Rheumatoid arthritis (RA)

Rheumatic diseases

Rheumatic diseases are different painful medical conditions, which primarily affect joints, tendons, ligaments, bones, and muscles. Rheumatic diseases can also affect internal organs, skin and blood vessels. Common symptoms are pain, swelling, and stiffness. Rheumatic diseases are characterized by loss of functions of connective or supportive tissues. There are many different types of rheumatic diseases, arthritis, and related conditions. The picture, from medicalgeek.com, demonstrates the arthritic and normal joints.

Rheumatoid arthritis (RA)
RA is an autoimmune rheumatic disease affecting millions of people, and is an important cause of disability and even mortality across the world. Arthritis means joint inflammation and is just a part of the rheumatic diseases. RA most often affects the joints of the hands and feet, which are usually inflamed in a symmetrical pattern so that both sides of the body are affected. RA is most likely triggered by a combination of factors such as genetic susceptibility, abnormal autoimmune responses and even environmental or biologic factors, such as infection.

Autoantigens
Autoantigens are normal tissue constituents, which can become the target of a humoral or cell-mediated immune response initiating autoimmune diseases. Determining autoantigens targeted by the autoimmune response in RA has been a priority and an essential step for understanding the molecular mechanisms involved in pathenogenesis of RA and also for the immunotherapy of patients. So far, several autoantogens such as cartilage antigens, heat shock proteins, viral/bacterial antigens and several other autoantigens have been shown to be asscociated with RA. It should be noted that RA is a systemic disease. Thus, the candidate autoantigens may not necessarily be restricted to the joint components.

Genetic factors
Genetic factors play key roles in RA either by increasing susceptibility to the disease or by worsening the disease process. The association of RA with the human leukocyte antigens (HLA) was discovered when the frequency of HLA haplotypes, such as HLA-Dw4, HLA-B27 and HLA-DR4, were found to be increased in RA patients. The HLA system or the human major histocompatibility complex (MHC) are composed of cell surface proteins, which are encoded by the genes located on chromosome 6. HLA play an essential role in normal  immune responses by presenting both non-self (microorganisms) and self antigens to T cell receptors (TCR) on T cells. This presentation may also lead to development of autoimmunity. Genetic mutation, for example, in type II collagen, has also been shown to be associated with some form of arthritis.

Immunology of RA
The immune responses in RA involve numerous different immune cell types, including B cells, T cells, neutrophils, professional antigen presenting cells such as DCs and macrophages. They also involve molecules such as antibodies and components of the complement system, which can cause further recruitment and activation of the macrophages and neutrophils to the site of inflammation. Cytokines that regulate a broad range of inflammatory responses are also involved in the pathogenesis of RA. Besides, chemokines, which are involved in recruitment of leukocytes to the site of inflammation have also been shown to play a role in the pathogenesis of RA by recruiting leukocytes to synovial tissues.

T cells
The strong association of RA with specific HLA molecules and the observations that in experimental animal models of RA the disease can be transferred by isolated T cells, are among the most acceptable arguments in favor of an essential role for T cells in RA. Among the T helper cell populations, Th1 and Th17 cells have been reported to play a pathogenic role in RA. Several reports support a role for IL-17 in promoting rheumatoid arthritis. However, careful investigations are required to further identify the importance of Th17 cells in RA. Regulatory T cells (Treg) can play a critical role in preventing autoimmune diseases. However, the importance of Treg cells in RA and whether or not defect in these cells can contribute to the pathogenesis RA is not completely known. It has been shown that patients with RA exhibited substantial increased frequency of Epstein Barr Virus (EBV)-specific effector memory CD8+ T cells, indicating a role for these cells in RA. Note that EBV can trigger RA.

B cells
B cells most likely play several roles in the development of RA via presentation of antigens, activation of T cells, secretion of antibodies and proinflammatory cytokines such as TNF and IL-6. Several autoantibodies, such as rheumatoid factor (RF), have been shown to be associated with RA. RF is an autoantibody produced against the Fc portion of IgG, which form immune complexes and contribute to RA. Conversely, a negative regulatory role for IL-10- and TGF beta-producing B cell population in animal model of RA has been reported.

Macrophages and Dendritic cells (DCs)
These professional antigen-presenting cells (APC) are very crucial for immune responces especially for activation of T cells via processing and presenting antigens bound to their MHC class II molecules. Macrophages are involved in leukocyte migration to the site of inflammation, matrix degradation and angiogenesis. These cells contribute significantly to the pathology of many chronic inflammatory diseases, including RA. The cytokine produced by these cells, such as TNF, IL-6 and IL-1 has been targeted by different biological therapies. DC also play a central role in immune and inflammatory responses and contribute significantly to the maintenance and progression of RA. Interestingly, a group of DC, plasmacytoid DC, have been shown to mediate immune tolerance. These cells play a regulatory role in RA via induction of IL-10- and TGF beta-producing Treg cells.

For further information, I encourage you to refer to the recently published review articles in the journal "Nature Reviews Rheumatology"  at: http://www.nature.com/nrrheum/index.html

Glucocorticoid hormones and immune system

In 1950, the Nobel Prize for Physiology or Medicine was awarded to three scientists for the discovery of glucocorticoid hormones (GC), and their therapeutic values in the treatment of rheumatoid arthritis.

Synthesis
GC are a group of steroid hormones and are synthesized from cholesterol in the cortex of the adrenal gland. We and others have previously shown that GC can also be synthesized in the thymus with some paracrine effects on the development of T lymphocytes. Synthesis of GC is under the control of corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) produced by hypothalamus and pituitary gland respectively. On the other hand, high blood concentration of GC inhibits ACTH and CRH secretion, which leads to inhibition of GC production. Stressful conditions leads to elevation of blood GC concentrations. (Picture from thebrain.mcgill.ca).

