Adolescents and Young Adults With Anti-N-methyl-D-aspartate Receptor Encephalitis With Excited Catatonia: Literature Review and 2 Illustrative Cases.

BACKGROUND: Catatonia is a complex neuropsychiatric syndrome that can be associated with several underlying etiologies including primary psychiatric and autoimmune disorders. Anti-N-methyl-D-aspartate receptor encephalitis is an autoimmune disorder typically characterized by seizures, movement abnormalities, and behavioral changes. Anti-N-methyl-D-aspartate can present with complex neuropsychiatric symptoms including catatonia which can be challenging for clinicians to identify as excited catatonia can mimic delirium and psychiatric disorders such as psychosis and mania. OBJECTIVES: To identify and present cases of anti-N-methyl-D-aspartate receptor encephalitis where excited catatonia is the presenting symptom. METHODS: We present 2 case studies of agitation and disinhibition in an adolescent and young adult that were ultimately found to be secondary to autoimmune receptor encephalitis, in both cases, confirmed by cerebrospinal fluid analysis to be due to anti-N-methyl-D-aspartate receptor antibodies. RESULTS: Excited catatonia was suspected and initially treated with immunological therapy and high doses of lorazepam. As the severity of catatonia progressed with limited improvement with lorazepam, both cases were ultimately effectively treated with electroconvulsive therapy. CONCLUSIONS: Excited catatonia should be considered with presentations of bizarre behavior, agitation, disinhibition, and other psychotic symptoms in patients with no prior psychiatric history. Although the primary treatment for catatonia associated with anti-N-methyl-D-aspartate receptor encephalitis is immunomodulatory therapy paired with benzodiazepines, electroconvulsive therapy has been shown to be an effective and safe adjuvant treatment that is especially useful for management of excited catatonia.

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study.

BACKGROUND AND AIMS: An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. METHODS: A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. RESULTS: Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. CONCLUSIONS: Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

Pediatric-onset Evans syndrome: Heterogeneous presentation and high frequency of monogenic disorders including LRBA and CTLA4 mutations.

Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune lymphoproliferative syndrome with FAS (ALPS-FAS), Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Lipopolysaccharide-Responsive vesicle trafficking Beige-like and Anchor protein (LRBA) defects. We report the clinical history and genetic results of 18 children with ES after excluding ALPS-FAS. Thirteen had organomegaly, five lymphocytic infiltration of non-lymphoid organs, nine hypogammaglobulinemia and fifteen anomalies in lymphocyte phenotyping. Seven patients had genetic defects: three CTLA4 mutations (c.151C>T; c.109+1092_568-512del; c.110-2A>G) identified by Sanger sequencing and four revealed by Next Generation Sequencing: LRBA (c.2450+1C>T), STAT3 gain-of-function (c.2147C>T; c.2144C>T) and KRAS (c.37G>T). No feature emerged to distinguish patients with or without genetic diagnosis. Our data on pediatric-onset ES should prompt physicians to perform extensive screening for mutations in the growing pool of genes involved in primary immune deficiencies with autoimmunity.

Atypical Manifestation of LPS-Responsive Beige-Like Anchor Deficiency Syndrome as an Autoimmune Endocrine Disorder without Enteropathy and Immunodeficiency.

Monogenic primary immunodeficiency syndromes can affect one or more endocrine organs by autoimmunity during childhood. Clinical manifestations include type 1 diabetes mellitus, hypothyroidism, adrenal insufficiency, and vitiligo. Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA) deficiency was described in 2012 as a novel primary immunodeficiency, predominantly causing immune dysregulation and early onset enteropathy. We describe the heterogeneous clinical course of LRBA deficiency in two siblings, mimicking an autoimmune polyendocrine disorder in one of them in presence of the same underlying genetic mutation. The third child of consanguineous Egyptian parents (Patient 1) presented at 6 months of age with intractable enteropathy and failure to thrive. Later on, he developed symptoms of adrenal insufficiency, autoimmune hemolytic anemia, thrombocytopenia, and infectious complications due to immunosuppressive treatment. The severe enteropathy was non-responsive to the standard treatment and led to death at the age of 22 years. His younger sister (Patient 2) presented at the age of 12 to the endocrinology department with decompensated hypothyroidism, perioral vitiligo, delayed pubertal development, and growth failure without enteropathy and immunodeficiency. Using whole exome sequencing, we identified a homozygous frameshift mutation (c.6862delT, p.Y2288MfsX29) in the LRBA gene in both siblings. To our knowledge, our patient (Patient 2) is the first case of LRBA deficiency described with predominant endocrine phenotype without immunodeficiency and enteropathy. LRBA deficiency should be considered as underlying disease in pediatric patients presenting with autoimmune endocrine symptoms. The same genetic mutation can manifest with a broad phenotypic spectrum without genotype-phenotype correlation. The awareness for disease symptoms among non-immunologists might be a key to early diagnosis. Further functional studies in LRBA deficiency are necessary to provide detailed information on the origin of autoimmunity in order to develop reliable predictive biomarkers for affected patients.

