HLA-Associated Diseases

What HLA genes do

Every cell carries HLA molecules on its surface, like a display stand. They hold up small pieces of protein from inside or around the cell. T cells inspect these fragments. If a fragment comes from a virus or bacterium, the T cell attacks.

There are two main classes:

• Class I (HLA-A, HLA-B, HLA-C): found on almost all cells. They display fragments from inside the cell to killer T cells.
• Class II (HLA-DR, HLA-DQ, HLA-DP): found on immune cells. They display fragments from outside the cell to helper T cells.

HLA genes are the most varied genes in humans, with thousands of versions. You inherit one set from each parent. This variety helps populations fight many germs, but some versions are more likely to present the body's own proteins, or certain drugs, in a way that triggers harmful immune attacks.

Major HLA-disease associations

HLA and drug reactions

Some HLA types make specific medicines trigger severe immune reactions. Testing before treatment prevents them:

• HLA-B*57:01 and abacavir (HIV treatment): life-threatening hypersensitivity. Testing is required before starting abacavir.
• HLA-B*15:02 and carbamazepine or phenytoin: Stevens-Johnson syndrome and toxic epidermal necrolysis. Testing is recommended before carbamazepine for people of Southeast and South Asian ancestry, where this type is common.
• HLA-B*58:01 and allopurinol (gout medicine): severe skin reactions. Testing is recommended for higher-risk groups, including people of Han Chinese, Korean, Thai and African ancestry.
• HLA-A*31:01 and carbamazepine: DRESS and other reactions, especially in European and Japanese populations.

What a positive HLA test means

A positive result tells you about risk, not diagnosis. For example, about 6% to 8% of white Americans carry HLA-B27, yet only a small minority of them develop ankylosing spondylitis. About a third of the general population carries HLA-DQ2 or DQ8, while only about 1% has celiac disease.

How doctors use HLA tests:

• To support a diagnosis: HLA-B27 adds weight when back pain, imaging and blood tests suggest spondyloarthritis.
• To rule a disease out: a negative HLA-DQ2/DQ8 test makes celiac disease extremely unlikely. This is useful when someone is already on a gluten-free diet.
• To prevent drug reactions: pharmacogenetic tests before abacavir, carbamazepine or allopurinol.
• To match organ and stem cell transplants: closer HLA matching between donor and recipient reduces rejection and graft-versus-host disease.

Symptoms that may prompt testing

There is no single set of symptoms. HLA testing is usually considered when you have features of a linked condition, such as:

• Chronic low back pain and stiffness that is worse in the morning and better with exercise
• Recurrent episodes of a painful red eye with light sensitivity
• Persistent diarrhea, bloating, weight loss or iron deficiency
• Swollen joints after a gut or genital infection
• Daytime sleepiness with sudden muscle weakness triggered by laughing (cataplexy)

Why some carriers get disease and others do not

HLA genes are only part of the picture. Other genes, infections, the gut microbiome, smoking, diet (gluten in celiac disease) and chance all contribute. For example, reactive arthritis typically follows infections with Salmonella, Shigella, Campylobacter or Chlamydia in HLA-B27 carriers.

Treatment

There is no treatment for an HLA type itself, and there is no reason to treat a positive test without disease. Each associated condition is treated on its own terms: NSAIDs and biologic drugs for spondyloarthritis, a strict gluten-free diet for celiac disease, insulin for type 1 diabetes, and so on. For drug-related HLA types, the solution is simple: choose a different medicine.

Family members

Because HLA genes are inherited together as a block, siblings have a 1 in 4 chance of an identical HLA match. Relatives of someone with an HLA-linked disease carry higher risk, but routine testing of healthy relatives is usually not useful, except in celiac disease and type 1 diabetes research or transplant donor searches.

Frequently asked questions

What does it mean to be HLA-B27 positive?

It means you carry a gene variant that increases the risk of ankylosing spondylitis, reactive arthritis and a type of eye inflammation. Most HLA-B27 positive people never develop these conditions. The test is meaningful only when combined with symptoms, examination and imaging.

Can you have ankylosing spondylitis without HLA-B27?

Yes. Around 10% of people with ankylosing spondylitis in European populations, and more in some other populations, are HLA-B27 negative. Diagnosis relies on symptoms, inflammatory back pain, imaging of the sacroiliac joints and other tests.

Does having HLA-DQ2 or DQ8 mean I have celiac disease?

No. About a third of people carry one of these types, but only about 1% have celiac disease. The test is most useful when negative, since celiac disease is very unlikely without DQ2 or DQ8. Diagnosis requires antibody blood tests and usually an intestinal biopsy.

Why is HLA testing done before some medicines?

Certain HLA types cause severe, sometimes fatal, immune reactions to specific drugs: abacavir, carbamazepine and allopurinol are the main examples. Testing beforehand identifies people at risk so a safer medicine can be chosen.

Is HLA typing the same as genetic testing?

It is a type of genetic test that looks only at your HLA genes. It does not test for other inherited diseases. It is used for disease risk, drug safety and transplant matching.