title: Human immunodeficiencies that predispose to intracellular bacterial infections.
abstract: OBJECTIVE
  Patients treated with anti-tumour necrosis factor agents have an increased risk of active tuberculosis. Mycobacteria are bacterial pathogens capable of surviving and multiplying within macrophages; these infections are characterised by granulomatous inflammation. This review addresses the effects of inherited and acquired immunodeficiencies on the susceptibility to the development of intracellular bacterial infections.
  
  
  RESULTS
  Primary and secondary immunodeficiencies that result in severely impaired T cell function or macrophage activation result in an increased risk of mycobacterial and Salmonella infection. Conversely, inherited or acquired antibody or complement deficiency does not lead to increased susceptibility to these pathogens. Inherited defects in the interleukin-12/interleukin-23-dependent interferon-gamma pathway due to mutations in genes encoding the p40 chain common to interleukin-12 and interleukin-23, the beta1 chain shared by interleukin-12 and interleukin-23 receptors, interferon-gamma receptor chains 1 or 2, or signal transducer and activator of transcription, predispose to severe infections caused by poorly pathogenic mycobacteria and Salmonella species. Acquired defects of cytokine function causing increased susceptibility to these pathogens include anti-tumor necrosis factor therapy and the generation of interferon-gamma-neutralising autoantibodies. Defective nuclear factor kappaB activation caused by hypomorphic mutations of the nuclear factor kappaB essential modulator gene, which compromises the function of Toll receptors, interleukin-IL receptors, and tumor necrosis factor-alpha receptors, also increases susceptibility to severe mycobacterial infections. Patients with inherited defects in the phagocyte nicotine-adenine dinucleotide phosphate oxidase system are highly susceptible to Salmonella infections but only exhibit slightly increased susceptibility to mycobacteria.
  
  
  CONCLUSIONS
  Collectively, these observations highlight immune mechanisms that are essential for protection against intracellular bacteria. This information provides clinicians with a framework for investigating patients with potentially life-threatening intracellular bacterial infections.
authors.affiliation: Department of Clinical Biochemistry and Immunology, Cambridge, United Kingdom.
authors.forename: Rainer
authors.initials: R
authors.lastname: Doffinger
authors.forename: Smita
authors.initials: S
authors.lastname: Patel
authors.forename: Dinakantha S
authors.initials: DS
authors.lastname: Kumararatne
mesh_terms: D004198:Disease Susceptibility / Q000276:immunology*; D006801:Humans; D016867:Immunocompromised Host; D007153:Immunologic Deficiency Syndromes / Q000276:immunology* / Q000382:microbiology*; D009164:Mycobacterium Infections / Q000276:immunology*; D012480:Salmonella Infections / Q000276:immunology*