Negative regulation of autoreactive B cells in transgenic mice expressing a human pathogenic cold agglutinin

Cold agglutinins (CA) are autoantibodies that bind to erythrocyte carbohydr ates at low temperatures and induce complement-mediated cell lysis, thus ca using hemolytic anemia. Tolerance mechanisms towards CA-expressing B cells and the factors inducing pathogenic CA production are unknown. In order to develop an animal model for CA disease, we have produced transgenic mice ex pressing the heavy or the light chain of a human CA, previously shown to be pathogenic to the mouse. Expression of the human H chain alone resulted in a B cell maturation block at the pro-B stage, and did not induce allelic e xclusion. In double-transgenic mice, co-expression of the human H and L cha ins restored B cell development but the majority of bone marrow cells expre ssing the human IgM were eliminated by deletion. In the periphery, B cells were depleted, and a large proportion of the remaining cells co-expressed a human and a murine H chain, secreting "mixed" IgM. A few autoreactive cell s, predominating in the peritoneal cavity, escaped tolerance mechanisms and secreted transgenic IgM. The autoreactive B cells are amenable to polyclon al stimulation, making these transgenic mice a suitable model for a human a utoimmune disease.