title: Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-gamma.
abstract: Genetic defects in the IFN-gamma response pathway cause unique susceptibility to intracellular pathogens, particularly mycobacteria, but are rare and do not explain mycobacterial disease in the majority of affected patients. We postulated that acquired defects in macrophage activation by IFN-gamma may cause a similar immunological phenotype and thus explain the occurrence of disseminated intracellular infections in some patients without identifiable immune deficiency. Macrophage activation in response to IFN-gamma and IFN-gamma production were studied in whole blood and PBMCs of 3 patients with severe, unexplained nontuberculous mycobacterial infection. In all 3 patients, IFN-gamma was undetectable following mitogen stimulation of whole blood, but significant quantities were detectable in the supernatants of PBMCs when stimulated in the absence of the patients' own plasma. The patients' plasma inhibited the ability of IFN-gamma to increase production of TNF-alpha by both autologous and normal donor PBMCs, and recovery of exogenous IFN-gamma from the patients' plasma was greatly reduced. Using affinity chromatography, surface-enhanced laser desorption/ionization mass spectrometry, and sequencing, we isolated an IFN-gamma-neutralizing factor from the patients' plasma and showed it to be an autoantibody against IFN-gamma. The purified anti-IFN-gamma antibody was shown to be functional first in blocking the upregulation of TNF-alpha production in response to endotoxin; second in blocking induction of IFN-gamma-inducible genes (according to results of high-density cDNA microarrays); and third in inhibiting upregulation of HLA class II expression on PBMCs. Acquired defects in the IFN-gamma pathway may explain unusual susceptibility to intracellular pathogens in other patients without underlying, genetically determined immunological defects.
authors.affiliation: Department of Paediatrics and Wellcome Centre for Clinical Tropical Medicine, Imperial College London, London, United Kingdom.
authors.forename: Beate
authors.initials: B
authors.lastname: Kampmann
authors.forename: Cheryl
authors.initials: C
authors.lastname: Hemingway
authors.forename: Alick
authors.initials: A
authors.lastname: Stephens
authors.forename: Robert
authors.initials: R
authors.lastname: Davidson
authors.forename: Anna
authors.initials: A
authors.lastname: Goodsall
authors.forename: Suzanne
authors.initials: S
authors.lastname: Anderson
authors.forename: Mark
authors.initials: M
authors.lastname: Nicol
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schölvinck
authors.forename: David
authors.initials: D
authors.lastname: Relman
authors.forename: Simon
authors.initials: S
authors.lastname: Waddell
authors.forename: Paul
authors.initials: P
authors.lastname: Langford
authors.forename: Brian
authors.initials: B
authors.lastname: Sheehan
authors.forename: Lynn
authors.initials: L
authors.lastname: Semple
authors.forename: Katalin A
authors.initials: KA
authors.lastname: Wilkinson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
authors.forename: Stanley
authors.initials: S
authors.lastname: Ress
authors.forename: Martin
authors.initials: M
authors.lastname: Hibberd
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D004198:Disease Susceptibility / Q000097:blood / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D005802:Genes, MHC Class II; D006680:HLA Antigens; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009164:Mycobacterium Infections / Q000097:blood / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D006680:HLA Antigens; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma