title: Cellular and humoral immunity in arthritis are profoundly influenced by the interaction between cigarette smoke effects and host HLA-DR and DQ genes.
abstract: Individuals carrying DRB1*0401 who smoke cigarettes are at an increased risk of developing severe seropositive RA. To determine how cigarette smoke (CS) interacts with host genetic factors in the induction of RA-associated autoimmunity, we used transgenic mice carrying the RA-susceptible HLA genes DR4 and DQ8, but lacking all endogenous murine class II molecules. Cigarette smoke exposure augmented peptidylarginine deiminase (PAD) enzyme expression, and enhanced immune responses to citrullinated collagen and vimentin. Here we show for the first time that DQ molecules can present citrullinated peptides much more efficiently than native peptides. Interestingly, CS exposure suppressed collagen-induced arthritis (CIA) in DRB1*0401 mice although innate immune response was enhanced. On the other hand, CS exposure exacerbated CIA in DQ8 mice, which was accompanied by an increased expression of Th17 gene transcripts in lungs. These observations suggest that cigarette smoke promotes antigen-specific autoimmunity that is profoundly influenced by host genetic factors.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical care Medicine, Mayo Clinic, Rochester, MN 55905.
authors.forename: Robert
authors.initials: R
authors.lastname: Vassallo
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905.
authors.forename: David
authors.initials: D
authors.lastname: Luckey
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Marshall
authors.initials: M
authors.lastname: Behrens
authors.affiliation: Medical Genome Facility, Mayo Clinic, Rochester, MN 55905.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Madden
authors.affiliation: Department of Medicine, Division of Rheumatology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Harvinder
authors.initials: H
authors.lastname: Luthra
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Chella
authors.initials: C
authors.lastname: David
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; Department of Medicine, Division of Rheumatology, Mayo Clinic, Rochester, MN 55905. Electronic address: taneja.veena@mayo.edu.
authors.forename: Veena
authors.initials: V
authors.lastname: Taneja
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000276:immunology; D016207:Cytokines / Q000097:blood; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics* / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D006867:Hydrolases / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000076342:Protein-Arginine Deiminases; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D014746:Vimentin / Q000276:immunology
chemical_list: D016207:Cytokines; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; C527195:HLA-DRB1*04 antigen; D012906:Smoke; D014746:Vimentin; D003094:Collagen; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases
keywords: Citrullination; HLA transgenic mice; Innate immune response; Rheumatoid arthritis; Smoking