scholarly journals The Complexity and Heterogeneity of Monoclonal Immunoglobulin–Associated Renal Diseases

2018 ◽  
Vol 29 (7) ◽  
pp. 1810-1823 ◽  
Author(s):  
Sanjeev Sethi ◽  
S. Vincent Rajkumar ◽  
Vivette D. D’Agati
Keyword(s):  
Renal Disease ◽  
B Cell ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Organ Damage ◽  
Renal Tissue ◽  
Renal Diseases ◽  
Malignant Neoplasms ◽  
Cast Nephropathy

Monoclonal gammopathies are characterized by the overproduction of monoclonal Ig (MIg) detectable in the serum or urine resulting from a clonal proliferation of plasma cells or B lymphocytes. The underlying hematologic conditions range from malignant neoplasms of plasma cells or B lymphocytes, including multiple myeloma and B-cell lymphoproliferative disorders, to nonmalignant small clonal proliferations. The term MGUS implies presence of an MIg in the setting of a “benign” hematologic condition without renal or other end organ damage. The term MGRS was recently introduced to indicate monoclonal gammopathy with MIg-associated renal disease in the absence of hematologic malignancy. Most MIg-associated renal diseases result from the direct deposition of nephrotoxic MIg or its light- or heavy-chain fragments in various renal tissue compartments. Immunofluorescence microscopy is essential to identify the offending MIg and define its tissue distribution. Mass spectrometry is helpful in difficult cases. Conditions caused by direct tissue deposition of MIg include common disorders, such as cast nephropathy, amyloidosis, and MIg deposition diseases, as well as uncommon disorders, such as immunotactoid glomerulopathy, proliferative GN with MIg deposits, light-chain proximal tubulopathy, and the rare entities of crystal-storing histiocytosis and crystalglobulinemia. Indirect mechanisms of MIg-induced renal disease can cause C3 glomerulopathy or thrombotic microangiopathy without tissue MIg deposits. Treatment of MIg-associated renal disease is aimed at eliminating the clonal plasma cell or B-cell population as appropriate. Both the renal and the underlying hematologic disorders influence the management and prognosis of MIg-associated renal diseases.

scholarly journals B lymphocytes express and lose syndecan at specific stages of differentiation.

1989 ◽  
Vol 1 (1) ◽  
pp. 27-35 ◽  
Author(s):  
R D Sanderson ◽  
P Lalor ◽  
M Bernfield
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Receptor Expression ◽  
Cell Stage ◽  
Precursor B Cells

Lymphopoietic cells require interactions with bone marrow stroma for normal maturation and show changes in adhesion to matrix during their differentiation. Syndecan, a heparan sulfate-rich integral membrane proteoglycan, functions as a matrix receptor by binding cells to interstitial collagens, fibronectin, and thrombospondin. Therefore, we asked whether syndecan was present on the surface of lymphopoietic cells. In bone marrow, we find syndecan only on precursor B cells. Expression changes with pre-B cell maturation in the marrow and with B-lymphocyte differentiation to plasma cells in interstitial matrices. Syndecan on B cell precursors is more heterogeneous and slightly larger than on plasma cells. Syndecan 1) is lost immediately before maturation and release of B lymphocytes into the circulation, 2) is absent on circulating and peripheral B lymphocytes, and 3) is reexpressed upon their differentiation into immobilized plasma cells. Thus, syndecan is expressed only when and where B lymphocytes associate with extracellular matrix. These results indicate that B cells differentiating in vivo alter their matrix receptor expression and suggest a role for syndecan in B cell stage-specific adhesion.

My Patient with Monoclonal Gammopathy of Undetermined Significance has a Kidney Problem

2017 ◽  
Vol 1 (1) ◽  
pp. 18-23 ◽  
Author(s):  
Nelson Leung
Keyword(s):  
Kidney Disease ◽  
B Cell ◽  
Monoclonal Gammopathy ◽  
Lymphoproliferative Disorder ◽  
Kidney Diseases ◽  
Organ Damage ◽  
Renal Diseases ◽  
Premalignant Condition ◽  
Definition Of ◽  
Undetermined Significance

