Severe Mycobacterial Disease Research Articles

Nontuberculous mycobacterial infections in children with inborn errors of the immune system

Severe mycobacterial disease is mostly confined to patients who are immunocompromized either by acquired or inherited causes. One such genetic disorder is Mendelian Susceptibility to Mycobacterial Disease (MSMD), a hot topic within the field of primary immunodeficiency. This single gene disorder is characterized by isolated infection with mycobacteria or Salmonella due to a defect in the type-1 cytokine response. In the last two decades, ten genes have been labeled as causing MSMD when they harbor germline mutations, namely IL12B, IL12RB1, IFNGR1, IFNGR2, STAT1, IKBKG, CYBB, TYK2, IRF8 and ISG15. The mutations lead to either insufficient production of IFN-γ, or to an insufficient response to the cytokine. Current treatment options include recombinant IFN-γ and hematologic stem cell transplantation (HSCT). In the future, gene therapy, antisense-mediated exon skipping and chemical intervention in glycosylation problems may become successful alternatives. Furthermore, it is likely that many new candidate genes and pathways crucial for mycobacterial immunity will be identified.

ISG15: leading a double life as a secreted molecule

ISG15 is a well-known intracellular ubiquitin-like molecule involved in ISGylation. However, a recent study has revived the notion first put forward two decades ago that ISG15 is also a secreted molecule. Human neutrophils, monocytes and lymphocytes can release ISG15, even though this protein has no detectable signal peptide sequence. ISG15 has also been found in the secretory granules of granulocytes. The mechanism underlying ISG15 secretion is unknown. Secreted ISG15 acts on at least T and natural killer (NK) lymphocytes, in which it induces interferon (IFN)-γ production. However, the mechanism by which ISG15 stimulates these cells also remains unclear. ISG15 and IFN-γ seem to define an innate circuit that operates preferentially, but not exclusively, between granulocytes and NK cells. Inherited ISG15 deficiency is associated with severe mycobacterial disease in both mice and humans. This infectious phenotype probably results from the lack of secreted ISG15, because patients and mice with other inborn errors of IFN-γ immunity also display mycobacterial diseases. In addition to raising mechanistic issues, the studies described here pave the way for clinical studies of various aspects, ranging from the use of recombinant ISG15 in patients with infectious diseases to the use of ISG15-blocking agents in patients with inflammatory diseases.

Polymorphism within the Interferon-γ/Receptor Complex Is Associated with Pulmonary Tuberculosis

Interferon-gamma (IFN-gamma) is of central interest in the study of tuberculosis. A number of single-gene mutations have been identified in the IFN-gamma signaling pathway that predispose to severe mycobacterial disease, but the relevance of polymorphism within these genes to the common phenotype of tuberculosis remains unclear. A total of 1,301 individuals were included in a large, detailed study of West African populations with pulmonary tuberculosis. We investigated disease association with the genes encoding IFN-gamma and its receptor subunits (IFNG, IFNGR1, and IFNGR2). Within the IFNG gene, two promoter variants showed evidence of novel disease association: -1616GG (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.11-2.00; p = 0.008) and +3234TT (OR, 1.40; 95% CI, 1.09-1.80; p = 0.009). The +874AA genotype was not significantly more frequent among cases over control subjects (OR, 1.16; 95%CI, 0.89-1.51; p = 0.25). In addition, novel disease association was also found with the -56CC genotype of the IFNGR1 promoter (OR, 0.75; 95% CI, 0.57-0.99; p = 0.041). No disease association was seen with the IFNGR2 locus. These results provide evidence of a significant role for genetic variation at the IFNG locus and provide detailed understanding of the genetic mechanisms underlying this association. The disease association with IFNGR1 is novel, and together these findings support the hypothesis that genetically determined variation in both IFN-gamma production and responsiveness influences the risk of developing tuberculosis.

HHV-8–associated Kaposi sarcoma in a child with IFNγR1 deficiency

Objectives Mediterranean classic Kaposi sarcoma (KS) of childhood is rare and unexplained. Our objective is to describe the case of a child with complete IFNγR1 deficiency and severe mycobacterial disease in whom Kaposi sarcoma (KS) developed. Results Disseminated mycobacterial infection began at the age of 5 months, and at 11 years of age the child had disseminated KS lesions. The histologic appearance of these lesions was typical, with endothelial and spindle cell proliferation. Human herpesvirus-8 (HHV-8)-associated antigens were detected in situ by immunohistochemistry. HHV-8 DNA of K1 molecular subtype A was amplified from tissue lesions, and HHV-8–specific antibodies were detected in the patient's serum. The child died at 12 years of age of disseminated mycobacterial disease and KS. Conclusions This is the first identification of a well-defined primary immunodeficiency in a child with KS. Inherited disorders of IFN-γ–mediated immunity and severe mycobacterial disease may predispose HHV-8–infected children to KS.