The Experts below are selected from a list of 222 Experts worldwide ranked by ideXlab platform
Nelson Leung - One of the best experts on this subject based on the ideXlab platform.
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Paraprotein related kidney disease diagnosing and treating monoclonal gammopathy of renal significance
Clinical Journal of The American Society of Nephrology, 2016Co-Authors: Mitchell H Rosner, Amaka Edeani, Motoko Yanagita, Ilya G Glezerman, Nelson LeungAbstract:Paraprotein–related kidney disease represents a complex group of diseases caused by an abnormal Paraprotein secreted by a clone of B cells. The disease manifestations range from tubulopathies, such as the Fanconi syndrome, to a spectrum of glomerular diseases that can present with varying degrees of proteinuria and renal dysfunction. Diagnosis of these diseases can be challenging because of the wide range of manifestations as well as the relatively common finding of a serum Paraprotein, especially in elderly patients. Thus, renal biopsy along with detailed hematologic workup is essential to link the presence of the Paraprotein to the associated renal disease. Recent advances in treatment with more effective and targeted chemotherapies, as well as stem cell transplantation, have improved the renal and overall prognosis for many of these disorders.
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the use of immunoglobulin light chain assays in the diagnosis of Paraprotein related kidney disease
Kidney International, 2015Co-Authors: Paul W Sanders, Nelson Leung, Punit Yadav, Paul CockwellAbstract:Kidney involvement is common in Paraprotein-related diseases. A diversity of clinical presentations and histopathological features can occur secondary to tissue injury caused by precipitation or deposition of a clonal immunoglobulin, usually an immunoglobulin light chain. The Paraprotein is either produced by multiple myeloma or by a clone of B-cell lineage that does not fulfill diagnostic criteria for multiple myeloma. The recent introduction of serum immunoglobulin free light chain assays, which accurately quantify both light chain isotypes to produce a ratio that indicates the presence or absence of a light chain Paraprotein, is a major clinical development. However, as the interpretation of the assay can be challenging, the aim of this review is to clarify the role of serum and urinary light chain assays in the screening and diagnosis of Paraprotein-related kidney disease.
Michael Pfreundschuh - One of the best experts on this subject based on the ideXlab platform.
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peripheral b cells from patients with mgus and multiple myeloma mm can be stimulated by Paraprotein target specific t helper cells to produce Paraprotein identical monoclonal antibodies rationale for pars a novel therapeutic approach with ultimate sp
Blood, 2015Co-Authors: Frank Neumann, Klaus Dieter Preuss, Boris Kubuschok, Claudia Schormann, Michael PfreundschuhAbstract:Background: Paratarg-7 (P-7) is the antigenic target of Paraproteins(Preuss et al. Int J Cancer 2009;125:656-61) from 15% of European and 37% of African-American MGUS/MM patients, stronlgy supporting a role of P-7 in the pathogenesis of MGUS/MM via chronic auto-antigenic stimulation. All patients with P-7 specific Paraproteins are carriers of the hyperphosphorylated version of p-7 (pP-7). We recently identified pP-7 specific T-helper cells which were restricted by certain "permissive" HLA-DR haplotypes (Neumann et al., Int J Cancer 2015; 137:1076-1084). These HLA-DR subtypes are overrepresented among patients with P-7 specific Paraproteins compared to the corresponding normal population indicating that there are two prerequisites for the development of MGUS/MM with a P-7 specific Paraprotein: 1st carriership of pP-7 and 2nd a permissive HLA-DR subtype. We now investigated the functional role of the pP-7 specific T-helper cells and their interaction with peripheral B cells with cognate specificity. Methods: Three patients with MGUS or MM, respectively, with a P-7 specific Paraprotein and pP-7 specific T-helper cells were included in this study so far. In addition, the B cells from one healthy pP-7 carrying son of one of the patients were also analyzed. In vitro stimulation of antigen-specific peripheral B cells by pP-7 specific T-helper cells followed a modified protocol previously described by Lanzavecchia et al. (Eur J Immunol. 