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Suppressive role of B cells in chronic colitis of T cell receptor alpha mutant mice.

Mizoguchi A, Mizoguchi E, Smith RN, Preffer FI, Bhan AK - J. Exp. Med. (1997)

Bottom Line: The role of antibodies (Abs) in the development of chronic colitis in T cell receptor (TCR)-alpha-/- mice was explored by creating double mutant mice (TCR-alpha-/- x immunoglobulin (Ig)mu-/-), which lack B cells.Administration of the purified Ig from TCR-alpha-/- mice and a mixture of monoclonal autoAbs reactive with colonic epithelial cells led to attenuation of colitis in TCR-alpha-/- x Ig mu-/- mice.These findings suggest that although B cells are not required for the initiation of colitis, B cells and Igs (autoAbs) can suppress colitis, presumably by affecting the clearance of apoptotic cells.

View Article: PubMed Central - PubMed

Affiliation: Immunopathology Unit, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.

ABSTRACT
The role of antibodies (Abs) in the development of chronic colitis in T cell receptor (TCR)-alpha-/- mice was explored by creating double mutant mice (TCR-alpha-/- x immunoglobulin (Ig)mu-/-), which lack B cells. TCR-alpha-/- x Ig mu-/- mice spontaneously developed colitis at an earlier age, and the colitis was more severe than in TCR-alpha-/- mice. Colitis was induced in recombination-activating gene-1 (RAG-1-/-) mice by the transfer of mesenteric lymph node (MLN) cells from TCR-alpha-/- x Ig mu-/- mice. When purified B cells from TCR-alpha-/- mice were mixed with MLN cells before cell transfer, colitis did not develop in RAG-1-/- mice. Administration of the purified Ig from TCR-alpha-/- mice and a mixture of monoclonal autoAbs reactive with colonic epithelial cells led to attenuation of colitis in TCR-alpha-/- x Ig mu-/- mice. Apoptotic cells were increased in the colon, MLN, and spleen of TCR-alpha-/- x Ig mu-/- mice as compared to Ig mu-/- mice and TCR-alpha-/- mice. Administration of the purified Ig from TCR-alpha-/- mice into TCR-alpha-/- x Ig mu-/- mice led to decrease in the number of apoptotic cells. These findings suggest that although B cells are not required for the initiation of colitis, B cells and Igs (autoAbs) can suppress colitis, presumably by affecting the clearance of apoptotic cells.

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(A) Circulating self  Ags from C57BL/6 (closed triangles), Igμ−/− (closed squares),  TCR-α−/− (open squares), and  TCR-α−/− × Igμ−/− mice with  injection of PBS (closed circles) or  Ig (open circles) purified from sera  of TCR-α−/− mice are quantified. 200 μl of sera (from various  mice)/CFA were injected to  C57BL/6 mice. On day 14 after  immunization, the reactivity of sera  from the immunized C57BL/6  mice against colonic epithelial  antigens was determined by  ELISA. (B and C) The reactivity  of sera from the immunized  C57BL/6 mice with sera of  TCR-α−/− × Igμ−/− mice with  (B) or without (C) Ig transfer  was confirmed by immunohistochemical analysis using sections  of colon (×40 objective) from  RAG-1−/− mice.
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Figure 6: (A) Circulating self Ags from C57BL/6 (closed triangles), Igμ−/− (closed squares), TCR-α−/− (open squares), and TCR-α−/− × Igμ−/− mice with injection of PBS (closed circles) or Ig (open circles) purified from sera of TCR-α−/− mice are quantified. 200 μl of sera (from various mice)/CFA were injected to C57BL/6 mice. On day 14 after immunization, the reactivity of sera from the immunized C57BL/6 mice against colonic epithelial antigens was determined by ELISA. (B and C) The reactivity of sera from the immunized C57BL/6 mice with sera of TCR-α−/− × Igμ−/− mice with (B) or without (C) Ig transfer was confirmed by immunohistochemical analysis using sections of colon (×40 objective) from RAG-1−/− mice.

