RA and the Autoimmune Response
Reviewed by: HU Medical Review Board | Last reviewed: September 2013.
RA is both an inflammatory arthritis and an autoimmune disorder, so immune system function and inflammatory response are key concepts in understanding how RA works, as well as in understanding how therapies are used to treat RA.
How does the autoimmune response develop in RA?
In its earliest stages, even before joint inflammation occurs, RA is thought to begin with a series of events in which the immune system loses its ability to distinguish between what belongs to the body (the “self”) and what is foreign to the body (the “non-self”). This process, which occurs systemically (throughout the body) begins with inadequate clearance of cells as they die. Normally, dying cells do not come in contact with the immune system and are not identified as a potential threat to the body.1
As cells reach the end of their lifespan, they undergo citrullination, a process in which enzymes called peptidylarginine deiminases (PADs) transform (citrullinate) proteins within the cell. This is a normal part of cell physiology.1
However, in most patients who develop RA (those with a common immune system gene variant associated with RA), citrullinated proteins and PADs leak from dying cells throughout the body. The leaked PADs transform (citrullinate) proteins in the extracellular fluid (outside of the cell). These citrullinated proteins are recognized as antigens by the immune system. In response to these antigens, the immune system generates anti-citrullinated protein antibodies (ACPA). The creation of ACPA indicates a loss of tolerance to the “self.” The presence of ACPA is an accurate predictor of RA, as is rheumatoid factor (RF) (accurate in about 80% of cases), and can even predict the disease some 15 years before it becomes clinically apparent with joint symptoms.1
RA and the autoimmune attack on joints
In patients with ACPA and/or RF, autoantibody production and inflammation occurs systemically (throughout the body) before it occurs in the joints. Therefore, it is thought that some other factor or trigger (not yet known) is involved in causing the early systemic autoimmune response to move to the synovium (joint), leading to the symptoms characteristic of RA.1
This unknown factor causes leukocyte (white blood cell) migration and infiltration into the synovium. As the immune system is activated and the disease progresses, a cascade of inflammatory cell types and immune system chemicals are produced. These immune system cells and the wide range of chemicals they produce play a role in the autoimmune process, which ultimately causes joint destruction.1
Major players in the autoimmune response: leukocytes
Leukocytes or white blood cells are key immune system cells that play a central role in the autoimmune response that occurs during RA. Leukocytes include a number of different types of white blood cells with different functions. Those with key involvement in the RA autoimmune response include neutrophils, lymphocytes (T- and B-cells), monocytes, macrophages, and dendritic cells (these last two types of cells are derived from monocytes). In addition to leukocytes, another immune system cell called a mast cell plays an important role in the autoimmune process, releasing cytokines, chemokines, and enzymes called proteases.
- Active in phagocytosis
- Synthesize range of immune system chemicals
- Recruit Th cells, which produce a range of ILs and TNF-α
- Produce autoantibodies and present antigens to T cells
- Secrete cytokines to stimulate synovial fibroblasts
- Produce plasma cells involved in production of autoantibodies
- Migrate from blood stream to synovium, differentiating into macrophages and dendritic cells
- Secrete range of chemicals (ILs, TNF-α) that promote inflammatory processes
- Involved in phagocytosis and antigen presentation
- Produce range of cytokines (IL-12, 15, 18, 23)
- Involved in presenting antigens to T-cells and activating T-cells
Major players in the autoimmune response: inflammatory mediators
A wide range of chemicals produced by immune system cells carry out the many functions involved in the autoimmune response. These chemicals, known as inflammatory mediators, include cytokines (eg, growth factors, interferon [IFN]-γ, TNF-α, interleukin 1 [IL-1] family), enzymes, chemokines (small cytokines that serve as signaling proteins) (eg, interleukin 8 [IL-1] family), signaling molecules (leukotrienes and prostaglandins), and antibodies, a type of protein also called an immunoglobulin (Ig).1
Additionally, another group of immune system chemicals called the complement system helps (complements) the ability of antibodies and phagocytic cells to clear antigens as part of the immune response. The complement system consists of more than 25 proteins and fragments of proteins, including cell membrane receptors.1
RA autoimmune process and evolution of joint damage
In RA, the immune system malfunctions and attacks healthy joint tissue as if it were a foreign invader. Leukocytes travel to joint cavities, launching an inflammatory response. White blood cells, including B- and T-cells, neutrophils, dendritic cells, and macrophages, and other types of immune cells including mast cells multiply in the joint cavity.2,3
These immune cells release inflammatory mediators, including cytokines, leukotrienes, and prostaglandins. Some of these substances promote the growth of blood vessels, which supply nutrients to the growing mass of leukocytes, resulting in the formation of pannus (this Latin word literally means a piece of cloth), a flap of fibrous tissue that forms over the synovial cartilage. The synovial lining on the inside of the joint becomes inflamed and swollen. With continued exposure to inflammation, thickening of the synovial lining and pannus formation, over time the joint space decreases and the bony structure of the joint itself may become deformed and, in extreme cases, the joint may cease to function.2,3