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition signifying the presence of a B-cell lymphoproliferative disorder. By connotation, it should not meet the definition of multiple myeloma, Waldenström macroglobulinemia, or lymphoma. In addition, it cannot be responsible for any end-organ damage. Similar to polyclonal immunoglobulins (Ig), monoclonal gammopathy has been increasingly recognized as an important cause of kidney disease. The recent introduction of the term “monoclonal gammopathy of renal significance” (MGRS) highlights this importance. MGRS is similar to MGUS in which the B-cell lymphoproliferative disorder has not reached a state considered to be malignant, but differentiates itself by the presence of a monoclonal gammopathy related kidney disease. This distinction is important since it separates MGRS, which is not benign, from the MGUS condition, which is benign. It also allows for a better classification of kidney diseases caused by monoclonal gammopathies. There are many renal diseases and lesions that have been identified to be secondary to MGRS. In addition, MGRS-associated renal diseases can mimic polyclonal Ig mediated kidney diseases. Kidney biopsy with immunofluorescence is the key for diagnosing MGRS-related kidney diseases. Once the diagnosis is made, a specific evaluation is needed for the diagnosis and treatment of MGRS-related kidney diseases that differs from the polyclonal Ig counterparts.

Evolution of a True B-Cell Chronic Lymphocytic Leukaemia (B-CLL) in a Diffuse Immunocytoma after Treatment with Fludarabine.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4973-4973
Author(s):  
Paolo Bernasconi ◽  
Marco Paulli ◽  
Ester Orlandi ◽  
Vittorio Perfetti ◽  
Ilaria Giardini ◽  
...  
Keyword(s):  
B Cell ◽  
B Lymphocytes ◽  
Cell Population ◽  
Plasma Cells ◽  
Opportunistic Infections ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Clonal Cell ◽  
Lp Cells

Abstract In B-CLL CD5, CD23 antigen-experienced B-cell are the neoplastic population. However, a small proportion of patients may present a monoclonal component (MC) and lymphoplasmacytoid (LP) cells, different from those CD5,CD23 negative of immunocytoma. Fludarabine, a very effective drug in the treatment of B-CLL and indolent lymphomas, may favour opportunistic infections and secondary cancers due to intense and prolonged immunosuppression. Herein we report on a 58-year old woman with night sweats and weakness. Physical examination revealed small peripheral lymphoadenopathies. WBC were 17.2x109/l; the marrow was infiltrated by 52% small mature lymphocytes presenting a monotypic kappa light chain restriction and CD5, CD19, CD20, CD23, CD38, ZAP70 antigens. Cytogenetics revealed a normal karyotype, whereas FISH detected 13q- in 48% nuclei. A diagnosis of B-CLL in Rai stage IA without any MC was made. The patient did not receive any treatment and nine months later developed multiple adenopathies and a progressive splenomegaly. WBC were 32.9x109/l; the marrow was infiltrated by 78% mature B lymphocytes and 5% LP cells sharing the original phenotype. Therefore a progression in Rai stage III had occurred and the patient started treatment with oral fludarabine (40mg/m2/day for 5 days, repeated every 4 weeks) which was well tolerated. A clinical response was achieved after fourth courses, with disappearance of adenopathies and splenomegaly, and normalization of peripheral blood. Few days later the patient complained of itching. Her blood tests revealed eosinophilia (42%), but twenty days later an IgG kappa MC (4,3g/dl) became apparent. Ten days later the patient was admitted to our ward because of liver, spleen and lymphonode enlargement and a doubled MC (10.9g/dl). The bone marrow was infiltrated by 60% mature B lymphocytes with the original phenotype and 20% plasma cells with cytoplasmic IgM and IgG, a monotypic restriction for kappa light chains, CD38, CD138, CD56 antigens. FISH showed that both cell populations presented a 13q- and the analysis of the CDRIII region detected only one clonal cell population with mutated Ig(V) genes. In addition a lymphonode biopsy showed a parafollicular and nodular pattern of infiltration by CD20+, CD79a+, CD5+, CD23 +/−, CD10- and Bcl1- B-cells, showing a trend towards differentiation in secreting elements, and by 18% prolymphocytes and paraimmunoblasts grouped in nodular aggregates. In conclusion, the lymphonode histology addressed to an immunocytoma in initial evolution in Richter’s syndrome. Our patient emphasizes the overlapping features between B-CLL and lymphoplasmacytoid lymphoma (LPL) since imunophenotypic, FISH, CDIII analysis demonstrated that the initial clonal cell population was able to undergo in vivo isotype switching to IgG, giving rise to LP elements and plasma cells producing high IgG levels. In addition, the correctness of the initial diagnosis is confirmed by the absence of t(9;14), a rearrangement typical of LPL, and the presence of 13q-, which prognostic impact in B-CLL with LP differentiation may be different than in typical B-CLL. The influence of fludarabine on the differentiation process remains unclear.