1983; 13:733-738). To this end, CD19+ B cells and CD3+ T cells were magnetically isolated from the proband9s PBMC. T cells were replaced by corresponding T-helper cell clones. Results: In all patients studied, the autologous pP-7 specific T-helper cells stimulated the peripheral B cells to produce P-7 specific antibodies. The P-7 specific B-cell responses were monoclonal and the immunoglobulin type was the same as the Paraprotein of the corresponding patient. In contrast, B-cell stimulation with CMV-pp65 specific T-helper cells used as controls always induced an antigen-specific, yet polyclonal response. When the peripheral B cells of a pP-7 carrying patient9s son were also stimulated with pP-7 specific T-helper cells, they induced - in contrast to the mother - a polyclonal P-7 specific antibody response in his B cells, even though mother and son shared a "permissive" HLA-DR haplotype (HLA-DRB1*1301). Conclusion: In patients with MGUS/MM monoclonal B cells are found in the peripheral blood that can be induced to produce monoclonal antibodies identical to the serum Paraprotein by T-helper cells with specificity for the antigenic target of the Paraprotein. This does not only support an indispensable role of these T-helper cells in the pathogenesis of MGUS/MM via chronic antigenic stimulation, it also proves that precursors of the malignant plasma cells can be found in the peripheral blood that might fuel the development of malignant plasma cells. Cytogenetic and molecular genetic analyses are underway to determine if these precursor B-cells share the malignant genotype of their malignant plasma cells. These B cells can now be targeted by PARs (p araprotein a ntigens for r everse targeting) conjugated to toxins, as parts of bispecific constructs (PAR/CD3 or PAR/CD16) and/or PAR/CAR T cells. Use of PARs can be envisaged prophylactically for carriers of modified autoantigens like pP-7 with a permissive HLA-DR haplotype and a monoclonal B-cell response in vitro or in MM patients achieving a VGPR or CR after treatment for the prevention of relapse. Disclosures No relevant conflicts of interest to declare.
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inactivation of protein phosphatase 2a causing hyperphosphorylation of autoantigenic Paraprotein targets in mgus mm is due to an exchange of its regulatory subunits
International Journal of Cancer, 2014Co-Authors: Klaus Dieter Preuss, Natalie Fadle, Evi Regitz, Gerhard Held, Michael PfreundschuhAbstract:Hyperphosphorylated paratarg-7 (pP-7) carrier state is the strongest molecularly defined risk factor for monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM). pP-7 is inherited as autosomal-dominant trait and depending on the ethnic background is found in over one-third of MGUS/MM patients. P-7, which is the antigenic Paraprotein target in these patients, is hyperphosphorylated at serine17. P-7 hyperphosphorylation can be induced in wild-type P-7 (wtP-7) carriers by PKCζ and reverted by protein-phosphatase 2A (PP2A). Here we show that dephosphorylation of pP-7 is defective in pP-7 carriers due to inactivation of the PP2A by substitution of the regulatory B55δ subunit with B56γ3. In lymphoblastoid cell lines from pP-7 carriers, transfection of recombinant B55δ or treatment with ceramide led to a partial reconstitution of PP2A activity and dephosphorylation of pP-7 to wtP7. Similar results were observed with other previously reported autoantigenic Paraproteins targets. In conclusion, the mechanisms responsible for the defective dephosphorylation and maintaining the hyperphosphorylated state of P-7 and other autoantigenic Paraprotein targets have been elucidated, facilitating the identification of the genetic basis underlying this phenomenon which is obviously common in the pathogenesis of MGUS/MM/WM and not restricted to pP-7 cases.
