B cells expressing the IgA receptor FcRL4 participate in the autoimmune response in patients with rheumatoid arthritis

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B cells expressing the IgA receptor FcRL4 participate in the autoimmune response in patients with rheumatoid arthritis. / Amara, Khaled; Clay, Elizabeth; Yeo, Lorraine; Ramskold, Daniel ; Spengler, Julia; Sippl, Natalie; Cameron, James; Israelsson, Lena; Titcombe, Philip; Gronwall, Caroline ; Sahbudin, Ilfita; Filer, Andrew; Raza, Karim; Malmstrom, Vivianne ; Scheel-Toellner, Dagmar.

In: Journal of Autoimmunity, Vol. 81, 07.2017, p. 34-43.

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Amara, Khaled ; Clay, Elizabeth ; Yeo, Lorraine ; Ramskold, Daniel ; Spengler, Julia ; Sippl, Natalie ; Cameron, James ; Israelsson, Lena ; Titcombe, Philip ; Gronwall, Caroline ; Sahbudin, Ilfita ; Filer, Andrew ; Raza, Karim ; Malmstrom, Vivianne ; Scheel-Toellner, Dagmar. / B cells expressing the IgA receptor FcRL4 participate in the autoimmune response in patients with rheumatoid arthritis. In: Journal of Autoimmunity. 2017 ; Vol. 81. pp. 34-43.

Bibtex

@article{69f6dbd4c7ee45aeb42f23e463e14a3c,
title = "B cells expressing the IgA receptor FcRL4 participate in the autoimmune response in patients with rheumatoid arthritis",
abstract = "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.",
keywords = "Antibodies, Autoimmunity, B cells, Rheumatoid Arthritis, FcRL4, IRTA1",
author = "Khaled Amara and Elizabeth Clay and Lorraine Yeo and Daniel Ramskold and Julia Spengler and Natalie Sippl and James Cameron and Lena Israelsson and Philip Titcombe and Caroline Gronwall and Ilfita Sahbudin and Andrew Filer and Karim Raza and Vivianne Malmstrom and Dagmar Scheel-Toellner",
year = "2017",
month = "7",
doi = "10.1016/j.jaut.2017.03.004",
language = "English",
volume = "81",
pages = "34--43",
journal = "Journal of Autoimmunity",
issn = "0896-8411",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - B cells expressing the IgA receptor FcRL4 participate in the autoimmune response in patients with rheumatoid arthritis

AU - Amara, Khaled

AU - Clay, Elizabeth

AU - Yeo, Lorraine

AU - Ramskold, Daniel

AU - Spengler, Julia

AU - Sippl, Natalie

AU - Cameron, James

AU - Israelsson, Lena

AU - Titcombe, Philip

AU - Gronwall, Caroline

AU - Sahbudin, Ilfita

AU - Filer, Andrew

AU - Raza, Karim

AU - Malmstrom, Vivianne

AU - Scheel-Toellner, Dagmar

PY - 2017/7

Y1 - 2017/7

N2 - 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.

AB - 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.

KW - Antibodies

KW - Autoimmunity

KW - B cells

KW - Rheumatoid Arthritis

KW - FcRL4

KW - IRTA1

U2 - 10.1016/j.jaut.2017.03.004

DO - 10.1016/j.jaut.2017.03.004

M3 - Article

VL - 81

SP - 34

EP - 43

JO - Journal of Autoimmunity

JF - Journal of Autoimmunity

SN - 0896-8411

ER -