Smoking activates cytotoxic CD8+ T cells and causes survivin release in rheumatoid arthritis

Abstract

CD8 T cells have an emerging role in RA. Resent research indicates a causal relationship between the non-exhausted state of CD8 T cells, defined by lost function of PD-1, and development of arthritis. We investigated how smoking contributes to the non-exhausted phenotype of CD8 T cells and cause survivin release to serum. We compared serum survivin levels between smokers and non-smokers in 252 RA and 168 healthy subjects. Nicotine effects on CD8 T cells were studied in peripheral blood of smoking women, bone marrow of nicotine treated mice and in sorted CD8 spleen cells in vitro using flow cytometry and quantitative PCR. Smoking increased the frequency of survivin release in serum of healthy women (OR 3.64, p = 0.025) and in RA patients (OR 1.98, p = 0.039). CD8 T cells of smokers gained a non-exhausted PD-1 deficient phenotype. Expression of the cytotoxic marker CD107 correlated to survivin levels in serum. In the experimental setting, nicotine exposure led to an accumulation of non-exhausted PD-1IL-7R CD8 T cells in the bone marrow that is abundant with survivin producing cells. The production of the cytolytic protein perforin in bone marrow correlated to serum survivin levels. In vitro stimulation of nicotinic receptors on murine CD8 T cells induced repressive transcription factors T-bet and Blimp-1 in support of the non-exhausted phenotype. We conclude that nicotine contributes to autoimmunity by supporting the non-exhausted state of CD8 T cells resulting in the release of survivin. This presents a new mechanism by which smoking may contribute to the pathogenesis of RA.

Survivin Measurement improves Clinical Prediction of Transition From Arthralgia to RA—Biomarkers to Improve Clinical Sensitivity of Transition From Arthralgia to RA

“…Evaluation of clinical symptoms in relation to serological parameters presented a diverse picture, in which survivin was identified adherent to most of them and served a common link to the symptoms associated with both CRP and autoantibodies. This provides further support to the hypothesis that survivin is critical for biological processes foregoing onset of RA ( 40 , 50 , 52 ). Translating those experimental findings into clinical practice, the adherence of early joint symptoms to survivin shows an independent added value of survivin measurement to identify arthralgia patients, that eventually develop RA.…”

“…Not surprising, high levels of survivin in serum are associated with severe course of joint disease, development of skeletal damage and resistance to anti-rheumatic treatment ( 45 – 47 ). It has also been associated with major known risk factors for the development of RA including carriage of HLA-DRB1 antigen ( 48 ), smoking ( 49 , 50 ) and production of RA-specific antibodies ( 23 , 46 , 48 ). Similar to RA-specific antibodies, survivin may be measured in preclinical phase of RA ( 51 ).…”

Environmental Exposures and Autoimmune Diseases: Contribution of Gut Microbiome

“…As a key regulator of cell apoptosis, survivin level correlates with reduced apoptosis and increased inflammation in multiple autoimmune disorders (54). Comparison of survivin levels between smokers and non-smokers of RA and healthy subjects suggest that nicotine contributes to autoimmunity by inducing the non-exhausted PD-1 − IL-7R + CD8 + T cells resulting in the release of survivin, and that potentially presents a new mechanism for smoke-mediated RA pathogenesis (55).…”

The Impact of Cigarette Smoking on Risk of Rheumatoid Arthritis: A Narrative Review

“…As mentioned above, CS can promote both Th1 and Th2 polarization. CD8 T cells, which are another major source of IFN-γ, have been reported to increase in number and be more prone to secreting cytokines due to CS in patients with chronic obstructive pulmonary disease (COPD) [103][104][105][106][107], and low soluble programmed death protein 1 ligand (sPD-L1) levels [108] and increased activated cytotoxic CD8 T cells [109] were also reported in RA patients. In contrast, the effects of CS on natural killer (NK) cells, which have similar cytotoxic functions as CD8 T cells, were variable in terms of the numbers and functions depending on an individual's health status [110][111][112][113][114][115][116].…”