Human leukocyte antigens

BACKGROUND

Human leukocyte antigens (HLA) are proteins that are present on the outer surface of nearly every cell in the body.

White blood cells contain especially high concentrations of HLA. This is because the HLA molecules help the body's immune system distinguish between self and non-self (foreign or invading) substances. HLA allows the immune cells to recognize the self cells, preventing them from mistakenly attacking and destroying body tissues.

There are many different HLA molecules, and each person is born with a relatively unique set that is passed down from his or her parents. During reproduction, each parent donates one-half of his or her HLA antigens to each offspring. Therefore, it is unlikely that two unrelated people will share the same HLA make-up, although, identical twins may match each other. This is particularly important when healthcare providers are trying to identify good matches for tissue grafts and organ transplants. If donors and recipients are not closely matched, the recipient may identify the donated organ as a foreign substance and attack it. This is called transplant rejection. Conversely, the donated organ may attack the recipient's cells if they are perceived as a foreign substance. This is called graft-versus-host disease (GVHD).

The major histocompatibility complex (MHC) is a group of genes that provides the instructions for the development of the HLA system. There are three subclasses of the MHC.

Class I MHC molecules are present in any cell that has a nucleus and they include HLA-A, HLA-B, and HLA-C. These molecules are used by specific white blood cells called suppressor T-cells. After suppressor T-cells internalize antigens (foreign substances like bacteria), they combine parts of the antigens to parts of their Class I molecules. When fragments of the antigen are combined with the MHC molecule, other immune cells are able recognize and destroy the foreign substance.

Class II MHC molecules include HLA-D. These molecules are used by specific white blood cells called helper T-cells, macrophages, and dendritic cells. These cells combine parts of the antigen to the class II MHC so that other immune system cells can recognize and destroy the foreign invader.

The MHC class III region provides the genetic instructions for other parts of the immune system, including cytokines, which are chemical messengers that stimulate the immune response.

Some individuals are born with mutations (abnormalities) in the MHC, which can potentially lead to autoimmune and/or inflammatory conditions. Autoimmune disorders occur when the immune system mistakenly attacks the body's own tissues because they are incorrectly identified as harmful substances like bacteria or viruses.

For instance, one type of MHC mutation can lead to the development of an HLA molecule called HLA-B27. This molecule is associated with several rheumatic diseases. For example, the HLA-B27 molecule is present in 80-90% of patients who have ankylosing spondylitis (rheumatic disease of the spine) and Reiter's syndrome. Patients who have the HLA-B27 molecule are about 87 times more likely to develop ankylosing spondylitis compared to the general population. Therefore, detecting HLA-B27 may help a healthcare provider diagnose the disease.

HLA-B27

Rheumatoid disease: Researchers discovered the sequence of HLA-B27 in 1985. While researchers estimate that only 1.4-8% of the general population has the molecule, it is prevalent among patients who have rheumatoid diseases, especially ankylosing spondylitis. Although there are six subtypes of HLA-B27, there is no association between one particular subtype and inflammatory disease.

Ankylosing spondylitis is a rheumatic disease of the spine that causes chronic inflammation of the spine and the sacroiliac joints (located in the lower back). More than 90% of patients who have spondylitis have the HLA-B27 molecule.

However, even though most patients with ankylosing spondylitis have the HLA-B27 molecule, it does not mean that everyone who has the gene will develop the disease. In fact, it is estimated that up to 75% of patients who have the gene never develop clinically significant rheumatic symptoms

The HLA-B27 molecule is also present in about 80% of patients who have reactive arthritis. In addition, about 50% of patients who have a combination of peripheral arthritis and either psoriasis (skin disease characterized by red patches of skin covered with white scales) or inflammatory bowel disease (IBD) have the HLA-B27 molecule.

It remains unknown exactly how the HLA-B27 molecule triggers an inflammatory response in the body. It has been suggested that it occurs when an infectious organism that looks similar to HLA-B27 enters the body. In such cases, researchers believe that the immune system cells mistake the HLA-B27 molecule for the infectious agent. As a result, the immune system attacks itself and symptoms of rheumatoid disease occur. It has also been suggested that the HLA-B27 molecules bind to infectious agents. This may cause the immune system to attack itself. A third theory is that the HLA-B27 molecule may be closely linked to a currently unidentified gene that is responsible for triggering the immune response.

Acute anterior uveitis: About 50-60% of patients who have acute anterior uveitis (AAU) are HLA-B27 positive. Acute anterior uveitis (AAU) is an inflammation of the uveal tract that lines the inside of the eye behind the cornea. The incidence of this disease varies according to racial background and nationality. AAU that is associated with the HLA-B27 molecule is most common among Caucasians and least common among African Americans. Symptoms often include severe eye pain, redness near the edge of the iris (colored part of the eye), and extreme sensitivity to light.

While the exact relationship between the HLA-B27 gene and AAU remains unknown, several theories exist. Based on several animal studies, many cases of AAU occur after a patient develops chlamydia or an infection that causes diarrhea. Disease-causing organisms that have shown to cause AAU include Shigella, Salmonella, Klebsiella, and Yersinia species. These organisms have similar structures to the HLA molecule. As the immune system fights off these organisms, the body may mistake the HLA-B27 molecules for the disease-causing agents. When this occurs, symptoms of AAU may subsequently develop.

HLA-DR4

Researchers suggest that patients who have the HLA-DR molecule may have an increased risk of developing autoimmune disorders. These disorders occur when the immune mistakenly attacks the body's own tissues because they are incorrectly identified as harmful substances like bacteria or viruses.

The most common autoimmune disorder associated with the HLA-DR molecule is rheumatoid arthritis. This condition causes the joints to become swollen and painful. Without treatment, the pain may make it difficult for the patient to perform normal daily activities such as walking.

The HLA-DR4 gene has also been associated with Lyme disease. Lyme disease is caused by bacteria called Borrelia burgdorferi that are transmitted to humans via deer ticks. Lyme disease typically causes joint pain, inflammation, and arthritis.

Patients who have severe cases of Lyme disease and do not respond well to the antibiotic treatment are more likely to have the HLA-DR4 molecule. It has been suggested that once the disease-causing organism moves to the joints, the immune system mistakes the body cells containing the HLA-DR4 molecule for the bacteria. This consequently causes an autoimmune reaction.

HISTOCOMPATIBILITY ANTIGEN TEST

A histocompatibility antigen blood test analyzes the HLA proteins on the surface of cells. Certain HLA proteins have been associated with specific disease. For instance, an HLA-B27 positive individual is about 87 times more likely to develop ankylosing spondylitis than someone who does not have the gene. Therefore, the test may help determine if an individual is at risk for certain diseases.

The test is most often used to identify good matches for tissue grafts and organ transplants. To help prevent serious complications, such as graft-versus-host disease or transplant rejection, the potential donor and recipient must be tested to determine whether their HLA molecules are closely matched making them compatible. Each person has unique HLA molecules (except for twins, who have identical molecules). Therefore, this test cannot prevent 100% of complications. However, the test can significantly reduce the number of patients who develop complications after transplantations.

AUTHOR INFORMATION

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

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