Plasma cells

Antiplatelet-antibody-producing B cells play a key role in immune thrombocytopenia (ITP) pathogenesis; however, little is known about T-cell dysregulations that support B-cell differentiation. During the past decade, T follicular helper cells (TFHs) have been characterized as the main T-cell subset within secondary lymphoid organs that promotes B-cell differentiation leading to antibody class-switch recombination and secretion. Herein, we characterized TFHs within the spleen of 8 controls and 13 ITP patients. We show that human splenic TFHs are the main producers of interleukin (IL)-21, express CD40 ligand (CD154), and are located within the germinal center of secondary follicles. Compared with controls, splenic TFH frequency is higher in ITP patients and correlates with germinal center and plasma cell percentages that are also increased. In vitro, IL-21 stimulation combined with an anti-CD40 agonist antibody led to the differentiation of splenic B cells into plasma cells and to the...

Mantle cell lymphoma is a mature lymphoid neoplasm characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. SOX11 is a transcription factor commonly overexpressed in these tumors but absent in most other mature B-cell lymphomas whose function is not well understood. Experimental studies have shown that silencing of SOX11 in mantle cell lymphoma cells promotes the shift from a mature B cell into an early plasmacytic differentiation phenotype, suggesting that SOX11 may contribute to tumor development by blocking the B-cell differentiation program. The relationship between SOX11 expression and terminal B-cell differentiation in primary mantle cell lymphoma and its relationship to the plasmacytic differentiation observed in occasional cases is not known. In this study we have investigated the terminal B-cell differentiation phenotype in 60 mantle cell lymphomas, 41 SOX11-positive and 19 SOX11-negative. Monotypic plasma cells and lymphoid cells with plasmacytic differentiatio...

Our previous work has shown that antigens adjuvanted with specific ligands for toll-like receptor 4 (TLR4) and TLR7/8 encapsulated in poly (lactic-co-glycolic acid) (PLGA) based nanoparticles (NP), induced robust and durable immune responses in mice and macaques. We investigated the efficacy of these NP adjuvants in inducing protective immunity against simian immunodeficiency virus (SIV). Rhesus macaques (RMs) were immunized with NP containing TLR4 and TLR7/8 agonists mixed with soluble recombinant SIVmac239 derived envelope (Env) gp140 and Gag p55 (Protein), or with virus like particles (VLP) containing SIVmac239 Env and Gag. NP adjuvanted vaccines induced robust innate responses, a greater magnitude and persistence of antigen specific antibody responses, and enhanced plasmablast responses, compared to Alum adjuvanted vaccines. NP adjuvanted vaccines induced antigen specific, long-lived plasma cells (LLPCs), which persisted in the bone marrow for several months after vaccination. N...

While analyzing the DNA methylome of multiple myeloma (MM), a plasma cell neoplasm, by whole-genome bisulfite sequencing and high-density arrays, we observed a highly heterogeneous pattern globally characterized by regional DNA hypermethylation embedded in extensive hypomethylation. In contrast to the widely reported DNA hypermethylation of promoter-associated CpG islands (CGIs) in cancer, hypermethylated sites in MM, as opposed to normal plasma cells, were located outside CpG islands and were unexpectedly associated with intronic enhancer regions defined in normal B cells and plasma cells. Both RNA-seq and in vitro reporter assays indicated that enhancer hypermethylation is globally associated with down-regulation of its host genes. ChIP-seq and DNase-seq further revealed that DNA hypermethylation in these regions is related to enhancer decommissioning. Hypermethylated enhancer regions overlapped with binding sites of B cell-specific transcription factors (TFs) and the degree of en...

We describe the cloning and characterization of Siglec-H, a novel murine CD33-related siglec-like molecule with 2 immunoglobulin domains. Unlike other CD33-related siglecs, Siglec-H lacks tyrosine-based signaling motifs in its cytoplasmic tail. Although Siglec-H has the typical structural features required for sialic acid binding, no evidence for carbohydrate recognition was obtained. Specific monoclonal and polyclonal antibodies (Abs) were raised to Siglec-H and used to define its cellular expression pattern and functional properties. By flow cytometry, Siglec-H was expressed specifically on plasmacytoid dendritic cell (pDC) precursors in bone marrow, spleen, blood, and lymph nodes. Staining of tissue sections showed that Siglec-H was also expressed in a subset of marginal zone macrophages in the spleen and in medullary macrophages in lymph nodes. Using bone marrow-derived pDC precursors that express Siglec-H, addition of Abs did not influence cytokine production, either in the pre...

