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 was independently identified in 1997 by 2 groups by positional cloning. The gene is approximately 13 kb in length and contains 14 exons that encode a polypeptide of 545 amino acids. APECED appears to occur worldwide, but is relatively common only in Iranian Jews, Sardinians, and Finns, where founder mutations were described. AIRE expression is found in several tissues, the highest being evident in thymus. 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 are still elusive. Chronic oral candidiasis, the well-known and useful hallmark of APECED, when detected, should bring APECED into mind. However, it is present at the first manifestation in fewer than two thirds of Finnish subjects, despite being associated with the predominant Finnish mutation. Candidiasis may be much less common elsewhere. Of 24 Iranian Jewish subjects, who have their own unique mutation, candidiasis was observed in only 4. 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. Anti-type 1 interferon antibodies have proven to be highly sensitive and specific markers for APECED and are not detected in CMC subjects;their pathophysiologic role has yet to be determined. So far, a few reports have associated CMC to chromosome 2p, or to intercellular adhesion molecule 1 (ICAM-1) shedding. More recently, the Dectin-1 signaling pathway was also implicated in the control of recurrent fungal infections in mice and humans. We are currently on the last steps of the process of getting our protocol approved by the IRB. Once our protocol is approved, we will start recruiting patients for our study that will allow us to: 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, and M.bovis BCG infections in patients with severe forms of primary immunodeficiencies. HAV infection is one of the most common viral infections in humans. HAV, a single stranded RNA Picornavirus transmitted by the fecal-oral route, is endemic in many countries, particularly those with poor sanitation. Most individuals infected with HAV develop mild or asymptomatic disease, a small number of patients develop self-limited liver inflammation, and very rarely, HAV infection can evolve into fulminant hepatic failure (FHF). In most developing countries, HAV infection remains the major cause of FHF and liver transplantation in pediatric patients. The reason(s) for the wide range in the severity of HAV infection is not yet understood, but is unlikely to be associated with the virus genotype: HAV genotype 1A, the most prevalent form of the virus, has been associated with endemic, epidemic, sporadic, asymptomatic, self-limited, as well as, FHF cases of HAV infection. We have recently found that a particular variant of the human HAV receptor (HAVcr1 or TIM1) was overrepresented among patients with HAV-induced FHF. Besides, we also detected that iNKT cells, some natural liver resident lymphocytes, express the HAVcr1 receptor, recognize Hepatitis A virus antigens on the hepatocyte's cell surface, and generate liver damage in a HAVcr1-dependent manner. Interestingly, these lymphocytes, when expressing this particular variant of the receptor, bound HAV significantly more efficiently and resulted in a significantly greater cytolytic activity against HAV-infected liver cells. Our work was recently published on the Journal of Clinical Investigation. Tuberculosis is a major epidemiological problem. Approximately one third of the world population is infected with Mycobacterium tuberculosis (MTB), with almost 14 million chronic cases, 10 million new cases and more than 2 million deaths being reported each year worldwide. The BCG (Bacille Calmette-Guerin) vaccine, applied to 87% of newborns worldwide, have had an important role in preventing disseminated forms of tuberculosis among the immune competent population since 1948. However, this live-attenuated vaccine can exert devastating complications on immunodeficient patients. In order to determine the incidence and clinical impact of BCG vaccination over the most severe forms of primary immunodeficiencies, we decided to conduct an international survey to analyze BCG complications on severe combined immunodeficient (SCID) patients. So far we collected information on 287 SCID patients from 23 centers in 16 countries. Our study, the first of its kind trying to address this problem in a multicenter/international way, will give us information regarding the real incidence of BCG complications, ways of searching and treating them, and also give us some clues on how to protect SCID patients from this devastating, however preventable, complications.
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