A pivotal role of cell-bound but not soluble CD4 molecules in full development of lupus-like manifestations in MRL-Fas(lprcg)/Fas(lprcg) mice

Y. Zhang, T. Yasuda, Chrong-Reen Wang, T. Yoshimoto, H. Nagase, M. Takamoto, A. Tsubura, M. Kimura, A. Matsuzawa

Research output: Contribution to journalArticle

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Abstract

The role of CD4 molecules in the autoimmune and lymphoproliferative syndrome caused by murine Fas mutations was studied using the novel systemic lupus erythematosus (SLE) model, MRL-Fas(lprcg)/Fas(lprcg) (MRL-lpr(cg)) mice, in combination with the novel mutant CD4 gene producing soluble CD4 (sCD4) instead of membrane-bound CD4 (mCD4). For this purpose, various autoimmune manifestations were compared among MRL-lpr(cg) mice homozygous (CD4(s)-lpr(cg)), heterozygous (CD4(s/m)-lpr(cg)), and wild-type (CD4(m)-lpr(cg)) for the CD4 mutation. The mortality, glomerulonephritis, proteinuria, and lymphadenopathy were significantly ameliorated in CD4(s)-lpr(cg) compared with CD4(m)-lpr(cg) and CD4(s/m)-lpr(cg) mice, both being comparable in these clinical characteristics. In parallel with the clinical improvement, the serum levels of immunoglobulin, anti-DNA antibodies, anti-nuclear antibodies and immune complexes, and the extent of glomerular immune deposition, were significantly lower in the former. The results indicate that mCD4 is important and can not be replaced by sCD4 in full development of SLE-like manifestations, and suggest that CD4+ T cells may aggravate the autoimmune disease by stimulating autoreactive B cells to produce autoantibodies through their helper activity in Fas mutant models. The sCD4 levels in the serum and spleen elevated with the increased accumulation of B220+CD4-CD8- (double-negative (DN)) T cells in CD4(s)-lpr(cg) mice. This, together with the significantly milder lymphadenopathy associated with lower DN T cell contents in CD4(s)-lpr(cg) than CD4(m)-lpr(cg) mice, implies that some of abnormal DN T cells may be derived from cells of the CD4 lineage.

Original languageEnglish
Pages (from-to)124-132
Number of pages9
JournalClinical and Experimental Immunology
Volume122
Issue number1
DOIs
Publication statusPublished - 2000 Oct 24

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CD4 Antigens
T-Lymphocytes
Systemic Lupus Erythematosus
Autoimmune Lymphoproliferative Syndrome
Mutation
Membranes
Antinuclear Antibodies
Cell Lineage
Glomerulonephritis
Antigen-Antibody Complex
Serum
Proteinuria
Autoantibodies
Autoimmune Diseases
Immunoglobulins
Anti-Idiotypic Antibodies
B-Lymphocytes
Spleen
recombinant soluble CD4
Mortality

