Exclusion of natural autoantibody-producing B cells from IgG memory B cell compartment during T cell-dependent immune responses.
In healthy individuals, a substantial proportion of circulating Abs exhibit polyreactivity and self-reactivity. These Abs are referred to as natural autoantibodies (NAAs). As part of the innate immunity, NAAs play an important role in eliminating pathogens. However, inherent to their poly/autoreactivity is the potential for NAAs to differentiate to high-affinity autoantibodies during an immune response. We recently generated site-directed transgenic mice that express a prototypic NAA, ppc1-5, which binds a variety of self- and non-self-Ags including DNA and phosphocholine. We have shown previously that B cells expressing the ppc1-5 NAA are positively selected during their primary development. In this study, we demonstrate that following immunization with the T-dependent Ag, phosphocholine conjugated to keyhole limpet hemocyanin, ppc1-5 NAA B cells mounted a quick IgM Ab response and entered germinal centers, but they failed to differentiate to IgG-producing cells during late primary and memory responses. Hybridomas and cDNA clones derived from the immunized mice included many IgM NAA-producing cells, but IgG NAA clones were extremely rare. Instead, many of the IgG B cells replaced their IgH transgene with an endogenous V(H) gene and produced non-autoreactive Abs. These results indicate that although NAA B cells are positively selected in the preimmune repertoire and can participate in early IgM Ab response, they are subjected to regulatory mechanisms that prevent them from developing to high-affinity IgG autoantibody production. This would explain, at least in part, why NAAs do not cause autoimmunity in most individuals.
Matejuk
Agata
A
Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Beardall
Michael
M
Xu
Yang
Y
Tian
Qi
Q
Phillips
Daniel
D
Alabyev
Boris
B
Mannoor
Kaiissar
K
Chen
Ching
C
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D018858:Germinal Center / Q000276:immunology; D006433:Hemocyanins / Q000276:immunology; D006825:Hybridomas; D007114:Immunization; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050440:Immunoglobulin Subunits / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007156:Immunologic Memory / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology*
D001323:Autoantibodies; D018076:DNA, Complementary; D007074:Immunoglobulin G; D050440:Immunoglobulin Subunits; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin