Complement C1s deficiency in a male Caucasian patient with systemic lupus erythematosus: a case report.

Deficiencies of the early complement components of the classical pathway (CP) are well-documented in association with systemic lupus erythematosus (SLE) or SLE-like syndromes and severe pyogenic infections. Among these, complete C1s deficiency has been reported in nine cases so far. Here, we describe a 34-year-old male patient who presented with severe, recurrent infections since childhood, including meningitides with pneumococci and meningococci, erysipelas, subcutaneous abscess, and recurrent infections of the upper airways. The patient also exhibited adult-onset SLE, meeting 7/11 of the ACR criteria and 34 of the 2019 EULAR/ACR classification criteria, along with class IV-G (A) proliferative lupus nephritis (LN). A screening of the complement cascade showed immeasurably low CH50, while the alternative pathway (AP) function was normal. Subsequent determination of complement components revealed undetectable C1s with low levels of C1r and C1q, normal C3, and slightly elevated C4 and C2 concentrations. The patient had no anti-C1q antibodies. Renal biopsy showed class IV-G (A) LN with complement C1q positivity along the glomerular basement membranes (GBMs) and weak deposition of IgG, IgM, and complement C3 and C4 in the mesangium and GBM. In an ELISA-based functional assay determining C4d deposition, the patient's absent complement activity was fully restored by adding C1s. The genome of the patient was analyzed by whole genome sequencing showing two truncating variants in the C1S gene. One mutation was located at nucleotide 514 in exon 5, caused by a nucleotide substitution from G to T, resulting in a nonsense mutation from Gly172 (p.Gly172*). The other mutation was located at nucleotide 750 in exon 7, where C was replaced by a G, resulting in a nonsense mutation from Tyr250 (p.Tyr250*). Both mutations create a premature stop codon and have not previously been reported in the literature. These genetic findings, combined with the absence of C1s in the circulation, strongly suggest a compound heterozygote C1s deficiency in our patient, without additional defect within the complement cascade. As in a previous C1s deficiency case, the patient responded well to rituximab. The present case highlights unanswered questions regarding the CP's role in SLE etiopathogenesis.

Anti-C1q Autoantibodies: Standard Quantification and Innovative ELISA.

Autoantibodies against complement C1q (anti-C1q) are an excellent marker for active nephritis in SLE patients. Here, we describe a typical protocol for the quantification of anti-C1q using immobilized C1q (important for the presentation of relevant cryptic epitopes) and a high salt buffer for the incubation steps (to prevent immune-complex binding to intact C1q). More recently, a linear epitope on the C1q A chain, that is targeted by anti-C1q, has been described (A08). The assay using this peptide seems to be more specific and more sensitive for the detection of active nephritis in SLE patients than the conventional anti-C1q assay, but further studies are required to establish the role of anti-A08 of C1q in the clinical routine.

Autoantibodies Against Albumin in Patients With Systemic Lupus Erythematosus.

Objectives: Autoantibodies and aberrant immune complexes are pathological hallmarks of systemic lupus erythematosus (SLE). This study aimed to determine the occurrence of IgG autoantibodies against human serum albumin (anti-HSA IgG) and their potential association with antibodies against bovine serum albumin (anti-BSA IgG) in patients with SLE. Methods: Sera of 180 SLE patients included to the Swiss SLE Cohort Study and 188 age- and sex-matched healthy controls were evaluated. Levels of anti-HSA IgG and anti-BSA IgG were quantified by ELISA. Selected samples were further characterized using serum fractions obtained by fast liquid chromatography (FPLC). Results: SLE patients had increased levels of anti-HSA IgG (p = 0.002) but similar levels of anti-BSA IgG compared to matched healthy controls. Anti-HSA IgG levels correlated with the SLE Disease Activity Index (SLEDAI), which was more pronounced in patients with an physician's global assessment (PGA) of ≥ 1 (r = 0.309, p = 0.0066). Anti-HSA IgG was partially complexed with serum albumin but also occurred as monomeric autoantibodies in highly positive SLE patients. A positive correlation between anti-HSA IgG and anti-BSA IgG was found that was stronger in SLE patients than in healthy controls (r = 0.3172, p < 0.001 vs. r = 0.2122, p < 0.0035). Binding of anti-BSA IgG was inhibited partially in the presence of HSA in samples with double positivity for anti-HSA and anti-BSA (median inhibition 47.9%, range 0.9-100%) and vice versa. Conclusion: In SLE patients there is an increased prevalence of anti-HSA IgG antibodies that are associated with SLE disease activity.

