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


Lammas, DA; De Heer, E; Edgar, JD; Novelli, V; Ben-Smith, A; Baretto, R; Drysdale, P; Binch, J; MacLennan, C; Kumararatne, DS; Panchalingam, S; Ottenhoff, TH; Casanova, JL; Emile, JF; (2002) Heterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12-dependent interferon-gamma production pathway. International journal of experimental pathology, 83 (1). pp. 1-20. ISSN 0959-9673 DOI: https://doi.org/10.1046/j.1365-2613.2002.00216.x

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Abstract

Patients 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 IFNgamma 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 IFNgamma (Fig. 9). At one pole of this spectrum, represented by the complete IFNgammaR1/2 deficient patients, there is a complete absence of mature granuloma formation, whereas with the less severe mutations (i.e. partial IFNgammaR1/2, complete IL-12p40 and complete IL-12Rbeta1 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 IFNgamma responses, other influences, including pathogen virulence and host genotype may also affect the type and scale of the cellular response elicited.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
PubMed ID: 12059906
Web of Science ID: 176130600001
URI: http://researchonline.lshtm.ac.uk/id/eprint/13053

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