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Abstract
B cells play a significant role in established Rheumatoid Arthritis (RA). However, it is unclear to what extent differentiated B cells are present in joint tissue already at the onset of disease. Here, we studied synovial biopsies (n = 8) captured from untreated patients at time of diagnosis. 3414 index-sorted B cells underwent RNA sequencing and paired tissue pieces were subjected to spatial transcriptomics (n = 4). We performed extensive bioinformatics analyses to dissect the local B cell composition. Select plasma cell immunoglobulin sequences were expressed as monoclonal antibodies and tested by ELISA. Memory and plasma cells were found irrespective of autoantibody status of the patients. Double negative memory B cells were prominent, but did not display a distinct transcriptional profile. The tissue architecture implicate both local B cell maturation via T cell help and plasma cell survival niches with a strong CXCL12–CXCR4 axis. The immunoglobulin sequence analyses revealed clonality between the memory B and plasma cell pools further supporting local maturation. One of the plasma cell-derived antibodies displayed citrulline autoreactivity, demonstrating local autoreactive plasma cell differentiation in joint biopsies captured from untreated early RA. Hence, plasma cell niches are not a consequence of chronic inflammation, but are already present at the time of diagnosis.
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1 Karolinska Institutet, Division of Rheumatology, Department of Medicine Solna, Center for Molecular Medicine, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); Karolinska University Hospital, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705); Karolinska Institutet, Department of Microbiology, Tumor and Cell Biology, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626)
2 KTH Royal Institute of Technology, Department of Gene Technology, Science for Life Laboratory, Stockholm, Sweden (GRID:grid.5037.1) (ISNI:0000000121581746)
3 Karolinska Institutet, Division of Rheumatology, Department of Medicine Solna, Center for Molecular Medicine, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); Karolinska University Hospital, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705)
4 Karolinska Institutet, Department of Microbiology, Tumor and Cell Biology, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626)
5 Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382)