Complement activation products in acute heart failure: Potential role in pathophysiology, responses to treatment and impacts on long-term survival.

BACKGROUND: Previous studies have indicated a correlation between heart failure, inflammation and poorer outcome. However, the pathogenesis and role of inflammation in acute heart failure (AHF) is incompletely studied and understood. The aim of our study was to explore the potential role of innate immunity - quantified by complement activation products (CAPs) - in pathophysiology, responses to treatment and impacts on long-term survival in AHF. METHODS: In a prospective study enrolling 179 unselected patients with AHF, plasma concentrations of C4d, C3a and sC5b-9 were measured in a blinded fashion on the first day of hospitalisation and prior to discharge. The final diagnosis, including the AHF phenotype, was adjudicated by two independent cardiologists. Long-term follow-up was obtained. Findings in AHF were compared to that obtained in 75 healthy blood donors (control group). RESULTS: Overall, concentrations of all three CAPs were significantly higher in patients with AHF than in healthy controls (all p < 0.001). In an age-adjusted subgroup analysis, significant differences could be confirmed for concentrations of C4d and sC5b-9, and these parameters further increased after 6 days of in-hospital treatment ( p < 0.001). In contrast, C3a levels in AHF patients did not differ from those of the control group in the age-adjusted subgroup analysis and remained constant during hospitalisation. Concentrations of C4d, C3a and sC5b-9 were significantly higher when AHF was triggered by an infection as compared to other triggers ( p < 0.001). In addition, CAP levels significantly correlated with each other ( r = 0.64-0.76), but did not predict death within 2 years. CONCLUSIONS: Activation of complement with increased plasma levels of C4d and sC5b-9 at admission and increasing levels during AHF treatment seems to be associated with AHF, particularly when AHF was triggered by an infection. However, CAPs do not have a prognostic value in AHF.

Immune complexes containing serum B-cell activating factor and immunoglobulin G correlate with disease activity in systemic lupus erythematosus.

METHODS: Levels of serum BAFF, IgG anti-BAFF and BAFF-IgG complexes were quantified by enzyme-linked immunosorbent assay. IgG anti-BAFF and BAFF-IgG complexes were further characterized using serum fractions obtained by fast protein liquid chromatography. To study the association of serum BAFF, IgG anti-BAFF and BAFF-IgG complex levels with SLE manifestations, 373 visits from 178 patients prospectively included in the Swiss SLE Cohort Study were analysed. RESULTS: While IgG anti-BAFF levels were not associated with clinical manifestations of SLE, serum BAFF levels correlated with disease activity and were higher in patients with renal involvement. Interestingly, we could also demonstrate the occurrence of BAFF-IgG complexes of different sizes in the sera of SLE patients, which were not due to treatment with belimumab and differed from complexes constructed in vitro. Most strikingly, the levels of these BAFF-IgG complexes were found to strongly correlate with overall disease activity, low complement levels and a history of lupus nephritis. CONCLUSION: BAFF-IgG complexes strongly correlate with disease activity in SLE patients, suggesting a pathogenic role in SLE.

Increased apolipoprotein deposits in early atherosclerotic lesions distinguish symptomatic from asymptomatic patients.

OBJECTIVE: Apolipoprotein E (apoE) and apolipoprotein B100 (apoB) are both involved in receptor-mediated uptake of atherogenic lipoproteins by the liver. Inefficient hepatic clearance of these lipoproteins leads to symptomatic atherosclerosis. Using arterial tissue microarrays, we tested the hypothesis that apoE and apoB accumulation in the arterial wall discriminates between patients with symptomatic atherosclerosis and patients who never experienced cardiovascular events. METHODS AND RESULTS: In a postmortem study involving 49 patients (22 patients with symptomatic atherosclerosis), we quantified apolipoprotein deposits in arterial rings obtained from the left main coronary, the common carotid, the common iliac, and the renal artery applying tissue microarray technology and semiquantitative immunohistochemistry. In early atherosclerotic lesions, even before atheroma appeared, symptomatic patients had significantly more arterial apoE and apoB deposits than patients without cardiovascular events (P<0.001). Among the symptomatic patients, those without diabetes had more intense apolipoprotein deposits than diabetics. Large amounts of apoE and apoB were found in advanced atherosclerotic lesions, regardless of the activity of the disease. CONCLUSIONS: Increased apolipoprotein deposits are an early sign of symptomatic atherosclerosis. They may reflect either enhanced retention of atherogenic lipoproteins or impaired local apolipoprotein degradation. The arterial lipoprotein turnover may be different in diabetic patients.