Short-lived Plasmablasts and Long-lived Plasma Cells Contribute to Chronic Humoral Autoimmunity in NZB/W Mice

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 × 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.

TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts

“…2 As both short-and long-lived Ig-secreting cells are involved in the pathology of SLE, signaling through both TACI and BCMA might contribute to the disease. 49 We have shown that TACI respond to oligomerized ligands, and it will be of interest to determine whether BAFF 60-mer may be produced in excess in these pathologies and whether the specific targeting of BAFF 60-mer may represent an alternative treatment for these autoimmune disorders.…”

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

“…Both SLE patients and lupus-prone mice have alterations in their B-cell subsets, such as an increased proportion of plasmablasts and/or plasma cells, GCs, etc., [39][40][41][42][43] which reflects the disturbed differentiation of B cells in SLE patients and lupus-prone mice. In the present study, we found that compared with wild-type mice, CD138 1 plasmablasts/plasma cells and B220 1 GL-7 1 GC B cells are increased in MRL/lpr mice and are CD180-negative.…”

CCL2 recruitment of IL‐6‐producing CD11b+ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity

“…After 3-5 days of culture, [ 3 H]thymidine was added to the culture for additional 18 h. [ 3 H]Thymidine uptake was measured using a liquid scintillation counter. In some experiments, stimulated and control cultures were stained after various intervals with anti-CD19 PerCP-Cy5.5 (1D3) and allophycocyanin-conjugated anti-CD138 (281-2) to visualize plasma cells, which were identified as CD19 low/-CD138 + cells [42].…”