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FRI0004 A Progressive Stepwise Accrual of T Cell Abnormalities Marks the Transition from Benign to Symptomatic Autoimmunity
  1. C. Landolt-Marticorena1,
  2. S. Rusta-Sallehy2,
  3. B. Noamani1,
  4. D. Bonilla1,
  5. L. Lisnevskaia3,
  6. S. Johnson1,
  7. E. Silverman4,
  8. A. Bookman1,
  9. J. Wither1
  1. 1University Health Network
  2. 2University of Toronto, Toronto
  3. 3Lakeridge Health Center, Oshawa
  4. 4The Hospital for Sick Children, Toronto, Canada

Abstract

Background The systemic autoimmune rheumatic diseases (SARD; Systemic Lupus Erythematosus, Rheumatoid Arthritis, Sjogren's Disease, Systemic Sclerosis) are proposed to have a prolonged period of pre-clinical autoimmunity culminating in clinical disease. Evidence from disease-specific studies (e.g., SLE, RA) suggests that the pre-clinical phase is marked by the accrual of immunological abnormalities such as pathogenic auto-antibodies (auto-Ab). Little is known about the cellular derangements that accompany the transition from benign to pathological autoimmunity. Abnormalities in T cell subsets including invariant NKT (iNKT) and T follicular helper (TFH) cells are implicated in the development of systemic autoimmunity. Both a decrease in iNKT cells and an increase in TFH cells are found in patients with established SARD.

Objectives To determine if T cell abnormalities associated with SARD are present in pre-clinical autoimmunity.

Methods Patients (n=87) who were ANA+ (titer ≥1:160) and healthy controls (HC, n=37) were recruited. Patients were stratified into clinical subsets: (1) no defining SARD symptoms (n=24); (2) undifferentiated connective tissue disease (UCTD, n=17), one or more SARD defining symptom; and (3) early SARD (n=46), fulfilling ACR criteria for a SARD diagnosis. Patients were immunosuppressive and steroid naïve. PBMCs were isolated over a Ficoll gradient, stained with combinations of fluorescently labeled antibodies and analyzed by flow cytometry. ANA titer and auto-Ab profile were determined.

Results A statistically significant decrease in the proportion of iNKT cells (CD3+Vα24Jα18 TCR+) was found for all ANA+ patients relative to HC (p=0.0001). Similar results were found for each patient subset when compared to HC; ANA+ asymptomatic (p=0.001), UCTD (p=0.02) and SARD (p=0.001), with no differences amongst groups. The proportion of TFH (CD4+CXCR5highPD-1high) cells was significantly elevated (p=0.01) in patients versus HC. While the proportion of TFH cells was similar between asymptomatic ANA+ patients and HC, there was a significant expansion of TFH in UCTD as compared to both groups (p=0.02 and p=0.04, respectively). SARD patients had a non-significant trend to increased proportions of TFH as compared to UCTD. Patients (n=50) with higher ANA titers (≥1:640) had a significant increase (p=001) in TFH when compared to individuals (n=13) with lower ANA levels (1:160). A positive correlation (p<0.0001) between the proportion of TFH and the number of auto-Abs within the patient population was found. No significant differences were noted in the iNKT or TFH cell proportions between SARD patients stratified by specific disease diagnosis.

Conclusions A decrease in the iNKT cell subset is present at the earliest phase of pre-clinical autoimmunity (asymptomatic ANA+) suggesting that loss of this T cell subset contributes to a breach of tolerance to nuclear antigens. In contrast, increases in the TFH compartment appear to parallel the onset of clinical symptoms and accrual of auto-Abs. These results suggest that an incremental development of T cell abnormalities marks the progression towards clinically significant autoimmunity.

Disclosure of Interest None declared

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