Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification

Abstract

Objectives The relationship of immune dysregulation and autoantibody production that may contribute to systemic lupus erythematosus (SLE) pathogenesis is unknown. This study evaluates the individual and combined contributions of autoantibodies, type I interferon (IFN-α) activity, and IFN-associated soluble mediators to disease development leading to SLE. Methods Serial serum specimens from 55 individuals collected prior to SLE classification (average timespan = 4.3 years) and unaffected healthy controls matched by age (± 5 years), gender, race, and time of sample procurement were obtained from the Department of Defense Serum Repository. Levels of serum IFN-α activity, IFN-associated mediators, and autoantibodies were evaluated and temporal relationships assessed by growth curve modeling, path analysis, Analysis of Covariance, and random forest models. Results In cases, but not matched controls, autoantibody specificities and IFN-associated mediators accumulated over a period of years, plateauing near the time of disease classification (p<0.001). Autoantibody positivity coincided with or followed type II IFN dysregulation, preceding IFN-α activity in growth curve models, with elevated IFN-α activity and BLyS levels occurring shortly before SLE classification (p≤0.005). Cases were distinguished by multivariate random forest models incorporating IFN-γ, MCP-3, anti-chromatin and anti-spliceosome antibodies (accuracy 93% > 4 years pre-classification; 97% within 2 years of SLE classification). Conclusions Years before SLE classification, enhancement of the type II IFN pathway allows for accumulation of autoantibodies and subsequent elevations in IFN-α activity immediately preceding SLE classification. Perturbations in select immunological processes may help identify at-risk individuals for further clinical evaluation or participation in prospective intervention trials.

Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies

“…3 ). Consistent with our previous findings, IFN-γ (Th 1 -type) levels also increased rapidly during the pre-classification period, as did the IFN-γ induced chemokine, MIG ([18] and Fig. 3 ).…”

“…3 ). In addition, cases continued to accumulate autoantibody specificities as they approached SLE classification [18, 45], with anti-Ro/SSA being among the first lupus-associated autoantibody specificities to be detected, followed by autoantibodies reactive to RNP, chromatin, Sm, dsDNA, and La/SSB as patients approached SLE classification ( Fig. 3 ).…”

“…Key mediators of such crosstalk, including Th-type cytokines IFN-γ (Th 1 ), interleukin (IL)-4 and IL-5 (Th 2 ), and IL-17 and IL-21 (Th 17 ) facilitate lymphocyte recruitment to germinal centers [13-15] and pathogenic autoantibody production [16, 17] with the help of T-follicular helper (T fh ) cells [17]. We have recently demonstrated that type II IFN (IFN-γ) becomes elevated prior to and concurrent with the development of lupus-associated autoantibodies [18]. The tumor necrosis factor (TNF) superfamily member B lymphocyte stimulator (BLyS), secreted in response to type I and type II IFNs [19, 20], further supports and propagates autoantibody production as a survival factor for self-reactive B-lymphocytes [21].…”

Combined role of vitamin D status and CYP24A1 in the transition to systemic lupus erythematosus

“…1 2 In rheumatic diseases in particular, 1,25[OH] 2 D regulates both innate and adaptive immunity, potentiating the innate response, [53][54][55][56] which has been shown to precede the development of autoimmunity in SLE, 57 but reducing adaptive immunity, 53-56 including reduced T cell activation 58 and working in conjunction with glucocorticoids on the inhibition of lymphocyte proliferation. 56 Vitamin D deficiency seems to play a role in increasing B cell activation 14 59 and therefore autoantibody production, and long-term supplementation with vitamin D increased the number of T-regulator cells in individuals with SLE.…”

Biomarkers in connective tissue diseases

“…51, 52 IFNα levels correlated with the number of autoantibody specificities in preclinical samples obtained from individuals later classified as SLE, suggesting a role for IFNα in autoantibody accrual. 12 Interestingly, IFNγ activity was increased before autoantibody positivity, and autoantibody positivity preceded increases in IFNα. IFNγ regulates both IFNα and B cell differentiation and possibly drives B cell maturation and class switching in early stages of SLE pathogenesis.…”