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CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes.

Inaoki M, Sato S, Weintraub BC, Goodnow CC, Tedder TF - J. Exp. Med. (1997)

Bottom Line: The CD19 cell surface molecule regulates signal transduction events critical for B lymphocyte development and humoral immunity.Therefore, altered signaling thresholds due to CD19 overexpression resulted in the breakdown of peripheral tolerance.Thus, CD19 overexpression shifts the balance between tolerance and immunity to autoimmunity by augmenting antigen receptor signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.

ABSTRACT
The CD19 cell surface molecule regulates signal transduction events critical for B lymphocyte development and humoral immunity. Increasing the density of CD19 expression renders B lymphocytes hyper-responsive to transmembrane signals, and transgenic mice that overexpress CD19 have increased levels of autoantibodies. The role of CD19 in tolerance regulation and autoantibody generation was therefore examined by crossing mice that overexpress a human CD19 transgene with transgenic mice expressing a model autoantigen (soluble hen egg lysozyme, sHEL) and high-affinity HEL-specific IgMa and IgDa (IgHEL) antigen receptors. In this model of peripheral tolerance, B cells in sHEL/IgHEL double-transgenic mice are functionally anergic and do not produce autoantibodies. However, it was found that overexpression of CD19 in sHEL/IgHEL double-transgenic mice resulted in a breakdown of peripheral tolerance and the production of anti-HEL antibodies at levels similar to those observed in IgHEL mice lacking the sHEL autoantigen. Therefore, altered signaling thresholds due to CD19 overexpression resulted in the breakdown of peripheral tolerance. Thus, CD19 overexpression shifts the balance between tolerance and immunity to autoimmunity by augmenting antigen receptor signaling.

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Signal transduction through surface IgM and CD19 in B cells  from sHEL/IgHEL/hCD19+/+ (A) or IgHEL/hCD19+/+ mice (B). Relative  [Ca++]i levels were assessed by flow cytometry after gating on the B220+  population of indo-1 loaded splenocytes. Baseline fluorescence ratios were  collected for 1 min before HEL and/or specific monoclonal antibodies  were added (arrows) at final concentrations of: HEL, 100 ng/ml; anti-mouse CD19, 40 μg/ml; anti-human CD19, 40 μg/ml. An increase in  [Ca++]i over time is shown as an increase in the ratio of indo-1 fluorescence. Values represent the ratios of fluorescence intensity of cell populations after treatment relative to the fluorescence intensity of untreated  cells. These results are representative of those obtained from three littermate pairs of mice.
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Figure 4: Signal transduction through surface IgM and CD19 in B cells from sHEL/IgHEL/hCD19+/+ (A) or IgHEL/hCD19+/+ mice (B). Relative [Ca++]i levels were assessed by flow cytometry after gating on the B220+ population of indo-1 loaded splenocytes. Baseline fluorescence ratios were collected for 1 min before HEL and/or specific monoclonal antibodies were added (arrows) at final concentrations of: HEL, 100 ng/ml; anti-mouse CD19, 40 μg/ml; anti-human CD19, 40 μg/ml. An increase in [Ca++]i over time is shown as an increase in the ratio of indo-1 fluorescence. Values represent the ratios of fluorescence intensity of cell populations after treatment relative to the fluorescence intensity of untreated cells. These results are representative of those obtained from three littermate pairs of mice.

Mentions: Peripheral tolerance in sHEL/IgHEL mice results in the failure of anergic B cells to mobilize intracellular Ca++ in response to HEL-mediated antigen receptor crosslinking in vitro (25). B cells from sHEL/IgHEL/hCD19+/+ mice were equivalent to anergic B cells from sHEL/IgHEL mice in their failure to mobilize Ca++ in response to HEL (Fig. 4 A). B cells from sHEL/IgHEL/hCD19+/+ mice that generated high levels of autoantibodies also failed to mobilize Ca++ in response to HEL (data not shown). B cells from IgHEL/hCD19+/+ mice generated normal Ca++ responses (Fig. 4 B). Therefore, the development of autoimmunity in sHEL/IgHEL/hCD19+/+ mice does not result from a CD19-induced recovery of early signaling responses in the bulk of anergic B cells.


CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes.

