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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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Related in: MedlinePlus

Long-lived plasma cells in NZB/W mice are resistant to conventional immunotherapy. Mice were fed BrdU for 2–4 wk and received the total cyclophosphamide dose indicated (divided over 3 d) 1 wk before sampling. BrdU-positive (short-lived) and -negative (long-lived) plasma cells were identified by FACS®. Representative data for 25 untreated and 12 treated mice are shown.
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fig5: Long-lived plasma cells in NZB/W mice are resistant to conventional immunotherapy. Mice were fed BrdU for 2–4 wk and received the total cyclophosphamide dose indicated (divided over 3 d) 1 wk before sampling. BrdU-positive (short-lived) and -negative (long-lived) plasma cells were identified by FACS®. Representative data for 25 untreated and 12 treated mice are shown.

Mentions: Unlike their short-lived counterparts, long-lived plasma cells are refractory to cyclophosphamide. Long-lived lymphocytes are considered to be resistant to immunosuppressive treatment (26). Our finding that roughly half of the splenic ASCs in NZB/W mice are long-lived plasma cells made us wonder whether these cells are responsible for treatment-resistant antibody titers and autoantibody production. To clarify these points, we analyzed the plasma cell compartment of NZB/W mice treated experimentally with cyclophosphamide, a drug also used to treat severe SLE in humans (Fig. 5). Three doses of 35 mg/kg BW, higher than the amount normally used for high dose human therapy, deleted short-lived BrdU-positive plasmablasts nearly completely while affecting long-lived BrdU-negative plasma cells to a much lesser extent. Higher doses (up to 140 mg/kg) depleted larger numbers of long-lived plasma cells, but a fraction of these cells survived even under these conditions. These results show that cyclophosphamide therapy prevents ongoing immune activation and formation of short-lived plasmablasts but does not delete long-lived plasma cells efficiently.


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)

Long-lived plasma cells in NZB/W mice are resistant to conventional immunotherapy. Mice were fed BrdU for 2–4 wk and received the total cyclophosphamide dose indicated (divided over 3 d) 1 wk before sampling. BrdU-positive (short-lived) and -negative (long-lived) plasma cells were identified by FACS®. Representative data for 25 untreated and 12 treated mice are shown.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Long-lived plasma cells in NZB/W mice are resistant to conventional immunotherapy. Mice were fed BrdU for 2–4 wk and received the total cyclophosphamide dose indicated (divided over 3 d) 1 wk before sampling. BrdU-positive (short-lived) and -negative (long-lived) plasma cells were identified by FACS®. Representative data for 25 untreated and 12 treated mice are shown.
Mentions: Unlike their short-lived counterparts, long-lived plasma cells are refractory to cyclophosphamide. Long-lived lymphocytes are considered to be resistant to immunosuppressive treatment (26). Our finding that roughly half of the splenic ASCs in NZB/W mice are long-lived plasma cells made us wonder whether these cells are responsible for treatment-resistant antibody titers and autoantibody production. To clarify these points, we analyzed the plasma cell compartment of NZB/W mice treated experimentally with cyclophosphamide, a drug also used to treat severe SLE in humans (Fig. 5). Three doses of 35 mg/kg BW, higher than the amount normally used for high dose human therapy, deleted short-lived BrdU-positive plasmablasts nearly completely while affecting long-lived BrdU-negative plasma cells to a much lesser extent. Higher doses (up to 140 mg/kg) depleted larger numbers of long-lived plasma cells, but a fraction of these cells survived even under these conditions. These results show that cyclophosphamide therapy prevents ongoing immune activation and formation of short-lived plasmablasts but does not delete long-lived plasma cells efficiently.

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