RESUMO
It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2â weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3â days or 1â month. Rag1-/- , Mmp12-/- , and Il17a-/- mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2â weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1â month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6â months. Adoptive T cell transfer and studies in T cells deficient Rag1-/- mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.
Assuntos
Elastina , Doença Pulmonar Obstrutiva Crônica , Animais , Autoimunidade , Modelos Animais de Doenças , Humanos , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Fumaça/efeitos adversos , Fumar/efeitos adversosRESUMO
BACKGROUND: Genetic variants of the genes encoding HIV-1 co-receptors and their ligands, CCR5-Delta32, CCR5m303A, CCR2-64I and SDF1-3'A, are implicated in the susceptibility to HIV-1 infection, and the prevalence of these mutations varies by ethnicity. However, little is known about their distribution in Uighurs. OBJECTIVES: This study aimed at characterizing the frequency of these HIV-related gene variants in a high-risk Uighur population. STUDY DESIGNS: A total of 251 HIV-1 seropositive and 238 seronegative high-risk Uighurs were recruited and their genotypes of CCR5-Delta32, CCR5m303A, CCR2-64I and SDF1-3'A were analyzed by PCR and PCR-ligase detection reaction (PCR-LDR). RESULTS: The allelic frequency of CCR5-Delta32, CCR5m303A, CCR2-64I and SDF1-3'A was 4.40%, 2.66%, 25.66% and 57.36%, respectively, in this population. Apparently, the Uighur population has low frequency of CCR5-Delta32 and CCR5m303A, but high frequency of CCR2-64I and SDF1-3'A. While there was no significant difference in the frequency of CCR5-Delta32, CCR2-64I and SDF1-3' A between HIV-1 seropositive and seronegative groups the frequency of CCR5m303A in HIV-1 seropositive group was significantly higher than that in seronegative group (P=0.006, OR=3.982 and 95%CI 1.514-10.476). CONCLUSIONS: Our data suggest that the CCR5-Delta32, CCR2-64I and SDF1-3'A variants may have limited effect on protecting from HIV-1 infection in Uighurs. Rather, the CCR5m303A may be associated with the risk for HIV-1 infection in high-risk Uighurs.