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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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Lack of B cell tolerance in TLK transgenic mice  crossed to anti-lysozyme Ig transgenic mice. (A) Two-color  FACS® analysis of spleen cells from  nontransgenic, Ig transgenic, and  Ig × TLK double-transgenic  mice. HEL-binding B cells were  identified by staining cells with  an excess of unlabeled HEL before secondary staining with a  complementary biotinylated anti-HEL monoclonal antibody. RS-3.1 (anti-IgMa) co-staining reveals  that the HEL-binding cells are all  expressing transgenic (a-allotype),  rather than endogenous (b-allotype),  receptor. For comparison, spleen  cells from Ig × ML-5 double-transgenic mice expressing soluble HEL systemically are shown,  illustrating the phenotypic changes  occurring in anergic self-reactive B cells (6). (B) Number of  anti-HEL splenic B cells in Ig  transgenic and Ig × TLK double-transgenic mice, measured  as in A. (C) Serum levels of anti-HEL IgMa (transgenic) antibody.  No reduction in spontaneous secretion of transgenic anti-lysozyme  antibody is seen in Ig × TLK  double-transgenic mice compared  to Ig-transgenic littermates.
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Figure 3: Lack of B cell tolerance in TLK transgenic mice crossed to anti-lysozyme Ig transgenic mice. (A) Two-color FACS® analysis of spleen cells from nontransgenic, Ig transgenic, and Ig × TLK double-transgenic mice. HEL-binding B cells were identified by staining cells with an excess of unlabeled HEL before secondary staining with a complementary biotinylated anti-HEL monoclonal antibody. RS-3.1 (anti-IgMa) co-staining reveals that the HEL-binding cells are all expressing transgenic (a-allotype), rather than endogenous (b-allotype), receptor. For comparison, spleen cells from Ig × ML-5 double-transgenic mice expressing soluble HEL systemically are shown, illustrating the phenotypic changes occurring in anergic self-reactive B cells (6). (B) Number of anti-HEL splenic B cells in Ig transgenic and Ig × TLK double-transgenic mice, measured as in A. (C) Serum levels of anti-HEL IgMa (transgenic) antibody. No reduction in spontaneous secretion of transgenic anti-lysozyme antibody is seen in Ig × TLK double-transgenic mice compared to Ig-transgenic littermates.

Mentions: The status of circulating HEL-specific B cells in the preimmune repertoire was directly examined by crossing TLK-1 and TLK-2 thyroid mHEL transgenic mice with Ig transgenic mice that express high-affinity HEL-specific IgM and IgD on 90% of circulating B cells (6). When Ig × TLK double-transgenic mice were compared with littermates carrying only the Ig transgene, no differences in B cell phenotype (Fig. 3 a) or number could be detected in spleen (Fig. 3, a and b), lymph node, or bone marrow (not shown). This contrasted with the change in B cell phenotype in mice expressing circulating sHEL antigen (Fig. 3 a) (6) or the deletion of HEL-binding B cells in mice expressing mHEL in a systemic distribution (9). In addition, serum levels of transgenic anti-HEL IgMa were not reduced in Ig-transgenic animals expressing thyroid mHEL compared with Ig transgenic mice lacking HEL (Fig. 3 c), unlike the inhibition of anti-HEL autoantibody secretion in mice expressing HEL systemically (6, 9).


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)

Lack of B cell tolerance in TLK transgenic mice  crossed to anti-lysozyme Ig transgenic mice. (A) Two-color  FACS® analysis of spleen cells from  nontransgenic, Ig transgenic, and  Ig × TLK double-transgenic  mice. HEL-binding B cells were  identified by staining cells with  an excess of unlabeled HEL before secondary staining with a  complementary biotinylated anti-HEL monoclonal antibody. RS-3.1 (anti-IgMa) co-staining reveals  that the HEL-binding cells are all  expressing transgenic (a-allotype),  rather than endogenous (b-allotype),  receptor. For comparison, spleen  cells from Ig × ML-5 double-transgenic mice expressing soluble HEL systemically are shown,  illustrating the phenotypic changes  occurring in anergic self-reactive B cells (6). (B) Number of  anti-HEL splenic B cells in Ig  transgenic and Ig × TLK double-transgenic mice, measured  as in A. (C) Serum levels of anti-HEL IgMa (transgenic) antibody.  No reduction in spontaneous secretion of transgenic anti-lysozyme  antibody is seen in Ig × TLK  double-transgenic mice compared  to Ig-transgenic littermates.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2199176&req=5

Figure 3: Lack of B cell tolerance in TLK transgenic mice crossed to anti-lysozyme Ig transgenic mice. (A) Two-color FACS® analysis of spleen cells from nontransgenic, Ig transgenic, and Ig × TLK double-transgenic mice. HEL-binding B cells were identified by staining cells with an excess of unlabeled HEL before secondary staining with a complementary biotinylated anti-HEL monoclonal antibody. RS-3.1 (anti-IgMa) co-staining reveals that the HEL-binding cells are all expressing transgenic (a-allotype), rather than endogenous (b-allotype), receptor. For comparison, spleen cells from Ig × ML-5 double-transgenic mice expressing soluble HEL systemically are shown, illustrating the phenotypic changes occurring in anergic self-reactive B cells (6). (B) Number of anti-HEL splenic B cells in Ig transgenic and Ig × TLK double-transgenic mice, measured as in A. (C) Serum levels of anti-HEL IgMa (transgenic) antibody. No reduction in spontaneous secretion of transgenic anti-lysozyme antibody is seen in Ig × TLK double-transgenic mice compared to Ig-transgenic littermates.
Mentions: The status of circulating HEL-specific B cells in the preimmune repertoire was directly examined by crossing TLK-1 and TLK-2 thyroid mHEL transgenic mice with Ig transgenic mice that express high-affinity HEL-specific IgM and IgD on 90% of circulating B cells (6). When Ig × TLK double-transgenic mice were compared with littermates carrying only the Ig transgene, no differences in B cell phenotype (Fig. 3 a) or number could be detected in spleen (Fig. 3, a and b), lymph node, or bone marrow (not shown). This contrasted with the change in B cell phenotype in mice expressing circulating sHEL antigen (Fig. 3 a) (6) or the deletion of HEL-binding B cells in mice expressing mHEL in a systemic distribution (9). In addition, serum levels of transgenic anti-HEL IgMa were not reduced in Ig-transgenic animals expressing thyroid mHEL compared with Ig transgenic mice lacking HEL (Fig. 3 c), unlike the inhibition of anti-HEL autoantibody secretion in mice expressing HEL systemically (6, 9).

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