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HLA-C and Killer Cell Immunoglobulin-like Receptor Genes in Idiopathic Bronchiectasis

Lung Immunology Group, Department of Biological Sciences and National Heart and Lung Institute, Faculty of Medicine, South Kensington Campus; Department of Occupational and Environmental Medicine, National Heart and Lung Institute, Brompton Campus; and Human Disease Immunogenetics Group, Department of Infectious Diseases, Hammersmith Campus, Imperial College; Host Defense Unit, Department of Respiratory Medicine, Royal Brompton and Harefield National Health Service Trust, London; Heart Science Centre, Harefield Hospital, Imperial College, Harefield; and Immunology Division, Department of Pathology, University of Cambridge, Cambridge, United Kingdom

Correspondence and requests for reprints should be addressed to Rosemary Boyton, M.D., Lung Immunology Group, Department of Biological Sciences/National Heart and Lung Institute, Sir Alexander Fleming Building, South Kensington Campus, Faculty of Medicine, Imperial College, London SW7 2AZ, UK. E-mail: r.boyton{at}imperial.ac.uk

Rationale: In idiopathic bronchiectasis, lung inflammation and chronic bacterial infection lead to progressive lung damage. A possible role for natural killer (NK) cells is suggested by the observation that familial bronchiectasis occurs in a rare group of individuals with impaired HLA class I expression and consequent NK cell dysfunction.

Objective: Because the HLA-C locus and killer cell immunoglobulin-like receptors (KIRs) are of key importance for NK cell recognition, we analyzed HLA-C/KIR combinations by genotyping patients with idiopathic bronchiectasis.

Methods: Genomic DNA from 96 individuals with idiopathic bronchiectasis and 101 control subjects was analyzed by polymerase chain reaction with sequence-specific primers. High-resolution HLA-C genotyping was performed in addition to KIR analysis.

Results: HLA-Cw*03 alleles and, in particular, HLA-C group 1 homozygosity are associated with the presence of bronchiectasis. Analysis of the relationship between HLA-C and KIR genes suggests a shift to activatory NK cell function.

Conclusion: This is the first demonstration of genetic susceptibility in idiopathic bronchiectasis. The association with HLA-C group 1 homozygosity, and the interplay between HLA-C and KIR genes, argue for a role for NK cells in the progressive lung damage seen in this disease. This will require further investigation using functional studies.

Key Words: bronchiectasis • HLA-C • humans • immunity • killer cell immunoglobulin-like receptor

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