Acadesine Inhibits Proliferation and Induces Apoptosis In Multiple Myeloma Cells, and Synergizes with Standard of Care Antimyeloma Agents

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5023-5023
Author(s):  
Susana Hernández-García ◽  
Mercè de Frias ◽  
Clara Campàs ◽  
Bruno Paiva ◽  
Enrique M. Ocio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Cell Lines ◽  
Plasma Cells ◽  
Cell Lymphoma ◽  
Hematologic Malignancy ◽  
B Cell Lymphoma ◽  
In Vivo Studies ◽  
Mutational Status

Abstract Abstract 5023 Multiple myeloma (MM) is a malignancy characterized by the accumulation of plasma cells. The disease represents the second most common hematologic malignancy and remains incurable, despite recent advances in its treatment. Therefore, studies to develop new therapies are still necessary, particularly in patients with bad prognostic factors, such as 17p deleted/p53 mutated patients. In this study we describe the preclinical activity of 5-Aminoimidazole-4-carboxamide-1–4-ribofuranoside (AICAR or acadesine) in multiple myeloma. Acadesine is an analog of AMP that is widely used as an activator of AMP-kinase (AMPK), a protein that regulates the responses of the cell to energy changes. Acadesine induces apoptosis in different cell types including CLL, mantle cell lymphoma (MCL) and splenic marginal zone B-cell lymphoma (SMZL) cells and tumor cell lines, without affecting primary T lymphocytes. Thus, acadesine is a promising drug for the treatment of B-cell neoplasms. A clinical phase I/II study of acadesine is currently being performed in CLL patients. We studied the effects of acadesine on the MTT metabolization of several multiple myeloma cell lines (MM1S, MM1R, RPMI-8266, RPMI-LR5, U266, U266-LR7, U266 Dox4, MM144, MGG, SJR, OPM-2, NCIH-929). Acadesine inhibited MM cell growth and induced apoptosis, with IC50 values in the micromolar range, and independently of the p53 mutational status. Cancer treatment, including myeloma, is generally based on combinations of drugs with different mechanisms of action. Thus, we studied the effect of acadesine in double combinations with drugs used in myeloma therapy, such as dexamethasone, melphalan, doxorubicin, bortezomib, and lenalidomide. Analyses of these data using the Chou and Talalay method indicated that acadesine was synergistic with dexamethasone (CI values of 0.60), and particularly with lenalidomide (CI values of 0.42). These promising results with double combinations promoted the investigation of triple combinations in the MM1S cell line. Triple combination of acadesine plus dexamethasone plus lenalidomide or bortezomib notably improved the efficacy of the respective double combinations, being the combination of acadesine plus lenalidomide plus dexamethasone especially efficient. Further studies to determinate the mechanism of action, and in vivo studies in MM1S xenograph are ongoing. Disclosures: de Frias: Advancell: Employment. Campàs:Advancell: Employment.

scholarly journals Mast cells enhance proliferation of B lymphocytes and drive their differentiation toward IgA-secreting plasma cells

Blood ◽  
2010 ◽  
Vol 115 (14) ◽  
pp. 2810-2817 ◽  
Author(s):  
Sonia Merluzzi ◽  
Barbara Frossi ◽  
Giorgia Gri ◽  
Serena Parusso ◽  
Claudio Tripodo ◽  
...  
Keyword(s):  
B Cells ◽  
Mast Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Close Contact ◽  
Spatial Interaction ◽  
Significant Inhibition ◽  
Cell Contact

