Better Treatments for Rheumatoid Arthritis Not Too Far Off

Rheumatoid Arthritis (RA) is an inflammatory autoimmune disease that most often targets peripheral joints, frequently resulting in pain, swelling, and possible deterioration and destruction of cartilage and bone located at the joint. RA afflicts more than 1.3 million people in the United States alone, and the disease is most prevalent among women and the elderly. For over 60 years, RA has been widely treated non-selectively with glucocorticoids (GCs), such as methotrexate, a type of steroid hormone, because of their unrivaled, potent anti-inflammatory effects. Despite the successful anti-inflammatory effects that GCs have on the joints of afflicted patients (in fact, GCs are successful in just about every type of inflammatory ailment), it is a costly treatment, and there are numerous, severe side effects due to their non-selective nature, including immunodeficiency, high blood sugar, and increased skin fragility and bruising, among others. Consequently, there is currently a necessity for research into possible steroid therapies better targeted to healing RA with greater efficiency and fewer adverse side effects.

When RA is treated with GC steroid hormones, the hormone binds to a glucocorticoid receptor (GR) located in host cells (and expressed nearly universally in all vertebrate cells). Once being bound by a GC, the GR then translocates into the host cell nucleus where it can act as a transcription factor, subsequently altering gene expression and helping to dampen the host immune response and reduce inflammation at the site of RA. The GR may carry out this function via two different modes of action: it may dimerize, or split into two separate subunits, and then bind to the gene promoter of GC-regulated genes, or it may remain as a single unit and interact with other DNA-bound transcription factors, thereby altering gene expression to induce anti-inflammatory function.

While it is well understood that GCs induce potent anti-inflammatory effects, the specific cells targeted by GCs and their underlying mechanisms are poorly characterized. Just yesterday, a study was published in the Proceedings of the National Academy of Science by Baschant and colleagues that identifies a potential mechanism by which GCs actually carry out their anti-inflammatory function. The paper suggests that the GR in T cells, which are cells that contribute to the inflammatory state in joints, is critical for the suppression of inflammation by GCs, and that the dimerization of GRs is necessary for the GC’s anti-inflammatory effects. To achieve this, the authors utilized a mouse model in which they used an antigen-induced arthritis (AIA) to mimic the severe inflammation in joints that is characteristic of RA, and serves as a model to examine the mechanism by which GCs carry out their function.

The authors infected mice with AIA by injecting methylated BSA (mBSA) into their arteries in the right knee joint, leading to severe, acute AIA (1). Firstly they determined a means to treat AIA with GCs by treating mice with the GR agonist dexamethasone, a GC that triggers a response from the GR. This significantly reduced joint swelling and other symptoms compared with control-treated AIA mice, and mice with AIA exhibited symptoms resembling those found in human RA. Therefore, the authors determined a treatment with the GC dexamethasone that resembles the therapeutic effects of GCs in human RA, thus providing a model for which to investigate cells involved in human RA steroid therapy.

Subsequently, Baschant and colleagues sought to identify precisely which cells are acted upon by GCs to trigger immune suppression of AIA. It is well known in the world of immunology that myeloid cells, including neutrophils and macrophages, are involved in the early clean-up and suppression of AIA. The authors examined inflammatory symptoms in AIA mice lacking the GR in these myeloid cells, and found that GCs were able to repress AIA just as well in these mice as in control mice, suggesting that the GR in myeloid cells is not essential for the anti-inflammatory effects of GCs in AIA. Next, since AIA is a T-cell dependant inflammatory disease, the authors examined the ability of GCs to suppress AIA symptoms in mice with non-functional GR in T cells, and found that inflammatory suppression was significantly impaired. Dexamethasone was unable to reduce swelling and production level of Il-17, a pro-inflammatory cytokine, in these cells, suggesting that T cells are the target for GC suppression of AIA symptoms.

Next, the authors sought to elucidate which mechanism T cell GRs use to induce their transcriptional alterations. Using mice with impaired GR dimerization, Baschant and colleagues examined inflammatory symptoms in relation to wild-type mice with functional T cell GRs, and found that GC steroid therapy failed to suppress inflammation in these mice, while GC therapy was successful in wild-type mice. Thus, they concluded that dimerized GR is required for anti-inflammatory effects of GCs in AIA, and these results held true for another analogous arthritis model, further solidifying their results.

Following this experiment, Baschant and colleagues investigated how, precisely, GCs regulate T cells in AIA. What they determined was that very few helper T cells, or CD4 T cells (which help B cells produce antibody in response to the presence of antigen) produced cytokines indicative of a T_H1 immune response – which typically is inflammatory in nature – upon re-stimulation with mBSA. This indicated that antigen-induced T_H1 response is diminished in WT mice but not the mice with impaired dimerizing function in GRs. A similar result was found for T_H17 cells, which also are involved with the inflammatory response. The authors ultimately concluded that a reduction of both T_H1 and T_H17 cells probably contributes to the anti-inflammatory effects of GCs in AIA.

Lastly, with this knowledge, the authors examined to what extent the reduction of T_H1 and T_H17 cells contributes to the anti-inflammatory effects of GCs. The cytokine Il-17 was previously mentioned to have a pro-inflammatory response, and is produced by T_H17 cells. Thus, the authors tested if this reduction in Il-17 is what is causing the anti-inflammatory effects of dexamethasone, and found that indeed mice deficient for Il-17 are resistant to dexamethasone treatment and exhibit AIA symptoms.

Moreover, the study wonderfully demonstrates that GR dimerization in T cells and the consequent reduction of IL-17 are critical for the anti-inflammatory effects of GCs in AIA. As this antigen-induced arthritis is analogous to human RA, this provides significant insight into the mechanisms that may underlie GC function in suppressing inflammation in patients, and will help focus future therapeutic endeavors, thereby hopefully avoiding the severe side effects of current non-focused GC treatments. These new drugs could potentially go to clinical trials in the not-too-distant future, propelling us one step closer to providing sufferers of rheumatoid arthritis with better means to cure their symptoms. The next step will be developing glucocorticoid treatments that specifically target T cell glucocorticoid receptors, while not having broad immunosuppressive implications.

Reference: Baschant, U., Frappart, L., Rauchhaus, U., Bruns, L., Reichardt, H. M., Kamradt, T., Bräuer, R., et al. (2011). Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells. Proceedings of the National Academy of Sciences of the United States of America, 108(48), 19317-19322. doi:10.1073/pnas.1105857108

Other References:

(1) Irmler, I. M., Gajda, M., & Bräuer, R. (2007). Exacerbation of antigen-induced arthritis in IFN-gamma-deficient mice as a result of unrestricted IL-17 response. Journal of immunology (Baltimore, Md. : 1950), 179(9), 6228-36. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17947698

Cronstein, B. N. (2005). Low-Dose Methotrexate : A Mainstay in the Treatment of Rheumatoid Arthritis. Pharmacological Reviews, 57(2), 163-172. doi:10.1124/pr.57.2.3.mittently