Genetic Aspects of Inherent B-cell Abnormalities Associated with SLE and B-cell Malignancy: Lessons from New Zealand Mouse Models

Abstract

Genes that predispose to SLE are closely related to key events in pathogenesis of this disease. As much of the pathology can be attributed to high affinity autoantibodies and/or their immune complexes, some of the genes may exert effects in the process of emergence, escape from tolerance mechanisms, activation, clonal expansion, differentiation, class switching and affinity maturation of self-reactive B cells. A number of growth and differentiation factors and signaling molecules, including positive and negative regulators, are involved in this process. Genetic variations associated with functional deficits in some of such molecules can be involved in the susceptibility for SLE. As is the case with SLE, hereditary factors play significant roles in the pathogenesis of B cell chronic lymphocytic leukemia (B-CLL). Patients with B-CLL or their family members frequently have immunological abnormalities, including those associated with SLE. It is suggested that certain genetically determined regulatory abnormalities of B cells may be a crossroad between B-CLL and SLE. A thorough understanding of the genetic pathways in B cell abnormalities leading to either SLE or B-CLL is expected to shed light on their association. New Zealand mouse strains are pertinent laboratory models for these studies. Chromosomal locations of several major genetic loci for abnormal proliferation, differentiation and maturation of B cells and relevant candidate genes, located in close proximity to these intervals and potentially related to the SLE pathogenesis, have been identified in these mice. Further studies make for a wider knowledge and understanding of the pathogenesis of SLE and related B-cell malignancy.