Heterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12‐dependent interferon‐gamma production pathway

SummaryPatients with genetic lesions in the Type‐1 cytokine/cytokine receptor pathway exhibit a selective susceptibility to severe infections with poorly pathogenic mycobacteria and non‐typhi salmonella spp. These experiments of nature demonstrate that IL‐12‐dependent IFNγ production is critical for granuloma formation and therefore host immunity against such pathogens. The essential role of granuloma formation for protective immunity to these organisms is emphasized by the differing granuloma forming capabilities and resultant clinical sequelae observed in these patients which seems to reflect their ability to produce or respond to IFNγ (Fig. 9). At one pole of this spectrum, represented by the complete IFNγR1/2 deficient patients, there is a complete absence of mature granuloma formation, whereas with the less severe mutations (i.e. partial IFNγR1/2, complete IL‐12p40 and complete IL‐12Rβ1 deficiency), granuloma formation is very heterogenous with wide variations in composition being observed. This suggests that in the latter individuals, who produce partial but suboptimal IFNγ responses, other influences, including pathogen virulence and host genotype may also affect the type and scale of the cellular response elicited. Spectrum of genetic susceptibility to intracellular bacteria. At one pole of this spectrum complete IFNγR deficiencies are found; at the other pole are healthy resistant individuals. Partial IFNγR1 deficiencies, and complete IL‐12Rβ1 and IL‐12p40 deficiencies can be positioned in between, albeit closer to the former end of the spectrum, with clinical outcome also depending on pathogen virulence and host compensatory immune mechanism(s). Abbreviations: IFNγR – interferon gamma receptor, IL‐12Rβ1 – interleukin 12 receptor‐1 (modified from Ottenhoff et al. (1998)).image