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Self-reactive B cells are not eliminated or inactivated by autoantigen expressed on thyroid epithelial cells.

Akkaraju S, Canaan K, Goodnow CC - J. Exp. Med. (1997)

Bottom Line: Nature. 353:765-769), selective expression of mHEL autoantigen on thyroid cells did not trigger elimination or inactivation of circulating HEL-reactive B cells.These results provide evidence that tolerance is not actively acquired to organ-specific antigens in the preimmune B cell repertoire, underscoring the importance of maintaining tolerance to such antigens by other mechanisms.The role of an intact endothelial barrier in sequestering organ-specific antigens from circulating preimmune B cells is discussed.

View Article: PubMed Central - PubMed

Affiliation: Program in Immunology, Department of Microbiology and Immunology, and The Howard Hughes Medical Institute, Beckman Center, Stanford University School of Medicine, Stanford, California 94305-5428, USA.

ABSTRACT
Graves' Disease results from the production of autoantibodies against receptors for thyroid stimulating hormone (TSH) on thyroid epithelial cells, and represents the prototype for numerous autoimmune diseases caused by autoantibodies that bind to organ-specific cell membrane antigens. To study how humoral tolerance is normally maintained to organ-specific membrane antigens, transgenic mice were generated selectively expressing membrane-bound hen egg lysozyme (mHEL) on the thyroid epithelium. In contrast to the deletion of autoreactive B cells triggered by systemic mHEL (Hartley, S.B., J. Crosbie, R. Brink, A.B. Kantor, A. Basten, and C.C. Goodnow. 1991. Nature. 353:765-769), selective expression of mHEL autoantigen on thyroid cells did not trigger elimination or inactivation of circulating HEL-reactive B cells. These results provide evidence that tolerance is not actively acquired to organ-specific antigens in the preimmune B cell repertoire, underscoring the importance of maintaining tolerance to such antigens by other mechanisms. The role of an intact endothelial barrier in sequestering organ-specific antigens from circulating preimmune B cells is discussed.

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Small numbers of circulating HEL-specific B cells are not  eliminated in thyroid mHEL transgenic mice. Non-transgenic, TLK-1, or  TLK-2 C57BL/6 mice were injected i.v. with a mixture of C57BL/6  (Ly5b) Ig-transgenic splenic B cells and C57BL/6 Ly5a/b non-transgenic  spleen cells. Cells were left in the primary recipients either 5 or 10 d. (A)  Frequency of transgenic anti-HEL B cells per spleen remaining in each  recipient (dots) and geometric mean (bars) after 10 d. To detect subtle  changes, the cell frequencies per recipient are corrected for the injected  dose of cells by dividing by the ratio of percentage of Ly5a+, nontransgenic B cells remaining in each recipient and average percentage of Ly5a+,  nontransgenic B cells in all recipients. (B) FACS® analysis of representative spleens from 10-d parking recipients. Transferred Ig transgenic B cells  are double-positive for IgDa and HEL binding; percentage of cells double-positive for IgDa staining and HEL binding is given in the upper right  corner. All transgenic cells express a high level of IgDa, but expression of  IgMa on these IgDa-positive, HEL-binding cells is reduced 2–3-fold by  exposure to the TLK-2 environment.
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Figure 4: Small numbers of circulating HEL-specific B cells are not eliminated in thyroid mHEL transgenic mice. Non-transgenic, TLK-1, or TLK-2 C57BL/6 mice were injected i.v. with a mixture of C57BL/6 (Ly5b) Ig-transgenic splenic B cells and C57BL/6 Ly5a/b non-transgenic spleen cells. Cells were left in the primary recipients either 5 or 10 d. (A) Frequency of transgenic anti-HEL B cells per spleen remaining in each recipient (dots) and geometric mean (bars) after 10 d. To detect subtle changes, the cell frequencies per recipient are corrected for the injected dose of cells by dividing by the ratio of percentage of Ly5a+, nontransgenic B cells remaining in each recipient and average percentage of Ly5a+, nontransgenic B cells in all recipients. (B) FACS® analysis of representative spleens from 10-d parking recipients. Transferred Ig transgenic B cells are double-positive for IgDa and HEL binding; percentage of cells double-positive for IgDa staining and HEL binding is given in the upper right corner. All transgenic cells express a high level of IgDa, but expression of IgMa on these IgDa-positive, HEL-binding cells is reduced 2–3-fold by exposure to the TLK-2 environment.

Mentions: The large number of HEL-specific B cells that are constantly produced in Ig-transgenic mice may in principle have obscured deletion of small, physiological frequencies of autoreactive B cells by encounter of HEL on the thyroid. To test this possibility, small numbers of naive, mature HEL-specific Ig-transgenic cells were introduced into the bloodstream of unirradiated nontransgenic or TLK transgenic mice and allowed to recirculate for 5 or 10 d. To provide an internal standard for the transfer and ensure detection of subtle losses of HEL-specific B cells, Ly5a-marked nontransgenic spleen cells were coinjected with the Ly5b Ig-transgenic cells. The behavior of these Ly5a nontransgenic B cells should not be affected by the presence or absence of HEL antigen. Despite the presence of only trace numbers of circulating HEL-reactive B cells, their number and ratio to nontransgenic standard B cells was not significantly different in TLK recipients with high expression of mHEL in the thyroid gland compared to non-transgenic recipients lacking HEL autoantigen (Fig 4 a).


