Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by autoantibodies production as a result of the breakage of immunological tolerance mechanisms. Different immune cell types including lymphocytes take part in both joints-restricted and extra-articular manifestations of the disease.
Autophagy is an evolutionarily conserved lysosomal degradation pathway involved in different aspects of lymphocytes functionality. It has been demonstrated that the relation between autophagy and apoptosis influences the survival and inflammatory potential of peripheral cells from RA patients. Besides, IL-6, one of the most relevant cytokines in RA pathogenesis, was found to stimulate autophagy in B cells suggesting an involvement of autophagy in the inflammatory events of the disease.
Similarity in serum cytokines panel of RA patients and patients affected by CoronaVirus Disease 19 (CoViD 19) has been recently demonstrated, suggesting that some immune-mediated mechanisms might be common to both. Several anti-rheumatic drugs, including IL-6 antagonist Tocilizumab, used to treat patients affected by RA, are now proposed for the treatment of Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2).
We hypothesize that autophagy dysregulation may have a role in the activation and functions of lymphocytes during conditions characterized by excessive inflammation and cytokines production such as RA as well as CoViD 19 infection. To this aim, we will evaluate ex vivo autophagy and apoptosis in lymphocytes subsets from patients with RA and CoViD 19 infection before and after therapy with anti-IL6 drug Tocilizumab.
The results of this study will provide important experimental evidences for the possible use of existing drugs targeting the autophagy pathway as a new therapeutic strategy against inflammatory disorders and for the control of future epidemic of SARS-CoV-2 infection.
The complicated feedback loop between inflammation and autophagy in RA is still under investigation. Hyperactive autophagy has been associated with hyperplasia and impaired apoptosis in RA and enhances the production of inflammatory cytokines (1,2). IL-6 is a pleiotropic cytokine that plays an important role in both autoimmune response against self-antigens and systemic immune defense against external pathogens, inducing a defensive response mediated by a wide range of cells, including B and T lymphocytes. It remains elusive whether IL-6 and autophagy are linked. Recent studies reported that IL-6 may have both inhibitory and stimulating effects on autophagy and data on the effect of pharmacological inhibition of IL-6 are lacking in lymphocytes.
In the light of the role of lymphocytes in the pathogenesis of RA and the imbalance between apoptosis and autophagy previously observed in these cells, we hypothesize that the IL-6 inhibitor tocilizumab might affect both autophagy and apoptosis of lymphocytes. Since autophagy is involved in the survival and activation of RA immune cells, the analysis of T cell autophagy, after ex vivo and in vitro treatment with tocilizumab, could reveal a new mechanism of action by which this drug improves inflammatory immune response.
The results of this project could clarify a mechanism of action by which tocilizumab could restore a more physiological phenotype of lymphocytes from RA patients by reducing the production of pro-inflammatory cytokines and by reactivating apoptosis. Moreover, the results of this project will allow us to understand whether the modulation of autophagy can represent a fascinating therapeutic option to complement standard therapies to enhance the therapeutic response.
Patients with CoViD 19 may have features mimicking rheumatic diseases, such as arthralgias, acute interstitial pneumonia, myocarditis, leucopenia, lymphopenia, and thrombocytopenia. For this reason, it could be reasonable to hypothesize that mechanisms leading to sustained immune response are in common to both. The SARS-CoV-2 binds to alveolar epithelial cells and then induces the activation of both the innate immune system and adaptive immune system, resulting in the release of a large number of cytokines, including IL-6. T cells and B cells not only play a key role in the defense from pathogen hosts, but also can directly or indirectly promote the secretion of inflammatory cytokines. Little is known about the direct effect that virus entry exerts on autophagy or how cytokine storm virus-induced could impact on autophagy. Since autophagy is involved in the activation of immune cells and the subsequent release of pro-inflammatory molecules, we can speculate that targeting autophagy can be considered a possible valid therapeutic tool in this context. Cytokine storm driven by the virus could dysregulate autophagy in lymphocytes, contributing to the progression of the disease.
Experimental evidence on the effect of several anti-rheumatic drugs, used to treat patients affected by RA and now proposed for the treatment of CoViD-19, are lacking. The relation between IL-6, IL-6 inhibition, and autophagy on lymphocytes homeostasis has not been investigated yet. The novelty of this study consists in the evaluation of the effect of tocilizumab on autophagy mechanism ex vivo and in vitro in lymphocytes from patients affected by RA and CoViD-19. Modulation of autophagy by drugs that target cytokines such as tocilizumab may have a role in the reduction of inflammation, which is a common feature in patients with RA and CoviD19.
Because upregulated autophagy inhibits apoptosis and promotes proliferation of lymphocytes, we hypothesize that blocking the IL6 receptor by tocilizumab could suppress lymphocytes activation and cytokines release by switching from autophagy to apoptosis.
This research may take advantage of previous studies, many of them conducted by our research team, in which autophagy in lymphocytes was investigated for the understanding of the pathogenic mechanisms underlying the onset of some autoimmune diseases, such as SLE and RA (1-4).
Based on studies of previous pandemics, experts suggest that a second wave of CoViD-19 is possible and, as published in the Lancet, scientists should prepare for the eventual second outbreak of infections (5). Our expertise in the field can implement the discovery of the right therapeutic approach, also resulting in the combination of different drug therapies, which is fundamental in this moment, in which we are waiting for SARS-CoV-2 vaccines.
References
1. Vomero M, Front Immunol. 2018
2. Vomero M, Arthritis Res Ther. 2019
3. Alessandri, C, FASEB J 2012
4. Colasanti T, Cell Death Dis. 2014
5. Xu S Lancet 2020