Abstract The evidence of a tight spatial interaction between mast cells (MCs) and B lymphocytes in secondary lymphoid organs, along with the data regarding the abundance of MCs in several B-cell lymphoproliferative disorders prompted us to investigate whether MCs could affect the proliferation and differentiation of B cells. To this aim, we performed coculture assays using mouse splenic B cells and bone marrow–derived MCs. Both nonsensitized and activated MCs proved able to induce a significant inhibition of cell death and an increase in proliferation of naive B cells. Such proliferation was further enhanced in activated B cells. This effect relied on cell-cell contact and MC-derived interleukin-6 (IL-6). Activated MCs could regulate CD40 surface expression on unstimulated B cells and the interaction between CD40 with CD40 ligand (CD40L) on MCs, together with MC-derived cytokines, was involved in the differentiation of B cells into CD138+ plasma cells and in selective immunoglobulin A (IgA) secretion. These data were corroborated by in vivo evidence of infiltrating MCs in close contact with IgA-expressing plasma cells within inflamed tissues. In conclusion, we reported here a novel role for MCs in sustaining B-cell expansion and driving the development of IgA-oriented humoral immune responses.

scholarly journals Occurrence of cytochrome b558 in B-cell lineage of human lymphocytes

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 458-461
Author(s):  
S Kobayashi ◽  
S Imajoh-Ohmi ◽  
M Nakamura ◽  
S Kanegasaki
Keyword(s):  
B Cells ◽  
Cell Surface ◽  
B Cell ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Human Lymphocytes ◽  
Cell Lineage ◽  
Superoxide Generation ◽  
Cell Stage ◽  
Cytochrome B558

Cytochrome b558, involved in superoxide generation in phagocytes, was found to be expressed on the cell surface of most normal peripheral B lymphocytes. The cytochrome was not found on the surface of peripheral T lymphocytes, natural killer cells, or peripheral lymphocytes derived from patients with X-linked chronic granulomatous disease. On stimulation, at least half of peripheral B lymphocytes could generate superoxide anion as detected by superoxide dismutase-sensitive nitroblue tetrazorium reduction. Cytochrome b558 was not present on the surface of pre-pre B cells or pre-B cells, but did appear at the early B-cell stage. It disappeared from the B-cell surface during terminal differentiation to plasma cells. The transient expression of the cytochrome in B-cell lineage may indicate that superoxide generation is important for the function of these cells at certain stages.

scholarly journals Predictors of hospitalisation and death due to SARS-CoV-2 infection in Finland: a population-based register study with implications to vaccinations

2021 ◽  
Author(s):  
Heini Salo ◽  
Toni Lehtonen ◽  
Kari Auranen ◽  
Ulrike Baum ◽  
Tuija Leino
Keyword(s):  
Renal Disease ◽  
Negative Binomial ◽  
Chronic Renal Disease ◽  
Hematologic Malignancy ◽  
Negative Binomial Regression ◽  
Population Based ◽  
Register Study ◽  
Malignant Neoplasms ◽  
Intensive Care Treatment ◽  
Cell Transplant

Abstract Introduction. The aim of this study was to investigate how age and underlying medical conditions affect the risk of severe outcomes following SARS-CoV-2 infection and how they should be weighed while prioritising vaccinations against COVID-19. Methods. This population-based register study includes all SARS-CoV-2 PCR-test-positive cases until 24 Feb 2021, based on the Finnish National Infectious Diseases Register. The cases were linked to other registers to identify presence of comorbidities and severe outcomes (hospitalisation, intensive care treatment, death). The odds of severe outcomes were compared in those with and without the pre-specified comorbidities using logistic regression. Furthermore, population-based rates were compared between those with a given comorbidity and those without any of the specified comorbidities using negative binomial regression. Results. Age and various comorbidities were found to be predictors of severe COVID-19. Compared to 60–69-year-olds, the odds ratio (OR) of death was 7.1 for 70–79-year-olds, 26.7 for 80–89-year-olds, and 55.8 for 90-year-olds and over. Among the 20–69-year-olds, chronic renal disease (OR 9.4), malignant neoplasms (5.8), hematologic malignancy (5.6), chronic pulmonary disease (5.4), and cerebral palsy or other paralytic syndromes (4.6) were strongly associated with COVID-19 mortality; severe disorders of the immune system (8.0), organ or stem cell transplant (7.2), chronic renal disease (6.7), and diseases of myoneural junction and muscle (5.5) were strongly associated with COVID-19 hospitalisation. Type 2 diabetes and asthma, two very common comorbidities, were associated with all three outcomes, with ORs from 2.1 to 4.3. The population-based rate of SARS-CoV-2 infection decreased with age. Taking the 60–69-year-olds as reference, the rate ratio was highest (3.0) for 20–29-year-olds but under 1 for 70–79-year-olds and 80–89-year-olds. Conclusion. Comorbidities predispose for severe COVID-19 among younger ages. In vaccine prioritisation both the risk of infection and the risk of severe outcomes, if infected, should be combined.

