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The cellular location of self-antigen determines the positive and negative selection of autoreactive B cells.

Ferry H, Jones M, Vaux DJ, Roberts IS, Cornall RJ - J. Exp. Med. (2003)

Bottom Line: In contrast to cell surface antigen, which causes the deletion of autoreactive B cells, the intracellularly sequestered self-antigen failed to induce B cell tolerance and was instead autoimmunogenic.The intracellular antigen positively selected antigen-binding B cells to differentiate into B1 cells and induced large numbers of IgM autoantibody-secreting plasma cells in a T-independent manner.By analyzing the impact of differences in subcellular distribution independently from other variables, such as B cell receptor affinity, antigen type, or tissue distribution, we have established that intracellular localization of autoantigen predisposes for autoantibody production.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.

ABSTRACT
Systemic autoimmune disease is frequently characterized by the production of autoantibodies against widely expressed intracellular self-antigens, whereas B cell tolerance to ubiquitous and highly expressed extracellular antigens is strictly enforced. To test for differences in the B cell response to intracellular and extracellular self-antigens, we sequestered a tolerogenic cell surface antigen intracellularly by addition of a two amino acid endoplasmic reticulum (ER) retention signal. In contrast to cell surface antigen, which causes the deletion of autoreactive B cells, the intracellularly sequestered self-antigen failed to induce B cell tolerance and was instead autoimmunogenic. The intracellular antigen positively selected antigen-binding B cells to differentiate into B1 cells and induced large numbers of IgM autoantibody-secreting plasma cells in a T-independent manner. By analyzing the impact of differences in subcellular distribution independently from other variables, such as B cell receptor affinity, antigen type, or tissue distribution, we have established that intracellular localization of autoantigen predisposes for autoantibody production. These findings help explain why intracellular antigens are targeted in systemic autoimmune diseases.

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Models to account for autoantibody production in response to intracellular HEL self-antigen. The positive selection of autoantibody-producing plasma cells in the spleen may arise after rare encounters between self-reactive B cells and high avidity intracellular self-antigens exposed on apoptotic cells or debris, and immunogenic costimuli, signaling through TLRs or other pathways. The autoimmune response may arise from the activation and differentiation of either (A) mature conventional B cells that are hitherto functionally ignorant of antigen or (B) B1 cells that are first positively selected and then migrate to the spleen from the body cavities.
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fig8: Models to account for autoantibody production in response to intracellular HEL self-antigen. The positive selection of autoantibody-producing plasma cells in the spleen may arise after rare encounters between self-reactive B cells and high avidity intracellular self-antigens exposed on apoptotic cells or debris, and immunogenic costimuli, signaling through TLRs or other pathways. The autoimmune response may arise from the activation and differentiation of either (A) mature conventional B cells that are hitherto functionally ignorant of antigen or (B) B1 cells that are first positively selected and then migrate to the spleen from the body cavities.

Mentions: The origin of autoreactive plasma cells in the IgHEL/mHEL-KK double transgenic mice is uncertain, since it is possible that they arise from conventional B cells including marginal zone B cells, B1 B cells, or both (Fig. 8) . Experiments using parabiotic mice have shown that B1 cells retain the capacity to recirculate through the secondary lymphoid organs (51), although they are Mac-1 negative and difficult to distinguish from large B220lo, IgD−/lo, IgM-bright transitional B cells. Therefore, IgHEL-specific B1 cells may differentiate into autoreactive plasma cells in the spleen of the mHEL-KK double transgenic mice (Fig. 8 B). Increased splenic plasma cells and B1 cells are frequently found together in mice with exaggerated BCR signaling due to B cell–specific mutations as, for example, in SHP1 deficiency (18). The alternative possibility is that the anti-HEL plasma cells derive from follicular B cells, which undergo T-independent activation when they bind the high avidity multivalent intracellular self-antigen exposed on dying cells, or from marginal zone B cells, since rapid differentiation into plasma cells and relocation to the red pulp cords could in part account for the reduced size of the marginal zone in the IgHEL/mHEL-KK double transgenics (Fig. 8 A). Distinguishing between these possibilities is likely to require genetics experiments targeted at the different cell populations.


