Nat Immunol: unknown pathogenic mechanism that causes immunodeficiency

Primary immunodeficiency, such as severe combined immunodeficiency (SCID), occurs when the immune system is not working properly, leading to increased susceptibility to various infections, autoimmunity, and cancer

The gene family called IKAROS zinc finger proteins (IKZFs) is related to the development of lymphocytes, which are white blood cells that participate in the immune response, which means that mutations in this family may be related to immune system defects

TMDU researchers discovered this new mechanism when investigating the cause of a previously undescribed hereditary B-cell deficiency observed in a family of patients

They continued to use a mouse model containing the equivalent AIOLOS mutations found in patients to outline the underlying pathogenic mechanism

"This is a new pathogenic mechanism, which we call heterodimer interference," said lead author Motoi Yamashita

Then, the research team saved some immune functions in the mouse model by deleting the dimerization domain of the mutant AIOLOS

"The fact that we can rescue the phenotype of the mouse model indicates a potential treatment," said senior author Tomohiro Morio

The discovery of heterodimer interference with this new pathogenic mechanism is likely to help elucidate many other disease processes, such as autoimmunity and cancer development, in which mutant proteins act in the same way

A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS