Abstract
A role for hereditary influences in the susceptibility for chronic obstructive pulmonary disease (COPD) is widely recognized. Cytotoxic lymphocytes are implicated in COPD pathogenesis, and functions of these leukocytes are modulated by interactions between their killer cell Ig-like receptors (KIR) and human leukocyte antigen–Class I (HLA–Class I) molecules on target cells. We hypothesized HLA–Class I and KIR inheritance affect risks for COPD. HLA–Class I alleles and KIR genotypes were defined by candidate gene analyses in multiple cohorts of patients with COPD (total n = 392) and control smokers with normal spirometry (total n = 342). Compared with controls, patients with COPD had overrepresentations of HLA-C*07 and activating KIR2DS1, with underrepresentations of HLA-C*12. Particular HLA-KIR permutations were synergistic; e.g., the presence of HLA-C*07 + KIR2DS1 + HLA-C12null versus HLAC*07null + KIR2DS1null + HLA-C12 was associated with COPD, especially among HLA-C1 allotype homozygotes. Cytotoxicity of COPD lymphocytes was more enhanced by KIR stimulation than those of controls and was correlated with lung function. These data show HLA-C and KIR polymorphisms strongly influence COPD susceptibility and highlight the importance of lymphocyte-mediated cytotoxicity in COPD pathogenesis. Findings here also indicate that HLA-KIR typing could stratify at-risk patients and raise possibilities that HLA-KIR axis modulation may have therapeutic potential.
Highlights
Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, and the prevalence, cumulative morbidity, and public health burden of this syndrome continue to increase [1]
An initial pilot trial comparing Human leukocyte antigens (HLAs)–Class I alleles among the 170 COPD lung transplant subjects versus the first evaluable cohort of smoke control (SC) subjects (n = 81) indicated that intergroup differences were greatest at the HLA-C locus, especially at HLA-C*07 (Supplemental Table 2)
An overrepresentation of HLA-B*07 in the COPD was less significant (Supplemental Table 2) and a likely feature of the interdependence of that allele with HLA-C*07, given that these 2 alleles are in strong linkage disequilibrium (LD) [15]
Summary
Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, and the prevalence, cumulative morbidity, and public health burden of this syndrome continue to increase [1]. Human leukocyte antigens (HLAs) are the strongest known genetic determinants of immunologically mediated diseases and key regulators of cytotoxic lymphocytes [8]. HLA–Class I molecules mediate antigen presentation to cytotoxic CD8+ T cells [9] and are cognate ligands for killer cell Ig-like receptors (KIR) on the surfaces of NK cells [10,11,12]. NK cells can be either stimulated or inhibited by KIR crosslinking, depending on the structural characteristics of these receptors [13]. HLA engagements with various KIR can either stimulate or inhibit effector functions of NK cells and cytotoxic lymphocytes, depending on the relative expressions of particular KIR [10,11,12]. Specific HLAKIR combinations modify the risks of developing several immunological syndromes, including diverse autoimmune diseases, malignancies, and infections [11, 12, 14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
