The clinical research program in the Infectious Diseases Susceptibility Unit (IDSU) of the Genetic Immunotherapy (GI) Section at the Laboratory of Host Defenses (LHD) is focused on susceptibility to infectious diseases and their management, and understanding the underlying pathophysiologic mechanisms involved. Currently, we have a particular interest in the study and treatment of subjects with 2 inherited immune deficiencies: autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) and chronic mucocutaneous candidiasis (CMC). Autoimmune-polyendocrinopathy candidiasis ectodermal dystrophy (APECED), also called autoimmune polyendocrine syndrome type I (APS-I), is a rare autosomal recessive disease (OMIM 240300) with a complex picture discovered over decades. Mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical failure are its most common components and are recognized as the classic triad. APECED has become of great theoretical interest because mutations of a previously unknown gene, autoimmune regulator gene (AIRE) (21q22.3), were shown to be its cause. AIRE is detected in a subpopulation of medullary thymic epithelial cells where it controls autoimmunity by regulating the expression of ectopic antigens. In the periphery, AIRE expression is found in blood monocytes and differentiated dendritic cells. In opposition to its autoimmune regulator function, the mechanisms by which AIRE controls Candida infections were just recently described. Anti-type 1 interferon antibodies have proven to be highly sensitive and specific markers for APECED and are not detected in CMC subjects;however, the pathophysiologic role of these antibodies has yet to be determined. Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency disorder with selective susceptibility to recurring and/or persistent debilitating infections with Candida. CMC subjects lack mutations in AIRE, as seen in APECED subjects, and can exhibit either dominant or recessive inheritance patterns. Even though CMC is often accompanied by inflammatory disorders that suggest dysregulation of the immune system, autoimmune endocrinopathies are only rarely present. Pathognomonic immunologic abnormalities that can be readily diagnosed by routine laboratory tests are also lacking, although skin tests and cytokine production in response to Candida antigens tend to be low or absent. Before year 2009, a few case reports have associated CMC to specific genetic traits as intercellular adhesion molecule 1 (ICAM-1) defective shedding or chromosome 2p, linkage. More recently, the Dectin-1 signaling pathway, due to mutations in Dectin-1 and also Card9, was unequivocally associated to the control of recurrent fungal infections in mice and humans. It was not until 2011 that STAT1 gain-of-function (GOF) heterozygous mutations were described as the most common genetic defect underlying CMC. Since our protocol was approved, we enrolled 43 individuals (3 pediatric patients). One patient was diagnosed as APECED due to homozygous AIRE mutations, three were diagnosed with CMC due to STAT1 GOF mutations, and 2 with HDR syndrome due to GATA3 mutations (a disease that shares endocrine defects with APECED but lacks candidiasis). Since our STAT1 mutated patients also presented with recurrent/severe viral infections, we are evaluating their NK cells function besides the regular studies we perform in our cohort of patients: 1. Characterize and compare the clinical and laboratory features of APECED, CMC, and other primary immunodeficiencies or particular conditions (such as infancy or diabetic subjects) with increased susceptibility to Candida or other fungal infections. 2. Determine the prevalence of AIRE mutttations in subjects with increased susceptibility to Candida or other fungal infections. 3. Establish a genotype-phenotype correlation in subjects with different AIRE mutations. 4. Determine and compare the functional integrity of Th17, Dectin1, and AIRE pathways in subjects with increased susceptibility to Candida or other fungal infections with and without AIRE mutations. Besides Candida infections, we are also interested on Hepatitis A virus (HAV) infection susceptibility, M.bovis BCG infections in patients with severe forms of primary immunodeficiencies, sterptococcus agalactiae suceptibility, and the effect of glycosylation on the immune system. Through our Primary Immunodeficiency Clinic (PID-C) we enrolled two siblings with glycosylation defects, severe hypoganmmaglobulinemia and a surprisingly low number of infections. While investigating these patients, we found that the same underlying glycosylation defect that was causing a shorten half-life on the immunoglobulin molecules and leading to hypogammaglobulinemia, was protective toward certain viral infections that depend on the glycosylation process for viral replication and viral infectivity. We are actively investigating this pathway as a mechanism to control certain viral infections in immunodeficient as well as immunocompetent individuals. This paper was submitted for publication and is under revision at a high impact factor journal. Also related to patients recruited through our PID-Clinic, we are investigating a family with increased susceptibility to S. agalactiae severe infections (sepsis, death) in which we are characterizing an heterozygous mutation we found using a high throughput sequencing technique. In relation to our interest on viral infection susceptibility, we are studying a family of 3 siblings who developed fulminant hepatitis A, an extremely rare complication not known to be associated with any genetic or familial trait. We are functionally testing the candidate genes associated with this phenotype that we found through complex genetic analysis (i.e., whole exome sequence). Mycobacterial infections in general and M.bovis BCG vaccine complications in particular, could be a major problem in patients with severe immunodeficiencies. We finalized a manuscript reporting the cumulative experience of 27 centers in 17 countries evaluating 821 severe combined immunodeficient (SCID) patients, 349 of whom received BCG vaccination. This paper was submitted for publication and is under review at a high impact factor journal.

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Lam, Christina; Ferreira, Carlos; Krasnewich, Donna et al. (2016) Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation. Genet Med :
Johnston, Alicia M; Niemela, Julie; Rosenzweig, Sergio D et al. (2016) A Novel Mutation in IKBKG/NEMO Leads to Ectodermal Dysplasia with Severe Immunodeficiency (EDA-ID). J Clin Immunol 36:541-3
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