Myelin oligodendrocyte glycoprotein antibody-associated disease as a novel presentation of central nervous system autoimmunity in a pediatric patient with Wiskott-Aldrich syndrome.

BACKGROUND: Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene that leads to increased susceptibility to infections, thrombocytopenia, eczema, malignancies, and autoimmunity. Central nervous system (CNS) autoimmune manifestations are uncommon. CASE PRESENTATION: We describe the case of a five-year-old boy with refractory thrombocytopenia and iron deficiency anemia who developed relapsing bilateral optic neuritis. Myelin oligodendrocyte glycoprotein antibody (MOG-IgG) via serum fluorescence-activated cell sorting assay was positive (titer 1:100), confirming a diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). At age six, molecular panel testing for genes associated with primary immunodeficiency identified a missense WAS gene variant. He was subsequently found to have decreased WAS protein expression, consistent with a diagnosis of WAS. CONCLUSIONS: This case expands the reported spectrum of CNS autoimmunity associated with WAS and may help to inform long-term therapeutic options.

Avapritinib versus Placebo in Indolent Systemic Mastocytosis.

BACKGROUND: Indolent systemic mastocytosis (ISM) is a clonal mast-cell disease driven by the KIT D816V mutation. We assessed the efficacy and safety of avapritinib versus placebo, both with best supportive care, in patients with ISM. METHODS: We randomized patients with moderate to severe ISM (total symptom score [TSS] of ≥28; scores range from 0 to 110, with higher numbers indicating more severe symptoms) two to one to avapritinib 25 mg once daily (n=141) or placebo (n=71). The primary end point was mean change in TSS based on the 14-day average of patient-reported severity of 11 symptoms. Secondary end points included reductions in serum tryptase and blood KIT D816V variant allele fraction (≥50%), reductions in TSS (≥50% and ≥30%), reduction in bone marrow mast cells (≥50%), and quality of life measures. RESULTS: From baseline to week 24, avapritinib-treated patients had a decrease of 15.6 points (95% CI, −18.6 to −12.6) in TSS compared to a decrease of 9.2 points (−13.1 to −5.2) in the placebo group; P<0.003. From baseline to Week 24, 76/141 patients (54%; 45% to 62%) in the avapritinib group compared to 0/71 patients in the placebo group achieved a ≥50% reduction in serum tryptase level; P<0.001. Edema and increases in alkaline phosphatase were more common with avapritinib than placebo; there were few treatment discontinuations because of adverse events. CONCLUSIONS: In this trial, avapritinib was superior to placebo in reducing uncontrolled symptoms and mast-cell burden in patients with ISM. The long-term safety and efficacy of this approach for patients with ISM remain the focus of the ongoing trial. (Funded by Blueprint Medicines Corporation; ClinicalTrials.gov number, NCT03731260.)

Future Prospects of Biologic Therapies for Immunologic Diseases.

This article presents an overview of future uses for biologic therapies in the treatment of immunologic and allergic conditions. Discussion is centered on the use of existing therapies outside of their current indication or on new therapies that are close to approval. This information may help familiarize practicing allergists and immunologists with therapies they may soon encounter in their practice as well as help identify conditions and treatments that will require further study in the near future.

Local thermal injury elicits immediate dynamic behavioural responses by corneal Langerhans cells.

