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Background: Paracoccidioides brasiliensis is a facultative intracellular dimorphic fungus that causes paracoccidioidomycosis (PCM), the most important deep mycosis in Latin America. Only a small percentage of individuals infected by P. brasiliensis develop clinical PCM, possibly in part because of genetically determined interindividual variability of host immunity. However, no primary immunodeficiency has ever been associated with PCM., Methods: We describe the first patient, to our knowledge, with PCM and a well-defined primary immunodeficiency in the beta 1 subunit of the interleukin (IL)-12/IL-23 receptor, a disorder previously shown to be specifically associated with impaired interferon (IFN)-gamma production, mycobacteriosis, and salmonellosis., Results: Our patient had a childhood history of bacille Calmette-Guérin disease and nontyphoid salmonellosis and, at the age of 20 years, presented to our clinic with a disseminated (acute) form of PCM. He responded well to antifungal treatment and is now doing well at 24 years of age., Conclusions: This unique observation supports previous studies of PCM suggesting that IL-12, IL-23, and IFN-gamma play an important role in protective immunity to P. brasiliensis. Tuberculosis and PCM are thus not only related clinically and pathologically, but also by their immunological pathogenesis. Our study further expands the spectrum of clinical manifestations of inherited defects of the IL-12/IL-23-IFN-gamma axis. Patients with unexplained deep fungal infections, such as PCM, should be tested for defects in the IL-12/IL-23-IFN- gamma axis.

Patients with inherited deficiency of the interleukin (IL)-12/IL-23-interferon (IFN)- gamma axis show increased susceptibility to invasive disease caused by the intramacrophage pathogens salmonellae and mycobacteria. We analyzed data on 154 patients with such deficiency. Significantly more patients with IL-12/IL-23-component deficiency had a history of salmonella disease than did those with IFN- gamma -component deficiency. Salmonella disease was typically severe, extraintestinal, and caused by nontyphoidal serovars. These findings strongly suggest that IL-12/IL-23 is a key cytokine for immunity against salmonella in humans and that IL-12/IL-23 mediates this protective effect partly through IFN- gamma -independent pathways. Investigation of the IL-12/IL-23-IFN- gamma axis should be considered in patients with invasive salmonella disease.

Complete interleukin-12/interleukin-23 receptor beta1 (IL-12Rbeta1) deficiency is the most frequent known genetic etiology of the syndrome of Mendelian susceptibility to mycobacterial disease. The patients described to date lack IL-12Rbeta1 at the surface of their natural killer (NK) and T cells due to IL12RB1 mutations, which either interrupt the open reading frame or disrupt protein folding. We describe a patient with a large in-frame deletion of 12165 nucleotides (nt) in IL12RB1, encompassing exons 8 to 13 and resulting in the surface expression of nonfunctional IL-12Rbeta1. These 6 exons encode the proximal NH2-terminal half of the extracellular domain downstream from the cytokine-binding domain. Five of 6 monoclonal anti-IL-12Rbeta1 antibodies tested recognized the internally truncated chain on the cell surface. However, IL-12 and IL-23 did not bind normally to the patient's IL-12Rbeta1-containing respective heterodimeric receptors. As a result, signal transducer and activator of transcription-4 (STAT4) was not phosphorylated and interferon-gamma (IFN-gamma) production was not induced in the patient's cells upon stimulation with even high doses of IL-12 or IL-23. The functional defect was completely rescued by retrovirus-mediated IL-12Rbeta1 gene transfer. Thus, the detection of IL-12Rbeta1 on the cell surface does not exclude the possibility of complete IL-12Rbeta1 deficiency in patients with mycobacteriosis or salmonellosis. Paradoxically, the largest IL12RB1 mutation detected is associated with the cell surface expression of nonfunctional IL-12Rbeta1, defining a novel genetic form of IL-12Rbeta1 deficiency.

Genetic deficiency of human IL-12 receptor beta1 chain (IL-12Rbeta1) results in increased vulnerability to weakly pathogenic strains of Mycobacteria and Salmonella. This phenotype results from the combined lack of IL-12 and IL-23 signaling as both cytokine receptors share IL-12Rbeta1. Such infections can be treated by administration of antibiotics and IFN-gamma; however, patients can succumb to infections despite these treatments. Reversion of patients' susceptibility by corrective gene transfer could prevent the infectious episodes, thus providing a beneficial alternative. We therefore evaluated the feasibility of retroviral-mediated gene correction of T cells obtained from patients carrying "null" mutations of IL-12Rbeta1. Transduction of the IL-12Rbeta1 cDNA restored the expression of IL-12Rbeta1 and resulted in the reconstitution of a functional IL-12 signaling pathway, as demonstrated by STAT4 phosphorylation and IFN-gamma production. IFN-gamma production in response to IL-23 was also corrected after gene transfer. These results indicate that the biological defects of T cells from patients carrying IL-12Rbeta1 deficiency can be corrected by gene transfer and form the basis for further development of gene therapy for this disease.

