre of Excellence in RA Pathogenesis, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Andrew
A
Filer
Rheumatology Research Group, RACE AR UK Centre of Excellence in RA Pathogenesis, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; Department of Rheumatology, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham UK.
Karim
K
Raza
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-17176 Solna, Stockholm, Sweden.
Vivianne
V
Malmström
Rheumatology Research Group, RACE AR UK Centre of Excellence in RA Pathogenesis, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: d.scheel@bham.ac.uk.
Dagmar
D
Scheel-Toellner
D000368:Aged; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D015415:Biomarkers; D005260:Female; D015870:Gene Expression; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000235:genetics / Q000276:immunology; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011961:Receptors, Fc / Q000235:genetics*; D013582:Synovial Fluid / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology; D059467:Transcriptome
D001324:Autoantigens; D015415:Biomarkers; C423544:FCRL4 protein, human; D007132:Immunoglobulin Isotypes; D007136:Immunoglobulins; D011961:Receptors, Fc
Antibodies; Autoimmunity; B cells; FcRL4; IRTA1; Rheumatoid arthritis