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Hyperphosphorylation of autoantigenic targets of Paraproteins is due to inactivation of PP2A
Blood, 2011Co-Authors: Klaus Dieter Preuss, Natalie Fadle, Evi Regitz, Michael Pfreundschuh, Sybille Raudies, Niels Murwaski, Manfred Ahlgrimm, Joerg Thomas Bittenbring, Markus Klotz, Karl-herbert SchäferAbstract:Paratarg-7, a frequent autoantigenic target, and all other autoantigenic targets of human Paraproteins molecularly defined to date are hyperphosphorylated in the respective patients compared with healthy controls, suggesting that hyperphosphorylation of autoantigenic Paraprotein targets is a general mechanism underlying the pathogenesis of these Paraproteins. We now show that hyperphosphorylation of paratarg-7 occurs because of an additional phosphorylation of Ser17, which is located within the Paraprotein-binding epitope. Coimmunoprecipitation identified phosphokinase C ζ (PKCζ) as the kinase responsible for the phosphorylation of most, and phosphatase 2A (PP2A) as the phosphatase responsible for the dephosphorylation of all hyperphosphorylated autoantigenic targets of Paraproteins. Single-nucleotide polymorphisms (SNPs) or mutations of PKCζ and PP2A were excluded. However, PP2A was inactivated by phosphorylation of its catalytic subunit at Y307. Stimulation of T cells from healthy carriers of wild-type paratarg-7 induced a partial and transient hyperphosphorylation between days 4 and 18, which was maintained by incubation with inhibitors of PP2A, again indicating that an inactivation of PP2A is responsible for the hyperphosphorylation of autoantigenic Paraprotein targets. We conclude that the genetic defect underlying the dominantly inherited hyperphosphorylation of autoantigenic Paraprotein targets is not in the PP2A itself, but in genes or proteins controlling PP2A activity by phosphorylation of its catalytic subunit.
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association of a dominantly inherited hyperphosphorylated Paraprotein target with sporadic and familial multiple myeloma and monoclonal gammopathy of undetermined significance a case control study
Lancet Oncology, 2009Co-Authors: Sandra Grass, Klaus Dieter Preuss, Natalie Fadle, Evi Regitz, Manfred Ahlgrimm, Niels Murawski, C Pfoehler, Michael PfreundschuhAbstract:Summary Background Chronic antigenic stimulation might have a role in the pathogenesis of monoclonal gammopathy of unknown significance (MGUS) and multiple myeloma. The aim of this study was to search for factors underlying the autoimmunogenicity of paratarg-7, a frequent antigenic target of Paraproteins in MGUS and multiple myeloma. Methods Between January, 2005, and February, 2009, serum and peripheral blood cells were obtained from consecutive patients with MGUS or multiple myeloma and healthy blood donors, and paratarg-7 was analysed by DNA sequencing, SDS-PAGE, isoelectric focusing, and western blotting. Findings Mutations or polymorphisms of paratarg-7 were not noted, but hyperphosphorylation was detected in 35 (13·9%) of 252 patients with MGUS or multiple myeloma, all of whom had an anti-paratarg-7-specific Paraprotein. Analysis of eight families showed that hyperphosphorylated paratarg-7 is inherited in a dominant fashion, and that carriers of hyperphosphorylated paratarg-7 have an increased risk of developing MGUS and multiple myeloma (odds ratio [OR] 7·9, 95% CI 2·8–22·6; p=0·0001). Interpretation Familial MGUS and multiple myeloma were associated with a dominant inheritance of hyperphosphorylated paratarg-7, enabling family members at increased risk for MGUS or multiple myeloma to be identified. That only patients with MGUS or multiple myeloma who are carriers of hyperphosphorylated paratarg-7 had a paratarg-7-specific Paraprotein suggests that the hyperphosphorylation of paratarg-7 induces auto-immunity and is involved in the pathogenesis of MGUS and multiple myeloma; for example, by chronic antigenic stimulation. Funding Forderverein Krebsforschung Saar-Pfalz-Mosel e.V. (eingetragener Verein: officially registered charity) and HOMFOR (the research programme of the Saarland University Faculty of Medicine).
