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Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice.

Hoyer BF, Moser K, Hauser AE, Peddinghaus A, Voigt C, Eilat D, Radbruch A, Hiepe F, Manz RA - J. Exp. Med. (2004)

Bottom Line: In the present study, we analyzed the life span of (auto)antibody-secreting cells in the spleens of NZB x NZW F1 (NZB/W) mice, a murine model of systemic lupus erythematosus.Less than 60% of the splenic (auto)antibody-secreting cells were short-lived plasmablasts, whereas 40% were nondividing, long-lived plasma cells with a half-life of >6 mo.Although antiproliferative immunosuppressive therapy depleted short-lived plasmablasts, long-lived plasma cells survived and continued to produce (auto)antibodies.

View Article: PubMed Central - PubMed

Affiliation: Department for Medicine, Rheumatology and Clinical Immunology, Charité University Hospital, D-10117 Berlin, Germany.

ABSTRACT
The current view holds that chronic autoimmune diseases are driven by the continuous activation of autoreactive B and T lymphocytes. However, despite the use of potent immunosuppressive drugs designed to interfere with this activation the production of autoantibodies often persists and contributes to progression of the immunopathology. In the present study, we analyzed the life span of (auto)antibody-secreting cells in the spleens of NZB x NZW F1 (NZB/W) mice, a murine model of systemic lupus erythematosus. The number of splenic ASCs increased in mice aged 1-5 mo and became stable thereafter. Less than 60% of the splenic (auto)antibody-secreting cells were short-lived plasmablasts, whereas 40% were nondividing, long-lived plasma cells with a half-life of >6 mo. In NZB/W mice and D42 Ig heavy chain knock-in mice, a fraction of DNA-specific plasma cells were also long-lived. Although antiproliferative immunosuppressive therapy depleted short-lived plasmablasts, long-lived plasma cells survived and continued to produce (auto)antibodies. Thus, long-lived, autoreactive plasma cells are a relevant target for researchers aiming to develop curative therapies for autoimmune diseases.

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Kinetics and incorporation of BrdU in the splenic plasma cell compartment of NZB/W mice. (A) Total number of ASCs in spleen, as determined by ELISPOT, at the times indicated. Some groups were fed BrdU continuously (B). Splenic CD138-positive cells consist of dividing and nondividing cells. NZB/W mice with confirmed SLE were continuously fed BrdU for 2 wk. CD138-positive cells were then FACS® sorted and stained for intracellular immunoglobulin (red) and BrdU (green/yellow); original magnification, 160 × (left) and 80 × (right). Plasma cells negative for BrdU had not undergone DNA synthesis or replication during the period of BrdU treatment. Dividing plasmablasts and plasma cells recently derived from proliferating precursors are BrdU positive.
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fig1: Kinetics and incorporation of BrdU in the splenic plasma cell compartment of NZB/W mice. (A) Total number of ASCs in spleen, as determined by ELISPOT, at the times indicated. Some groups were fed BrdU continuously (B). Splenic CD138-positive cells consist of dividing and nondividing cells. NZB/W mice with confirmed SLE were continuously fed BrdU for 2 wk. CD138-positive cells were then FACS® sorted and stained for intracellular immunoglobulin (red) and BrdU (green/yellow); original magnification, 160 × (left) and 80 × (right). Plasma cells negative for BrdU had not undergone DNA synthesis or replication during the period of BrdU treatment. Dividing plasmablasts and plasma cells recently derived from proliferating precursors are BrdU positive.

Mentions: In NZB × NZW F1 mice (NZB/W) at least 4–5 mo of age with full-blown murine SLE (18), the total number of ASCs is normal in the BM but severely increased in the spleen (19), the organ where B cells are induced to form plasma cells. In the spleens of healthy mice, ASCs do not make up >0.1% of the total number of mononuclear cells even after immunization (14). The vast majority of these ASCs are short-lived plasmablasts; only a few are long-lived (20). The frequency of splenic plasma cells increases about threefold (to 1–2%) in NZB/W mice between the ages of 1–5 mo and before the development of proteinuria. The numbers of ASCs in NZB/W mice 5 mo of age are ∼20-fold higher than in healthy mice (19). Thereafter, the frequencies and absolute numbers of splenic plasma cells remain stable (Fig. 1 A).


Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice.

