Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice.
Delineating the relative contributions of B lymphocytes during the course of autoimmune disease has been difficult. Therefore, the effects of depleting all mature B cells using a potent CD20 mAb, or of depleting circulating and marginal zone B cells using a ligand-blocking CD22 mAb, were compared in NZB/W F(1) mice, a model for human systemic lupus erythematosus. Single low-dose mAb treatments depleted B cells efficiently in both NZB/W F(1) and C57BL/6 mice. Prophylactic B cell depletion by repeated CD20 mAb treatments prolonged survival during pristane-accelerated lupus in NZB/W F(1) mice, whereas CD22 mAb had little effect. Despite effective B cell depletion, neither mAb treatment prevented autoantibody generation. In addition, CD20, CD22, and control mAb-treated NZB/W F(1) mice developed anti-mouse IgG autoantibodies in contrast to parental NZB and NZW strains, which may have reduced the effectiveness of B cell depletion. Despite this, low-dose CD20 mAb treatment initiated in 12-28-wk-old mice, and administered every 4 wk thereafter, significantly delayed spontaneous disease in NZB/W F(1) mice. By contrast, B cell depletion initiated in 4-wk-old mice hastened disease onset, which paralleled depletion of the IL-10-producing regulatory B cell subset called B10 cells. B10 cells were phenotypically similar in NZB/W F(1) and C57BL/6 mice, but were expanded significantly in young NZB/W F(1) mice. Thus, B cell depletion had significant effects on NZB/W F(1) mouse survival that were dependent on the timing of treatment initiation. Therefore, distinct B cell populations can have opposing protective and pathogenic roles during lupus progression.
Haas
Karen M
KM
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Watanabe
Rei
R
Matsushita
Takashi
T
Nakashima
Hiroko
H
Ishiura
Nobuko
N
Okochi
Hitoshi
H
Fujimoto
Manabu
M
Tedder
Thomas F
TF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D018951:Antigens, CD20 / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D008181:Lupus Nephritis / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology; D015996:Survival Rate; D013729:Terpenes / Q000633:toxicity
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D001323:Autoantibodies; C497868:Cd22 protein, mouse; D051918:Sialic Acid Binding Ig-like Lectin 2; D013729:Terpenes; C009042:pristane