Session Title: Cytokines, Mediators, and Gene Regulation I
Session Type: Abstract Submissions (ACR)
Background/Purpose: The processes that lead to clinical illness in systemic lupus erythematosus (SLE) years before diagnosis are not well characterized. Several cytokines have been associated with increased activity in established disease after diagnosis. This study evaluates the temporal relationship between autoantibody production, cytokine levels and the onset of SLE clinical disease.
Methods: Serial sera from 60 SLE cases before diagnosis with no ACR criteria to SLE classification (average timespan= 4.4 years) were obtained from the Department of Defense Serum Repository (DODSR). Sera samples were tested for C-reactive protein (hs-CRP), Von Willebrand’s Factor (VWF) and 32 soluble inflammatory mediators, including cytokines, chemokines, and soluble receptors using xMAP multiplex bead-based assays or sandwich ELISA (BLyS, APRIL, hs-CRP, and VWF). In addition, samples were assessed for the presence of SLE-associated autoantibodies, including Ro, La, nRNP, Sm, Ribosomal P, dsDNA, and ANA by ELISA and immunofluorescence. Interferon (IFN) activity was assessed by a cell reporter assay measuring interferon responsive gene expression (MX1, PKR, and IFIT1) by serum.
Patient samples before ACR classification had significant (p ≤ 0.01) alterations in 16 soluble mediators of inflammation, as well as VWF and hs-CRP. Levels of particular TNF Receptor (TNFR) family members, TNFRI, TNFRII, BLyS, and APRIL, dramatically increased as lupus classification approached (levels at clinical symptoms versus pre-clinical sera, p ≤ 0.001). The increase in these TNFR mediators affecting B-lymphocyte activation parallels the accumulation of autoantibodies seen leading up to diagnosis in SLE cases. Interferon (IFN)-associated mediators of inflammation are also of particular interest and were assessed. An initial evaluation of 20 SLE cases from this study revealed a significant increase in IFN activity leading up to diagnosis (p = 0.0279). We find a similar pattern of increased IFN-γ, IP-10, MIG, and MIP-1α (p ≤ 0.01) leading up to diagnosis. Mediators such as VWF, hs-CRP, stem cell factor and resistin also increase over the pre-clinical course to SLE transition (p ≤ 0.01). Inflammatory mediators IL-12 and IL-17 were significantly elevated (p ≤ 0.01) in pre-clinical samples compared with first ACR criterion and lupus classification.
Conclusion: Before SLE patients transition to clinical disease, they have significantly elevated levels of soluble inflammatory mediators. Further elevation of select markers occurs between early clinical symptoms and classified disease. That these alterations are present prior to the transition to active SLE suggests that multiple perturbations in immune-mediated inflammatory processes occur long before clinical classification and suggest that high-risk, pre-clinical individuals, destined to become SLE patients, can be identified before their illness is clinically manifested and damaging.
M. E. Munroe,
J. R. Anderson,
J. M. Robertson,
T. B. Niewold,
G. C. Tsokos,
M. P. Keith,
J. B. Harley,
J. A. James,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/select-soluble-inflammatory-mediators-are-detected-prior-to-and-increase-at-systemic-lupus-erythematosus-classification/