Mechanism of action
GC diffuse through the cell membrane and binds to the glucocorticoid receptor (GR), which is a transcription factor expressed in almost all cell types. GR is sequestered in the cytoplasm. However, after binding to the GC, the hormone-receptor complex will translocate into the nucleus, where GR binds to its DNA response elements in the promoter region of target genes and by which modulates the gene transcription.

Immunological importance
GCs have wide spectrum of physiological effects involved in, for example, development, glucose metabolism and immune system. GC are well-known for their anti-inflammatory and immunosuppressive properties and thus have been widely used for the treatment of various autoimmune diseases, allergic reaction and also in transplantation. This is particularly the case when they are used at pharmacological doses. However, we and others have shown that GC at the physiological concentrations can also play important roles in the development and functions of immune system.

Glucocorticoids can inhibit expression of several genes involved in both cell-mediated and humoral immunity such as interleukin (IL)-1, IL-2, IL-3, IL-4, IL-6, IL-8, IL-12, IL-17, IFN gamma, FC receptors etc. These immunosuppressive actions of GC is known to be mainly via cross-talk between GR and other transcription factors such as nuclear factor-kappa B (NF-kappaB), which is a major transcription factor required for the expression of many molecules involved in different types of cell-mediated and humoral immunity. GC may also prevent the transcriptional activities of NF-kappaB by inducing the expression of I-KappaB alpha, which is the natural inhibitor of NF-kappaB.

Other important functions of GC are induction of apoptosis and inhibition of immune cell proliferation. This is particularly the case for T and B lymphocytes. These are the key mechanisms mediating the therapeutic effects of GC in the treatment of leukemias and lymphomas.

T lymphocyte family at a glance

T lymphocytes constitute the most important cells of the immune system. The ”T” stands for the thymus, where these cells are developed in. The vast majority of these cells express T cell receptor (TCR) molecules, which are required for recognition of antigenic peptides presented by the major histocompatibility complex (MHC) molecules expressed on different cell types. Recognition of antigens is followed by activation and proliferation of these cells, which is required for different types of immune responses. Below, different groups of T cells are described.

CD8+ T cells
These cells are also called cytotoxic T cells (CTL), and are characterized by expression of CD8 molecules. CTL recognize their targets by binding to antigenic peptide presented by MHC-I molecules expressed by almost all cells. CTL can recognize and destroy virally infected cells and tumor cells by inducing apoptosis in these cells. This is done by releasing the cytotoxic molecules such as perforin and granzymes. Perforin forms pores in the target cell's membrane. This is followed by activation of caspases by granzymes, which leads to  cell death by a programed cell death (apoptosis). CTL are also involved in graft rejection.

CD4+ T cells
These cells constitute a big group of T cells, which play a central and key role in the immune responses. CD4+ T cells recognize their targets by binding to antigenic peptides presented by MHC-II molecules expressed by antigen presenting cells sush as macrophages or dendritic cells.

Naive CD4+ T cells can differentiate into 4 distinct T cell populations including T helper 1 (Th1), Th2, regulatory T cells (Treg) and Th17 cells depending on what kind of cytokines or growth factors are present in cells' environment. The presence of interleukin (IL)-12 skews towards Th1, IL-4 towards Th2, transforming growth factor beta (TGF beta)  towards Treg and finally a combination of IL-6 and TGF-beta stimulates differentiastion of naive CD4+  T cells towards Th17 cells. The differentiated cells are characterized by expression of different transcription factors such as T-bet, GATA-3, FoxP3 and  RORγ for Th1, Th2, Tregs and Th17 cells respectively.

CD4+ T cells have different characteristics and are involved in different types of immune responses. Th1 cells secret IFN gamma and TNF beta and are mainly involved in cellular immune responses via stimulating macrophages, dendritic cells and CD8+ cytotoxic T cells. They can also stimulate B cells to generate antibodies involved in the antibody-dependent cell-mediated cytotoxicity. Th2 cells produce IL-4, IL-5,.IL-10, IL-13 and are mainly involved in humoral immune response via stimulating B cells to proliferate and generate antibodies. Interestingly, Th1 and Th2 cells can regulate each others differentiation or activation. For example, Th1-derived IFN gamma prevents IL-4 production. On the other hand, Th2-derived IL-10 can prevent IFN gamma  and L-12 production. Treg cells secert IL-10 and TGF beta, and are known to play a suppressive or regulatory roles in immune responses. Absence of these cells has been reported to be associated with the development of autoimmunity. Unlike Treg cells, which have anti-inflammatory properties, the Th17 cells are involved in induction of local inflammation and autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, allergic reactions and in mediating allograft rejection via secretion of proinflammatory cytokines IL-21, IL-22 and IL-17, which may further stimulate secretion of other proinflammatory cytokines.

Natural killer T (NKT) cells 
NKT cells are small group of T cells, which co-express some of the NK cells' and T cells' markers such as CD16 and TCR. After activation, they can produce cytokines or cytolytic molecules. Thus, they have both T cell and NK cell activities as well. These cells normally recognize glycolipid antigens presented by CD1d molecules. They are also able to recognize and eliminate some tumor cells and cells infected with some viruses. They can also be involved in autoimmunity, allergic inflammation or transplant immunity.

γδ T cells
These cells are present mainly within the intraepithelial lymphocytes in the gut. The nature of antigens and the mechanism by which these cells recognize them is not fully understood. However, unlike the majority of T cells, the γδ T cells are not MHC restricted. They have also been shown to have some phagocytic activities. These cells can apparently participate in both innate and adaptive immune responses.