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- Title
Rheumatoid Arthritis–Specific Autoimmunity in the Lung Before and at the Onset of Disease.
- Authors
Joshua, Vijay; Loberg Haarhaus, Malena; Hensvold, Aase; Wähämaa, Heidi; Gerstner, Christina; Hansson, Monika; Israelsson, Lena; Stålesen, Ragnhild; Sköld, Magnus; Grunewald, Johan; Klareskog, Lars; Grönwall, Caroline; Réthi, Bence; Catrina, Anca; Malmström, Vivianne
- Abstract
Objective: The lung is implicated as a site for breach of tolerance prior to onset of seropositive rheumatoid arthritis (RA). To substantiate this, we investigated lung‐resident B cells in bronchoalveolar lavage (BAL) samples from untreated early RA patients and anti–citrullinated protein antibody (ACPA)–positive individuals at risk for developing RA. Methods: Single B cells (n = 7,680) were phenotyped and isolated from BAL samples from individuals at risk of RA (n = 3) and at RA diagnosis (n = 9). The immunoglobulin variable region transcripts were sequenced and selected for expression as monoclonal antibodies (n = 141). Monoclonal ACPAs were tested for reactivity patterns and binding to neutrophils. Results: Using our single‐cell approach, we found significantly increased proportions of B lymphocytes in ACPA+ compared to ACPA– individuals. Memory and double‐negative B cells were prominent in all subgroups. Upon antibody re‐expression, 7 highly mutated citrulline‐autoreactive clones originating from different memory B cell subsets were identified, both in individuals at risk of RA and early RA patients. Lung IgG variable gene transcripts from ACPA+ individuals carried frequent mutation‐induced N‐linked Fab glycosylation sites (P < 0.001), often in the framework 3 of the variable region. Two of the lung ACPAs bound to activated neutrophils, 1 from an individual at risk of RA and 1 from an early RA patient. Conclusion: T cell–driven B cell differentiation resulting in local class switching and somatic hypermutation are evident in lungs before as well as in early stages of ACPA+ RA. Our findings add to the notion of lung mucosa being a site for initiation of citrulline autoimmunity preceding seropositive RA.
- Subjects
AUTOANTIBODY analysis; RHEUMATOID arthritis risk factors; B cells; BRONCHOALVEOLAR lavage; IMMUNOGLOBULINS; SEQUENCE analysis; GENETIC mutation; LUNGS; MONOCLONAL antibodies; RISK assessment; GENE expression; NEUTROPHILS; AGE factors in disease; DESCRIPTIVE statistics; PHENOTYPES
- Publication
Arthritis & Rheumatology, 2023, Vol 75, Issue 11, p1910
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.42549