Mendelian susceptibility to poorly pathogenic mycobacteria, such as bacillus Calmette-Guérin (BCG) and environmental nontuberculous mycobacteria (EM), is a rare human syndrome. Some patients present with mutations in the genes encoding IL-12p40 or IL12Rβ1, associated with impaired production of IFNγ. Others carry mutations in the genes encoding IFNγ R1, IFNγ R2, or STAT1, associated with impaired response to IFNγ. Knockout mice for IL-12, IFNγ, or their receptors are also vulnerable to experimental infection with nonvirulent mycobacteria. Studies with knockout mice also implicate other molecules involved in the induction of, or response to, IFNγ, such as IL-18, IL-1, TNFα, IRF-1, and NOS2, in the control of mycobacterial infection. It is now clear that the IL-12-IFNγ loop is crucial for protective immunity to experimental and natural mycobacterial infection in both mice and men.

INTRODUCTION

Bacillus Calmette-Guérin (BCG) vaccines and environmental mycobacteria (EM) are poorly pathogenic in humans. However, they cause disseminated disease in severely immunodeficient individuals, but such patients are also susceptible to a broad range of pathogens (Reichenbach et al., 2001; Casanova and Abel, 2002). BCG and EM may also lead to severe disease in otherwise healthy individuals without any overt immunodeficiency. These patients present a selective vulnerability to mycobacterial infections (Casanova et al., 1995; 1996; Levin et al., 1995; Frucht and Holland, 1996), without any other associated infections, apart from salmonellosis, which affects less than half of the cases (reviewed in Dorman and Holland, 2000, and Casanova and Abel, 2002).