Plasma cells in immunopathology: concepts and therapeutic strategies

Abstract

Plasma cells are terminally differentiated B cells that secrete antibodies, important for immune protection, but also contribute to any allergic and autoimmune disease. There is increasing evidence that plasma cell populations exhibit a considerable degree of heterogeneity with respect to their immunophenotype, migration behavior, lifetime, and susceptibility to immunosuppressive drugs. Pathogenic long-lived plasma cells are refractory to existing therapies. In contrast, short-lived plasma cells can be depleted by steroids and cytostatic drugs. Therefore, long-lived plasma cells are responsible for therapy-resistant autoantibodies and resemble a challenge for the therapy of antibody-mediated autoimmune diseases. Both lifetime and therapy resistance of plasma cells are supported by factors produced within their microenviromental niches. Current results suggest that plasma cell differentiation and survival factors such as IL-6 also signal via mammalian miRNAs within the plasma cell to modulate downstream transcription factors. Recent evidence also suggests that plasma cells and/or their immediate precursors (plasmablasts) can produce important cytokines and act as antigen-presenting cells, exhibiting so far underestimated roles in immune regulation and bone homeostasis. Here, we provide an overview on plasma cell biology and discuss exciting, experimental, and potential therapeutic approaches to eliminate pathogenic plasma cells.

Pharmacokinetics and pharmacodynamics of the cytolytic anti‐CD38 human monoclonal antibody TAK‐079 in monkey – model assisted preparation for the first in human trial

“…We did not measure the effect of TAK‐079 on tissue plasma cells or plasmablasts, however, NK cells have high levels of CD38 on their surface and we could demonstrate that cell depletion efficiency of a specific lymphocyte subset depends, at least in part, on the expression levels of CD38. Therefore, we speculate that the cytolytic effect of TAK‐079 on plasmablasts and plasma cells is comparable to the effect on NK cells …”

“…Therefore, we speculate that the cytolytic effect of TAK-079 on plasmablasts and plasma cells is comparable to the effect on NK cells. 8,19,25 The immunogenicity of TAK-079 was assessed by measuring ADA levels. In the 13-weeks repeated dose studies it was evident Based on the scaled monkey PK and PK-PD models 5 single IV and SC dose PK and cell depletion profiles were simulated (from 0.0003 to 1 mg/kg).…”

Landscape of infiltrating B cells and their clinical significance in human hepatocellular carcinoma

“…They can also serve as APC and express some costimulatory molecules, including CD80 and CD86. 37 However, some studies provide evidence that the regulatory PCs had the ability to inhibit T cell response by producing IL-10 38 and IL-35. 39 Therefore, it is tempting to suggest both pro-tumorigenic and antitumorigenic subsets of PCs may exist in human cancer, including HCC.…”

IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement-mediated neutrophil migration

“…There is increasing evidence that B cells/plasma cells modulate CD4 T-cell responses, including T follicular helper cell responses, as well as inflammation, through their capacity to present antigen through MHC class II and to produce multiple cytokines, such as IL-6, IL-17, and IL-35, among others, in addition to IL-10. [25][26][27][65][66][67] Hence the GMD-activated B cells and MOPC315.BM myeloma plasma cells used in this study might influence immune responses and inflammatory processes in multiple ways. Nevertheless, our data indicate that IL-10 production is a key immunosuppressive factor and that blockade of the IL-10 signaling pathway might be useful to prevent plasmacytosis-associated susceptibility to infections.…”