Self-reactive B cells are not eliminated or inactivated by autoantigen expressed on thyroid epithelial cells.

Akkaraju S, Canaan K, Goodnow CC - J. Exp. Med. (1997)

Small numbers of circulating HEL-specific B cells are not  eliminated in thyroid mHEL transgenic mice. Non-transgenic, TLK-1, or  TLK-2 C57BL/6 mice were injected i.v. with a mixture of C57BL/6  (Ly5b) Ig-transgenic splenic B cells and C57BL/6 Ly5a/b non-transgenic  spleen cells. Cells were left in the primary recipients either 5 or 10 d. (A)  Frequency of transgenic anti-HEL B cells per spleen remaining in each  recipient (dots) and geometric mean (bars) after 10 d. To detect subtle  changes, the cell frequencies per recipient are corrected for the injected  dose of cells by dividing by the ratio of percentage of Ly5a+, nontransgenic B cells remaining in each recipient and average percentage of Ly5a+,  nontransgenic B cells in all recipients. (B) FACS® analysis of representative spleens from 10-d parking recipients. Transferred Ig transgenic B cells  are double-positive for IgDa and HEL binding; percentage of cells double-positive for IgDa staining and HEL binding is given in the upper right  corner. All transgenic cells express a high level of IgDa, but expression of  IgMa on these IgDa-positive, HEL-binding cells is reduced 2–3-fold by  exposure to the TLK-2 environment.
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Figure 4: Small numbers of circulating HEL-specific B cells are not eliminated in thyroid mHEL transgenic mice. Non-transgenic, TLK-1, or TLK-2 C57BL/6 mice were injected i.v. with a mixture of C57BL/6 (Ly5b) Ig-transgenic splenic B cells and C57BL/6 Ly5a/b non-transgenic spleen cells. Cells were left in the primary recipients either 5 or 10 d. (A) Frequency of transgenic anti-HEL B cells per spleen remaining in each recipient (dots) and geometric mean (bars) after 10 d. To detect subtle changes, the cell frequencies per recipient are corrected for the injected dose of cells by dividing by the ratio of percentage of Ly5a+, nontransgenic B cells remaining in each recipient and average percentage of Ly5a+, nontransgenic B cells in all recipients. (B) FACS® analysis of representative spleens from 10-d parking recipients. Transferred Ig transgenic B cells are double-positive for IgDa and HEL binding; percentage of cells double-positive for IgDa staining and HEL binding is given in the upper right corner. All transgenic cells express a high level of IgDa, but expression of IgMa on these IgDa-positive, HEL-binding cells is reduced 2–3-fold by exposure to the TLK-2 environment.
Mentions: The large number of HEL-specific B cells that are constantly produced in Ig-transgenic mice may in principle have obscured deletion of small, physiological frequencies of autoreactive B cells by encounter of HEL on the thyroid. To test this possibility, small numbers of naive, mature HEL-specific Ig-transgenic cells were introduced into the bloodstream of unirradiated nontransgenic or TLK transgenic mice and allowed to recirculate for 5 or 10 d. To provide an internal standard for the transfer and ensure detection of subtle losses of HEL-specific B cells, Ly5a-marked nontransgenic spleen cells were coinjected with the Ly5b Ig-transgenic cells. The behavior of these Ly5a nontransgenic B cells should not be affected by the presence or absence of HEL antigen. Despite the presence of only trace numbers of circulating HEL-reactive B cells, their number and ratio to nontransgenic standard B cells was not significantly different in TLK recipients with high expression of mHEL in the thyroid gland compared to non-transgenic recipients lacking HEL autoantigen (Fig 4 a).

Bottom Line: Nature. 353:765-769), selective expression of mHEL autoantigen on thyroid cells did not trigger elimination or inactivation of circulating HEL-reactive B cells.These results provide evidence that tolerance is not actively acquired to organ-specific antigens in the preimmune B cell repertoire, underscoring the importance of maintaining tolerance to such antigens by other mechanisms.The role of an intact endothelial barrier in sequestering organ-specific antigens from circulating preimmune B cells is discussed.

View Article: PubMed Central - PubMed

Affiliation: Program in Immunology, Department of Microbiology and Immunology, and The Howard Hughes Medical Institute, Beckman Center, Stanford University School of Medicine, Stanford, California 94305-5428, USA.

ABSTRACT
Graves' Disease results from the production of autoantibodies against receptors for thyroid stimulating hormone (TSH) on thyroid epithelial cells, and represents the prototype for numerous autoimmune diseases caused by autoantibodies that bind to organ-specific cell membrane antigens. To study how humoral tolerance is normally maintained to organ-specific membrane antigens, transgenic mice were generated selectively expressing membrane-bound hen egg lysozyme (mHEL) on the thyroid epithelium. In contrast to the deletion of autoreactive B cells triggered by systemic mHEL (Hartley, S.B., J. Crosbie, R. Brink, A.B. Kantor, A. Basten, and C.C. Goodnow. 1991. Nature. 353:765-769), selective expression of mHEL autoantigen on thyroid cells did not trigger elimination or inactivation of circulating HEL-reactive B cells. These results provide evidence that tolerance is not actively acquired to organ-specific antigens in the preimmune B cell repertoire, underscoring the importance of maintaining tolerance to such antigens by other mechanisms. The role of an intact endothelial barrier in sequestering organ-specific antigens from circulating preimmune B cells is discussed.

Show MeSH
Related in: MedlinePlus