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Zhang, Y. ; Yasuda, T. ; Wang, Chrong-Reen ; Yoshimoto, T. ; Nagase, H. ; Takamoto, M. ; Tsubura, A. ; Kimura, M. ; Matsuzawa, A. / A pivotal role of cell-bound but not soluble CD4 molecules in full development of lupus-like manifestations in MRL-Fas(lprcg)/Fas(lprcg) mice. In: Clinical and Experimental Immunology. 2000 ; Vol. 122, No. 1. pp. 124-132.
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abstract = "The role of CD4 molecules in the autoimmune and lymphoproliferative syndrome caused by murine Fas mutations was studied using the novel systemic lupus erythematosus (SLE) model, MRL-Fas(lprcg)/Fas(lprcg) (MRL-lpr(cg)) mice, in combination with the novel mutant CD4 gene producing soluble CD4 (sCD4) instead of membrane-bound CD4 (mCD4). For this purpose, various autoimmune manifestations were compared among MRL-lpr(cg) mice homozygous (CD4(s)-lpr(cg)), heterozygous (CD4(s/m)-lpr(cg)), and wild-type (CD4(m)-lpr(cg)) for the CD4 mutation. The mortality, glomerulonephritis, proteinuria, and lymphadenopathy were significantly ameliorated in CD4(s)-lpr(cg) compared with CD4(m)-lpr(cg) and CD4(s/m)-lpr(cg) mice, both being comparable in these clinical characteristics. In parallel with the clinical improvement, the serum levels of immunoglobulin, anti-DNA antibodies, anti-nuclear antibodies and immune complexes, and the extent of glomerular immune deposition, were significantly lower in the former. The results indicate that mCD4 is important and can not be replaced by sCD4 in full development of SLE-like manifestations, and suggest that CD4+ T cells may aggravate the autoimmune disease by stimulating autoreactive B cells to produce autoantibodies through their helper activity in Fas mutant models. The sCD4 levels in the serum and spleen elevated with the increased accumulation of B220+CD4-CD8- (double-negative (DN)) T cells in CD4(s)-lpr(cg) mice. This, together with the significantly milder lymphadenopathy associated with lower DN T cell contents in CD4(s)-lpr(cg) than CD4(m)-lpr(cg) mice, implies that some of abnormal DN T cells may be derived from cells of the CD4 lineage.",
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A pivotal role of cell-bound but not soluble CD4 molecules in full development of lupus-like manifestations in MRL-Fas(lprcg)/Fas(lprcg) mice. / Zhang, Y.; Yasuda, T.; Wang, Chrong-Reen; Yoshimoto, T.; Nagase, H.; Takamoto, M.; Tsubura, A.; Kimura, M.; Matsuzawa, A.

In: Clinical and Experimental Immunology, Vol. 122, No. 1, 24.10.2000, p. 124-132.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A pivotal role of cell-bound but not soluble CD4 molecules in full development of lupus-like manifestations in MRL-Fas(lprcg)/Fas(lprcg) mice

AU - Zhang, Y.

AU - Yasuda, T.

AU - Wang, Chrong-Reen

AU - Yoshimoto, T.

AU - Nagase, H.

AU - Takamoto, M.

AU - Tsubura, A.

AU - Kimura, M.

AU - Matsuzawa, A.

PY - 2000/10/24

Y1 - 2000/10/24

N2 - The role of CD4 molecules in the autoimmune and lymphoproliferative syndrome caused by murine Fas mutations was studied using the novel systemic lupus erythematosus (SLE) model, MRL-Fas(lprcg)/Fas(lprcg) (MRL-lpr(cg)) mice, in combination with the novel mutant CD4 gene producing soluble CD4 (sCD4) instead of membrane-bound CD4 (mCD4). For this purpose, various autoimmune manifestations were compared among MRL-lpr(cg) mice homozygous (CD4(s)-lpr(cg)), heterozygous (CD4(s/m)-lpr(cg)), and wild-type (CD4(m)-lpr(cg)) for the CD4 mutation. The mortality, glomerulonephritis, proteinuria, and lymphadenopathy were significantly ameliorated in CD4(s)-lpr(cg) compared with CD4(m)-lpr(cg) and CD4(s/m)-lpr(cg) mice, both being comparable in these clinical characteristics. In parallel with the clinical improvement, the serum levels of immunoglobulin, anti-DNA antibodies, anti-nuclear antibodies and immune complexes, and the extent of glomerular immune deposition, were significantly lower in the former. The results indicate that mCD4 is important and can not be replaced by sCD4 in full development of SLE-like manifestations, and suggest that CD4+ T cells may aggravate the autoimmune disease by stimulating autoreactive B cells to produce autoantibodies through their helper activity in Fas mutant models. The sCD4 levels in the serum and spleen elevated with the increased accumulation of B220+CD4-CD8- (double-negative (DN)) T cells in CD4(s)-lpr(cg) mice. This, together with the significantly milder lymphadenopathy associated with lower DN T cell contents in CD4(s)-lpr(cg) than CD4(m)-lpr(cg) mice, implies that some of abnormal DN T cells may be derived from cells of the CD4 lineage.

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