scholarly journals Immunotherapeutic strategies targeting B cell maturation antigen in multiple myeloma

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Yi Fang ◽  
Jian Hou
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Plasma Cells ◽  
Residual Disease ◽  
Hematologic Malignancy ◽  
Therapeutic Strategies ◽  
Cell Maturation ◽  
B Cell Maturation ◽  
Clone Evolution ◽  
B Cell Maturation Antigen

AbstractMultiple myeloma (MM) is the second most common hematologic malignancy, and is characterized by the clonal expansion of malignant plasma cells. Despite the recent improvement in patient outcome due to the use of novel therapeutic agents and stem cell transplantation, all patients eventually relapse due to clone evolution. B cell maturation antigen (BCMA) is highly expressed in and specific for MM cells, and has been implicated in the pathogenesis as well as treatment development for MM. In this review, we will summarize representative anti-BCMA immune therapeutic strategies, including BCMA-targeted vaccines, anti-BCMA antibodies and BCMA-targeted CAR cells. Combination of different immunotherapeutic strategies of targeting BCMA, multi-target immune therapeutic strategies, and adding immune modulatory agents to normalize anti-MM immune system in minimal residual disease (MRD) negative patients, will also be discussed.

Induction and regulation ofTrypanosoma bruceiVSG-specific antibody responses

Parasitology ◽  
2009 ◽  
Vol 137 (14) ◽  
pp. 2041-2049 ◽  
Author(s):  
S. J. BLACK ◽  
P. GUIRNALDA ◽  
D. FRENKEL ◽  
C. HAYNES ◽  
V. BOCKSTAL
Keyword(s):  
B Cell ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Surface Glycoprotein ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Variable Surface ◽  
Underlying Causes ◽  
Specific Receptors ◽  
The Impact

SUMMARYThe review addresses how infection withTrypanosoma bruceiaffects the development, survival and functions of B lymphocytes in mice. It discusses (1) the contributions of antibodies to trypanosome clearance from the bloodstream, (2) how B lymphocytes, the precursors of antibody producing plasma cells, interact with membrane form variable surface glycoprotein (VSG), i.e. with monovalent antigen that is free to diffuse within the lipid bilayer of the trypanosome plasma membrane and consequently can cross-link B cell antigen specific receptors by indirect processes only and (3) the extent and underlying causes of dysregulation of humoral immune responses in infected mice, focusing on the impact of wild type and GPI-PLC−/−trypanosomes on bone marrow and extramedullary B lymphopoiesis, B cell maturation and survival.

scholarly journals Evidence for a bone marrow B cell transcribing malignant plasma cell VDJ joined to C mu sequence in immunoglobulin (IgG)- and IgA-secreting multiple myelomas.

1993 ◽  
Vol 178 (3) ◽  
pp. 1091-1096 ◽  
Author(s):  
P Corradini ◽  
M Boccadoro ◽  
C Voena ◽  
A Pileri
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Bone Marrow Cells ◽  
Indirect Evidence ◽  
Specific Marker

Multiple myeloma is a B cell malignancy characterized by the expansion of plasma cells producing monoclonal immunoglobulins (Ig). It has been regarded as a tumor arising at the B, pre-B lymphocyte, or even stem cell level. Precursor cells are presumed to proliferate and differentiate giving rise to the plasma cell clonal expansion. Antigenic features and specific Ig gene rearrangement shared by B lymphocytes and myeloma cells have supported this hypothesis. However, the existence of such a precursor is based upon indirect evidence and is still an open question. During differentiation, B cells rearrange variable (V) regions of Ig heavy chain genes, providing a specific marker of clonality. Using an anchor polymerase chain reaction assay, these rearranged regions from five patients with multiple myeloma were cloned and sequenced. The switch of the Ig constant (C) region was used to define the B cell differentiation stage: V regions are linked to C mu genes in pre-B and B lymphocytes (pre-switch B cells), but to C gamma or C alpha in post-switch B lymphocytes and plasma cells (post-switch B cells). Analysis of bone marrow cells at diagnosis revealed the presence of pre-switch B cells bearing plasma cell V regions still joined to the C mu gene. These cells were not identified in peripheral blood, where tumor post-switch B cells were detected. These pre-switch B cells may be regarded as potential myeloma cell precursors.

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