Pathogenic Long-Lived Plasma Cells and Their Survival Niches in Autoimmunity, Malignancy, and Allergy

Abstract

Long-lived plasma cells survive in a protected microenvironment for years or even a lifetime and provide humoral memory by establishing persistent Ab titers. Long-lived autoreactive, malignant, and allergen-specific plasma cells are likewise protected in their survival niche and are refractory to immunosuppression, B cell depletion, and irradiation. Their elimination remains an essential therapeutic challenge. Recent data indicate that long-lived plasma cells reside in a multicomponent plasma cell niche with a stable mesenchymal and a dynamic hematopoietic component, both providing essential soluble and membrane-bound survival factors. Alternative niches with different hematopoietic cell components compensate fluctuations of single cell types but may also harbor distinct plasma cell subsets. In this Brief Review, we discuss conventional therapies in autoimmunity and multiple myeloma in comparison with novel drugs that target plasma cells and their niches. In the future, such strategies may enable the specific depletion of pathogenic plasma cells while leaving the protective humoral memory intact.

STAT-3 Activation by Differential Cytokines Is Critical for Human In Vivo–Generated Plasma Cell Survival and Ig Secretion

“…Furthermore, comparative studies of the phenotype, BLIMP1 expression, gene expression profiling, and IGVH gene somatic hypermutation support the view that human PCs obtained from tonsil (To) and lymph node (as examples of early PCs from inductive SLOs), from the peripheral blood (PB) drawn at the peak time of appearance of Ag-induced PCs (as a source of transitional PCs), and from the BM (as terminally differentiated PCs) exhibit a gradient of increasing maturation in the following direction: SLOs→blood→BM (16)(17)(18)(19)(20). Besides this well-established migratory pathway, evidence in both humans and mice indicates that a non-negligible fraction of PCs survives in the SLOs, as well as in inflamed tissues, where they continue to produce Abs for prolonged periods (21)(22)(23)(24).…”

“…These latter are generated in tissue niches, which provide the PCs with appropriate survival factors. The different auxiliary cell types, and the cytokines and other molecules reported as participants in PC survival niches have been recently revised (24,31). In a previous study, we have demonstrated that human SLO, but not BM, PCs express IL-21R and respond to IL-21 by activating STAT-3 and increasing their survival (32).…”

Siglec-G Deficiency Leads to Autoimmunity in Aging C57BL/6 Mice

“…We therefore conclude that our Siglec-G B6 2/2 mice were sufficiently backcrossed to B6 to exclude unspecific genetic background effects of the remaining 5.4% BALB/c genome. A hallmark of many autoimmune diseases is the occurrence of pathogenic autoantibodies produced by self-reactive plasma cells (39,40). In Siglec-G B6 2/2 and Siglec-G B6 2/2 3 FcgRIIb B6…”

Cerebrospinal Fluid Analysis in Immunoglobulin G4-related Hypertrophic Pachymeningitis

“…Qualitative studies evidenced 2 IgG oligoclonal bands (OCB) with 3 IgG4 OCB in the CSF of Patient 1 ( Figure 1B) and a single IgG OCB with 2 IgG4 OCB in the CSF of Patient 2; no corresponding bands were detected in the patients' sera. OCB are the expression of a CNS and CSF compartmentalization of a highly restricted number of antigen specific B-cell clones that were transformed, after affinity maturation, into Ig-secreting plasma cells 8,9 . Therefore, our results demonstrate that oligoclonally restricted IgG4-positive plasma cells residing in meningeal inflammatory niches are involved in the pathogenesis of IgG4-HP and support a pathogenetic model in which a fibroinflammatory immune reaction is initially triggered by a specific response against a still unknown antigen.…”