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A frequent target of Paraproteins in the sera of patients with multiple myeloma and MGUS
International Journal of Cancer, 2009Co-Authors: Klaus Dieter Preuss, Natalie Fadle, Evi Regitz, Michael Pfreundschuh, Manfred Ahlgrimm, Niels Murawski, Sandra GrassAbstract:Antigenic targets of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) Paraproteins might play a role in the pathogenesis of these neoplasms. We screened a human fetal brain-derived macroarray with the IgA or IgG containing sera of 192 consecutive MGUS and MM patients. Twenty-nine of 192 (15.1%) Paraproteins reacted with paratarg-7, a protein of unknown function which is expressed in all human tissues. Paratarg-7 reactivity was similarly frequent among IgA and IgG Paraproteins, but all paratarg-7 reactive IgG Paraproteins belonged to the IgG3 subtype with 24/57 IgG3 (42.1%) Paraproteins displaying this specificity. Sequence analysis of paratarg-7 derived from patients having a Paraprotein with specificity for paratarg-7 revealed no differences to paratarg-7 derived from patients with Paraproteins of other specificities or healthy controls, excluding mutations or polymorphisms as a reason for its autoimmunogenicity. Similarly, Western-blot analysis showed identical bands for paratarg-7 derived from patients and controls. The above-random frequency of paratarg-7 as a Paraprotein target suggests that paratarg-7 might be involved in the development of the respective clonal proliferations. The identification of paratarg-7 as an antigenic target enables the more detailed analysis of tumor–host interactions in these patients and their role in the pathogenesis of MM and MGUS. © 2009 UICC
Jeffrey L Medeiros - One of the best experts on this subject based on the ideXlab platform.
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chronic lymphocytic leukemia small lymphocytic lymphoma associated with igm Paraprotein a clinicopathologic study of 26 cases
American Journal of Clinical Pathology, 2005Co-Authors: Dennis A. Carney, Michael J. Keating, Beverly Carol Handy, George Z Rassidakis, Joan H Admirand, Jeffrey L MedeirosAbstract:We studied the clinicopathologic, immunophenotypic, and cytogenetic features of 26 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) associated with serum IgM Paraprotein. The study group (16 men; 10 women; median age, 64 years; range, 40-82 years) represents approximately 2.5% of CLL/SLL cases at our institution. The Paraprotein level ranged from 1 to 14 g/L (median, 4 g/L). Neoplasms in bone marrow were composed of small round lymphocytes arranged in nodular (n = 6), diffuse (n = 5), interstitial (n = 5), or mixed (n = 10) patterns. All cases were positive for monotypic surface immunoglobulin light chain, IgM/IgD, CD5, CD19, CD20, and CD23. CD11c (14/20 [70%]), CD79b (11/19 [58%]), FMC-7 (11/26 [42%]), CD22 (8/20 [40%]), and ZAP- 70 (6/19 [32%]) were expressed in subsets of cases. Of 17 bone marrow specimens assessed by conventional cytogenetics, 6 were abnormal and 11 were diploid. The overall survival of this group (median follow-up, 24 months) was not significantly different from that for an age-, sex-, and stage-matched group of 52 CLL/SLL patients without IgM Paraprotein (P =.60). We conclude that CLL/SLL cases with serum IgM Paraprotein are similar to other CLL/SLL cases in their clinicopathologic and immunophenotypic features.
