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Infection and Immunity, October 2003, p. 5690-5699, Vol. 71, No. 10
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.10.5690-5699.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Deregulated Production of Protective Cytokines in Response to Candida albicans Infection in Patients with Chronic Mucocutaneous Candidiasis

Desa Lilic,1* Ian Gravenor,1,{dagger} Neil Robson,1,{ddagger} David A. Lammas,2 Pam Drysdale,2 Jane E. Calvert,1 Andrew J. Cant,3 and Mario Abinun3

School of Cell and Molecular Biosciences, University of Newcastle,1 Center for Bone Marrow Transplantation in Children with Primary Immunodeficiencies, The Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne,3 Division of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom2

Received 11 April 2003/ Returned for modification 15 May 2003/ Accepted 14 June 2003

Patients with chronic mucocutaneous candidiasis (CMC) are selectively unable to clear the yeast Candida, which results in persistent debilitating infections affecting the skin, nails, and mucous membranes. The underlying defect is unknown. Recent animal studies highlighted the importance of type 1 cytokines in protection against Candida, and previous work suggested that CMC patients may exhibit altered cytokine production in response to Candida. Based on these findings, in this study we investigated cytokine production in CMC patients by assessing a range of inflammatory, anti-inflammatory, type 1, and type 2 cytokines (interleukin-2 [IL-2], IL-4, IL-5, IL-6, IL-10, IL-12, gamma interferon [IFN-{gamma}], tumor necrosis factor alpha [TNF-{alpha}]) in whole-blood cultures in response to five different fractions of Candida albicans (carbohydrate, purified mannan, and protein-rich fractions, etc.), as well as non-Candida antigens. Our results demonstrate that cytokine production is deregulated in a Candida-specific way for some cytokines (IL-2, IL-10), is deregulated more generally for other cytokines (IL-12, IL-6, IFN-{gamma}), and is not markedly altered for still other cytokines (TNF-{alpha}, IL-4, IL-5). The most notable finding in CMC patients was the markedly impaired production of IL-12 in parallel with dramatically increased levels of IL-6 and IL-10 that occurred selectively in response to Candida. These results suggest that patients with CMC have impaired production of type 1-inducing cytokines (possibly a macrophage or dendritic cell defect?), which could result in an inability to mount protective cell-mediated responses and a failure to clear Candida. Continued tissue damage and inflammation may trigger production of high levels of inhibitory cytokines, such as the IL-10 production seen in our study, which would further reduce production of type 1-inducing cytokines in a positive feedback loop leading to persistent infection.

* Corresponding author. Mailing address: School of Cell and Molecular Biosciences, The Medical School, University of Newcastle, Newcastle upon Tyne, United Kingdom, NE2 4HH. Phone: 44 191 222 7244. Fax: 44 191 222 7736. E-mail: desa.lilic{at}ncl.ac.uk.

Editor: T. R. Kozel

{dagger} Present address: ORION Clinical Services Ltd., Slough, Berkshire, United Kingdom, RG1 2NU.

{ddagger} Present address: Department of Immunology and Bacteriology, University of Glasgow, Glasgow, United Kingdom, G11 6NT.

Infection and Immunity, October 2003, p. 5690-5699, Vol. 71, No. 10
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.10.5690-5699.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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