LRBA deficiency with autoimmunity and early onset chronic erosive polyarthritis.

LRBA (lipopolysaccharide-responsive and beige-like anchor protein) deficiency associates immune deficiency, lymphoproliferation, and various organ-specific autoimmunity. To date, prevalent symptoms are autoimmune cytopenias and enteropathy, and lymphocytic interstitial lung disease. In 2 siblings from a consanguineous family presenting with early onset polyautoimmunity, we presumed autosomal recessive inheritance and performed whole exome sequencing. We herein report the first case of early-onset, severe, chronic polyarthritis associated with LRBA deficiency. A novel 1bp insertion in the LRBA gene, abolishing protein expression, was identified in this family. Among the 2 brothers homozygous for LRBA mutation, one developed Evans syndrome and deceased at age 8.5 from complications of severe autoimmune thrombocytopenia. His brother, who carried the same homozygous LRBA mutation, early-onset erosive polyarthritis associated with chronic, bilateral, anterior uveitis and early onset type 1 diabetes mellitus. This report widens the clinical spectrum of LRBA deficiency and, in lights of the variable phenotypes described so far, prompts us to screen for this disease in patients with multiple autoimmune symptoms in the family, including severe, erosive, polyarticular juvenile arthritis.

Gene therapy-mediated reprogramming tumor infiltrating T cells using IL-2 and inhibiting NF-κB signaling improves the efficacy of immunotherapy in a brain cancer model.

Immune-mediated gene therapy using adenovirus expressing Flt3 ligand and thymidine kinase followed by ganciclovir administration (Flt3/TK) effectively elicits tumor regression in preclinical glioma models. Herein, we assessed new strategies to optimize Flt3L/TK therapeutic efficacy in a refractory RG2 orthotopic glioblastoma model. Specifically, we aimed to optimize the therapeutic efficacy of Flt3L/TK treatment in the RG2 model by overexpressing the following genes within the brain tumor microenvironment: 1) a TK mutant with enhanced cytotoxicity (SR39 mutant TK), 2) Flt3L-IgG fusion protein that has a longer half-life, 3) CD40L to stimulate DC maturation, 4) T helper cell type 1 polarizing dendritic cell cytokines interleukin-12 or C-X-C motif ligand 10 chemokine (CXCL)-10, 5) C-C motif ligand 2 chemokine (CCL2) or C-C motif ligand 3 chemokine (CCL3) to enhance dendritic cell recruitment into the tumor microenvironment, 6) T helper cell type 1 cytokines interferon-γ or interleukin-2 to enhance effector T-cell functions, and 7) IκBα or p65RHD (nuclear factor kappa-B [NF-κB] inhibitors) to suppress the function of Foxp3+ Tregs and enhanced effector T-cell functions. Anti-tumor immunity and tumor specific effector T-cell functions were assessed by cytotoxic T lymphocyte assay and intracellular IFN-γ staining. Our data showed that overexpression of interferon-γ or interleukin-2, or inhibition of the nuclear factor kappa-B within the tumor microenvironment, enhanced cytotoxic T lymphocyte-mediated immune responses and successfully extended the median survival of rats bearing intracranial RG2 when combined with Flt3L/TK. These findings indicate that enhancement of T-cell functions constitutes a critical therapeutic target to overcome immune evasion and enhance therapeutic efficacy for brain cancer. In addition, our study provides novel targets to be used in combination with immune-therapeutic strategies for glioblastoma, which are currently being tested in the clinic.

Antimicrobial activity of mucosal-associated invariant T cells.

Mucosal-associated invariant T lymphocytes (MAIT lymphocytes) are characterized by two evolutionarily conserved features: an invariant T cell antigen receptor (TCR) alpha-chain and restriction by the major histocompatibility complex (MHC)-related protein MR1. Here we show that MAIT cells were activated by cells infected with various strains of bacteria and yeast, but not cells infected with virus, in both humans and mice. This activation required cognate interaction between the invariant TCR and MR1, which can present a bacteria-derived ligand. In humans, we observed considerably fewer MAIT cells in blood from patients with bacterial infections such as tuberculosis. In the mouse, MAIT cells protected against infection by Mycobacterium abscessus or Escherichia coli. Thus, MAIT cells are evolutionarily conserved innate-like lymphocytes that sense and help fight off microbial infection.

Distinct roles of TLR4 and CD14 in LPS-induced inflammatory responses of neonates.

During infections, pathogens bind to toll-like receptor (TLR)4 and CD14 receptors and induce cytokine release, leading to inflammation. Here, we investigated TLR4 and CD14 expression on peripheral blood leukocytes (PBLs) and their roles in lipopolysaccharide (LPS)-induced cytokine and chemokine release. Full-term and preterm neonates and adults were studied. PBLs were pretreated with anti-TLR4- and anti-CD14-blocking antibodies and stimulated with LPS. Cytokine and chemokine levels were measured in supernatants. TLR4, CD14 expression, and LPS-induced CXCL8 release were higher in neonates, possibly contributing to aberrant inflammation. TLR4 blockade resulted in approximately 3-fold greater suppression of LPS-induced CXCL8 release in preterm neonates (38%) than in adults (14%). CD14 blockade (approximately 80%) in neonates induced approximately 3-fold greater inhibition of CXCL8 release, compared with anti-TLR4 (approximately 30%). Anti-TLR4 partly (50-60%) inhibited IL-10 and TNF-alpha, whereas anti-CD14 completely suppressed their release. Our findings reveal that neonates depend more on TLR4 for CXCL8 release. Furthermore, neonatal LPS-induced CXCL8 release, apart from TLR4/CD14-mediated signaling, is regulated by LPS interactions with other TLRs and/or immune receptors. IL-10 and TNF-alpha release depends on LPS binding not only to CD14/TLR4 but also to CD14 associated with another TLR. Our findings reveal the contribution of TLR4 and CD14 in neonatal cytokine and chemokine release and could aid in design of antagonists to prevent harmful inflammation.

Controlling tumor growth by modulating endogenous production of reactive oxygen species.

Paradoxically, reactive oxygen species (ROS) can promote normal cellular proliferation and carcinogenesis, and can also induce apoptosis of tumor cells. In this report, we study the contribution of ROS to various cellular signals depending on the nature and the level of ROS produced. In nontransformed NIH 3T3 cells, ROS are at low levels and originate from NADPH oxidase. Hydrogen peroxide (H(2)O(2)), controlled by the glutathione system, is pivotal for the modulation of normal cell proliferation. In CT26 (colon) and Hepa 1-6 (liver) tumor cells, high levels of ROS, close to the threshold of cytotoxicity, are produced by mitochondria and H(2)O(2) is controlled by catalase. N-acetylcysteine, which decreases H(2)O(2) levels, inhibits mitogen-activated protein kinase and normal cell proliferation but increases tumor cell proliferation as H(2)O(2) concentration drops from the toxicity threshold. In contrast, antioxidant molecules, such as mimics of superoxide dismutase (SOD), increase H(2)O(2) levels through superoxide anion dismutation, as well as in vitro proliferation of normal cells, but kill tumor cells. CT26 tumors were implanted in mice and treated by oxaliplatin in association with one of the three SOD mimics manganese(III)tetrakis(4-benzoic acid) porphyrin, copper(II)(3,5-diisopropylsalicylate)2, or manganese dipyridoxyl diphosphate. After 1 month, the volumes of tumors were respectively 35%, 31%, and 63% smaller than with oxaliplatin alone (P < 0.001). Similar data were gained with Hepa 1-6 tumors. In conclusion, antioxidant molecules may have opposite effects on tumor growth. SOD mimics can act in synergy with cytotoxic drugs to treat colon and liver cancers.