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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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Humoral immune responses of sHEL/IgHEL (A) and IgHEL(B)  mice that overexpress CD19 in response to immunization with HEL.  2-mo-old mice were injected i.p. with HEL or PBS mixed with CFA on  days 0 and 21 (arrows), and were bled at the indicated times. Levels of  serum anti-HEL IgMa antibodies for individual mice (dots or squares) were  determined by ELISA. Mean antibody levels are shown as solid  (hCD19+/+) or dashed (hCD19–/–) lines. The dashed horizontal lines (arrowhead) delimit the 95% confidence interval for the log normal distribution of anti-HEL antibody levels observed in unimmunized sHEL/IgHEL  mice.
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Figure 2: Humoral immune responses of sHEL/IgHEL (A) and IgHEL(B) mice that overexpress CD19 in response to immunization with HEL. 2-mo-old mice were injected i.p. with HEL or PBS mixed with CFA on days 0 and 21 (arrows), and were bled at the indicated times. Levels of serum anti-HEL IgMa antibodies for individual mice (dots or squares) were determined by ELISA. Mean antibody levels are shown as solid (hCD19+/+) or dashed (hCD19–/–) lines. The dashed horizontal lines (arrowhead) delimit the 95% confidence interval for the log normal distribution of anti-HEL antibody levels observed in unimmunized sHEL/IgHEL mice.

Mentions: Whether B cell anergy could be surmounted in young mice that overexpress CD19 was assessed by immunizing 2-mo-old mice with HEL in CFA. Mice without detectable levels of spontaneous anti-HEL antibodies were also injected with CFA alone to mimic a nonspecific inflammatory stimulus. Immunization of sHEL/IgHEL/hCD19+/+ mice with HEL generated primary anti-HEL antibody responses in some mice, and a mean secondary antibody response that was 200-fold higher (P <0.05) than that of sHEL/IgHEL mice (Fig. 2 A). A measurable antibody response was only detected in sHEL/IgHEL mice after secondary immunization (Fig. 2 A). A striking result was that the inflammation induced by CFA alone induced sHEL/IgHEL/ hCD19+/+ mice to produce anti-HEL antibodies in response to endogenous sHEL autoantigen (Fig. 2 A). In this case, the mean secondary antibody response was 4,000-fold higher than in sHEL/IgHEL mice (P <0.05). In fact, the anti-HEL antibody levels induced in some sHEL/IgHEL/hCD19+/+ mice were equivalent to those of IgHEL mice (Fig. 2 B). Similar results were obtained with sHEL/IgHEL/hCD19+/– mice although anti-HEL autoantibody levels were intermediate (data not shown). In sHEL/IgHEL/hCD19+/+ mice that already expressed detectable anti-HEL antibodies, autoantibody levels were also dramatically augmented after CFA administration (data not shown). Therefore, inflammatory responses induced by the administration of CFA revealed a breakdown in tolerance and resulted in autoantibody production in anergic mice that overexpressed CD19.


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)

Humoral immune responses of sHEL/IgHEL (A) and IgHEL(B)  mice that overexpress CD19 in response to immunization with HEL.  2-mo-old mice were injected i.p. with HEL or PBS mixed with CFA on  days 0 and 21 (arrows), and were bled at the indicated times. Levels of  serum anti-HEL IgMa antibodies for individual mice (dots or squares) were  determined by ELISA. Mean antibody levels are shown as solid  (hCD19+/+) or dashed (hCD19–/–) lines. The dashed horizontal lines (arrowhead) delimit the 95% confidence interval for the log normal distribution of anti-HEL antibody levels observed in unimmunized sHEL/IgHEL  mice.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199156&req=5

Figure 2: Humoral immune responses of sHEL/IgHEL (A) and IgHEL(B) mice that overexpress CD19 in response to immunization with HEL. 2-mo-old mice were injected i.p. with HEL or PBS mixed with CFA on days 0 and 21 (arrows), and were bled at the indicated times. Levels of serum anti-HEL IgMa antibodies for individual mice (dots or squares) were determined by ELISA. Mean antibody levels are shown as solid (hCD19+/+) or dashed (hCD19–/–) lines. The dashed horizontal lines (arrowhead) delimit the 95% confidence interval for the log normal distribution of anti-HEL antibody levels observed in unimmunized sHEL/IgHEL mice.
Mentions: Whether B cell anergy could be surmounted in young mice that overexpress CD19 was assessed by immunizing 2-mo-old mice with HEL in CFA. Mice without detectable levels of spontaneous anti-HEL antibodies were also injected with CFA alone to mimic a nonspecific inflammatory stimulus. Immunization of sHEL/IgHEL/hCD19+/+ mice with HEL generated primary anti-HEL antibody responses in some mice, and a mean secondary antibody response that was 200-fold higher (P <0.05) than that of sHEL/IgHEL mice (Fig. 2 A). A measurable antibody response was only detected in sHEL/IgHEL mice after secondary immunization (Fig. 2 A). A striking result was that the inflammation induced by CFA alone induced sHEL/IgHEL/ hCD19+/+ mice to produce anti-HEL antibodies in response to endogenous sHEL autoantigen (Fig. 2 A). In this case, the mean secondary antibody response was 4,000-fold higher than in sHEL/IgHEL mice (P <0.05). In fact, the anti-HEL antibody levels induced in some sHEL/IgHEL/hCD19+/+ mice were equivalent to those of IgHEL mice (Fig. 2 B). Similar results were obtained with sHEL/IgHEL/hCD19+/– mice although anti-HEL autoantibody levels were intermediate (data not shown). In sHEL/IgHEL/hCD19+/+ mice that already expressed detectable anti-HEL antibodies, autoantibody levels were also dramatically augmented after CFA administration (data not shown). Therefore, inflammatory responses induced by the administration of CFA revealed a breakdown in tolerance and resulted in autoantibody production in anergic mice that overexpressed CD19.

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