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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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Anti-lysozyme IgG response in high-responder H-2k/b F1  nontransgenic and TLK transgenic mice. (A) Mice were immunized i.p.  with 100 μg HEL in RIBI adjuvant. (B) Mice were immunized i.p. with  25 μg HEL-cGG in RIBI adjuvant. In both cases, day 35 data represent  secondary responses 7 d after boosting with HEL/RIBI or HEL-cGG/ RIBI, respectively. HEL binding IgG was measured by ELISA in serum  of individual mice (dots), and geometric means are shown in bars.
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Figure 2: Anti-lysozyme IgG response in high-responder H-2k/b F1 nontransgenic and TLK transgenic mice. (A) Mice were immunized i.p. with 100 μg HEL in RIBI adjuvant. (B) Mice were immunized i.p. with 25 μg HEL-cGG in RIBI adjuvant. In both cases, day 35 data represent secondary responses 7 d after boosting with HEL/RIBI or HEL-cGG/ RIBI, respectively. HEL binding IgG was measured by ELISA in serum of individual mice (dots), and geometric means are shown in bars.

Mentions: To determine whether or not thyroid mHEL expression resulted in tolerance to HEL, TLK-1 or TLK-2 transgenic mice and nontransgenic littermates were immunized with HEL. Nontransgenic mice mounted normal primary and secondary IgG responses to HEL, whereas very little antibody was produced in transgenic mice (Fig. 2 a). Thus, thyroid mHEL animals actively acquired tolerance to HEL either at the B or T cell level, or both. To focus on the B cell repertoire, any T cell tolerance to HEL that may have been acquired was bypassed by immunizing with HEL antigen covalently linked to a foreign carrier, chicken gamma globulin (HEL-cGG). After HEL-cGG immunization, HEL-specific IgG was produced in equal titers in nontransgenic and transgenic mice from both TLK lines (Fig. 2 b). This result therefore indicated either that preimmune B cells were not censored to HEL or that provision of potent T cell help to the cGG carrier was able to override B cell elimination or inactivation.


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)

Anti-lysozyme IgG response in high-responder H-2k/b F1  nontransgenic and TLK transgenic mice. (A) Mice were immunized i.p.  with 100 μg HEL in RIBI adjuvant. (B) Mice were immunized i.p. with  25 μg HEL-cGG in RIBI adjuvant. In both cases, day 35 data represent  secondary responses 7 d after boosting with HEL/RIBI or HEL-cGG/ RIBI, respectively. HEL binding IgG was measured by ELISA in serum  of individual mice (dots), and geometric means are shown in bars.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199176&req=5

Figure 2: Anti-lysozyme IgG response in high-responder H-2k/b F1 nontransgenic and TLK transgenic mice. (A) Mice were immunized i.p. with 100 μg HEL in RIBI adjuvant. (B) Mice were immunized i.p. with 25 μg HEL-cGG in RIBI adjuvant. In both cases, day 35 data represent secondary responses 7 d after boosting with HEL/RIBI or HEL-cGG/ RIBI, respectively. HEL binding IgG was measured by ELISA in serum of individual mice (dots), and geometric means are shown in bars.
Mentions: To determine whether or not thyroid mHEL expression resulted in tolerance to HEL, TLK-1 or TLK-2 transgenic mice and nontransgenic littermates were immunized with HEL. Nontransgenic mice mounted normal primary and secondary IgG responses to HEL, whereas very little antibody was produced in transgenic mice (Fig. 2 a). Thus, thyroid mHEL animals actively acquired tolerance to HEL either at the B or T cell level, or both. To focus on the B cell repertoire, any T cell tolerance to HEL that may have been acquired was bypassed by immunizing with HEL antigen covalently linked to a foreign carrier, chicken gamma globulin (HEL-cGG). After HEL-cGG immunization, HEL-specific IgG was produced in equal titers in nontransgenic and transgenic mice from both TLK lines (Fig. 2 b). This result therefore indicated either that preimmune B cells were not censored to HEL or that provision of potent T cell help to the cGG carrier was able to override B cell elimination or inactivation.

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