Rheumatoid arthritis (RA) is an autoimmune disease, which is characterized by chronic inflammation at the skeletal joints. Most times, the bone and cartilage of the joints affected are destroyed, and tendons and ligaments weakened. As the disease progresses, it eventually affects the skin, eye, heart, kidneys and lungs.
According to reports, RA affects more females than males, and is predominantly observed in the elderly. The prevalence rate of RA reported in 2002 ranged from 0.5% to 1% of the population. It also has regional variation. It primarily affects the lining of the synovial joints and can cause progressive disability, premature death, as well as socioeconomic burdens.
Symptoms of Rheumatoid Arthritis (RA)
Common symptoms of RA include:
- Stiffness at affected joints, especially in the morning
- Weight loss
- Tender, swollen and warm joints
- Rheumatoid nodules under the skin
Early stage of Rheumatoid arthritis tends to affect the smaller joints, particularly the joints that join the fingers to the hands and toes to the feet. As the disease progresses, the symptoms may progress to the wrists, knees, ankles, elbows, shoulders and hips.
Pathogenic Roles of Immune Cells in Rheumatoid Arthritis (RA)
As an autoimmune disorder, immune cells such as B-cells, T-cells and macrophages play important roles in RA pathogenesis. They can either reside in synovium or circulate in peripheral blood.
Roles of B-Lymphocytes in RA Pathogenesis
B-cells secrete physiologically important proteins such as rheumatoid factors (RFs), anti-citrullinated protein antibodies (ACPA) and pro-inflammatory cytokines in supporting RA.
Auto-reactive B-cells are B-cells that identify host antigens and go on to destroy such cell or tissue. Normally, auto-reactive B-cells are eliminated by repair mechanisms either at the time when it is still immature B-cells in the bone marrow, or before the B-cells become mature naïve B-cells. Both processes of repair mechanisms are highly regulated by two immune checkpoints; they are
- The central B-cell tolerance checkpoint and,
- The peripheral B-cell tolerance checkpoint.
The central B-cell tolerance checkpoint is controlled by B-cell growth factors that regulate B-cell receptor (BCR) and toll-like receptor (TLR) signaling. But the peripheral B-cell tolerance checkpoint involves extrinsic B-cell factors such as regulatory T-cells (Treg) and serum B-cell activating factor (BAFF).
In patients with RA, both checkpoints are defective, which leads to the larger production of auto-reactive mature naïve B-cells. Such defect is usually caused by a mutation in PTPN22 gene that disrupts the BCR signaling pathway in central B-cell tolerance checkpoint. This impairment is irreversible and cannot be treated effectively with anti-inflammatory drugs.
In impaired peripheral tolerance checkpoint, mature naïve B-cell levels are elevated. The elevated mature naïve B-cell expresses both poly-reactive and human epithelia (HEP-2) reactive antibodies in RA patients. This dysfunction in peripheral checkpoint results in defective Tregs and in B-cell resistance to suppression and apoptosis.
Also, in patients with RA, BAFF is increased in the presence of cytokines and chemokines, as well as through TLRs activation. The increased BAFF expression further prolongs the survival and maturation of auto-reactive B-cells, exacerbate autoimmune conditions.
Roles of T-Lymphocytes in RA Pathogenesis
The chronic immune response of RA is contributed by CD4+ T-cells. During activation of T-cells, CD4+T-cells interact with human leukocyte antigen (HLA) or major histocompatibility complex class II (MHC-II) molecules and also co-stimulate molecules such as CD28, that are expressed on the surface of APC. This leads to the onset of downstream PI3K signaling pathway, which leads to the maturation of CD4+ cells. Subsequently, the interaction leads to the antigenic activation of naive CD8+ T-cells, which promote inflammation.
CD4+ T-cells also associate with particular MHC-II alleles, HLA-DR4, which contains similar amino acid motifs in the third hyper-variable region of DRB-chain. This interaction then leads to a more aggressive form of RA. The systemic morbidity associated with RA such as vasculitis and acute coronary syndrome is correlated with CD4+CD28 null.