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chronic lymphocytic leukemia small lymphocytic lymphoma associated with igm Paraprotein
American Journal of Clinical Pathology, 2005Co-Authors: Dennis A. Carney, Michael J. Keating, Beverly Carol Handy, George Z Rassidakis, Joan H Admirand, Jeffrey L MedeirosAbstract:We studied the clinicopathologic, immunophenotypic, and cytogenetic features of 26 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) associated with serum IgM Paraprotein. The study group (16 men; 10 women; median age, 64 years; range, 40–82 years) represents approximately 2.5% of CLL/SLL cases at our institution. The Paraprotein level ranged from 1 to 14 g/L (median, 4 g/L). Neoplasms in bone marrow were composed of small round lymphocytes arranged in nodular (n = 6), diffuse (n = 5), interstitial (n = 5), or mixed (n = 10) patterns. All cases were positive for monotypic surface immunoglobulin light chain, IgM/IgD, CD5, CD19, CD20, and CD23. CD11c (14/20 [70%]), CD79b (11/19 [58%]), FMC-7 (11/26 [42%]), CD22 (8/20 [40%]), and ZAP-70 (6/19 [32%]) were expressed in subsets of cases. Of 17 bone marrow specimens assessed by conventional cytogenetics, 6 were abnormal and 11 were diploid. The overall survival of this group (median follow-up, 24 months) was not significantly different from that for an age-, sex-, and stage-matched group of 52 CLL/SLL patients without IgM Paraprotein ( P = .60). We conclude that CLL/SLL cases with serum IgM Paraprotein are similar to other CLL/SLL cases in their clinicopathologic and immunophenotypic features.
Paul Cockwell - One of the best experts on this subject based on the ideXlab platform.
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the use of immunoglobulin light chain assays in the diagnosis of Paraprotein related kidney disease
Kidney International, 2015Co-Authors: Paul W Sanders, Nelson Leung, Punit Yadav, Paul CockwellAbstract:Kidney involvement is common in Paraprotein-related diseases. A diversity of clinical presentations and histopathological features can occur secondary to tissue injury caused by precipitation or deposition of a clonal immunoglobulin, usually an immunoglobulin light chain. The Paraprotein is either produced by multiple myeloma or by a clone of B-cell lineage that does not fulfill diagnostic criteria for multiple myeloma. The recent introduction of serum immunoglobulin free light chain assays, which accurately quantify both light chain isotypes to produce a ratio that indicates the presence or absence of a light chain Paraprotein, is a major clinical development. However, as the interpretation of the assay can be challenging, the aim of this review is to clarify the role of serum and urinary light chain assays in the screening and diagnosis of Paraprotein-related kidney disease.
Kevin W Finkel - One of the best experts on this subject based on the ideXlab platform.
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Paraprotein related kidney disease attack of the killer m proteins
Clinical Journal of The American Society of Nephrology, 2016Co-Authors: Mark A Perazella, Kevin W FinkelAbstract:Paraproteins are monoclonal Igs or their components (light or heavy chains) that are produced by a clonal population of mature B cells, most commonly plasma cells. These Paraproteins or monoclonal proteins are secreted into the blood and subsequently filtered by the glomerulus before entering into urine, where they can cause various types of kidney disease, including both glomerular and tubulointerstitial injuries. Furthermore, a monoclonal protein that causes a specific glomerular or tubulointerstitial lesion in a human can reproducibly cause the same pathology when injected into an animal, supporting unique Paraprotein characteristics. This Moving Points in Nephrology will provide an update for the Clinical Journal of the American Society of Nephrology readership on some of the clinically relevant kidney lesions associated with monoclonal Paraprotein production and the pathophysiology underlying these kidney lesions.
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Paraprotein–Related Kidney Disease: Attack of the Killer M Proteins
Clinical Journal of The American Society of Nephrology, 2016Co-Authors: Mark A Perazella, Kevin W FinkelAbstract:Paraproteins are monoclonal Igs or their components (light or heavy chains) that are produced by a clonal population of mature B cells, most commonly plasma cells. These Paraproteins or monoclonal proteins are secreted into the blood and subsequently filtered by the glomerulus before entering into urine, where they can cause various types of kidney disease, including both glomerular and tubulointerstitial injuries. Furthermore, a monoclonal protein that causes a specific glomerular or tubulointerstitial lesion in a human can reproducibly cause the same pathology when injected into an animal, supporting unique Paraprotein characteristics. This Moving Points in Nephrology will provide an update for the Clinical Journal of the American Society of Nephrology readership on some of the clinically relevant kidney lesions associated with monoclonal Paraprotein production and the pathophysiology underlying these kidney lesions.
