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Rheumatoid arthritis (RA) symptoms — pain, redness, and tissue damage — are caused by an immune response called a hypersensitivity.
There are four main types of hypersensitivity reactions produced by the human immune system. The best known is the type 1 hypersensitivity response, which is caused by allergens and is usually referred to as an allergic reaction. Type 2 hypersensitivity reactions occur when antibodies directly attack healthy cells. Type 4 hypersensitivity reactions do not involve antibodies, but T cells. Type 4 hypersensitivity is cell-mediated and is also called “delayed type” because it can take days to develop.
In the case of rheumatoid arthritis, symptoms are caused by type 3 hypersensitivity responses — also known as an immune complex mediated response. Many immune cells join to form immune complexes to attack antigens, or foreign invaders that could harm the body. If the body’s immune system fails to clear out these accumulating immune complexes, they can build up in tissue — including the skin and joints — and cause inflammation.
To understand more about how a type 3 hypersensitivity response occurs, it’s necessary to know the basics of the immune system. Our immune systems protect us against outside antigens — bacteria, viruses, fungus, and other toxins that could injure the body.
One function of the immune system is producing antibodies to fight these antigens. When an antigen enters the body, the immune response goes into action. A white blood cell called a B cell “learns” to produce antibodies designed to protect against a particular antigen. The newly formed antibodies then move through the bloodstream, searching for their dedicated antigens.
Many antibodies are shaped like the letter Y, with sites that can grab the cell surface of a soluble antigen with the end of each arm of the Y. When the antibody grabs the antigen — for example, a virus — it marks it for destruction with certain chemicals. After the antibody marks the invading antigen, other immune system cells arrive and kill the invasive pathogen.
There are five classes of antibodies: IgG, IgM, IgA, IgD, and IgE antibodies. The two classes of antibodies involved in type 3 hypersensitivity are IgM and IgG antibodies. IgM antibodies are the first class of antibody that new B cells produce. IgG antibodies are the antibodies most commonly found in the blood.
A type 3 hypersensitivity reaction occurs when too many antibodies and antigens clump together at once. Because of their Y shapes, more than one antibody can attach to an antigen at the same time. If many antibodies and antigens link together in this manner, they can form a chain. These chains are called antigen-antibody complexes, or more commonly, immune complexes.
If these immune complexes are large enough, they are destroyed in the spleen. However, smaller immune complexes can avoid detection and destruction. They build up in small blood vessels called capillaries. The immune complexes can get stuck in the blood vessel walls. They can also pass through these blood vessel walls — a process called vascular permeability — and settle on the cell surfaces of other tissues.
Immune complexes are especially likely to settle in the skin and joints, which are two areas commonly affected by RA. They are also likely to deposit in the pleura (membranes around the lungs), the pericardium (a membrane around the heart), and the glomeruli (parts of the kidneys).
Once the immune complexes are wedged in these tissues, an immune complex reaction begins. First, the antibodies in the immune complexes begin to produce mast cells in a process called degranulation, which prompts the release of inflammatory chemicals. These inflammatory chemicals are called histamines.
Second, the immune complexes trigger a process called “complement activation” or the “complement cascade.” The complement cascade is a normal immune system process that the body uses to kill diseased cells. During the complement cascade, molecules are produced that promote phagocytosis (cell destruction by immune cells called macrophages) and attract other immune system cells, like neutrophils, to destroy invading antigens.
However, in a type 3 hypersensitivity reaction, the immune complexes are lodged where they shouldn’t be. So the macrophages and neutrophils produced by the complement cascade don’t kill the immune complexes. Instead, they inadvertently destroy nearby healthy cells.
This inflames healthy tissue and causes clinical features like pain and swelling. This acute inflammatory response is called an Arthus reaction if it occurs in the skin and an “Arthus-like” or “Arthus-type” reaction when it is observed elsewhere. Other symptoms of a type 3 hypersensitivity reaction include rash, fever, urticaria (better known as hives), and purpura, which is a rash caused by breakdowns in blood vessel walls.
Several conditions are associated with type 3 hypersensitivity responses. These include systemic lupus erythematosus — better known as simply lupus — and glomerulonephritis (a group of kidney diseases).
Some infectious diseases can also cause type 3 hypersensitivity responses. There is evidence that the dangerous vasculitis (blood vessel inflammation) of COVID-19 infection is a type 3 hypersensitivity response. Rarer conditions caused by type 3 hypersensitivity include serum sickness, which occurs when the immune system reacts to animal proteins in an injection, and a condition called farmer’s lung, which is caused by inhaling crop mold.
Rheumatoid arthritis is an autoimmune disease. Usually, antigens are dangerous substances from outside the body. However, in autoimmune diseases, the body mistakenly identifies its own healthy cells as antigens and attacks them with an immune response.
In RA, the body produces an antibody called rheumatoid factor (RF), which attacks these self-antigens. During these attacks, immune complexes form and that starts the type 3 hypersensitivity response. In people with RA, the hypersensitivity reaction can affect the joint tissue, as well as the skin, eyes, heart, and lungs.
Scientists don’t know what causes people with rheumatoid arthritis to first develop type 3 hypersensitivity responses. Certain viruses, such as the Epstein-Barr virus (which causes mononucleosis or “mono”), parvovirus B19, or retroviruses, might cause genetic changes that “trick” the body into attacking its own cells. Another theory is that bacterial infections (such as gum disease) could be the source of immune reactions that trigger type 3 hypersensitivity responses.
There currently is no known cure for a type 3 hypersensitivity inflammatory reaction. The way to treat it is to reduce the inflammation associated with the reaction. Most treatments for RA, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and disease-modifying antirheumatic drugs (DMARDs), are useful to help calm hypersensitivity responses. They each work through different mechanisms. For example, the DMARD Methotrexate helps act against neutrophils, while some biologic DMARDs work by deactivating the B cells that would begin the type III hypersensitivity response in the first place.
Have you discussed type 3 hypersensitivity reactions with your health care provider? Have you found treatments that reduce your inflammatory symptoms? Comment below or start a conversation on myRAteam.
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