Faculty Bibliography

OBJECTIVE: Systemic lupus erythematosus (SLE) is associated with the premature development of cardiovascular disease. The platelet-endothelium interaction is important in the pathogenesis of cardiovascular disease. In this study, we investigated the platelet phenotype from patients with SLE and matched controls, and their effect on endothelial cells. APPROACH AND RESULTS: Platelet aggregability was measured in 54 SLE subjects off antiplatelet therapy (mean age 40.1+/-12.8 years; 82% female; 37% white) with age- and sex-matched controls. Platelets were coincubated with human umbilical vein endothelial cells (HUVECs) and changes to gene expression assessed by an RNA array and quantitative reverse transcription polymerase chain reaction. SLE disease activity index ranged from 0 to 22 (mean 5.1+/-3.9). Compared with controls, patients with SLE had significantly increased monocyte and leukocyte-platelet aggregation and platelet aggregation in response to submaximal agonist stimulation. An agnostic microarray of HUVECs cocultured with SLE platelets found a platelet-mediated effect on endothelial gene pathways involved in cell activation. Sera from SLE versus control subjects significantly increased (1) activation of control platelets; (2) platelet adhesion to HUVECs; (3) platelet-induced HUVEC gene expression of interleukin-8, and ICAM-1; and (4) proinflammatory gene expression in HUVECs, mediated by interleukin-1beta-dependent pathway. Incubation of SLE-activated platelets with an interleukin-1beta-neutralizing antibody or HUVECs pretreated with interleukin-1 receptor antibodies attenuated the platelet-mediated activation of endothelial cells. CONCLUSIONS: Platelet activity measurements and subsequent interleukin-1beta-dependent activation of the endothelium are increased in subjects with SLE. Platelet-endothelial interactions may play a role in the pathogenesis of cardiovascular disease in patients with SLE.

Background and aims Autoantibodies targeting Ro52 occur in systemic lupus erythematosus, Sjogren's syndrome and idiopathic inflammatory myopathies. Yet the most compelling evidence for their pathogenesis is the development of cardiac conduction abnormalities, a manifestation of neonatal lupus, in foetuses exposed to maternal anti-Ro52 autoantibodies. Recent studies investigating other pathogenic autoantibodies (antiinterferon, anti-desmoglein) report that they arise as a result of somatic mutation. The aim of this study was to determine how anti-Ro52 autoantibodies originate. Methods We traced the evolution of two anti-Ro52 autoantibodies isolated from circulating IgG-switched memory B-cells from a mother of two children with cardiac neonatal lupus. Each antibody was expressed as its immune form or preimmune ancestor by reverting somatic mutations to germline sequence. Antibody reactivity against autoantigens Ro52, Ro60, La and dsDNA were tested by ELISA. Results Both anti-Ro52 autoantibodies utilised the same heavy and light chain genes (IGHV3-23 and IGLV1-44) but represented distinct clones based on differing complementarity determining region sequences. Anti-Ro52 autoantibodies exhibited a low frequency (3%-4%) of somatic mutations compared to the average rate of 8% in healthy switched memory B-cells. In contrast to other pathogenic autoantibodies, the preimmune (germlined) anti-Ro52 autoantibodies showed specific binding to Ro52. However, Ro52 reactivity was higher for the mutated post-immune antibodies compared to their preimmune counterparts demonstrating that autoreactivity was enhanced by affinity maturation. Conclusions These data demonstrate that Ro52 reactivity is an intrinsic property of the germline antibody repertoire in a mother of children affected by neonatal lupus and indicate defects in central and peripheral tolerance pathways allow propagation of pathogenic autoantibodies

Congenital heart block (CHB) is a characteristic manifestation of the neonatal lupus (NL) syndrome, mainly due to passive transplacental diffusion of maternal antibodies (anti-SSA/Ro and, to a lesser extent, anti-SSB/La) to the fetal circulation. Cardiac NL syndrome typically includes, besides CHB (usually complete), further cardiac abnormalities such as endocardial fibroelastosis, dilated cardiomyopathy, and valve fibrosis. Other conduction abnormalities may be present (sinus bradycardia, PR interval prolongation)

OBJECTIVE: Atherosclerosis is exaggerated in African American (AA) systemic lupus erythematosus (SLE) patients, with doubled cardiovascular disease (CVD) risk compared to White patients. The extent to which common Apolipoprotein L1 (APOL1) risk alleles (RA) contribute to this trend is unknown. This retrospective cohort study assessed prevalent atherosclerotic disease across APOL1 genotypes in AA SLE patients. METHODS: One hundred thirteen AA SLE subjects were APOL1-genotyped and stratified as having: zero risk alleles, one risk allele, or two risk alleles. Chart review assessed CVD manifestations including abdominal aortic aneurysm, angina, carotid artery disease, coronary artery disease, myocardial infarction, peripheral vascular disease, stroke, and vascular calcifications. Associations between the genotypes and a composite endpoint defined as one or more CVD manifestations were calculated using logistic regression. Symptomatic atherosclerotic disease, excluding incidental vascular calcifications, was also assessed. RESULTS: The 0-risk-allele, 1-risk-allele and 2-risk-allele groups, respectively, comprised 34%, 53%, and 13% of the cohort. Respectively, 13.2%, 41.7%, and 60.0% of the 0-risk allele, 1-risk-allele, and 2-risk-allele groups met the composite endpoint of atherosclerotic CVD (p = 0.001). Adjusting for risk factors-including smoking, ESRD, BMI >25 and hypertension-we observed an association between carrying one or more RA and atherosclerotic CVD (OR = 7.1; p = 0.002). For symptomatic disease, the OR was 3.5 (p = 0.02). In a time-to-event analysis, the proportion of subjects free from the composite primary endpoint, symptomatic atherosclerotic CVD, was higher in the 0-risk-allele group compared to the 1-risk-allele and 2-risk-allele groups (chi2 = 6.5; p = 0.04). CONCLUSIONS: Taken together, the APOL1 RAs associate with prevalent atherosclerotic CVD in this cohort of AA SLE patients, perhaps reflecting a potentiating effect of SLE on APOL1-related cardiovascular phenotypes.