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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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Increased binding of early MHCII-positive plasma cells to annexin V. Fixed cells from mice fed with BrdU for 2 wk were stained for CD138, BrdU, and MHCII. Result is shown on cells gated for CD138 expression (top). Frequencies of BrdU-positive, MHCII-negative CD138-positive cells were 32.5 ± 9% (n = 5). Living early plasma cells were distinguished from mature plasma cells by MHCII expression (below) and were stained for annexin V. Dead cells and debris were excluded according to propidium iodide staining and forward scatter profile. Histogram plots were additionally gated on CD138-negative, CD138-positive/MHCII-negative or CD138-positive/MHCII-positive cells.
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fig4: Increased binding of early MHCII-positive plasma cells to annexin V. Fixed cells from mice fed with BrdU for 2 wk were stained for CD138, BrdU, and MHCII. Result is shown on cells gated for CD138 expression (top). Frequencies of BrdU-positive, MHCII-negative CD138-positive cells were 32.5 ± 9% (n = 5). Living early plasma cells were distinguished from mature plasma cells by MHCII expression (below) and were stained for annexin V. Dead cells and debris were excluded according to propidium iodide staining and forward scatter profile. Histogram plots were additionally gated on CD138-negative, CD138-positive/MHCII-negative or CD138-positive/MHCII-positive cells.

Mentions: Despite the presence of large numbers of BrdU-positive, dividing plasmablasts, the numbers of nondividing, BrdU-negative plasma cells in the spleens of NZB/W mice did not significantly increase over time, i.e., they were not significantly replaced by newly generated plasma cells. Therefore, we investigated the possibility that the newly generated plasmablasts might be short-lived themselves or that they might differentiate into short-lived plasma cells. MHCII is expressed on early ASCs but is absent on mature plasma cells (14). Expression of this marker correlates well with the expansion phase of the ASC population and could therefore be used as a surrogate marker to distinguish proliferating plasmablasts from noncycling plasma cells (14). This is in accordance with the observation that all long-lived BrdU-negative CD138-positive plasma cells expressed little MHCII (Fig. 4). Roughly half of the BrdU-positive, CD138-positive cells expressed high levels of this molecule; the other half expressed low levels. This finding suggests that during the period of BrdU feeding, a fraction of the dividing plasmablasts differentiated into more mature plasma cells, expressing little MHCII. Compared with CD138-negative splenic cells and CD138-positive/MHCII-low plasma cells, binding of annexin V, a marker for early apoptosis, was increased on CD138-positive/MHCII-positive early plasma cells (Fig. 4).


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)

Increased binding of early MHCII-positive plasma cells to annexin V. Fixed cells from mice fed with BrdU for 2 wk were stained for CD138, BrdU, and MHCII. Result is shown on cells gated for CD138 expression (top). Frequencies of BrdU-positive, MHCII-negative CD138-positive cells were 32.5 ± 9% (n = 5). Living early plasma cells were distinguished from mature plasma cells by MHCII expression (below) and were stained for annexin V. Dead cells and debris were excluded according to propidium iodide staining and forward scatter profile. Histogram plots were additionally gated on CD138-negative, CD138-positive/MHCII-negative or CD138-positive/MHCII-positive cells.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Increased binding of early MHCII-positive plasma cells to annexin V. Fixed cells from mice fed with BrdU for 2 wk were stained for CD138, BrdU, and MHCII. Result is shown on cells gated for CD138 expression (top). Frequencies of BrdU-positive, MHCII-negative CD138-positive cells were 32.5 ± 9% (n = 5). Living early plasma cells were distinguished from mature plasma cells by MHCII expression (below) and were stained for annexin V. Dead cells and debris were excluded according to propidium iodide staining and forward scatter profile. Histogram plots were additionally gated on CD138-negative, CD138-positive/MHCII-negative or CD138-positive/MHCII-positive cells.
Mentions: Despite the presence of large numbers of BrdU-positive, dividing plasmablasts, the numbers of nondividing, BrdU-negative plasma cells in the spleens of NZB/W mice did not significantly increase over time, i.e., they were not significantly replaced by newly generated plasma cells. Therefore, we investigated the possibility that the newly generated plasmablasts might be short-lived themselves or that they might differentiate into short-lived plasma cells. MHCII is expressed on early ASCs but is absent on mature plasma cells (14). Expression of this marker correlates well with the expansion phase of the ASC population and could therefore be used as a surrogate marker to distinguish proliferating plasmablasts from noncycling plasma cells (14). This is in accordance with the observation that all long-lived BrdU-negative CD138-positive plasma cells expressed little MHCII (Fig. 4). Roughly half of the BrdU-positive, CD138-positive cells expressed high levels of this molecule; the other half expressed low levels. This finding suggests that during the period of BrdU feeding, a fraction of the dividing plasmablasts differentiated into more mature plasma cells, expressing little MHCII. Compared with CD138-negative splenic cells and CD138-positive/MHCII-low plasma cells, binding of annexin V, a marker for early apoptosis, was increased on CD138-positive/MHCII-positive early plasma cells (Fig. 4).

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