What is the role of genetics in the pathophysiology of cold agglutinin disease?

Updated: Aug 28, 2018
  • Author: Salman Abdullah Aljubran, MD; Chief Editor: Michael A Kaliner, MD  more...
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The 9G4 idiotope is localized to the V4-34 encoded portion of the variable region. [21] It is found on cold agglutinin-producing malignant lymphoid cells in the bone marrow in persons with lymphoproliferative disorders, on a small proportion of normal lymphoid cells, and in the spleen of a 15-week-old fetus. In contrast, the cold agglutinins found in healthy individuals, those with no clinical symptoms, are often derived from a variable segment other than the V4-34 portion. [22, 23]

The VH genes appear to regulate not only the production of cold agglutinins, but also the formation of normal antibodies to other carbohydrate antigens, both sharing the same fundamental mechanism of production. The I/i antigen analogues are present on human lymphocytes, neutrophils, and monocytes and in human saliva, milk, and amniotic fluid. Thus, in disease states, the finding of a clone of B cells producing this antibody may be the result of expansion of a normal clone that is specific for the production of an immunoglobulin with these properties. Autoimmune and lymphoproliferative disorders can also be associated with the production of cold agglutinins.

In vitro studies have shown that human monoclonal antibodies encoded by the V4-34 gene segment not only have cold agglutinin properties but also exhibit multireactivity. This is in contrast to the generally monospecific I/i reactivity of sera from patients with cold agglutinin disease. [18]

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