TY - JOUR
T1 - Light chain skewing in autoantibodies and B-cell receptors of the citrullinated antigen-binding B-cell response in rheumatoid arthritis
AU - Slot, Linda M.
AU - Vergroesen, Rochelle D.
AU - Kerkman, Priscilla F.
AU - Staudinger, Ellen
AU - Reijm, Sanne
AU - van Dooren, Hugo J.
AU - van der Voort, Ellen I. H.
AU - Huizinga, Tom W. J.
AU - Toes, René E. M.
AU - Scherer, Hans U.
N1 - Funding Information: Funding:Thisstudywassupportedbygrantsfrom theDutchArthritisFoundation(projectno.12-2-403,REMToes;no.15-2-402,HUSchererandno. 18-1-205,HUScherer),theNetherlands OrganizationforScientificResearch(NWO;project no.91214031,REMToes),aZonMWclinical fellowship(projectno.90714509,HUScherer), ZonMWVENIgrant(no.91617107,HUScherer), ZonMWOffRoadgrant(no.451001012,HU Scherer),theIMI-fundedconsortiumprojects BeTheCure(contractno.115142-2,REMToes) andRTCure(contractno.777357,REMToes)and hasbeenfundedaspartoftheTarget-to-B! consortiumby‘Samenwerkende Gezondheidsfondsen’(SGF)consistingof20health fundsincludingKWFKankerbestrijding, ReumaNederland,TopsectorLifeSciences& Health(Health*Holland)andtheBusinessLife (LSHM18055-SGF).R.E.M.T.istherecipientofan EuropeanResearchCouncil(ERC)Advancedgrant (AdG2019-884796).Thefundershadnorolein studydesign,datacollectionandanalysis,decision topublish,orpreparationofthemanuscript. Publisher Copyright: © 2021 Slot et al.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 1% of the world population. RA is associated with the presence of autoantibodies, of which anti-citrullinated protein antibodies (ACPA) are most prominent. ACPA are produced by citrullinated antigen-binding B cells that have presumably survived tolerance checkpoints. So far, it is unclear how and when such autoreactive B cells emerge. Light chain (LC) rearrangement and mutation rates can be informative with regard to selection steps during B-cell development. Therefore, we studied LC characteristics of ACPA-expressing B cells and secreted ACPA with the aim to better understand the development of this disease-specific, autoreactive B-cell response. Paired ACPA-IgG and ACPA-depleted IgG were isolated from serum (n = 87) and synovial fluid (SF, n = 21) of patients with established RA. We determined the LC composition for each fraction by ELISA using kappa(Igκ)- and lambda(Igλ) LC-specific antibodies. Cellular LC expression was determined using flow cytometry. In addition, we used a B-cell receptor (BCR)-specific PCR to obtain LC variable region sequences of citrullinated antigen- and tetanus toxoid (TT)-binding B cells. In serum, we observed an increased frequency of lambda LC in ACPA-IgG (1.64:1) compared to control IgG (2.03:1) and to the κ/λ ratio reported for healthy individuals (2:1). A similar trend towards higher frequencies of lambda LCs was observed for ACPA-IgG in SF (1.84:1). Additionally, the percentage of Igλ-expressing B cells was higher for citrullinated antigen-binding B cells (51%) compared to TT-specific (43%) and total CD19+CD20+ B cells (36%). Moreover, an increased Igλ percentage was observed in BCR-sequences derived from ACPA-expressing (49%) compared to TT-specific B cells (34%). Taken together, we report an enhanced frequency of lambda LCs in the secreted ACPA-IgG repertoire and, on the cellular level, in BCR sequences of ACPA-expressing B cells compared to control. This skewing in the autoreactive B-cell repertoire could reflect a process of active selection.
AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 1% of the world population. RA is associated with the presence of autoantibodies, of which anti-citrullinated protein antibodies (ACPA) are most prominent. ACPA are produced by citrullinated antigen-binding B cells that have presumably survived tolerance checkpoints. So far, it is unclear how and when such autoreactive B cells emerge. Light chain (LC) rearrangement and mutation rates can be informative with regard to selection steps during B-cell development. Therefore, we studied LC characteristics of ACPA-expressing B cells and secreted ACPA with the aim to better understand the development of this disease-specific, autoreactive B-cell response. Paired ACPA-IgG and ACPA-depleted IgG were isolated from serum (n = 87) and synovial fluid (SF, n = 21) of patients with established RA. We determined the LC composition for each fraction by ELISA using kappa(Igκ)- and lambda(Igλ) LC-specific antibodies. Cellular LC expression was determined using flow cytometry. In addition, we used a B-cell receptor (BCR)-specific PCR to obtain LC variable region sequences of citrullinated antigen- and tetanus toxoid (TT)-binding B cells. In serum, we observed an increased frequency of lambda LC in ACPA-IgG (1.64:1) compared to control IgG (2.03:1) and to the κ/λ ratio reported for healthy individuals (2:1). A similar trend towards higher frequencies of lambda LCs was observed for ACPA-IgG in SF (1.84:1). Additionally, the percentage of Igλ-expressing B cells was higher for citrullinated antigen-binding B cells (51%) compared to TT-specific (43%) and total CD19+CD20+ B cells (36%). Moreover, an increased Igλ percentage was observed in BCR-sequences derived from ACPA-expressing (49%) compared to TT-specific B cells (34%). Taken together, we report an enhanced frequency of lambda LCs in the secreted ACPA-IgG repertoire and, on the cellular level, in BCR sequences of ACPA-expressing B cells compared to control. This skewing in the autoreactive B-cell repertoire could reflect a process of active selection.
UR - http://www.scopus.com/inward/record.url?scp=85103618841&partnerID=8YFLogxK
U2 - https://doi.org/10.1371/journal.pone.0247847
DO - https://doi.org/10.1371/journal.pone.0247847
M3 - Article
C2 - 33784344
SN - 1932-6203
VL - 16
JO - PLOS ONE
JF - PLOS ONE
IS - 3 March
M1 - e0247847
ER -