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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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Autoreactive cells can enter the long-lived plasma cell compartment. D42 knock-in mice with an NZB/W genetic background were fed BrdU for 12 wk. The spleens of the mice were then analyzed by FACS® for the presence of BrdU-negative plasma cells (left). D42 transgene-bearing plasma cells were detected by CD138 and intracellular staining with an VH11-specific anti-idiotypic antibody. On the NZB/W background, ∼90% of cells detected with that reagent bind to DNA with high affinity (24) (middle). Gating on D42-positive/CD138-positive plasma cells as shown allowed the identification of BrdU-positive and BrdU-negative plasma cells expressing the D42 transgene (right). Results are representative data from four mice.
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fig6: Autoreactive cells can enter the long-lived plasma cell compartment. D42 knock-in mice with an NZB/W genetic background were fed BrdU for 12 wk. The spleens of the mice were then analyzed by FACS® for the presence of BrdU-negative plasma cells (left). D42 transgene-bearing plasma cells were detected by CD138 and intracellular staining with an VH11-specific anti-idiotypic antibody. On the NZB/W background, ∼90% of cells detected with that reagent bind to DNA with high affinity (24) (middle). Gating on D42-positive/CD138-positive plasma cells as shown allowed the identification of BrdU-positive and BrdU-negative plasma cells expressing the D42 transgene (right). Results are representative data from four mice.

Mentions: To determine whether ASCs were present in the short- or long-lived plasma cell compartments, we took advantage of the preferential deletion of short-lived cells by cyclophosphamide and used ELISPOT to determine whether anti-DNA ASCs were among the remaining cells. Although BrdU-positive short-lived plasmablasts were eliminated by high doses (three to four times 35 mg/kg) of cyclophosphamide (Fig. 5), an average of ∼20% of the total IgG/IgM anti-DNA ASC survived this extreme treatment (Table I). Although these findings suggest that a fraction of the autoreactive cells is contained within the therapy-resistant long-lived plasma cell compartment, it could not formally be excluded that the remaining BrdU-positive cells are those secreting anti-DNA antibodies. To further investigate this point, we analyzed the plasma cell compartment in knock-in NZB/W mice transgenic for the anti-DNA D42 heavy chain. With this autoimmunogenic background, the D42 heavy chain transgene combines with the appropriate light chain to produce high affinity anti-DNA IgM and IgG autoantibodies (24). With this model, plasma cells producing DNA-binding antibodies can also be monitored by staining intracellular immunoglobulins with an VH11-specific rabbit anti-idiotypic antibody. On the NZB/W background, ∼90% of cells detected with that reagent bind to DNA with high affinity (24). Based on BrdU incorporation, the frequencies of short-lived plasmablasts and long-lived plasma cells in the spleens of D42H transgenic NZB/W mice were very similar to those observed in nontransgenic NZB/W mice (Fig. 6). About 20% of the D42 transgene–expressing plasma cells were contained within the BrdU-negative long-lived plasma cell compartment after 12 wk of BrdU feeding. This is a direct indication that autoreactive cells can enter the compartment of long-lived plasma cells. These results show that a considerable proportion of the persistent autoantibody production in lupus can be mediated by long-lived plasma cells.


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)

Autoreactive cells can enter the long-lived plasma cell compartment. D42 knock-in mice with an NZB/W genetic background were fed BrdU for 12 wk. The spleens of the mice were then analyzed by FACS® for the presence of BrdU-negative plasma cells (left). D42 transgene-bearing plasma cells were detected by CD138 and intracellular staining with an VH11-specific anti-idiotypic antibody. On the NZB/W background, ∼90% of cells detected with that reagent bind to DNA with high affinity (24) (middle). Gating on D42-positive/CD138-positive plasma cells as shown allowed the identification of BrdU-positive and BrdU-negative plasma cells expressing the D42 transgene (right). Results are representative data from four mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211779&req=5

fig6: Autoreactive cells can enter the long-lived plasma cell compartment. D42 knock-in mice with an NZB/W genetic background were fed BrdU for 12 wk. The spleens of the mice were then analyzed by FACS® for the presence of BrdU-negative plasma cells (left). D42 transgene-bearing plasma cells were detected by CD138 and intracellular staining with an VH11-specific anti-idiotypic antibody. On the NZB/W background, ∼90% of cells detected with that reagent bind to DNA with high affinity (24) (middle). Gating on D42-positive/CD138-positive plasma cells as shown allowed the identification of BrdU-positive and BrdU-negative plasma cells expressing the D42 transgene (right). Results are representative data from four mice.
Mentions: To determine whether ASCs were present in the short- or long-lived plasma cell compartments, we took advantage of the preferential deletion of short-lived cells by cyclophosphamide and used ELISPOT to determine whether anti-DNA ASCs were among the remaining cells. Although BrdU-positive short-lived plasmablasts were eliminated by high doses (three to four times 35 mg/kg) of cyclophosphamide (Fig. 5), an average of ∼20% of the total IgG/IgM anti-DNA ASC survived this extreme treatment (Table I). Although these findings suggest that a fraction of the autoreactive cells is contained within the therapy-resistant long-lived plasma cell compartment, it could not formally be excluded that the remaining BrdU-positive cells are those secreting anti-DNA antibodies. To further investigate this point, we analyzed the plasma cell compartment in knock-in NZB/W mice transgenic for the anti-DNA D42 heavy chain. With this autoimmunogenic background, the D42 heavy chain transgene combines with the appropriate light chain to produce high affinity anti-DNA IgM and IgG autoantibodies (24). With this model, plasma cells producing DNA-binding antibodies can also be monitored by staining intracellular immunoglobulins with an VH11-specific rabbit anti-idiotypic antibody. On the NZB/W background, ∼90% of cells detected with that reagent bind to DNA with high affinity (24). Based on BrdU incorporation, the frequencies of short-lived plasmablasts and long-lived plasma cells in the spleens of D42H transgenic NZB/W mice were very similar to those observed in nontransgenic NZB/W mice (Fig. 6). About 20% of the D42 transgene–expressing plasma cells were contained within the BrdU-negative long-lived plasma cell compartment after 12 wk of BrdU feeding. This is a direct indication that autoreactive cells can enter the compartment of long-lived plasma cells. These results show that a considerable proportion of the persistent autoantibody production in lupus can be mediated by long-lived plasma cells.

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