FRI0004 A Progressive Stepwise Accrual of T Cell Abnormalities Marks the Transition from Benign to Symptomatic Autoimmunity
Authors: C. Landolt-Marticorena, S. Rusta-Sallehy, B. Noamani, D. Bonilla, L. Lisnevskaia, S. Johnson, E. Silverman, A. Bookman, J. Wither
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> The systemic autoimmune rheumatic diseases (SARD; Systemic Lupus Erythematosus, Rheumatoid Arthritis, Sjogren9s 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 (T<sub>FH</sub>) cells are implicated in the development of systemic autoimmunity. Both a decrease in iNKT cells and an increase in T<sub>FH</sub> cells are found in patients with established SARD. <h3>Objectives</h3> To determine if T cell abnormalities associated with SARD are present in pre-clinical autoimmunity. <h3>Methods</h3> Patients (n=87) who were ANA<sup>+</sup> (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. <h3>Results</h3> A statistically significant decrease in the proportion of iNKT cells (CD3<sup>+</sup>Vα24Jα18 TCR<sup>+</sup>) was found for all ANA<sup>+</sup> patients relative to HC (p=0.0001). Similar results were found for each patient subset when compared to HC; ANA<sup>+</sup> asymptomatic (p=0.001), UCTD (p=0.02) and SARD (p=0.001), with no differences amongst groups. The proportion of T<sub>FH</sub> (CD4<sup>+</sup>CXCR5<sup>high</sup>PD-1<sup>high</sup>) cells was significantly elevated (p=0.01) in patients versus HC. While the proportion of T<sub>FH</sub> cells was similar between asymptomatic ANA<sup>+</sup> patients and HC, there was a significant expansion of T<sub>FH</sub> 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 T<sub>FH</sub> as compared to UCTD. Patients (n=50) with higher ANA titers (≥1:640) had a significant increase (p=001) in T<sub>FH</sub> when compared to individuals (n=13) with lower ANA levels (1:160). A positive correlation (p&lt;0.0001) between the proportion of T<sub>FH</sub> and the number of auto-Abs within the patient population was found. No significant differences were noted in the iNKT or T<sub>FH</sub> cell proportions between SARD patients stratified by specific disease diagnosis. <h3>Conclusions</h3> A decrease in the iNKT cell subset is present at the earliest phase of pre-clinical autoimmunity (asymptomatic ANA<sup>+</sup>) suggesting that loss of this T cell subset contributes to a breach of tolerance to nuclear antigens. In contrast, increases in the T<sub>FH</sub> 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. <h3>Disclosure of Interest</h3> None declared