Ultrastructural studies indicate that galactoflavin-induced riboflavin deficiency induces asynchrony of rat erythroblast maturation. During the latter stages of maturation erythroblasts retain significantly larger numbers of ribosomes as compared to control cells. Nucleoli are not evident in erythroblasts whose nuclei indicate cells in the latter stages of development. Membrane whorls develop within the mitochondria of plasma cells, eosinophils and neutrophils during the fifth week of riboflavin deficiency. No further evidence of degeneration was noted among additional cell organelles.

Our purpose in this paper is to make a case for the need to question whether Riedel's thyroiditis is in fact a rare variety of subacute thyroiditis. Total thyroidectomy was performed on a patient with a huge thyroid mass. The histopathological diagnosis was Riedel's thyroiditis with classical lymphoplasmacytic infiltration destroying thyroid tissue and invading perithyroidal soft tissue. However, in addition, histopathology showed epithelioid granulomas containing multinuclear giant cells. The existence of these giant cells led us to place this case somewhere between Hashimoto's thyroiditis and subacute thyroiditis (de Quervain's). Since giant cells are seen in the histopathology of subacute thyroiditis, we propose that the possibility of Riedel's thyroiditis being a form of subacute thyroiditis be observed and studied.

Castleman's disease (CD) is a group of rare lymphoproliferative disorders sharing characteristic clinical and histological features, and usually accompanied by a marked systemic inflammatory response. Two histological patterns of lymph nodes were described: the hyaline-vascular and plasma-cell types. The former is more common (80-90%) and tends to be localized. The plasma cell type is more aggressive and usually multicentric. It is interesting that the inflammatory manifestations seem to be related to a lymph node lesion, because the systemic symptoms and inflammatory activity can return to normal after surgical excision or successful medical treatment of the disease. We report here our 15-year experience with this rare disease in King Fahd Hospital of the University, Al-Khobar, Saudi Arabia, focusing on the clinical features, therapy, and patients'outcome.

Rats of inbred DA strain were given 20 intraperitoneal injections of typhoid-paratyphoid bacilli at 10 day intervals. Thymic lymph follicles with germinal centres were formed in females but not in males. However, orchidectomy permitted the formation of large numbers of thymic lymph follicles with germinal centres in males. The formation of lymph follicles with germinal centres in the thymus was not affected by ovariectomy. These results would appear to suggest an inhibitory role of androgens on the formation of thymic lymph follicles with germinal centres. In addition, large numbers of plasma cells, mast cells, and reticular cells, or macrophages with haemosiderin in their cytoplasm, appeared in the parenchma of the thymus in close association with the formation of thymic germinal centres.

Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells in the bone marrow (BM). Despite the significant advances in treatment, MM is still a fatal malignancy. This is mainly due to the supportive role of the BM microenvironment in differentiation, migration, proliferation, survival, and drug resistance of the malignant plasma cells. The BM microenvironment is composed of a cellular compartment (stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells) and a non-cellular compartment. In this review, we discuss the interaction between the malignant plasma cell and the BM microenvironment and the strategy to target them.

Long-lived plasma cells (LLPCs) develop under the help of follicular helper T (Tfh) cells and reside mainly in the bone marrow. However, these cells are unusually abundant in the spleen of several autoimmune models including K/BxNsf mice, yet their pathogenic impact remains unknown. To investigate a previously unappreciated role of splenic LLPCs, we sorted splenic plasma cells (PCs) from K/BxNsf and K/BxN mice, corresponding to LLPCs and conventional short-lived PCs, respectively, and compared their phenotypes and ability to prime and induce the differentiation of naive CD4(+) T cells into effector cells in vitro and in vivo. We found that K/BxNsf PCs had lower levels of the Ag presentation machinery and costimulators than K/BxN PCs, and also a lower CD4(+) T cell priming capacity. Autoantigen-pulsed K/BxNsf PCs selectively polarized cognate CD4(+) T cells toward the expression of molecules necessary for Tfh development and function. As a result, the K/BxNsf PC-primed CD4(+) T cells...

