The impact of cigarette smoke (CS), a risk factor for rheumatoid arthritis (RA), on autoantibody production was studied in humans and mice with and without chronic lung disease (LD). Rheumatoid factor (RF), anti-cyclic citrullinated peptides (CCPs), and anti-HSP70 autoantibodies were measured in several mouse strains and in cohorts of smokers and nonsmokers with and without autoimmune disease. Chronic smoking-induced RFs in AKR/J mice, which are most susceptible to LD. RFs were identified in human smokers, preferentially in those with LD. Anti-HSP70 autoantibodies were identified in CS-exposed AKR/J mice but not in ambient air exposed AKR/J controls. Whereas inflammation could induce anti-HSP70 IgM, smoke exposure promoted the switch to anti-HSP70 IgG autoantibodies. Elevated anti-CCP autoantibodies were not detected in CS-exposed mice or smokers. AKR/J splenocytes stimulated in vitro by immune complexes (ICs) of HSP70/anti-HSP70 antibodies produced RFs. The CD91 scavenger pathway was required as anti-CD91 blocked the HSP70-IC-induced RF response. Blocking Toll-like receptors did not influence the HSP70-IC-induced RFs. These studies identify both anti-HSP70 and RFs as serological markers of smoke-related LD in humans and mice. Identification of these autoantibodies could suggest a common environmental insult, namely CS, in a number of different disease settings.Keywords: Autoantibodies r Heat shock protein 70 r Lung disease r Rheumatoid factor
IntroductionSmoking is a very strong environmental risk factor that is linked to rheumatoid arthritis (RA) [1,2] and other autoimmune disCorrespondence: Dr. Marianna M. Newkirk e-mail: Marianna.newkirk@mcgill.ca eases [3][4][5]. Furthermore, there is little information on the association between the most common smoke-induced lung disease (LD), chronic obstructive pulmonary disease (COPD), and serological markers associated with autoimmunity.In North American Native (NAN) populations the prevalence of RA can be three times that of Caucasians [6]. Whereas smoking rates have decreased in the past decade in Caucasians, with 18% of Canadians >15 years of age smoking, 60-70% C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu1052 Marianna M. Newkirk et al. Eur. J. Immunol. 2012. 42: 1051-1061 of NANs (residing mostly on reservations) smoke (Health Canada). Although smoking cessation can lower RA risk and disease burden, the risk continues 10 years after cessation [1] and similarly, prolonged smoking cessation is critical for the reduction of lung cancer [7]. Lung inflammation, oxidative stress, and protease burden remain elevated for several months after smoking cessation [8]. Early diagnosis of those at risk of smoking-related diseases ideally by the use of informative biomarkers is critical with sustained cessation an important goal. Rheumatoid factor (RF), used in the diagnosis of RA [9], is an autoantibody of any isotype that binds IgG Fc. Epidemiological studies have shown that RF-positive RA patients are most associated with an increased risk conferred f...