Objective To describe the clinical, laboratory, and histopathologic features, current treatment, and outcome of patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA). Methods In this multinational, multicenter study, pediatric rheumatologists and hemato‐oncologists entered patient data collected retrospectively into a web‐based database. Results A total of 362 patients, 22% of whom had MAS at the onset of systemic JIA, were included in the study by 95 investigators from 33 countries. The most frequent clinical manifestations were fever (96%), hepatomegaly (70%), and splenomegaly (58%). Central nervous system dysfunction and hemorrhages were recorded in 35% and 20% of the patients, respectively. Platelet count and liver transaminase, ferritin, lactate dehydrogenase, triglyceride, and d‐dimer levels were the sole laboratory biomarkers showing a percentage change of >50% between the pre‐MAS visit and MAS onset. Evidence of macrophage hemophagocytosis was found in 60% of the patients who underwent bone marrow aspiration. MAS occurred most frequently in the setting of active underlying disease, in the absence of a specific trigger. Nearly all patients were given corticosteroids, and 61% received cyclosporine. Biologic medications and etoposide were given to 15% and 12% of the patients, respectively. Approximately one‐third of the patients required admission to the intensive care unit (ICU), and the mortality rate was 8%. Conclusion This study provides information on the clinical spectrum and current management of systemic JIA–associated MAS through the analysis of a very large patient sample. MAS remains a serious condition, as a sizeable proportion of patients required admission to the ICU or died.

Classic hyperacute rejection is dependent on the activation of the terminal components of complement. Recently, xenoantibodies with limited abilities to activate the classical pathway of complement in vitro have been implicated in the acute vascular rejection of xenografts. It is unclear how these Abs affect their pathogenic activities in vivo. In this study, we demonstrate the ability of an anti-Gal-α1,3Gal (Gal) IgG1, with modest complement-activating abilities in vitro, to induce xenograft rejection. This rejection was dependent on the activation of complement, on FcγR-mediated interactions, and on the presence of NK cells. Inhibition of any one of these factors resulted in the abrogation of IgG1-mediated rejection. In contrast, an anti-Gal IgG3 mAb induced classic, hyperacute rejection that was solely dependent on complement activation. Our observations implicate two types of IgG-mediated rejection; one that is dependent on complement activation, and a second that is uniquely dependent on complement, FcγR, and NK cells.

Penicilliosis is a severe disease causing high mortality in children. As an AIDS-defining illness, penicilliosis should be regarded as an indicator for underlying immunodeficiency in HIV-negative individuals. Immunological investigations should be performed, especially in those with recurrent infections. Multicentered collaborative studies are needed to collect information on long-term prognosis and define immune defects underlying penicilliosis.

We previously reported that the immunosuppressive malononitrileamides leflunomide and FK778 exert antiviral activity against cytomegalovirus (CMV). In the current investigation, we tested the hypothesis that leflunomide exerts concurrent antiviral activity and immune suppression in CMV-infected cardiac allograft recipients. Lewis rats were transplanted with Brown Norway hearts and then inoculated with rat CMV. Plaque assay demonstrated that leflunomide (30 mg/kg/day) reduced viral loads by 4-6 logs, and that the reduction in viral load was unaffected by administration of uridine. Leflunomide was as effective as cyclosporine A (CsA) or tacrolimus in preservation of allograft integrity through day 28. These studies directly demonstrate the bifunctionality of leflunomide as concurrently immunosuppressive and antiviral, enhancing the promise of this agent as a clinical option for treatment of transplant recipients.

BackgroundMonogenic autoinflammatory disorders are characterized by dysregulation of the innate immune system, for example by gain-of-function mutations in inflammasome-forming proteins, such as NOD-like receptor family CARD-containing 4 protein (NLRC4).ObjectiveHere we investigate the mechanism by which a novel mutation in the leucine-rich repeat (LRR) domain of NLRC4 (c.G1965C, p.W655C) contributes to autoinflammatory disease. Methods: We studied 2 unrelated patients with early-onset macrophage activation syndrome harboring the same de novo mutation in NLRC4. In vitro inflammasome complex formation was quantified by using flow cytometric analysis of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 techniques and lentiviral transduction were used to generate THP-1 cells with either wild-type or mutant NLRC4 cDNA. Cell death and release of IL-1β/IL-18 were quantified by using flow cytometry and ELISA, respectively.ResultsThe p.W655C NLRC4 mutation caused increased ASC speck formation, caspase-1–dependent cell death, and IL-1β/IL-18 production. ASC contributed to p.W655C NLRC4–mediated cytokine release but not cell death. Mutation of p.W655 activated the NLRC4 inflammasome complex by engaging with 2 interfaces on the opposing LRR domain of the oligomer. One key set of residues (p.D1010, p.D1011, p.L1012, and p.I1015) participated in LRR-LRR oligomerization when triggered by mutant NLRC4 or type 3 secretion system effector (PrgI) stimulation of the NLRC4 inflammasome complex.ConclusionThis is the first report of a mutation in the LRR domain of NLRC4 causing autoinflammatory disease. c.G1965C/p.W655C NLRC4 increased inflammasome activation in vitro. Data generated from various NLRC4 mutations provides evidence that the LRR-LRR interface has an important and previously unrecognized role in oligomerization of the NLRC4 inflammasome complex.