David S. Pisetsky

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease in which immune complexes (ICs) consisting of antinuclear autoantibodies (ANAs) and nuclear antigens induce complement activation and contribute to disease pathogenesis. The impact of antigen form on ICs formation and subsequent complement activation is not well understood. To elucidate the formation of these ICs, we used an immunocapture assay (immune complex complement assay [ICCA]) to determine the influence of antigen form on complement activation. In the ICCA, ICs are formed in vitro with SLE patient plasmas and different nuclear antigen preparations (ApoS, a supernatant of apoptotic cells; calf thymus DNA; nucleosomes; or purified Smith [Sm]/ribonucleoprotein [RNP]); healthy donor whole blood or plasma served as a complement source. Complement activation was detected by capturing ICs with either a monoclonal anti-DNA or anti-Sm antibody and assaying for bound C3 fragments. Results show that ICs formed with ApoS produced 4- to 8-fold higher complement activation than those with soluble DNA or nucleosomes. Patient samples with antibodies to RNA binding proteins (anti-Sm/RNP) induced significant complement activation with an Sm/RNP antigen preparation but not with ApoS. Despite a general correlation with anti-DNA antibody titers in patient samples, anti-DNA antibody levels did not fully predict complement activation. These findings highlight the influence of nuclear antigen form on complement activation by ANA ICs and support ICCA as a potential biomarker platform to elucidate disease mechanisms and evaluate new therapies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by protean clinical manifestations that are associated with immune system dysregulation. Of these manifestations, pain and pain-related symptoms such as fatigue, mood disturbance and cognitive impairment are the most common features reported by patients and represent important determinants of quality of life. Nevertheless, the relationship of these symptoms to underlying immune mechanisms is unclear. To advance scientific study and patient-centric care, this Review will consider the origin of pain in SLE and the clinical ramifications. Although many of the inflammatory aspects of SLE, including arthritis, serositis and skin disease, can be associated with nociceptive pain, patients frequently report pain that seems out of proportion to the degree of inflammation. In many of these patients, pain might reflect central and peripheral nervous system sensitization that mediates nociplasticity, a change in brain processing; with nociplasticity, changes in neuronal function and brain connections can amplify the experience of pain and pain-related symptoms. The close interplay between the immune and the nervous systems means that widespread pain and the associated symptoms can be considered as essential features of SLE; these features might share pathogenic mechanisms with other autoimmune diseases and nociplastic pain syndromes such as fibromyalgia.

Background: HLA homozygosity of specific alleles at a single locus is associated with increased risk for autoimmunity and/or more severe clinical phenotypes. However, the contribution of the overall limitation of HLA diversity across multiple loci to autoimmunity risk remains to be determined. Methods: We conducted a proof-of-concept case–control study of 413 individuals (279 cases with pediatric-onset autoimmune rheumatic diseases, 134 matched controls) examining the “Limitation of HLA Diversity” (LoHLAD) across multiple loci as an allele-independent risk factor for autoimmunity. We examined the association of LoHLAD with pediatric-onset autoimmune rheumatic diseases at five HLA loci (A, B, DQB1, DRB1, DRB3/4/5). LoHLAD was defined as (1) homozygosity at any of the examined loci, and/or (2) the presence of a single allele or the complete lack of an allele at the HLA-DRB3/4/5 locus. Results: The frequency of LoHLAD at any locus was significantly higher in cases compared to controls (65.95% vs. 30.60%, OR 4.39 [2.82–6.84], p < 0.0001). Higher frequencies of LoHLAD in cases compared to controls were observed at both class I (19.35% vs. 10.45%, OR 2.06 [1.10–3.86], p = 0.031) and class II (54.48% vs. 20.15%, OR 4.74 [2.92–7.69], p < 0.0001) loci. Specifically, significant differences between cases and controls were observed at the B (OR 8.63 [1.14–65.55], p = 0.016), DQB1 (OR 3.34 [1.27–8.78], p = 0.016), and DRB3/4/5 (OR 4.64 [2.77–7.75], p < 0.0001) loci. Multiple logistic regression models confirmed the ability of LoHLAD to positively predict autoimmunity. Conclusions: LoHLAD is a significant allele-independent risk factor for pediatric-onset autoimmune rheumatic disease.

Multiple sclerosis (MS) is a debilitating autoimmune disease of the CNS, which is characterized by demyelination and axonal injury and frequently preceded by a demyelinating event called clinically isolated syndrome (CIS). Despite the importance of B cells and autoantibodies in MS pathology, their target specificities remain largely unknown. For an agnostic and comprehensive evaluation of autoantibodies in MS, we developed and employed what we believe to be a novel autoantigen discovery technology, the Antigenome Platform. This Platform is a high-throughput assay comprising large-fragment (approximately 100 amino acids) cDNA libraries, phage display, serum antibody screening technology, and robust bioinformatics analysis pipelines. For autoantibody discovery, we assayed serum samples from CIS patients who received either placebo or treatment who were enrolled in the REFLEX clinical trial, which assessed the effects of IFN-β-1a (Rebif) clinical and MRI activity in patients with CIS. Serum autoantibodies from patients with CIS were significantly and reproducibly enriched for known and previously unreported protein targets; 166 targets were selected by over 10% of patients’ sera. Further, 10 autoantibody biomarkers associated with disease activity and 17 associated with patient response to IFN-β-1a therapy. These findings indicate widespread autoantibody production in MS and provide biomarkers for continued study and prediction of disease progression.