SERPINB3 Delays Glomerulonephritis and Attenuates the Lupus-Like Disease in Lupus Murine Models by Inducing a More Tolerogenic Immune Phenotype.

Objective: To explore the effects of SERPINB3 administration in murine lupus models with a focus on lupus-like nephritis. Methods: 40 NZB/W F1 mice were subdivided into 4 groups and intraperitoneally injected with recombinant SERPINB3 (7.5 µg/0.1 mL or 15 µg/0.1 mL) or PBS (0.1 mL) before (group 1 and 2) or after (group 3 and 4) the development of proteinuria (≥100 mg/dl). Two additional mice groups were provided by including 20 MRL/lpr mice which were prophylactically injected with SERPINB3 (10 mice, group 5) or PBS (10 mice, group 6). Time of occurrence and levels of anti-dsDNA and anti-C1q antibodies, proteinuria and serum creatinine, overall- and proteinuria-free survival were assessed in mice followed up to natural death. Histological analysis was performed in kidneys of both lupus models. The Th17:Treg cell ratio was assessed by flow-cytometry in splenocytes of treated and untreated MRL/lpr mice. Statistical analysis was performed using non parametric tests and Kaplan-Meier curves, when indicated. Results: Autoantibody levels and proteinuria were significantly decreased and time of occurrence significantly delayed in SERPINB3-treated mice vs. controls. In agreement with these findings, proteinuria-free and overall survival were significantly improved in SERPINB3-treated groups vs. controls. Histological analysis demonstrated a lower prevalence of severe tubular lesions in kidneys of group 5 vs. group 6. SERPINB3-treated mice showed an overall trend toward a reduced prevalence of severe lesions in both strains. Th17:Treg ratio was significantly decreased in splenocytes of MRL/lpr mice treated with SERPINB3, compared to untreated control mice. Conclusions: SERPINB3 significantly improves disease course and delays the onset of severe glomerulonephritis in lupus-prone mice, possibly inducing a more tolerogenic immune phenotype.

Acute immunomodulatory changes during controlled ovarian stimulation: evidence from the first trial investigating the short-term effects of estradiol on biomarkers and B cells involved in autoimmunity.

PURPOSE: The aim of the present study was to evaluate the in vivo immunomodulatory effects of an acute short-term estradiol (E(2)) increase on serum levels of B cell-activating factor (BAFF), immunoglobulins (Ig), anti-nuclear antibodies (ANA), and the peripheral B cell phenotype. METHODS: We conducted, at the Infertility Center of the University of Padua, a prospective case-control study on a cohort of infertile normo-responder women (group-A, 63 patients) undergoing controlled ovarian stimulation (COS) compared with an age-matched cohort of normo-ovulatory healthy women (group-B, 39 patients). Three serial blood sample assays were conducted in both groups, at T0, hypothalamic suppression; T1, ovulation induction; and T2, ßhCG test in group A, and at T0, 2nd day; T1, 14th day; and T2, 21st day of cycle in group B, and serum levels of E(2) and BAFF, BAFF/E(2) ratio, circulating IgM, IgG, and IgA, ANA titer, and peripheral B cell phenotype were measured. We compared group-A versus group-B in terms of absolute and E(2) normalized values of BAFF at baseline (T0) to verify for possible differences between healthy and infertile women, at T1 to verify for possible differences occurring after spontaneous ovulation versus COS, and at T2 to evaluate differences in serum BAFF levels between pregnant versus non-pregnant patients (considering only group-A) and between non-pregnant women after spontaneous versus COS cycles (group-B versus group-A). In group-A, we also evaluated IgM, IgG, IgA levels, ANA titer, and peripheral B cell phenotype at T0 versus T1 versus T2. RESULTS: With the exception of E(2) levels at T1 (as expected), no significant differences were found between the two groups for all outcome measures. In group-A, BAFF at T0 positively correlated with IgM levels; marginal zone CD19+/CD27+/IgD+ memory B cell compartment tended to be expanded at T1 when compared with T0. CONCLUSIONS: Despite several mechanistic and clinical studies supporting a stimulatory role of E(2) on autoimmunity, the acute increase of E(2) during COS for infertility treatment does not seem to have a major impact on the immune system.

Myositis autoantibodies and clinical phenotypes.

Autoantibodies are powerful diagnostic tools in idiopathic inflammatory myopathies, especially for confirming the diagnosis and contributing to the definition of disease subsets. They are present in over 80 % of patients with immuno-mediated myositis and directed towards ubiquitously expressed intracellular complexes. Most of these autoantibodies are reported also in other autoimmune diseases, while some are considered myositis-specific. Myositis autoantibodies are traditionally categorized in two groups, based on their diagnostic accuracy: myositis-specific antibodies (MSA) and myositis-associated antibodies (MAA), the latter mostly occurring in myositis-overlap syndromes. Besides the so-called traditional MSA, including anti-synthetases, anti-SRP and anti-Mi-2 antibodies, additional newly conceived immune targets have been recently identified, mostly in patients with severe forms of dermatomyositis or necrotizing myopathy. They mainly encompass enzymatic proteins essentially involved in the regulation of gene transcription or post-translational modifications, i.e., TIF1-γ, NXP-2, MDA5, SAE and HMGCR. Among the MAA, anti-PM/Scl and anti-Ku characterize an overlap polydermatomyositis/systemic sclerosis syndrome with severe interstitial lung involvement.