MICE WITH AN INACTIVATED JOINING CHAIN LOCUS HAVE PERTURBED IGM SECRETION

A mouse with an inactivated joining chain locus was produced by gene t argeting in embryonic stem cells by deleting the first exon. Heterozyg ote (J(+/-)) and homozygote (J(-/-)) offspring from these mice showed normal total serum immunoglobulin levels and a normal peripheral B cel l compartment when compared to wild-type littermates. The distribution of serum immunoglobulin isotypes in serum was different; IgA levels w ere elevated while IgM levels were reduced in J(-/-) mice as compared to wild-type mice. High molecular weight serum IgM was reduced in J(+/ -) and J(-/-) mice and instead found in oligomeric form of undefined s tructure. Furthermore, serum IgM from J(+/-) and J(-/-) mice showed a reduced ability to activate complement. The number of splenic and bone marrow IgM plaque-forming cells were reduced in unimmunized J(+/-) as well as in J(-/-) mice. Furthermore, the number of plaque-forming cel ls was reduced in B cells from both J(+/-) and J(-/-) mice after stimu lation with lipopolysaccharide in vitro. The perturbation of IgM produ ction in J(-/-) mice appears to affect a late stage of differentiation , because cells with intracellular IgM were readily detected both in v ivo and in vitro. Finally, after immunization with T-dependent or T-in dependent antigens the IgM component of the immune response was reduce d in J(-/-) mice while only a marginal reduction of the IgG response w as detected.