TYPE I INTERFERON ACTIVATION IN A COHORT OF PATIENTS FROM THE EUROFEVER REGISTRY: CLINICAL AND MOLECULAR ANALYSIS

The role of type I interferon (IFN-I) in autoimmune and autoinflammatory diseases has been widely demonstrated, but its diagnostic role in clinical practice remains a controversial topic. We evaluated 214 consecutive patients, enrolled in the Eurofever Registry with defined or undefined pediatric conditions, for IFN-I activation using real-time quantitative PCR. IFN-I signature was calculated as the median of the relative quantification of six IFN-I -inducible genes compared to healthy controls. Lymphoid involvement was more frequent among patients with activation of the IFN-I pathway (34.5% vs. 20%; p<0.02) compared to IFN-I negative patients. All patients presenting with erythema nodosum had a positive IFN-I score. A significant percentage of patients with activation of the IFN-I pathway had autoantibodies, confirming the strong link between autoimmunity and innate immune activation. We identified 14 patients with genetically determined interferonopathy, 18 with autoinflammatory diseases, 69 with autoimmune disorders, 5 with immunodeficiency and 108 patients presenting with other conditions, including undifferentiated systemic autoinflammatory diseases (USAID) (69/198) and undifferentiated recurrent fever syndrome (SURF) (7/108). Most of the patients affected by systemic erythematosus lupus (SLE) revealed a positive IFN-I signature and six patients with interferonopathies showed a phenotype similar to SLE. The latter had a significantly lower median age at onset and high median values of the interferon signature. These findings could be indicators of the presence of a monogenic disease in patients with atypical SLE. Six patients in this cohort received JAK inhibitors, with a good response in the absence of adverse effects. The possibility of targeted treatment by JAK kinase inhibitors is the real advantage of early genetic diagnosis with the aim of preventing organ damage and reducing the use of steroid therapy or other immunosuppressants

Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases

The complement system consists of effector proteins, regulators, and receptors that participate in host defense against pathogens. Activation of the complement system, via the classical pathway (CP), has long been recognized in immune complex-mediated tissue injury, most notably systemic lupus erythematosus (SLE). Paradoxically, a complete deficiency of an early component of the CP, as evidenced by homozygous genetic deficiencies reported in human, are strongly associated with the risk of developing SLE or a lupus-like disease. Similarly, isotype deficiency attributable to a gene copy number variation, and/or the presence of autoantibodies directed against a CP component or a regulatory protein that result in an acquired deficiency are relatively common in SLE patients. Applying accurate assay methodologies with rigorous data validations, low gene copy numbers of total C4, heterozygous and homozygous deficiencies of C4A have been shown as medium to large effect size risk factors, while high copy numbers of total C4 or C4A as prevalent protective factors, of European and East-Asian SLE. Here, we summarize the current knowledge related to genetic deficiency and insufficiency, and acquired protein alterations for C1q, C1r, C1s, C4A/C4B, and C2 in disease pathogenesis and prognosis of SLE, and, briefly, for other systemic autoimmune diseases. As the complement system is increasingly found to be associated with autoimmune diseases, it has become an attractive therapeutic target. We highlight the recent developments and offer a balanced perspective concerning future investigations and therapeutic applications with a focus on early components of the CP in human systemic autoimmune diseases

Smoking and Second Hand Smoking in Adolescents with Chronic Kidney Disease: A Report from the Chronic Kidney Disease in Children (CKiD) Cohort Study

The goal of this study was to determine the prevalence of smoking and second hand smoking [SHS] in adolescents with CKD and their relationship to baseline parameters at enrollment in the CKiD, observational cohort study of 600 children (aged 1-16 yrs) with Schwartz estimated GFR of 30-90 ml/min/1.73m2. 239 adolescents had self-report survey data on smoking and SHS exposure: 21 [9%] subjects had “ever” smoked a cigarette. Among them, 4 were current and 17 were former smokers. Hypertension was more prevalent in those that had “ever” smoked a cigarette (42%) compared to non-smokers (9%),