Abstract
High amount of polyclonal free light chains (FLC) are reported in systemic autoimmune diseases (SAD) and we took advantage of the PRECISESADS study to better characterize them. Serum FLC levels were explored in 1979 patients with SAD (RA, SLE, SjS, Scl, APS, UCTD, MCTD) and 614 healthy controls. Information regarding clinical parameters, disease activity, medications, autoantibodies (Ab) and the interferon α and/or γ scores were recorded. Among SAD patients, 28.4% had raised total FLC (from 12% in RA to 30% in SLE and APS) with a normal kappa/lambda ratio. Total FLC levels were significantly higher in SAD with inflammation, active disease in SLE and SjS, and an impaired pulmonary functional capacity in SSc, while independent from kidney impairment, infection, cancer and treatment. Total FLC concentrations were positively correlated among the 10/17 (58.8%) autoantibodies (Ab) tested with anti-RNA binding protein Ab (SSB, SSA-52/60 kDa, Sm, U1-RNP), anti-dsDNA/nucleosome Ab, rheumatoid factor and negatively correlated with complement fractions C3/C4. Finally, examination of interferon (IFN) expression as a potential driver of FLC overexpression was tested showing an elevated level of total FLC among patients with a high IFNα and IFNγ Kirou's score, a strong IFN modular score, and the detection in the sera of B-cell IFN dependent factors, such as TNF-R1/TNFRSF1A and CXCL10/IP10. In conclusion, an elevated level of FLC, in association with a strong IFN signature, defines a subgroup of SAD patients, including those without renal affectation, characterized by increased disease activity, autoreactivity, and complement reduction.
Highlights
Chronic multisystem autoimmune diseases, referred to as systemic autoimmune diseases (SAD), are diseases of unknown etiology with genetic, epigenetic, sex bias and environmental predispositions [1]
Regarding the physiological impact of elevated free light chains (FLC) levels, it has been suggested that FLC are able to inhibit innate immune functions that can contribute to an increase in infections [8], to activate mast cells leading to their degranulation [9], and to promote alternative complement cascade activation and, in turn, nephropathy [10]
A total of 2593 individuals were included in the study with 1979 SAD patients and 614 healthy controls (HC), see Table 1
Summary
Chronic multisystem autoimmune diseases, referred to as systemic autoimmune diseases (SAD), are diseases of unknown etiology with genetic, epigenetic, sex bias and environmental predispositions [1]. In SAD, B cell homeostasis is disturbed [3,4,5,6] and B cell activation into plasma cells is associated with exaggerated polyclonal synthesis of immunoglobulins together with a slight excess of polyclonal free light chains (FLC) concurrently, with normal kappa(κ)/lambda(λ) ratios. It is likely that SAD patients present renal impairment in which case an FLC level increase can result from overproduction, and from reduced clearance due to reduced glomerular filtration. Regarding the physiological impact of elevated FLC levels, it has been suggested that FLC are able to inhibit innate immune functions that can contribute to an increase in infections [8], to activate mast cells leading to their degranulation [9], and to promote alternative complement cascade activation and, in turn, nephropathy [10]. The possible use of FLC as a biomarker in SAD is further supported by its correlation with disease activity and autoantibody production
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