Chronic smoke exposure induces rheumatoid factor and anti‐heat shock protein 70 autoantibodies in susceptible mice and humans with lung disease

Abstract

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...

The lung may play a role in the pathogenesis of rheumatoid arthritis

“…Another potential interesting mechanism for the role of smoking and autoantibody generation in RA was recently proposed by Newkirk and colleagues [55]. In this study, they evaluated serum anti-HSP-70 autoantibodies, and they found IgM-HSP-70 autoantibodies were associated with presence of chronic lung disease independent of smoking.…”

“…Exposure to tobacco smoke has long been associated with increased risk for development of clinically classifiable RA as well as RA-associated lung disease [3,36,55]. In addition, recent studies of subjects with smoking associated chronic airways disease, specifically chronic obstructive lung disease (COPD), without joint inflammation have identified an increased prevalence of serum ACPA positivity further supporting that the lung may be a site of generation of RA-related autoimmunity [55,56].…”

“…In addition, recent studies of subjects with smoking associated chronic airways disease, specifically chronic obstructive lung disease (COPD), without joint inflammation have identified an increased prevalence of serum ACPA positivity further supporting that the lung may be a site of generation of RA-related autoimmunity [55,56]. Specifically, Ruiz-Esquide and colleagues evaluated subjects without RA who had a heavy smoking history and COPD, and in these subjects, they found a higher prevalence of serum ACPA positivity (4–7%) compared with controls without a history of smoking (2%) [56].…”

Plasma Autoantibodies against Heat Shock Protein 70, Enolase 1 and Ribonuclease/Angiogenin Inhibitor 1 as Potential Biomarkers for Cholangiocarcinoma

“…Expression of HSP70 was found in CCA metastasis tissues [38] and could be used as marker in CCA [39]. Moreover, autoantibodies against HSP70 have been identified in esophageal squamous cell carcinoma, lung disease and alcohol-related disease [40]–[42] but not in CCA where elevated levels of carbonylated HSP70 protein were reported [34]. Our ELISA data support the view that autoantibodies against HSP70 may discriminate CCA from cholangitis, a risk condition for bile duct cancer, cholangitis from healthy individuals and CCA from healthy individuals (Table 5).…”

Circulating anti-Hsp70 levels in nascent metabolic syndrome: the Casale Monferrato Study

“…In logistic regression analysis, serum anti-Hsp70 antibody levels greater than 108 μg/ml were associated with an almost 80 % higher likelihood of MetS with respect to lower values, independently of age and sex. Although smoking (Newkirk et al 2012), hypercholesterolemia (Guisasola et al 2009), and microalbuminuria (Bianchi et al 2008) have been associated with increased circulating anti-Hsp70 levels and cases had greater prevalence/levels of these risk factors, the strength of the association was only slightly reduced by further adjustment for apoB, smoking, and AER. Previous studies have shown an association between circulating anti-Hsp70 antibody levels and single parameters of the MetS, such as hypertension, obesity, and dyslipidemia (Wu et al 2001;Ghayour-Mobarhan et al 2005, 2007; however, these clinically based studies also included patients with type 2 diabetes and established CVD, making detangling analysis open to imprecision.…”