Antibody feedback regulation in MRL/lpr mice.
MRL/Mp-lpr/lpr (MRL/l) mice spontaneously develop autoimmune disease, characterized by glomerulonephritis, polyarteritis and polyarthritis. The lpr mice have defects in the Fas antigen, which plays a role in apoptosis, and it has been suggested that lack of negative selection of autoreactive T cells explains the initiation of the disease. The extremely high amount of autoantibodies may reflect additional immunoregulatory abnormalities. Antibody feedback regulation is an efficient way of up- or downregulating antibody responses. We have for the first time determined whether IgG-mediated suppression as well as IgM-mediated enhancement operates normally in these mice. MRL/l and MRL/Mp(-)+/+ (MRL/n) mice of different ages were therefore immunized with sheep erythrocyte (SRBC)-specific IgG or IgM antibodies followed by SRBC. Control groups received antigen alone. Five days later, the antigen-specific plaque-forming cell response was measured. IgG induced more than 90% suppression in both MRL/l and MRL/n in mice of all ages tested. This degree of suppression is in the same range as for other, normal mouse strains. In contrast, IgM-mediated enhancement was completely absent in 12-week-old MRL/l mice but normal in 8-week-old MRL/l as well as in MRL/n mice of all ages tested. When spleens and lymph nodes were immunohistochemically studied using a mAb specific for complement receptors 1 and 2 (CR1/CR2), an abnormal follicular structure was demonstrated in 12-week-old MRL/l mice. The antibody response of both 8- and 13-week-old MRL/l mice in vivo, after downregulation of these receptors, was inhibited by 85-96%. Thus, the presented data demonstrate that MRL/l mice with overt autoimmune disease are refractory to IgM-mediated enhancement of antigen-specific antibody production. We believe that this abnormal antibody feedback regulation is due to abnormal follicular structure in lymphoid organs of old MRL/l mice, hence the inability to localize and present antigen in a normal way.
Heyman
B
B
Department of Pathology, Uppsala University Hospital, Sweden.
Gustavsson
S
S
Kusakari
C
C
Nose
M
M
Kinoshita
T
T
Klareskog
L
L
Tarkowski
A
A
D000818:Animals; D001323:Autoantibodies / Q000502:physiology*; D001327:Autoimmune Diseases / Q000276:immunology*; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology*; D005246:Feedback / Q000502:physiology; D006736:Horses; D007074:Immunoglobulin G / Q000494:pharmacology / Q000502:physiology; D007075:Immunoglobulin M / Q000494:pharmacology / Q000502:physiology; D008198:Lymph Nodes / Q000502:physiology; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D017463:Receptors, Complement 3b / Q000502:physiology; D017464:Receptors, Complement 3d / Q000502:physiology; D012756:Sheep; D013154:Spleen / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology*
D001323:Autoantibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d