Autoimmune diseases are caused by a combination of genetic and environmental factors. HLA antigens are one of the primary genetic influences.
Autoimmune diseases are caused by a combination of genetic and environmental factors. The genes that cause susceptibility to autoimmune diseases include organ-specific genes and immune system or major histocompatibility (MHC) genes. Genes of the major histocompatibility complex located on chromosome six determine what specific protein antigens the immune system will react with and they determine the severity of the reaction. In humans, the MHC genes are known as human leukocyte antigens or HLA markers. Specific HLA markers are associated with specific autoimmune diseases. For instance, persons who develop Hashimoto’s thyroiditis usually have the HLA DR5 marker, and persons with Graves’ disease usually have HLA B8 and HLA DR3 antigens.
Protective Markers
Some HLA antigens are associated with an absence of specific autoimmune diseases. These markers offer protection against the development of specific autoimmune disorders. For instance, persons with the genetic marker HLA B7 are unlikely to develop Graves’ disease even when other markers associated with Graves disease are present.
Heterozygous and Homozygous Markers
Alleles are individual genetic markers. Because each parent contributes one genetic allele for each of the different genes, we can have no dose, a single dose, or a double dose of each of the specific HLA markers. When only one gene allele or one dose of HLA DR3 is present this is called a heterozygous gene. In people with heterozygous genes for HLA markers, the effect is less pronounced than if a double or homozygous gene dose is present. That is, persons with one dose of HLA DR3, which they inherited from only one parent, have a milder genetic influence than persons who inherited two doses of HLA DR3, one from each parent.
Genetic Associations
Certain combinations of HLA markers, for instance the combination of HLA B8, HLA DR3 and HLA A1, are associated with several different autoimmune diseases, including Graves’ disease, systemic lupus erythematosus (SLE), celiac disease, type 1 diabetes, autoimmune hepatitis, and others. HLA marker DR3 is also associated with low levels of T suppressor (CD8) cells, which is a known risk factor for autoimmune disease development. When sufficient T suppressor cells are present, they destroy autoreactive cells before they go on to induce autoantibody production. Having adequate T suppressor cells helps protect us from developing autoimmune diseases.
Diagnostic Uses of HLA Markers
Although specific diseases are associated with specific HLA markers, outside of research studies, only the HLA B27 marker is used as a diagnostic tool. Because HLA B27 is seen in 80 percent of patients with the systemic connective tissue disorder known as ankylosing spondylitis blood tests for HLA B27 are used to help diagnose ankylosing spondylitis and to differentiate it from rheumatoid arthritis. Blood tests for HLA B27 are also used to help diagnose Reiter’s disease and uveitis.
