LEMS and Genetics

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by the production of antibodies that mistakenly attack the calcium channels found on the nerve cells’ endings where they meet muscles, the so-called neuromuscular junctions. This blocks the nerve signals required for muscle contraction and causes muscle weakness, mostly in the arms, legs, shoulders, hips, eyes, and throat.

LEMS is not a hereditary disease, but people who have some variants of immune-related HLA genes are more susceptible to LEMS.

LEMS and HLA genes

Nearly half of LEMS cases are associated with cancers, especially small cell lung cancer (SCLC), whereas the remaining cases are non-tumor related.

The HLA (human leukocyte antigen) genes encode for proteins that help the immune system distinguish between the body’s own proteins and those made by foreign invaders such as viruses and bacteria.

Several studies have shown that non-tumor related LEMS occurs more often in individuals who have the HLA-B8, HLA-DR3, and HLA-DQ2 variants than other variants of HLA genes.

More about HLA genes and proteins

There are three classes of HLA proteins: I, II, and III.

Class I HLA proteins are found on the surface of most cells in the human body. They present either small fragments of the body’s own proteins (self-antigens) or the viral and bacterial proteins (foreign antigens). When immune cells recognize HLA proteins presenting a foreign antigen, they launch an immune response to clear the infection caused by the virus or bacteria. There are three major class I genes — HLA-A, HLA-B, and HLA-C — and several subtypes for each subclass. HLA-B8 is one of the HLA class I subtypes.

HLA proteins from class II are found on different types of immune cells, such as the T-lymphocytes and B-lymphocytes. They also present self or foreign antigens to other immune cells. There are five major class II genes, namely HLA-DP, HLA-DM, HLA-DO, HLA-DQ, and HLA-DR. Again, there are several variant subtypes of these class II genes. HLA-DR3 and HLA-DQ2 are examples of HLA class II subtypes.

HLA class III proteins are pro-inflammatory cytokines such as TNF-α and proteins of the complement system such as C2 and C4.

The HLA subtypes are different for each individual and are generally inherited from the parents.

How are HLA proteins associated with LEMS?

The mechanisms by which HLA proteins may cause autoimmune diseases such as LEMS are speculative and not conclusively proven.

One of the probable mechanisms suggested is that when some subtypes of HLA proteins, such as  HLA-B8, HLA -DR3, and HLA-DQ2 display self-antigens, under some circumstances, the immune cells recognize them as foreign instead of self and launch an immune response against them.

A study published in the scientific journal Human Immunology showed that individuals with HLA-B8 and HLA-DR3 variants have higher levels of TNF-α, which is normally absent and is only produced when the immune system recognizes a foreign antigen and is required to eliminate it as part of the immune response. High levels of TNF-α in the case of no infection can cause medical problems, including autoimmune diseases like LEMS.


Last updated: Oct. 1, 2019


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