Langerhans cells (LCs) represent a special subset of immature dendritic cells (DCs) that reside in epithelial tissues at the environmental interfaces. Although dynamic interactions of mature DCs with T cells have been visualized in lymph nodes, the cellular behaviours linked with the surveillance of tissues for pathogenic signals, an important function of immature DCs, remain unknown. To visualize LCs in situ, bone marrow cells from C57BL/6 mice expressing the enhanced green fluorescent protein (EGFP) transgene were transplanted into syngeneic wild-type recipients. Motile activities of EGFP(+) corneal LCs in intact organ cultures were then recorded by time lapse two-photon microscopy. At baseline, corneal LCs exhibited a unique motion, termed dendrite surveillance extension and retraction cycling habitude (dSEARCH), characterized by rhythmic extension and retraction of their dendritic processes through intercellular spaces between epithelial cells. Upon pinpoint injury produced by infrared laser, LCs showed augmented dSEARCH and amoeba-like lateral movement. Interleukin (IL)-1 receptor antagonist completely abrogated both injury-associated changes, suggesting roles for IL-1. In the absence of injury, exogenous IL-1 caused a transient increase in dSEARCH without provoking lateral migration, whereas tumour necrosis factor-alpha induced both changes. Our results demonstrate rapid cytokine-mediated behavioural responses by LCs to local tissue injury, providing new insights into the biology of LCs.

Roles for IL-1 and TNFalpha in dynamic behavioral responses of Langerhans cells to topical hapten application.

BACKGROUND: To understand the behavioral biology of Langerhans cells (LCs), we recently recorded time-lapse images of LCs in the knock-in mice expressing the I-Abeta chain tagged with the enhanced green fluorescence protein (EGFP). EGFP(+) LCs showed relatively limited motility in the steady state, whereas topical application of dinitrofluorobenzene (DNFB) markedly augmented a unique movement of dendrites characterized by rhythmic extension and retraction, termed dSEARCH, and triggered amoeba-like lateral migration of cell bodies. OBJECTIVE: To define underlying mechanisms by which hapten treatment alters LC behaviors. METHODS: The I-Abeta-EGFP mice received subcutaneous (s.c.) injection of recombinant IL-1alpha or TNFalpha (50 ng/animal) and dynamic behaviors of EGFP(+) LCs were recorded by time-lapse confocal microscopy at several time points to measure their dSEARCH activities and lateral migration. In a different set of experiments, IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptor-2 (sTNFR2) (0.5 microg/animal) was s.c. injected into the ear skin 30 min before topical application of DNFB, and LC behaviors analyzed 30 h later. RESULTS: Local injection of IL-1alpha or TNFalpha induced significant, albeit modest, augmentation of both dSEARCH and lateral migration. Co-injection of TNFalpha and IL-1alpha further exacerbated motile activities in a synergistic manner by similar magnitudes observed after DNFB application. Conversely, DNFB-induced behavioral changes were inhibited completely by local injection of IL-1Ra or sTNFR2. CONCLUSION: IL-1 and TNFalpha serve as equally important mediators of hapten-induced alteration of LC behaviors. Motile activities of epidermal LCs are reprogrammed by selected cytokines known to be produced by keratinocytes under pathological conditions.

Behavioral responses of epidermal Langerhans cells in situ to local pathological stimuli.

Pathological stimuli provoke coordinated changes in gene expression, surface phenotype, and function of dendritic cells (DCs), thereby facilitating the induction of adaptive immune responses. This concept of DC maturation was established mainly by studying epidermal Langerhans cells (LCs), a prototypic immature DC subset at the environmental interface. Taking advantage of I-Abeta-enhanced green fluorescent protein (EGFP) knock-in mice in which LCs can be visualized in intact skin, we recorded the dynamic movement of EGFP+ LCs by time-lapse confocal microscopy. LCs exhibited a unique behavior, termed dendrite surveillance extension and retraction cycling habitude (dSEARCH), characterized by rhythmic extension and retraction of dendrites through intercellular spaces between keratinocytes. When monitored after skin organ culture or subcutaneous injection of tumor necrosis factor alpha, LCs showed amplified dSEARCH and amoeba-like lateral migration between keratinocytes. Intravital imaging experiments further revealed steady-state dSEARCH motion in 5-10% of LCs. Topical application of a reactive hapten, DNFB, augmented dSEARCH and triggered lateral migration of LC in vivo. These observations introduce a new concept that in situ maturation of LCs is further accompanied by coordinated reprogramming of motile activities.