title: CD46 protects against chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease and emphysema develops in 15% of ex-smokers despite sustained quitting, while 10% are free of emphysema or severe lung obstruction. The cause of the incapacity of the immune system to clear the inflammation in the first group remains unclear.
  
  
  RESULTS
  We searched genes that were protecting ex-smokers without emphysema, using microarrays on portions of human lungs surgically removed; we found that loss of lung function in patients with chronic obstructive pulmonary disease and emphysema was associated with a lower expression of CD46 and verified this finding by qRT-PCR and flow cytometry. Also, there was a significant association among decreased CD46(+) cells with decreased CD4(+)T cells, apoptosis mediator CD95 and increased CD8(+)T cells that were protecting patients without emphysema or severe chronic obstructive pulmonary disease. CD46 not only regulates the production of T regulatory cells, which suppresses CD8(+)T cell proliferation, but also the complement cascade by degradation of C3b. These results were replicated in the murine smoking model, which showed increased C5a (produced by C3b) that suppressed IL12 mediated bias to T helper 1 cells and elastin co-precipitation with C3b, suggesting that elastin could be presented as an antigen. Thus, using ELISA from elastin peptides, we verified that 43% of the patients with severe early onset of chronic obstructive pulmonary disease tested positive for IgG to elastin in their serum compared to healthy controls.
  
  
  CONCLUSIONS
  These data suggest that higher expression of CD46 in the lungs of ex-smoker protects them from emphysema and chronic obstructive pulmonary disease by clearing the inflammation impeding the proliferation of CD8(+) T cells and necrosis, achieved by production of T regulatory cells and degradation of C3b; restraining the complement cascade favors apoptosis over necrosis, protecting them from autoimmunity and chronic inflammation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Sandra
authors.initials: S
authors.lastname: Grumelli
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.forename: Leif
authors.initials: L
authors.lastname: Peterson
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Maeno
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
mesh_terms: D000368:Aged; D000818:Animals; D003179:Complement C3b / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism; D008297:Male; D051916:Membrane Cofactor Protein / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012907:Smoking / Q000009:adverse effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D051916:Membrane Cofactor Protein; D019014:fas Receptor; D003179:Complement C3b; D004549:Elastin