Blog

THE IMPORTANCE AND INFLUENCE OF NEUTROPHILS IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS

Among the numerous cells implicated in the pathology of rheumatoid arthritis (RA), neutrophils possess a strong cytotoxic potential, thanks to their ability to release degradative enzymes and reactive oxygen species (ROS).

As parts of immune cells, neutrophils also contribute to the cytokine and chemokine cascades that accompany inflammation and regulate immune responses through cell-cell interactions.

In addition, they are the first responders during acute inflammation and the main weapons at their disposal are phagocytosis and the degranulation of their targets (pathogens). In 2004, a new and third form of attack was discovered by Brinkmann et al [3]: neutrophil extracellular traps (NETs).

NETs are mainly composed of histones and DNA fibers that trap and facilitate the killing of pathogens.

Since the discovery of NETs, ​​the research field has been extremely active and continues to expand. Extracellular extrusion of DNA and histones and other proteins that stimulate immune responses lead to the subsequent inflammatory process and cause tissue damage [5].

Neutrophils are the most abundant cell type present in the synovial fluid in RA patients although they are fewer in the synovial tissue but are in greater numbers at the cartilage-panel junction where the synovial tissue invades the cartilage [18].

Neutrophils in patients with rheumatoid arthritis are functionally different from those of healthy individuals since neutrophils in the former are ready for the production of reactive oxygen species [20].

Extracellular neutrophil traps (NETs) are a source of citrullinated autoantigens and activate the synovial fibroblasts of the AR (FLS), crucial cells in joint damage (as anticipated several times in previous articles).

Thus, in the complex inflammatory mechanism of RA, neutrophils are involved in its pathogenesis, through mechanisms that include the following: release of ROS and proteases that are involved in damage to host tissues (e.g. cartilage and vascular tissue) and activation of neighboring cells, secretion of cytokines and chemokines that regulate the activity of both innate and adaptive immune systems and the production of extracellular neutrophil traps involved in the exposure to the immune system of citrullinated proteins in RA.

Medicines currently licensed for the treatment of RA include TNFi (adalimumab, infliximab, golimumab, and biosimilars), an IL-6R inhibitor (tocilizumab), and drugs that target immune cell markers (eg, rituximab).

Unfortunately, even today, 30-40% of patients do not respond adequately to any first-line biologic (usually TNFi) within 6 months and are forced to switch to another class of biologics.

Different approaches were adopted to further define the role of neutrophils in the pathogenesis of RA [2] and among these emerges an interesting study involving 20 patients with RA, who met the American College of Rheumatology criteria for RA [24] .

Many different studies reported gene expression profiles induced by interferon (IFN) in peripheral blood neutrophils of patients with RA, which was related to the response to the tumor necrosis factor inhibitor (TNFi) [23]; this gene expression profile was not seen in healthy individuals.

The gene expression analysis showed that:

10 IFN-induced genes predict TNFi response and 13 genes predict TNFi non-response.

Importantly, the 23 genes are selective for predicting the response to TNFi.

We as iCareX, have adopted a unique approach for the identification of biomarkers in order to predict an adequate and qualitatively more precise response through an examination of the synovial tissue obtained through ultrasound-guided biopsy for the entire class of drugs currently adopted. 

These studies often failed to identify significant biomarkers that predict drug response, and there is little correlation of results between studies.

This is likely due to the heterogeneity of leukocyte cell populations within the peripheral blood among different individuals.

This heterogeneity has been exemplified by exploRA, which takes into account the different genetic profiles typical of the single individual and evaluates the single gene alterations by predicting which pharmacological treatment intended for the patient is the best and personal.

We believe that this new approach could have important consequences for prescribing correct drug treatment and have the potential to inform both physician and patient of the development of the disease.

References:

2. Brink M, Hansson M, Mathsson L, Jakobsson PJ, Holmdahl R, Hallmans G, Stenlund H, Ronnelid J, Klareskog L, Rantapaa-Dahlqvist S. Multiplex analyzes of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis. Arthritis and rheumatism. 2013 Apr; 65: 899.

3. Wright, H. L., Moots, R. J., Bucknall, R. C., Edwards, S. W. (2010) Neutrophil function in inflammation and inflammatory diseases. Rheumatology (Oxford) 49, 1618–1631.

5. Wright, H. L., Thomas, H. B., Moots, R. J., Edwards, S. W. (2013) RNA ‐ seq reveals activation of both common and cytokine ‐ specific pathways following neutrophil priming. PLoS One 8, e58598.

13. MacIsaac, KD, Baumgartner, R., Kang, J., Loboda, A., Peterfy, C., DiCarlo, J., Riek, J., Beals, C. (2014) Pre ‐ treatment whole blood gene expression is associated with 14 ‐ week response assessed by dynamic contrast enhanced magnetic resonance imaging in infliximab ‐ treated rheumatoid arthritis patients. PLoS One 9, e113937.

Crossref Google Scholar

14. Tanino, M., Matoba, R., Nakamura, S., Kameda, H., Amano, K., Okayama, T., Nagasawa, H., Suzuki, K., Matsubara, K., Takeuchi, T . (2009) Prediction of efficacy of anti ‐ TNF biologic agent, infliximab, for rheumatoid arthritis patients using a comprehensive transcriptome analysis of white blood cells. Biochem. Biophys. Res. Commun. 387, 261-265.

18. Oswald, M., Curran, ME, Lamberth, SL, Townsend, RM, Hamilton, JD, Chernoff, DN, Carulli, J., Townsend, MJ, Weinblatt, ME, Kern, M., Pond, CM, Lee , A., Gregersen, PK (2015) Modular analysis of peripheral blood gene expression in rheumatoid arthritis captures reproducible gene expression changes in tumor necrosis factor responders. Arthritis Rheumatol. 67, 344–351.

20. Cross, A., Bucknall, R. C., Cassatella, M. A., Edwards, S. W., Moots, R. J. (2003) Synovial fluid neutrophils transcribe and express class II major histocompatibility complex molecules in rheumatoid arthritis. Arthritis Rheum. 48, 2796-2806.

23. Wright, H. L., Thomas, H. B., Moots, R. J., Edwards, S. W. (2015) Interferon gene expression signature in rheumatoid arthritis neutrophils correlates with a good response to TNFi therapy. Rheumatology (Oxford) 54, 188– 193.

24. Fransen, J., van Riel, P. L. (2005) The disease activity score and the EULAR response criteria. Clin. Exp. Rheumatol. 23 (5 :, Suppl 39), S93– S99.

Share on facebook
Facebook
Share on twitter
Twitter
Share on linkedin
LinkedIn
Share on whatsapp
WhatsApp
Share on email
Email