Inaoki M, Sato S, Weintraub BC, Goodnow CC, Tedder TF - J. Exp. Med. (1997)

Signal transduction through surface IgM and CD19 in B cells  from sHEL/IgHEL/hCD19+/+ (A) or IgHEL/hCD19+/+ mice (B). Relative  [Ca++]i levels were assessed by flow cytometry after gating on the B220+  population of indo-1 loaded splenocytes. Baseline fluorescence ratios were  collected for 1 min before HEL and/or specific monoclonal antibodies  were added (arrows) at final concentrations of: HEL, 100 ng/ml; anti-mouse CD19, 40 μg/ml; anti-human CD19, 40 μg/ml. An increase in  [Ca++]i over time is shown as an increase in the ratio of indo-1 fluorescence. Values represent the ratios of fluorescence intensity of cell populations after treatment relative to the fluorescence intensity of untreated  cells. These results are representative of those obtained from three littermate pairs of mice.
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Related In: Results  -  Collection

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Figure 4: Signal transduction through surface IgM and CD19 in B cells from sHEL/IgHEL/hCD19+/+ (A) or IgHEL/hCD19+/+ mice (B). Relative [Ca++]i levels were assessed by flow cytometry after gating on the B220+ population of indo-1 loaded splenocytes. Baseline fluorescence ratios were collected for 1 min before HEL and/or specific monoclonal antibodies were added (arrows) at final concentrations of: HEL, 100 ng/ml; anti-mouse CD19, 40 μg/ml; anti-human CD19, 40 μg/ml. An increase in [Ca++]i over time is shown as an increase in the ratio of indo-1 fluorescence. Values represent the ratios of fluorescence intensity of cell populations after treatment relative to the fluorescence intensity of untreated cells. These results are representative of those obtained from three littermate pairs of mice.
Mentions: Peripheral tolerance in sHEL/IgHEL mice results in the failure of anergic B cells to mobilize intracellular Ca++ in response to HEL-mediated antigen receptor crosslinking in vitro (25). B cells from sHEL/IgHEL/hCD19+/+ mice were equivalent to anergic B cells from sHEL/IgHEL mice in their failure to mobilize Ca++ in response to HEL (Fig. 4 A). B cells from sHEL/IgHEL/hCD19+/+ mice that generated high levels of autoantibodies also failed to mobilize Ca++ in response to HEL (data not shown). B cells from IgHEL/hCD19+/+ mice generated normal Ca++ responses (Fig. 4 B). Therefore, the development of autoimmunity in sHEL/IgHEL/hCD19+/+ mice does not result from a CD19-induced recovery of early signaling responses in the bulk of anergic B cells.

Bottom Line: The CD19 cell surface molecule regulates signal transduction events critical for B lymphocyte development and humoral immunity.Therefore, altered signaling thresholds due to CD19 overexpression resulted in the breakdown of peripheral tolerance.Thus, CD19 overexpression shifts the balance between tolerance and immunity to autoimmunity by augmenting antigen receptor signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.

ABSTRACT
The CD19 cell surface molecule regulates signal transduction events critical for B lymphocyte development and humoral immunity. Increasing the density of CD19 expression renders B lymphocytes hyper-responsive to transmembrane signals, and transgenic mice that overexpress CD19 have increased levels of autoantibodies. The role of CD19 in tolerance regulation and autoantibody generation was therefore examined by crossing mice that overexpress a human CD19 transgene with transgenic mice expressing a model autoantigen (soluble hen egg lysozyme, sHEL) and high-affinity HEL-specific IgMa and IgDa (IgHEL) antigen receptors. In this model of peripheral tolerance, B cells in sHEL/IgHEL double-transgenic mice are functionally anergic and do not produce autoantibodies. However, it was found that overexpression of CD19 in sHEL/IgHEL double-transgenic mice resulted in a breakdown of peripheral tolerance and the production of anti-HEL antibodies at levels similar to those observed in IgHEL mice lacking the sHEL autoantigen. Therefore, altered signaling thresholds due to CD19 overexpression resulted in the breakdown of peripheral tolerance. Thus, CD19 overexpression shifts the balance between tolerance and immunity to autoimmunity by augmenting antigen receptor signaling.

Show MeSH
Related in: MedlinePlus