Mentions: Since apoptotic cells are the major source of self Ags (35, 36), the presence of circulating colonic Ags (self Ags) was examined. C57BL/6 mice were immunized with sera from TCR-α−/−, Igμ−/−, or TCR-α−/− × Igμ−/− mice (8 wk of age), and the reactivity of sera from the immunized C57BL/6 mice (14 d after immunization) to colonic epithelial Ags was analyzed by ELISA. The sera from C57BL/6 mice immunized with sera of TCR-α−/− × Igμ−/− mice showed significantly higher (P <0.001) reactivity to colonic Ags compared to the other groups including the sera from the C57BL/6 mice immunized with sera from Ig-transferred TCR-α−/− × Igμ−/− mice (Fig. 6 A). Immunohistochemical analysis confirmed these results; the sera from C57BL/6 mice immunized with sera from TCR-α−/− × Igμ−/− mice, but not from other groups, strongly reacted with colonic epithelial cells. The reactivity was mostly associated with the nucleus of the cells (Fig. 6, B and C). These findings indicate that in TCR-α−/− × Igμ−/− mice, there is an increase of circulating colon-associated self Ags as compared to TCR-α+/−, Igμ−/−, and TCR-α−/− mice, and the transfer of Ig into TCR-α−/− × Igμ−/− mice leads to marked decrease of circulating self Ags. Furthermore, these findings support the hypothesis that failure of normal clearance mechanisms for apoptotic cells by lack of autoAbs leads to an increase of circulating self Ags. The increased circulating self Ags may activate self-reactive T cells and provoke organ-specific autoimmune diseases (40) such as IBD. The increase of apoptotic cells shown in lamina propria cells of colon as well as spleen and MLNs in TCR-α−/− × Igμ−/− mice is likely to reflect the activation-induced cell death (41) of effector cells caused by harmful exposure to the increased local and circulating self Ags.


Suppressive role of B cells in chronic colitis of T cell receptor alpha mutant mice.

Mizoguchi A, Mizoguchi E, Smith RN, Preffer FI, Bhan AK - J. Exp. Med. (1997)

(A) Circulating self  Ags from C57BL/6 (closed triangles), Igμ−/− (closed squares),  TCR-α−/− (open squares), and  TCR-α−/− × Igμ−/− mice with  injection of PBS (closed circles) or  Ig (open circles) purified from sera  of TCR-α−/− mice are quantified. 200 μl of sera (from various  mice)/CFA were injected to  C57BL/6 mice. On day 14 after  immunization, the reactivity of sera  from the immunized C57BL/6  mice against colonic epithelial  antigens was determined by  ELISA. (B and C) The reactivity  of sera from the immunized  C57BL/6 mice with sera of  TCR-α−/− × Igμ−/− mice with  (B) or without (C) Ig transfer  was confirmed by immunohistochemical analysis using sections  of colon (×40 objective) from  RAG-1−/− mice.
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Related In: Results  -  Collection

