Studies of Inherited Causes of Fungal Susceptability

National Institute Of Allergy And Infectious Diseases

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Abstract

Our clinical research program within the Genetic Immunotherapy (GI) Section at the Laboratory of Clinical Immunology and Microbiology (LCIM)is focused on susceptibility to infectious diseases and their management, and understanding the underlying pathophysiologic mechanisms involved. Historically, we had 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 more than 150 (adult and pediatric) patients with increased susceptibility to infections, mostly fungal. Our aims are: 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 mutations 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, we are also particularly interested in other other fungal infections, as pneumocystis jirovecii (PCP). Since 2018 we have described 3 novel genetic diseases associayted with an exquisite susceptibility to PCP: IKAROS dominant negative mutations, AIOLOS dominant negative mutations and IRF4 multimorphic mutations. In FY25 we published 8 new papers associated with this protocol, including the description of hematopoietic stem cell transplant as a curative option for IKAROS GOF disease (Clin Immunol. 2024 Mar;260:109922. doi: 10.1016), a new allelic form of IKAROS haploinsufficinecy due to protein isntability (Clin Immunol. 2025 May; 274:110469); and the T-cell and thymic defects associated with PSMB10 severe combined immunodefiency and Omenn syndrome (J Allergy Clin Immunol. 2024 Dec 27:S0091-6749(24)02416-3. doi: 10.1016/j.jaci.2024.12.1082).