Causes of Cold Agglutinin Disease

Overview

Cold agglutinin disease (CAD) can manifest as a primary or a secondary disease. In both these CAD types, the cold agglutinins bind to red blood cells when exposed to cold temperatures and activate the classical complement pathway, which then targets these blood cells for destruction by other components of the immune system.

The production of cold agglutinins in primary CAD is attributed to B-cell lymphoproliferative disease, or blood disorders involving the uncontrolled growth of lymphocytes (white blood cells). Primary CAD is a chronic condition that will persist and require constant care and treatment.

Secondary CAD is the result of an underlying primary disease such as bacterial, viral or parasitic infections, another autoimmune disease, or a lymphoid malignancy such as lymphoma. Secondary CAD is mostly transient, and in most cases, treating the primary disease will resolve CAD.

Cancer

While the actual mechanism by which cancer leads to CAD is not fully known, scientists think that antibodies produced by the immune system against cancer proteins mistakenly bind to proteins normally found on the surface of red blood cells and activate their destruction. The most common malignancies associated with CAD are lymphomas or leukemias, both blood cancers that can be caused by the abnormal growth of a subset of immune cells called B-cells.

Learn more

Genetics

CAD is not a hereditary condition, and no genetic mutations are directly linked to the disease. However, a recent study identified mutations in two different genes in antibody-producing B-cells: KMT2D and CARD11. The mutation in KMT2D resulted in the production of a non-working enzyme, which can overstimulate the production of autoantibodies from B-cells. The CARD11 mutation resulted in the proliferation of B-cells and triggered autoantibody production.

Learn more

Complement System

The complement system is made up of a series of proteins activated when the immune system is responding to a threat. When complement proteins are bound to antibodies that have recognized a target, the complex dramatically increases the immune response to the threat — more so than would occur when an antibody alone binds to the target. In CAD, the adaptive portion of the immune system mistakenly produces antibodies called cold agglutinins.

Learn more