Interleukin-12 (IL12) is a cytokine that is secreted by activated phagocytes and dendritic cells and that induces interferon-gamma production by natural-killer and T lymphocytes. It consists of two subunits, p35 and p40, which are encoded by IL12A and IL12B, respectively. The first reported patient with a genetic cytokine disorder was a Pakistani child, who was homozygous for a large loss-of-function deletion (g.482+82_856-854del) in IL12B. This IL12-deficient child suffered from infections caused by bacille Calmette-Guérin (BCG) and Salmonella enteritidis. We herein report 12 additional patients from five other kindreds. In one kindred from India, the same large deletion that was described elsewhere (g.482+82_856-854del) was identified. In four kindreds from Saudi Arabia, a recessive loss-of-function frameshift insertion (g.315_316insA) was found. A conserved haplotype encompassing the IL12B gene suggested that a founder effect accounted for the recurrence of each mutation. The two founder mutational events-g.482+82_856-854del and g.315_316insA-were estimated to have occurred approximately 700 and approximately 1,100 years ago, respectively. Among a total of 13 patients with IL12 deficiency, 1 child had salmonellosis only and 12 suffered from clinical disease due to BCG or environmental nontuberculous mycobacteria. One patient also had clinical disease caused by virulent Mycobacterium tuberculosis, five patients had clinical disease caused by Salmonella serotypes, and one patient had clinical disease caused by Nocardia asteroides. The clinical outcome varies from case to case, since five patients (aged 2-11 years) died of overwhelming infection, whereas eight patients (aged 3-12 years) are still in good health and are not currently taking antibiotics. In conclusion, IL12 deficiency is not limited to a single kindred, shows significant variability of outcome, and should be considered in the genetic diagnosis of patients with mycobacteriosis and/or salmonellosis. To date, two founder IL12B mutations have been identified, accounting for the recurrence of a large deletion and a small insertion within populations from the Indian subcontinent and from the Arabian Peninsula, respectively.

T-helper (Th)2 cells, which produce the cytokines interleukins (IL)-4, IL-5 and IL-13, dominate T cell responses in allergic diseases. The Th1-type cytokines IL-12 and interferon-gamma (IFNgamma) are important in down-regulating Th2 responses to allergens. Patients with defects in the IL-12 receptor (IL-12R) or IFNgamma receptor (IFNgammaR) have abnormal responses to IL-12 or IFNgamma and a failure to produce normal levels of IFNgamma. Current paradigms of T-helper subset balance would predict a high prevalence of atopic illness in this group. We have studied a cohort of patients (n =29) with defects in these pathways to assess the prevalence of allergic disease. A questionnaire based on those developed for the International Study of Asthma and Allergy in Childhood (ISAAC) was used in conjunction with analysis of total and specific IgE to common aeroallergens. The prevalence of asthma, eczema and rhino-conjunctivitis (13.7%, 17.5% and 6.8% respectively) in this group was no higher than in comparable populations where prevalences of 13.9%, 7.9% and 13.5% are reported for asthma, eczema and rhinoconjunctivitis respectively. Patients with IFNgammaR defects had higher rates of clinical atopic illness than control populations and patients with IL-12R defects, with 28.5% prevalences for asthma and eczema, respectively. None of the patients suffered from severe clinical atopic disease. Defects in interferon-gamma receptor/interleukin-12 receptor responses are not sufficient to cause clinical allergic disease. Patients with defects in the interferon-gamma receptor pathway have a higher prevalence of high IgE and clinical atopic illness compared to control populations, supporting the concept that interferon-gamma receptor signalling plays a role in down-regulating type-2 cytokine responses. [ABSTRACT FROM AUTHOR]

Background. Paracoccidioides brasiliensis is a facultative intracellular dimorphic fungus that causes paracoccidioidomycosis (P CM), the most important deep mycosis in Latin America. Only a small percentage of individuals infected by P. brasiliensis develop clinical PCM, possibly in part because of genetically determined interindividual variability of host immunity. However, no primary immunodeficiency has ever been associated with PCM. Methods. We describe the first patient, to our knowledge, with PCM and a well-defined primary immunodeficiency in the β1 subunit of the interleukin (IL)-12/IL-23 receptor, a disorder previously shown to be specifically associated with impaired interferon (IFN)-γ production, mycobacteriosis, and salmonellosis. Results. Our patient had a childhood history of bacille Calmette-Guérin disease and nontyphoid salmonellosis and, at the age of 20 years, presented to our clinic with a disseminated (acute) form of PCM. He responded well to antifungal treatment and is now doing well at 24 years of age. Conclusions. This unique observation supports previous studies of PCM suggesting that IL-12, IL-23, and IFN-γ play an important role in protective immunity to P. brasiliensis. Tuberculosis and PCM are thus not only related clinically and pathologically, but also by their immunological pathogenesis. Our study further expands the spectrum of clinical manifestations of inherited defects of the IL-12/IL-23-IFN-γ axis. Patients with unexplained deep fungal infections, such as PCM, should be tested for defects in the IL-12/IL-23-IFN-γ axis. [ABSTRACT FROM AUTHOR]

An 11-year-old girl who presented with disseminated tuberculosis associated with secondary hemophagocytosis received a diagnosis of interleukin-12 receptor β1 chain deficiency. This diagnosis of immuno deficiency should, therefore, be considered for children with disseminated tuberculosis, even in the absence of any personal or familial history of prior infection by weakly pathogenic Salmonella and Mycobacterium species. [ABSTRACT FROM AUTHOR]