Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection.

Interferon-gamma receptor ligand-binding chain (IFN-gammaR1) or signaling chain (IFN-gammaR2) deficiency, like interleukin 12 receptor beta1 chain (IL-12Rbeta1) deficiency, predispose to severe infections due to poorly virulent mycobacteria and salmonella. A child with bacille Calmette-Guérin and Salmonella enteritidis infection was investigated. Mutations in the genes for IFN-gammaR1, IFN-gammaR2, IL-12Rbeta1, and other molecules implicated in IL-12- or IFN-gamma-mediated immunity were sought. A large homozygous deletion within the IL-12 p40 subunit gene was found, precluding expression of functional IL-12 p70 cytokine by activated dendritic cells and phagocytes. As a result, IFN-gamma production by lymphocytes was markedly impaired. This is the first discovered human disease resulting from a cytokine gene defect. It suggests that IL-12 is essential to and appears specific for protective immunity to intracellular bacteria such as mycobacteria and salmonella.

Interferon-gamma receptor deficiency: relationship between genotype, environment, and phenotype (Review).

Interferon-gamma receptor ligand binding chain (IFNgammaR1) deficiency is an autosomal recessive inherited immune disorder. Mutations in the IFNgR1 gene are associated with severe infections due to mycobacteria. However, several aspects of the phenotype of IFNgammaR1-deficient children have recently been found to vary from case to case. This review thus discusses the respective roles of the genotype and of the environment in determining phenotypic variations among affected children.

Mendelian susceptibility to mycobacterial infection in man.

Selective susceptibility to poorly pathogenic mycobacteria, such as bacille Calmette-Guérin vaccine and environmental non-tuberculous mycobacteria, has long been suspected to be a mendelian disorder but its molecular basis has remained elusive. Recently, recessive mutations in the interferon-gamma-receptor receptor ligand-binding chain, interferon-gamma-receptor signalling chain, IL-12 p40 subunit and IL-12-receptor beta 1 chain genes have been identified in a number of patients with disseminated mycobacterial infection. Although genetically distinct, these conditions are immunologically related and highlight the essential role of interferon-gamma-mediated immunity in the control of mycobacteria in man.

Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency.

In humans, interferon gamma (IFN-gamma) receptor deficiency leads to a predisposition to mycobacterial infections and impairs the formation of mature granulomas. Interleukin-12 (IL-12) receptor deficiency was found in otherwise healthy individuals with mycobacterial infections. Mature granulomas were seen, surrounded by T cells and centered with epithelioid and multinucleated giant cells, yet reduced IFN-gamma concentrations were found to be secreted by activated natural killer and T cells. Thus, IL-12-dependent IFN-gamma secretion in humans seems essential in the control of mycobacterial infections, despite the formation of mature granulomas due to IL-12-independent IFN-gamma secretion.

Fatal disseminated Mycobacterium smegmatis infection in a child with inherited interferon gamma receptor deficiency.

Mycobacterium smegmatis is a common environmental mycobacterium that was first identified in 1884, yet is a rare pathogen in humans. The few M. smegmatis infections reported to date have been localized and have occurred in association with a primary lesion in otherwise immunocompetent individuals. To our knowledge, no case of disseminated M. smegmatis infection has ever been reported, even in patients with severe immune deficiencies. We report a case of disseminated mycobacterial infection that was diagnosed in a 3-year-old girl. The pathogen was not identified as M. smegmatis until the patient was 6 years old. Her condition gradually worsened, and she died when she was 8 years old despite appropriate antimycobacterial therapy. No other opportunistic infections were documented. Immunological investigations revealed an inherited interferon gamma receptor 1 deficiency. This report identifies M. smegmatis as a new opportunistic agent that may be responsible for disseminated disease in immunocompromised individuals.

Correlation of granuloma structure with clinical outcome defines two types of idiopathic disseminated BCG infection.

Bacillus Calmette Guérin (BCG) is an attenuated strain of Mycobacterium bovis that is currently used as a live vaccine for human tuberculosis. Disseminated BCG infection may rarely occur following vaccination of children. In half of the cases, regarded as idiopathic, no well-defined immunodeficiency condition can account for the infection. However, the high rates of parental consanguinity and familial forms and the associated opportunistic infections with Salmonella suggest that these idiopathic BCG infections result from one or several new type(s) of inherited immune disorder(s). As an approach to the description and understanding of this newly described condition, the associated lesions were examined. Samples from 14 patients collected from a French national retrospective study were analysed. Pathological data from 22 cases reported in the world literature were also reviewed. Two types of granuloma were found. The first type (type I, tuberculoid) consisted of well-circumscribed and well-differentiated granulomas, with epithelioid and multinucleated giant cells containing very few acid-fast rods, surrounded by lymphocytes and fibrosis and occasionally with central caseous necrosis. The second type (type II, lepromatous-like) consisted of ill-defined and poorly differentiated granulomas, with few if any giant cells and lymphocytes but widespread macrophages loaded with acid-fast bacilli. Most children displayed a single type of granuloma. One half displayed type 1 lesions and the other half displayed type II lesions. There was a strong correlation between the type of granuloma and the clinical outcome. Tuberculoid lesions were associated with survival, whilst lepromatous-like lesions correlated with death. Correlation of granuloma structure with clinical outcome defines two types of idiopathic disseminated BCG infection. The phenotypic heterogeneity of the course of BCG infection reflects distinct pathogenic mechanisms and probably results from a genotypic heterogeneity of the underlying inherited immune disorder.

Idiopathic disseminated bacillus Calmette-Guérin infection: a French national retrospective study.

OBJECTIVE: Disseminated bacillus Calmette-Guérin (BCG) infection after inoculation of live vaccine is considered to result from impaired immunity of the child. However, in half of the cases, regarded as idiopathic, no well-defined immunodeficiency condition can account for the infection. The objective of the present study is to report the prevalence, clinical features, associated infections, and outcomes of children with idiopathic disseminated BCG infection. DESIGN: National retrospective survey during the period from 1974 through 1994 in France. SETTING: All neonatology and pediatrics units in primary care and referral centers throughout France. PATIENTS: Data were collected from 595 (82%) of 721 units, 377 (93%) of 407 centers, and 320 (93%) of 345 cities. Selection criteria included BCG infection, dissemination to at least two areas beyond the inoculation site, and no well-defined immunodeficiency condition. Sixteen children (8 girls and 8 boys), born to families unrelated to each other but often consanguinous (5 of 16) or abroad (5 of 16). RESULTS: The minimal prevalence rate was estimated at 0.59 cases per 1 million vaccinated children born in France. Clinical features included fever and cachexia, disseminated BCG infection to lymph nodes (15 of 16), skin (13 of 16), soft tissues (11 of 16), lungs (11 of 16), spleen (11 of 16), liver (11 of 16), and bones (9 of 16). Eight children had associated or subsequent severe opportunistic infection (50%), with either nontyphi Salmonella enterica serotypes (7 of 16) or Mycobacterium abscessus (1 of 16). The outcome was poor: 8 children (50%) died; the cause of death was BCG infection for most children (7 of 8); 8 survived until the last follow-up (50%). CONCLUSIONS: Idiopathic disseminated BCG infection is a rare but severe complication of BCG vaccination. The infection probably results from an as yet unknown genetically determined immunodeficiency condition that affects the killing of intracellular bacteria such as BCG and Salmonella.