The cellular location of self-antigen determines the positive and negative selection of autoreactive B cells.

Ferry H, Jones M, Vaux DJ, Roberts IS, Cornall RJ - J. Exp. Med. (2003)

Models to account for autoantibody production in response to intracellular HEL self-antigen. The positive selection of autoantibody-producing plasma cells in the spleen may arise after rare encounters between self-reactive B cells and high avidity intracellular self-antigens exposed on apoptotic cells or debris, and immunogenic costimuli, signaling through TLRs or other pathways. The autoimmune response may arise from the activation and differentiation of either (A) mature conventional B cells that are hitherto functionally ignorant of antigen or (B) B1 cells that are first positively selected and then migrate to the spleen from the body cavities.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2194246&req=5

fig8: Models to account for autoantibody production in response to intracellular HEL self-antigen. The positive selection of autoantibody-producing plasma cells in the spleen may arise after rare encounters between self-reactive B cells and high avidity intracellular self-antigens exposed on apoptotic cells or debris, and immunogenic costimuli, signaling through TLRs or other pathways. The autoimmune response may arise from the activation and differentiation of either (A) mature conventional B cells that are hitherto functionally ignorant of antigen or (B) B1 cells that are first positively selected and then migrate to the spleen from the body cavities.
Mentions: The origin of autoreactive plasma cells in the IgHEL/mHEL-KK double transgenic mice is uncertain, since it is possible that they arise from conventional B cells including marginal zone B cells, B1 B cells, or both (Fig. 8) . Experiments using parabiotic mice have shown that B1 cells retain the capacity to recirculate through the secondary lymphoid organs (51), although they are Mac-1 negative and difficult to distinguish from large B220lo, IgD−/lo, IgM-bright transitional B cells. Therefore, IgHEL-specific B1 cells may differentiate into autoreactive plasma cells in the spleen of the mHEL-KK double transgenic mice (Fig. 8 B). Increased splenic plasma cells and B1 cells are frequently found together in mice with exaggerated BCR signaling due to B cell–specific mutations as, for example, in SHP1 deficiency (18). The alternative possibility is that the anti-HEL plasma cells derive from follicular B cells, which undergo T-independent activation when they bind the high avidity multivalent intracellular self-antigen exposed on dying cells, or from marginal zone B cells, since rapid differentiation into plasma cells and relocation to the red pulp cords could in part account for the reduced size of the marginal zone in the IgHEL/mHEL-KK double transgenics (Fig. 8 A). Distinguishing between these possibilities is likely to require genetics experiments targeted at the different cell populations.

Bottom Line: In contrast to cell surface antigen, which causes the deletion of autoreactive B cells, the intracellularly sequestered self-antigen failed to induce B cell tolerance and was instead autoimmunogenic.The intracellular antigen positively selected antigen-binding B cells to differentiate into B1 cells and induced large numbers of IgM autoantibody-secreting plasma cells in a T-independent manner.By analyzing the impact of differences in subcellular distribution independently from other variables, such as B cell receptor affinity, antigen type, or tissue distribution, we have established that intracellular localization of autoantigen predisposes for autoantibody production.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.

ABSTRACT
Systemic autoimmune disease is frequently characterized by the production of autoantibodies against widely expressed intracellular self-antigens, whereas B cell tolerance to ubiquitous and highly expressed extracellular antigens is strictly enforced. To test for differences in the B cell response to intracellular and extracellular self-antigens, we sequestered a tolerogenic cell surface antigen intracellularly by addition of a two amino acid endoplasmic reticulum (ER) retention signal. In contrast to cell surface antigen, which causes the deletion of autoreactive B cells, the intracellularly sequestered self-antigen failed to induce B cell tolerance and was instead autoimmunogenic. The intracellular antigen positively selected antigen-binding B cells to differentiate into B1 cells and induced large numbers of IgM autoantibody-secreting plasma cells in a T-independent manner. By analyzing the impact of differences in subcellular distribution independently from other variables, such as B cell receptor affinity, antigen type, or tissue distribution, we have established that intracellular localization of autoantigen predisposes for autoantibody production. These findings help explain why intracellular antigens are targeted in systemic autoimmune diseases.

Show MeSH
Related in: MedlinePlus