Hoyer BF, Moser K, Hauser AE, Peddinghaus A, Voigt C, Eilat D, Radbruch A, Hiepe F, Manz RA - J. Exp. Med. (2004)

Kinetics and incorporation of BrdU in the splenic plasma cell compartment of NZB/W mice. (A) Total number of ASCs in spleen, as determined by ELISPOT, at the times indicated. Some groups were fed BrdU continuously (B). Splenic CD138-positive cells consist of dividing and nondividing cells. NZB/W mice with confirmed SLE were continuously fed BrdU for 2 wk. CD138-positive cells were then FACS® sorted and stained for intracellular immunoglobulin (red) and BrdU (green/yellow); original magnification, 160 × (left) and 80 × (right). Plasma cells negative for BrdU had not undergone DNA synthesis or replication during the period of BrdU treatment. Dividing plasmablasts and plasma cells recently derived from proliferating precursors are BrdU positive.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211779&req=5

fig1: Kinetics and incorporation of BrdU in the splenic plasma cell compartment of NZB/W mice. (A) Total number of ASCs in spleen, as determined by ELISPOT, at the times indicated. Some groups were fed BrdU continuously (B). Splenic CD138-positive cells consist of dividing and nondividing cells. NZB/W mice with confirmed SLE were continuously fed BrdU for 2 wk. CD138-positive cells were then FACS® sorted and stained for intracellular immunoglobulin (red) and BrdU (green/yellow); original magnification, 160 × (left) and 80 × (right). Plasma cells negative for BrdU had not undergone DNA synthesis or replication during the period of BrdU treatment. Dividing plasmablasts and plasma cells recently derived from proliferating precursors are BrdU positive.
Mentions: In NZB × NZW F1 mice (NZB/W) at least 4–5 mo of age with full-blown murine SLE (18), the total number of ASCs is normal in the BM but severely increased in the spleen (19), the organ where B cells are induced to form plasma cells. In the spleens of healthy mice, ASCs do not make up >0.1% of the total number of mononuclear cells even after immunization (14). The vast majority of these ASCs are short-lived plasmablasts; only a few are long-lived (20). The frequency of splenic plasma cells increases about threefold (to 1–2%) in NZB/W mice between the ages of 1–5 mo and before the development of proteinuria. The numbers of ASCs in NZB/W mice 5 mo of age are ∼20-fold higher than in healthy mice (19). Thereafter, the frequencies and absolute numbers of splenic plasma cells remain stable (Fig. 1 A).

Bottom Line: In the present study, we analyzed the life span of (auto)antibody-secreting cells in the spleens of NZB x NZW F1 (NZB/W) mice, a murine model of systemic lupus erythematosus.Less than 60% of the splenic (auto)antibody-secreting cells were short-lived plasmablasts, whereas 40% were nondividing, long-lived plasma cells with a half-life of >6 mo.Although antiproliferative immunosuppressive therapy depleted short-lived plasmablasts, long-lived plasma cells survived and continued to produce (auto)antibodies.

View Article: PubMed Central - PubMed

Affiliation: Department for Medicine, Rheumatology and Clinical Immunology, Charité University Hospital, D-10117 Berlin, Germany.

ABSTRACT
The current view holds that chronic autoimmune diseases are driven by the continuous activation of autoreactive B and T lymphocytes. However, despite the use of potent immunosuppressive drugs designed to interfere with this activation the production of autoantibodies often persists and contributes to progression of the immunopathology. In the present study, we analyzed the life span of (auto)antibody-secreting cells in the spleens of NZB x NZW F1 (NZB/W) mice, a murine model of systemic lupus erythematosus. The number of splenic ASCs increased in mice aged 1-5 mo and became stable thereafter. Less than 60% of the splenic (auto)antibody-secreting cells were short-lived plasmablasts, whereas 40% were nondividing, long-lived plasma cells with a half-life of >6 mo. In NZB/W mice and D42 Ig heavy chain knock-in mice, a fraction of DNA-specific plasma cells were also long-lived. Although antiproliferative immunosuppressive therapy depleted short-lived plasmablasts, long-lived plasma cells survived and continued to produce (auto)antibodies. Thus, long-lived, autoreactive plasma cells are a relevant target for researchers aiming to develop curative therapies for autoimmune diseases.

Show MeSH
Related in: MedlinePlus