A single autosomal gene defect severely limits IgG but not IgM responses in B lymphocyte-deficient A/WySnJ mice.
Antigen-stimulated B lymphocytes either differentiate into IgM-secreting plasma cells or into memory B cells that secrete other immunoglobulin isotypes upon antigen restimulation. The mechanisms that generate and maintain memory B cells are poorly understood. Previously, we described a severe B lymphocyte deficiency in adult strain A/WySnJ mice compared to subline A/J. Here we show that the single, autosomal co-dominant locus responsible for the deficiency also diminishes IgG-secreting B cell formation without interfering with IgM-secreting plasma cell differentiation. A/WySnJ secondary IgG1 responses to the protein antigens hemocyanin, bovine gamma-globulin, ovalbumin, lysozyme and beta-galactosidase were 6- to 50-fold lower than A/J responses. The defect also decreased secondary IgG2a and IgG3 responses, and primary IgG1 and IgG2a responses. The reduced A/WySnJ secondary IgG1 response was not due to differential response kinetics or dose responsiveness, and could not be augmented to A/J levels by repeated immunizations. Serum IgG1, IgG2a and IgG3 levels from nonimmune A/WySnJ mice were similarly reduced. The secondary IgG1 response and splenic B cell percentage showed significant positive correlation (r = 0.72) in F2 mice, suggesting that a single locus controlled both traits. In contrast, A/WySnJ mice made good primary IgM responses to hemocyanin, beta-galactosidase, and the thymus-independent antigen trinitrophenyl-Ficoll. The A/WySnJ splenic adherent cells were competent in antigen-presenting function, and A/WySnJ immune T cells proliferated in response to antigen and provided the requisite B cell stimulatory signals for an IgG1 response. Together, our results suggest that A/WySnJ mice have a genetic lesion that causes a selective IgG immune response dysfunction. The absence of IgG-secreting cell precursors or a defect in precursor activation or differentiation are two possible mechanisms which could precipitate a selective IgG response dysfunction. We propose that the defective A/WySnJ and normal A/J strain pair offer the opportunity to use a natural genetic variation as a tool to investigate B lymphocyte development and function.
Miller
D J
DJ
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison 53706.
Hanson
K D
KD
Carman
J A
JA
Hayes
C E
CE
D000818:Animals; D000917:Antibody Formation; D000938:Antigen-Presenting Cells / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007075:Immunoglobulin M / Q000096:biosynthesis*; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D007156:Immunologic Memory; D008211:Lymphocyte Cooperation; D051379:Mice; D008817:Mice, Mutant Strains; D013601:T-Lymphocytes / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D007074:Immunoglobulin G; D007075:Immunoglobulin M