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Frontiers in Immunology 2023The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological... (Review)
Review
The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological ecosystem. Most of the diversity is generated by two mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM introduces changes in the variable domain of antibodies, mostly in the regions that form the paratope, yielding antibodies with higher antigen binding affinity. However, antigen recognition is only possible if the antibody folds into a stable functional conformation. Therefore, a key force determining the survival of B cell clones undergoing somatic hypermutation is the ability of the mutated heavy and light chains to efficiently fold and assemble into a functional antibody. The antibody is the structural context where the selection of the somatic mutations occurs, and where both the heavy and light chains benefit from protective mechanisms that counteract the potentially deleterious impact of the changes. However, in patients with monoclonal gammopathies, the proliferating plasma cell clone may overproduce the light chain, which is then secreted into the bloodstream. This places the light chain out of the protective context provided by the quaternary structure of the antibody, increasing the risk of misfolding and aggregation due to destabilizing somatic mutations. Light chain-derived (AL) amyloidosis, light chain deposition disease (LCDD), Fanconi syndrome, and myeloma (cast) nephropathy are a diverse group of diseases derived from the pathologic aggregation of light chains, in which somatic mutations are recognized to play a role. In this review, we address the mechanisms by which somatic mutations promote the misfolding and pathological aggregation of the light chains, with an emphasis on AL amyloidosis. We also analyze the contribution of the variable domain (V) gene segments and somatic mutations on light chain cytotoxicity, organ tropism, and structure of the AL fibrils. Finally, we analyze the most recent advances in the development of computational algorithms to predict the role of somatic mutations in the cardiotoxicity of amyloidogenic light chains and discuss the challenges and perspectives that this approach faces.
Topics: Animals; Humans; Multiple Myeloma; Friends; Ecosystem; B-Lymphocytes; Paraproteinemias
PubMed: 37520549
DOI: 10.3389/fimmu.2023.1203425 -
Acta Medica Portuguesa May 2021Monoclonal gammopathy of renal significance (MGRS) is described as a hematologic condition characterized by nephrotoxicmonoclonal proteins produced by a non-malignant... (Review)
Review
INTRODUCTION
Monoclonal gammopathy of renal significance (MGRS) is described as a hematologic condition characterized by nephrotoxicmonoclonal proteins produced by a non-malignant B-cell or plasma cell clone. Nevertheless, MGRS can cause serious renal lesions, leading to high morbidity. In C3 glomerulonephritis, a monoclonal protein can cause renal damage indirectly. Acting as an autoantibody, the protein cannot be detected in the kidney biopsy, promoting the dysregulation of the alternative pathway of the complement system.
MATERIAL AND METHODS
This non-systematic review was based on a comprehensive search in databases and scientific journals, such as PubMed, Nature Reviews Nephrology and Kidney International, including the terms 'C3 Glomerulonephritis' and 'Monoclonal gammopathy of renal significance'. We review the pathophysiology, presentation, diagnosis, differential diagnosis and treatment of C3 glomerulonephritis associated with MGRS.
DISCUSSION
With the increasing understanding of the complex interaction between monoclonal gammopathy and renal damage, such as C3 glomerulonephritis, it becomes clear that an early recognition is crucial, as Ig-directed therapy might improve outcomes. In this context, and in order to maximize the chance of a correct diagnosis, renal biopsy is mandatory to determine the exact nature of the lesion, and the severity of renal disease. Conclusion: It is important to make an early diagnosis of MGRS-associated C3 glomerulonephritis in order to prevent not only the progression to a hematological malignancy, but also end-stage renal disease.
Topics: Autoantibodies; Glomerulonephritis; Humans; Hypergammaglobulinemia; Kidney; Kidney Diseases; Monoclonal Gammopathy of Undetermined Significance; Paraproteinemias
PubMed: 33819437
DOI: 10.20344/amp.13823 -
Blood Cancer Journal Oct 2017Multiparameter flow cytometry (MFC) has become standard in the management of patients with plasma cell (PC) dyscrasias, and could be considered mandatory in specific... (Review)
Review
Multiparameter flow cytometry (MFC) has become standard in the management of patients with plasma cell (PC) dyscrasias, and could be considered mandatory in specific areas of routine clinical practice. It plays a significant role during the differential diagnostic work-up because of its fast and conclusive readout of PC clonality, and simultaneously provides prognostic information in most monoclonal gammopathies. Recent advances in the treatment and outcomes of multiple myeloma led to the implementation of new response criteria, including minimal residual disease (MRD) status as one of the most relevant clinical endpoints with the potential to act as surrogate for survival. Recent technical progress led to the development of next-generation flow (NGF) cytometry that represents a validated, highly sensitive, cost-effective and widely available technique for standardized MRD evaluation, which also could be used for the detection of circulating tumor cells. Here we review current applications of MFC and NGF in most PC disorders including the less frequent solitary plasmocytoma, light-chain amyloidosis or Waldenström macroglobulinemia.