Ox40 ligand (Ox40L) locus genetic variants are associated with the risk for systemic lupus erythematosus (SLE); however, it is unclear how Ox40L contributes to SLE pathogenesis. In this study, we evaluated the contribution of Ox40L and its cognate receptor, Ox40, using in vivo agonist and antagonist approaches in the NZB × NZW (NZB/W) F1 mouse model of SLE. Ox40 was highly expressed on several CD4 Th cell subsets in the spleen and kidney of diseased mice, and expression correlated with disease severity. Treatment of aged NZB/W F1 mice with agonist anti-Ox40 mAbs potently exacerbated renal disease, which was accompanied by activation of kidney-infiltrating T cells and cytokine production. The agonist mAbs also induced activation and inflammatory gene expression in splenic CD4 T cells, including IFN-regulated genes, increased the number of follicular helper T cells and plasmablasts in the spleen, and led to elevated levels of serum IgM and enhanced renal glomerular IgM deposition. In ...

We report a case of successful diagnosis of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome based on monoclonality that was confirmed by an osteosclerotic lesion biopsy in a patient without pathognomonic symptoms or monoclonal gammopathy, probably because of comorbidities, which included systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome. A 57-year-old woman presented with an approximately 2-year history of numbness in the toes that had gradually spread, along with muscle weakness in both arms and legs. She had been receiving immunosuppressant and corticosteroid therapy since being diagnosed with systemic lupus erythematosus and Sjögren syndrome at the age of 31 years and rheumatoid arthritis at the age of 44 years. Neurological examination revealed predominantly distal hypoesthesia and weakness in a typical stocking-and-glove pattern. Immunoelectrophoresis revealed elevated polyclonal immunoglobulin, which...

Idiopathic granulomatous mastitis (IGM) is a benign, frequently severe chronic inflammatory lesion of the breast. Its etiology remains unknown and reported cases vary in their presentation and histologic findings with an optimal treatment algorithm yet to be described owing mainly to the disease's heterogeneity. IgG4-related disease (IgG4-RD) is a newly recognized systemic fibroinflammatory condition characterized by a dense lymphoplasmacytic infiltrate with many IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Immunosuppressive therapy is considered to be an effective first-line therapy for IgG4-RD. We sought to clarify and classify chronic mastitis according to the histologic findings of IgG4-RD mastitis with respect to IGM and to develop a robust diagnostic framework to help select patients for optimal treatment strategies. Using the largest collection to date (43 cases from Egypt and Morocco), we show that despite sharing many features, IGM and IgG...

B cells, as an important part of the humoral immune response, are generated in the BM, migrate to secondary lymphoid organs, and upon activation, differentiate into antibody-producing memory B cells or plasma cells. Despite the pivotal roles that they play in different diseases, a comprehensive characterization in healthy rhesus macaques, which serve as valuable models for a variety of human diseases, is still missing. With the use of multiparameter flow cytometry, we analyzed B cells in BM collected from two locations, i.e., the iliac crest (BMca) and the femur (BMfem), PB, as well as secondary lymphoid organs of healthy rhesus macaques. We assessed the frequencies of immature and mature B cells, as well as CD19(+) CD20(-) CD38(+/++) CD138(+/++) plasmablasts/plasma cells. Furthermore, we found site-specific differences in the expression of markers for B cell activation and proliferation, chemokine receptors and Igs, as well as the distribution of memory B cell subpopulations. As se...

Aberrant expression of genes regulating apoptosis/survival seems to be essential in the stepwise development of human multiple myeloma (MM). In this paper we have compared the expression of bcl-2 family pro- and anti-apoptotic genes in MM cell lines, primary MM cells and normal plasma cells. The Bcl-2, Mcl-1, Bcl-xL/S, Bcl-w, Bax, Bak, and Bad were shown to be expressed in both malignant and non-neoplastic, normal plasma cells. Quantitative analysis revealed that the malignant phenotype seemed to correlate with an elevated expression of Mcl-1, a decreased expression of Bax and, to a lesser extent, an increased Bcl-2/Bax expression ratio. The possible influence of interleukin-6 (IL-6) in regulating the expression of the bcl-2-related genes was also examined. Using the IL-6-dependent MM cell lines U-1958 and U-266-1970 it was clearly shown that IL-6 deprivation induced cell cycle arrest in both cell lines, whereas apoptosis was only detected in the U-1958 cells. Furthermore, the anti-...