Background/Purpose: Patients with systemic autoimmune rheumatic diseases (SARD) often have a prolonged pre-clinical phase during which they are anti-nuclear antibody (ANA)⁺ but lack clinical symptoms.  It has been proposed that progression from asymptomatic autoimmunity to clinical disease is accompanied by immunologic changes that could be used as predictors of disease development.  However, little is known about the cellular derangements that accompany the transition from benign to pathological autoimmunity.  Previous studies indicate that a number of B cell phenotypic changes are seen in SARD patients including changes in the proportions of various naïve and memory B cell subsets, increased B cell activation and elevated levels of plasmablasts/plasma cells.  Here we examined whether ANA⁺individuals who lack sufficient symptoms for a SARD diagnosis share any of the B cell phenotypic changes seen in early SARD.

Methods: ANA⁺individuals who: 1) lacked clinical symptoms of SARD (ANS); 2) had a least one clinical symptom of SARD (UCTD); or 3) had a recently diagnosed steroid and immunosuppressive naïve SARD (SLE, SS, SSc, MCTD, DM) were recruited from clinics at UHN/MSH hospitals.  Healthy controls (HC) were also recruited.  PBMCs were isolated over a Ficoll gradient, stained with various combinations of fluorescently labeled antibodies and analyzed by flow cytometry.  ANAs were measured through the hospital laboratory.

Results: B cell phenotypes were examined for 35 HC, 40 ANS, 24 UCTD, and 53 early SARD (22 SS, 19 SSc, 7 SLE, 2 MCTD, 1 DM) patients.  Although significantly increased proportions of CD19^lo/-CD38⁺⁺⁺CD27⁺⁺⁺ plasmablasts/plasma cells were seen in all SARD patients (except those with SSc), these were not seen in ANS and UCTD patients and significant increases in CD138⁺ plasma cells were not seen in any of the ANA⁺ subsets except SS.  Patients with early SARD had a number of changes in their naïve and memory B cell subsets, as previously reported for patients with established disease including: increased proportions of mature naïve B cells (SSc); increased proportions of T1T2 cells (SLE and SS); and decreased proportions of switched memory B cells (CD27⁺IgD^–) in all SARD.  However, in contrast to some reports no changes were seen in the proportion of CD27⁺IgD⁺ un-switched or CD27^–IgD^– memory cells.  Similar decreases in the proportion of switched memory B cells were seen in ANS and UCTD patients, and as seen for the SARD patients these cells were activated with elevated levels of CD86 as compared to HC.  Significantly increased activation of the CD27^–IgD^– memory compartment was also seen in ANS, SLE and SS patients, with trends observed for the other patient subsets.  When all ANA⁺ individuals were examined there was a significant association between ANA titer and the proportion of CD19^lo/-CD38⁺⁺⁺CD27⁺⁺⁺ and CD138⁺plasmablast/plasma cells as well as the reduced size and increased activation of the switched memory B cell compartment.  This was also seen when the ANS subset was examined alone.

Conclusion: B cell phenotypic abnormalities appear to precede the onset of clinical disease in ANA⁺ individuals and correlate with autoantibody levels as reflected by the ANA titer.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/b-cell-phenotypic-changes-in-anti-nuclear-antibody-positive-individuals-prior-to-the-onset-of-systemic-autoimmune-rheumatic-disease/