In addition to cell-to-cell interaction, CD4+ T-helper (Th) cells contribute to the pathogenesis of RA through the secretion of cytokines and chemokines, which are important immune modulators in cell-mediated immunity.
Type 1 T-helper (Th1) cells, which are highly activated in RA, secrete pro-inflammatory cytokines such as IFNϒ, IL-2, and TNF-α. Th1 cells also activate macrophages to act as an APC to present MHC-II molecules to the T-cells. Meanwhile, CD4+ Th2 cells on the other hand secrete anti-inflammatory cytokines such as IL-4 and IL-5 and play central roles in B-cell activation and in immunoglobulin (Ig) class switching to IgE. A T-cell subset, Th17 cells secrete Il-17 which stimulates production of pro-inflammatory cytokines, chemokines, and matrix metalloproteinases (MMps).
Roles of Macrophages in RA Pathogenesis
Macrophages are found in synovial tissue where most of it resides within the tissue in a resting state under normal conditions. But in an inflamed joint, they regulate the secretion of pro-inflammatory cytokines and damaging enzymes, which are associated with inflammatory responses and subsequently, joint destruction. They also mediate the recruitment of lymphocytes, cartilage damage, joint erosion, angiogenesis and fibroblast proliferation. Macrophages act as APC and are found to highly express HLA-DR and leukocyte adhesion molecules, which allow macrophages to participate in T-cell activation alongside B-cells.
The macrophage-mediated T-cell activation results in the production of effectors T-cells as well as expression of resulting pro-inflammatory mediators like IL-1α, IL-1β, and MMPs, which support RA pathogenesis.
The Role of Cytokines in RA pathogenesis
Cytokines are proteins that function as mediators in cell signaling; they comprise monokines, lymphocytes, ILs, IFNs, colony stimulating factors (CFS) and chemokines. Pro-inflammatory cytokines play pivotal roles in the pathogenesis of RA.
In early pathogenesis, the predominant cytokines that are secreted from T-cells and stroma cells are IL-13, IL-14 and IL-15. These cytokines cause the inflammatory response and contribute to chronic inflammation. In RA patients, pro-inflammatory cytokines such as TNF-α, IL-1 and IL-17 usually outweigh the protective effects of the anti-inflammatory cytokines such as IL-4, IL-11 and IL-13, which results in the cytokine-mediated inflammation.
In RA, B-cells and macrophages, which are APCs, present arthritis-associated antigens to T-cells and activate the signaling cascades to secrete cytokines. The cytokines so activated stimulate the activation of chondrocytes and osteoclasts and produce MMPs, which degrades the matrix of articular cartilage leading to bone resorption.
Role of NF-kB in RA Pathogenesis
NF-kB activation plays a pivotal role at the stage of initiation and also at the stage of perpetuation of chronic inflammation in RA. The NF-kB activation is triggered in T cells by the engagement of the T cell receptor and the CD28 receptor with their ligands, MHC-II and the co-stimulatory molecule CD80 and CD86 presented by APCs. The T cell receptor CD28 work in synergy in induction for T cells activation and proliferation, such as IL-2, IL-2 receptor (IL-2R), and IFNϒ. In turn, activated T cells elicit NF-kB activation in APCs.
The suppression of NF-kB inhibited expression of many proinflammatory molecules, including IL-1, TNFα, IL-6, IL-8, ICAM-1 and VCAM-1 but had no effect on the expression of anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist. It thus suggests that NF-kB activation facilitates the impaired balance of proinflammatory and anti-inflammatory molecules in the arthritic joint.
Treatment of Rheumatoid Arthritis (RA)
There is presently no cure for rheumatoid arthritis. However, symptoms of RA can be abated when treated with disease-modifying antirheumatic drugs (DMARDs). Some of the medications for Rheumatoid Arthritis include:
Steroids. Corticosteroid medications reduce inflammation and slow joint damage.
NSAIDS. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce pain and inflammation. E.g. includes Ibuprofen and Naproxen sodium.
DMARDs. Conventional DMARDs can slow the progress of rheumatoid arthritis and prevent the joints and other tissues from permanent damage.