HLA-C and Killer Cell Immunoglobulin-like Receptor Genes in Idiopathic Bronchiectasis
Lung Immunology Group, Department of Biological Sciences/National Heart and Lung Institute, Sir Alexander Fleming Building, South Kensington Campus, London SW7 2AZ, UK. American Journal of Respiratory and Critical Care Medicine
(Impact Factor: 13).
03/2006; 173(3):327-33. DOI: 10.1164/rccm.200501-124OC
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.
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.
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.
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.
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.
Available from: Gilbert Seda
- "It has been reported that functional polymorphisms in IFNγ, neutrophil chemokine CXCR1, or a combination of both are associated with 5.6-, 8.3- and 56-fold increased susceptibility to BC-associated UC, respectively . The genetic alterations in mediators of immunity and BC may be emphasized by the data that HLA-Cw*03 alleles, HLA-C homozygocity, as well as the HLA-DR1, DQ5 haplotype are associated with increased susceptibility to BC [49, 50]. "
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ABSTRACT: Bronchiectasis (BC) is a chronic pulmonary disease with tremendous morbidity and significant mortality. As pathogen infection has been advocated as a triggering insult in the development of BC, a central role for the immune response in this process seems obvious. Inflammatory cells are present in both the airways as well as the lung parenchyma, and multiple mediators of immune cells including proteases and cytokines or their humoral products are increased locally or in the periphery. Interestingly, a defect in the immune system or suppression of immune response during conditions such as immunodeficiency may well predispose one to the devastating effects of BC. Thus, the outcome of an active immune response as detrimental or protective in the pathogenesis of BC may be dependent on the state of the patient's immunity, the severity of infection, and the magnitude of immune response. Here we reassess the function of the innate and acquired immunity in BC, the major sites of immune response, and the nature of the bioactive mediators. Furthermore, the potential link(s) between an ongoing immune response and structural alterations accompanying the disease and the success of therapies that can modulate the nature and extent of immune response in BC are elaborated upon.
Pulmonary Medicine 10/2012; 2012:280528. DOI:10.1155/2012/280528
Available from: Khalid F Tabbara
- "Several studies have shown the influence of killer cell immunoglobulin-like receptors (KIRs), and KIR-ligand pairs, in terms of the susceptibility to and outcome of various autoimmune and infectious diseases, such as AIDS [7,8], hepatitis C virus infection , tuberculosis , leprosy , bird-shot chorioretinopathy , idiopathic brochiectasis , diabetes mellitus [14,15], Systemic lupus erythromatous , Scleroderma , Sjogren’s syndrome , and ankylosing spondilitis . "
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ABSTRACT: Vogt-Koyanagi-Harada (VKH) disease is a serious ocular inflammatory autoimmune insult directed against antigens associated with melanocytes. The repertoire of killer cell immunoglobulin-like receptors (KIRs) is known to play a significant role in the pathogenesis of various autoimmune disorders. Accordingly, we sought to determine the incidence of KIR genes and KIR ligand (Human leukocytes antigen [HLA-C]) interaction in a cohort of Saudi VKH patients and to compare the findings to normal controls.
A total of 30 patients with VKH and 125 control subjects were included. PCR using sequence-specific oligonucleotide primers were employed to determine the genotype of the KIR genes and HLA-C alleles.
The frequency of KIR2DS3 was significantly higher in the VKH patients than in the control group (p=0.048). Two unique genotypes; VKHN*1 and VKHN*2 were observed in the VKH patients and not in normal controls. In addition, the majority of the VKH patients (82%) in this study carry Bx genotypes that encode 2-5 activating KIR receptors. The genotype Bx5 was found to be positively associated with the VKH patients (p=0.053). Significantly higher homozygosity of HLA-C2 was observed in the VKH patients than in controls (p=0.005). Furthermore, HLA-C alleles-Cw*14 and Cw*17 were significantly prevalent in the VKH patients (p=0.037 and p=0.0001, respectively), whereas, Cw*15 significantly increased in the control group (p=0.0205). Among potential KIR-HLA interactions, we observed KIR2DL2/2DL3+HLA-C1 to be higher in the control subjects compared with the VKH patients (p=0.018).
Our findings indicated that KIR2DS3 and HLA-class I alleles (-Cw*14 and -Cw*17) may play a role in the pathogenesis of VKH disease. Additionally, the predominance of KIR2DL2/2DL3+HLA-C1 in the controls may imply that this KIR-ligand interaction could possibly play a role in the prevention of VKH disease, or could decrease its severity. These observations may contribute to our understanding of the pathogenesis of VKH and other autoimmune diseases.
Molecular vision 12/2011; 17:3523-8. · 1.99 Impact Factor
Available from: Alessandro Soria
- "KIRs 2DL2, 2DL3 and 2DS2 have as their ligand the C1 epitope (Serine at position 77, Asparagine at position 80) present in most of HLA-Cw1, -Cw3, -Cw7, -Cw8, -Cw12, -Cw14, -Cw16 alleles . "
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ABSTRACT: In HIV-infected individuals, mechanisms underlying unsatisfactory immune recovery during effective combination antiretroviral therapy (cART) have yet to be fully understood. We investigated whether polymorphism of genes encoding immune-regulating molecules, such as killer immunoglobulin-like receptors (KIR) and their ligands class I human leukocyte antigen (HLA), could influence immunological response to cART.
KIR and HLA frequencies were analyzed in 154 HIV-infected and cART-treated patients with undetectable viral load divided into two groups: 'immunological non responders' (INR, N = 50, CD4(+) T-cell count <200/mm(3)) and full responders (FR, N = 104, CD4(+) T-cell count >350/mm(3)). Molecular KIR were typed using polymerase chain reaction-based genotyping. Comparisons were adjusted for baseline patient characteristics.
The frequency of KIR2DL3 allele was significantly higher in FR than in INR (83.7% vs. 62%, P = 0.005). The functional compound genotype HLA-C1(+)/KIR2DL3(+), even at multivariable analysis, when adjusted for nadir CD4(+) T-cell count, was associated with reduced risk of INR status: odds ratio (95% Confidence Intervals) 0.34 (0.13-0.88), P = 0.03.
Reduced presence of the inhibitory KIR2DL3 genotype detected in INR might provoke an imbalance in NK function, possibly leading to increased immune activation, impaired killing of latently infected cells, and higher proviral burden. These factors would hinder full immune recovery during therapy.
PLoS ONE 11/2011; 6(11):e27349. DOI:10.1371/journal.pone.0027349 · 3.23 Impact Factor
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