The Immune System - What Is Arthritis: Arthritis

Content provided by the Faculty of the Harvard Medical School

The immune system

Inflammation is the hallmark of a number of types of arthritis, including rheumatoid arthritis, gout, pseudogout, ankylosing spondylitis, reactive arthritis, psoriatic arthritis, enteropathic arthritis, and infectious arthritis. Such conditions all appear to stem, directly or indirectly, from an inflammatory response instigated by the immune system.

In inflammatory rheumatic diseases, the immune system reacts to elements that the body perceives as foreign — be they actual invaders, such as bacteria, or simply cell components wrongly identified as foreign. Research shows that certain people may be more genetically susceptible than others to such inflammatory rheumatic diseases.

The normal immune response

The skin covering your body and the mucous membranes lining your respiratory system and gastrointestinal tract are protective barriers that keep out most of the harmful substances in the environment that might enter your body. When these barriers are insufficient, the immune system activates special cells, proteins, and powerful chemicals to eradicate the invader. Although surveillance and policing go on quietly all the time, major confrontations can result in inflammation and tissue damage.

When bacteria, viruses, or other foreign substances invade the body, specialized cells release cytokines, chemical messengers that increase blood flow to the site and direct an army of white blood cells, microbe-fighters, and other protective substances to flow into the invaded tissue. Here, white blood cells release potent chemicals including leukotrienes, prostaglandins, and additional cytokines. These and other chemical mediators are responsible for intense reactions that include inflammation in the form of pain, redness, swelling, and heat. After the attackers have been eradicated, the immune system is no longer stimulated, and the symptoms of inflammation subside.

In order for this process to occur, however, the immune system must first identify the invaders as "non-self" in contrast to normal "self" cells. This requires a complex interaction of numerous recognition and signaling molecules. In simplified terms, the immune system works via several types of cells. First, cells known as phagocytes encounter the invaders, digest them, and present an antigen (a distinguishing protein or carbohydrate) on their surface (see Figure 3). The antigen binds to a special molecule called a human leukocyte antigen (HLA) complex, which in turn presents it to a second class of immune cells launching an attack on the "non-self" invaders.

Figure 3: Immune response T cells attack and destroy invaders, then multiply to prepare for a future invasion.

This second cell type includes several classes of lymphocytes (white blood cells). T lymphocytes recognize the antigen signal and recruit killer lymphocytes to destroy the foreign cells. At other times, T lymphocytes stimulate B lymphocytes to make antibodies, proteins that are designed especially to attack the invader. Natural killer cells and macrophages are other white blood cells involved in fighting foreign molecules. The immune system can also target body cells that become abnormal because of injury, cancerous transformation, or invasion by certain viruses.

Given this complexity, it's not hard to imagine how autoimmune injury might occur. Antibodies made against foreign molecules might mistakenly attack normal body proteins; lymphocytes might misidentify "self" and "non-self" cells; or normal cells could get caught up in the immunological crossfire of harmful enzymes and toxic molecules.

When the system malfunctions

Inflammatory rheumatic disease occurs when something goes awry with the immune response, perhaps because B lymphocytes continue producing antibodies or because the "self" tissues are affected in some way by the original attack that makes them seem "foreign." However it occurs, the result is an inflammatory response that continues far longer than it should.

This prolonged inflammation can be devastating. In rheumatoid arthritis, inflammation may involve internal organs as well as joints. And in ankylosing spondylitis and related disorders, inflammation often centers on an enthesis, a spot where tendons or ligaments attach to bone. The different patterns of tissue damage account for the symptoms that are unique to each of these ailments.

It's become clear that for most forms of inflammatory joint disease, the cause isn't a single infectious agent that could affect anyone. Rather, such diseases occur through a combination of several inciting events in an individual who is genetically susceptible or predisposed at a given time by otherwise unrelated factors.

Much like fingerprints, each person's immune response is unique. This is because a group of genes that regulate the immune system can produce responses to a very large array of potential antigens. On the short arm of chromosome 6 lies an area called the major histocompatibility complex (MHC), containing genes that underpin the immune response.

These genes function as a sort of headquarters for the immune system by determining the structure of the HLA molecules that present antigens to T lymphocytes and enable immune cells to distinguish "self" from "non-self." They were first discovered in the 1950s when immunologists were trying to understand why organ transplants were often rejected by the recipient's immune system. This line of research led to the discovery that people who received transplants had a better chance of recovery if certain of their HLA molecules matched the donor's.

A number of HLA molecules are associated with particular types of inflammatory arthritis. For example, a genetic marker for HLA-B27 is present in nearly all people who have ankylosing spondylitis and in most of those with reactive arthritis, which is triggered by bacterial infection elsewhere in the body. Similarly, a genetic marker for HLA-DR4 can be found in many people with rheumatoid arthritis.

Last updated:	September 05, 2008