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Figure 6: (A) Circulating self Ags from C57BL/6 (closed triangles), Igμ−/− (closed squares), TCR-α−/− (open squares), and TCR-α−/− × Igμ−/− mice with injection of PBS (closed circles) or Ig (open circles) purified from sera of TCR-α−/− mice are quantified. 200 μl of sera (from various mice)/CFA were injected to C57BL/6 mice. On day 14 after immunization, the reactivity of sera from the immunized C57BL/6 mice against colonic epithelial antigens was determined by ELISA. (B and C) The reactivity of sera from the immunized C57BL/6 mice with sera of TCR-α−/− × Igμ−/− mice with (B) or without (C) Ig transfer was confirmed by immunohistochemical analysis using sections of colon (×40 objective) from RAG-1−/− mice.
Mentions: Since apoptotic cells are the major source of self Ags (35, 36), the presence of circulating colonic Ags (self Ags) was examined. C57BL/6 mice were immunized with sera from TCR-α−/−, Igμ−/−, or TCR-α−/− × Igμ−/− mice (8 wk of age), and the reactivity of sera from the immunized C57BL/6 mice (14 d after immunization) to colonic epithelial Ags was analyzed by ELISA. The sera from C57BL/6 mice immunized with sera of TCR-α−/− × Igμ−/− mice showed significantly higher (P <0.001) reactivity to colonic Ags compared to the other groups including the sera from the C57BL/6 mice immunized with sera from Ig-transferred TCR-α−/− × Igμ−/− mice (Fig. 6 A). Immunohistochemical analysis confirmed these results; the sera from C57BL/6 mice immunized with sera from TCR-α−/− × Igμ−/− mice, but not from other groups, strongly reacted with colonic epithelial cells. The reactivity was mostly associated with the nucleus of the cells (Fig. 6, B and C). These findings indicate that in TCR-α−/− × Igμ−/− mice, there is an increase of circulating colon-associated self Ags as compared to TCR-α+/−, Igμ−/−, and TCR-α−/− mice, and the transfer of Ig into TCR-α−/− × Igμ−/− mice leads to marked decrease of circulating self Ags. Furthermore, these findings support the hypothesis that failure of normal clearance mechanisms for apoptotic cells by lack of autoAbs leads to an increase of circulating self Ags. The increased circulating self Ags may activate self-reactive T cells and provoke organ-specific autoimmune diseases (40) such as IBD. The increase of apoptotic cells shown in lamina propria cells of colon as well as spleen and MLNs in TCR-α−/− × Igμ−/− mice is likely to reflect the activation-induced cell death (41) of effector cells caused by harmful exposure to the increased local and circulating self Ags.

Bottom Line: The role of antibodies (Abs) in the development of chronic colitis in T cell receptor (TCR)-alpha-/- mice was explored by creating double mutant mice (TCR-alpha-/- x immunoglobulin (Ig)mu-/-), which lack B cells.Administration of the purified Ig from TCR-alpha-/- mice and a mixture of monoclonal autoAbs reactive with colonic epithelial cells led to attenuation of colitis in TCR-alpha-/- x Ig mu-/- mice.These findings suggest that although B cells are not required for the initiation of colitis, B cells and Igs (autoAbs) can suppress colitis, presumably by affecting the clearance of apoptotic cells.

View Article: PubMed Central - PubMed

Affiliation: Immunopathology Unit, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.

ABSTRACT
The role of antibodies (Abs) in the development of chronic colitis in T cell receptor (TCR)-alpha-/- mice was explored by creating double mutant mice (TCR-alpha-/- x immunoglobulin (Ig)mu-/-), which lack B cells. TCR-alpha-/- x Ig mu-/- mice spontaneously developed colitis at an earlier age, and the colitis was more severe than in TCR-alpha-/- mice. Colitis was induced in recombination-activating gene-1 (RAG-1-/-) mice by the transfer of mesenteric lymph node (MLN) cells from TCR-alpha-/- x Ig mu-/- mice. When purified B cells from TCR-alpha-/- mice were mixed with MLN cells before cell transfer, colitis did not develop in RAG-1-/- mice. Administration of the purified Ig from TCR-alpha-/- mice and a mixture of monoclonal autoAbs reactive with colonic epithelial cells led to attenuation of colitis in TCR-alpha-/- x Ig mu-/- mice. Apoptotic cells were increased in the colon, MLN, and spleen of TCR-alpha-/- x Ig mu-/- mice as compared to Ig mu-/- mice and TCR-alpha-/- mice. Administration of the purified Ig from TCR-alpha-/- mice into TCR-alpha-/- x Ig mu-/- mice led to decrease in the number of apoptotic cells. These findings suggest that although B cells are not required for the initiation of colitis, B cells and Igs (autoAbs) can suppress colitis, presumably by affecting the clearance of apoptotic cells.

Show MeSH
Related in: MedlinePlus