Background There are many genetic influences documented on both lung function and susceptibility to COPD. In GWAS of pulmonary function several hits in the region of the MHC on chromosome 6 have been found, and we have shown previously that HLADR3 positive individuals have lower FEV1 than those without this HLA type. This is an HLA type classically associated with autoimmunity. Interactions between HLA type and cigarette smoke are recognised in autoimmune diseases.
Hypothesis HLA type influences differentiation of monocytes in the presence of cigarette smoke.
Methods 15 ex and never smokers with COPD and 5 healthy controls were studied. PBMCs were isolated and exposed to varying concentrations of cigarette smoke extract (CSE) for 90 min. CD14 and CD16 markers were used in flow cytometry to ascertain relative expression and absolute cell counts for each monocyte subpopulation, defined as CD14++CD16- (classical), CD14++CD16+ (anti-inflammatory) and CD14+CD16++ (non-classical). Within the patient group differences in baseline profile and response to CSE were compared between ex-smokers and those that had never smoked. Patients were HLA class II typed as described previously1 and the same comparisons made between DR3 positive and negative patients.
Results At baseline the MFI for CD14 was lower in COPD than health (p=0.04), although no clear differences in cell counts were seen. Counts were generally higher in ex-smokers, although no clear differences in subpopulations were seen. On exposure to cigarette smoke there was a dose dependent rise in classical monocytes, which was more marked in DR3+ patients and never smokers.
Conclusions CSE induces a pro-inflammatory phenotype of monocytes, and this occurs most in HLADR3+ individuals. This could be the mechanism behind lower FEV1 in DR3+ individuals.
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