Topics: Flow Cytometry; Humans; Paraproteinemias
PubMed: 29053157
DOI: 10.1038/bcj.2017.90 -
Clinical Chemistry and Laboratory... Jun 2016
Topics: Blood Protein Electrophoresis; Humans; Immunoassay; Immunoelectrophoresis; Immunoglobulin Light Chains; Multiple Myeloma; Myeloma Proteins; Paraproteinemias; Practice Guidelines as Topic
PubMed: 27107838
DOI: 10.1515/cclm-2016-0268 -
Frontiers in Endocrinology 2023
Topics: Humans; Paraproteinemias
PubMed: 36733528
DOI: 10.3389/fendo.2023.1107283 -
Tidsskrift For Den Norske Laegeforening... Sep 2021Monoclonal gammopathy is a frequent finding and may be associated with severe cancer such as myelomatosis and other B-cell lymphoproliferative disorders. However, the...
Monoclonal gammopathy is a frequent finding and may be associated with severe cancer such as myelomatosis and other B-cell lymphoproliferative disorders. However, the monoclonal component can also be the direct cause of serious disease, namely monoclonal gammopathy of clinical significance (MGCS). MGCS is most likely significantly underdiagnosed and is consequently also undertreated. In order to achieve a good therapeutic outcome, it is crucial that the condition is recognised at an early stage, so that treatment can be initiated before the patient has developed irreversible organ damage. Increased awareness of MCGS is therefore essential.
Topics: Humans; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Paraproteinemias
PubMed: 34596996
DOI: 10.4045/tidsskr.20.0981 -
Clinical Journal of the American... Apr 2022Patients with monoclonal gammopathy and concomitant kidney diseases are frequently found in clinical practice. Some of them are diagnosed with monoclonal gammopathy of...
BACKGROUND AND OBJECTIVES
Patients with monoclonal gammopathy and concomitant kidney diseases are frequently found in clinical practice. Some of them are diagnosed with monoclonal gammopathy of renal significance (MGRS) due to the presence of monoclonal Ig-related kidney injuries. This study aimed to investigate the histopathologic spectrum and clinical characteristics associated with MGRS in a large cohort of patients with monoclonal gammopathy and biopsy-proven kidney diseases from a single Chinese nephrology referral center.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Patients who presented with monoclonal gammopathy (monoclonal spike on serum and/or urine immunofixation tests) and underwent kidney biopsy in the Peking University First Hospital from January 1, 1999 to December 31, 2020 were enrolled in this retrospective study. Patients with malignant hematologic diseases were excluded. Clinical and laboratory data were collected from the electronic medical record system. Comparisons of patients with and without MGRS and with and without amyloidosis were performed. The clinical characteristics associated with MGRS were identified using multivariable logistic regression.
RESULTS
A total of 700 patients with monoclonal gammopathy and kidney biopsy were identified. Thirteen patients with repeat kidney biopsies were analyzed separately. For the remaining 687 patients with one kidney biopsy, 261 patients (38%) had MGRS lesions, and the rest (426 patients, 62%) had non-MGRS kidney diseases. Ig-related amyloidosis accounted for the most MGRS cases (=164, 63%), followed by monoclonal Ig deposition disease (=23, 9%) and thrombotic microangiopathy (=22, 8%). In the non-MGRS group, membranous nephropathy was the most common diagnosis (=171, 40%). In the multivariable logistic regression model, the presence of abnormal serum free light chain ratio, older age, and greater proteinuria were independently associated with MGRS.
CONCLUSIONS
Monoclonal Ig amyloidosis is the leading cause of MGRS in Chinese patients with monoclonal gammopathy. The presence of abnormal free light chain ratio, older age, and greater proteinuria were associated with MGRS.
Topics: Amyloidosis; Humans; Immunoglobulin Light Chains; Kidney; Kidney Diseases; Monoclonal Gammopathy of Undetermined Significance; Paraproteinemias; Proteinuria; Retrospective Studies
PubMed: 35210280
DOI: 10.2215/CJN.12890921 -
Veterinary Clinical Pathology Oct 2019Protein electrophoresis and immunotyping can be a useful adjunct to the standard biochemical techniques for characterizing serum and urine proteins. This paper reviews... (Review)
Review
Protein electrophoresis and immunotyping can be a useful adjunct to the standard biochemical techniques for characterizing serum and urine proteins. This paper reviews currently available and commonly used methods for diagnostic protein electrophoresis, including both agarose gel and capillary zone electrophoretic techniques and total protein assessments. Immunofixation and immunosubtraction methods for identification of immunoglobulin location and class are also presented. Practical application of quality assurance and quality control strategies in compliance with American Society of Veterinary Clinical Pathology (ASVCP) best practices are discussed. Commonly encountered serum and urine electrophoretic diagnostic patterns, including electrophoretically normal, acute-phase protein responses, polyclonal gammopathies, restricted polyclonal/oligoclonal gammopathies, paraproteinemias (monoclonal or biclonal gammopathies), and Bence-Jones proteinurias are also reviewed using relevant case material. Cases in which immunofixation electrophoresis are particularly useful are highlighted, and methodologies to more accurately quantify serum monoclonal proteins (M-proteins), monitoring tests commonly used in human medicine, are discussed.
Topics: Animals; Blood Proteins; Cat Diseases; Cats; Dog Diseases; Dogs; Electrophoresis, Capillary; Immunoelectrophoresis; Immunoglobulins; Paraproteinemias; Pathology, Clinical; Pathology, Veterinary; Proteinuria
PubMed: 31270837
DOI: 10.1111/vcp.12760 -
Blood Jan 2018Monoclonal gammopathy of undetermined significance (MGUS) is, in many ways, a unique hematologic entity. Unlike most hematologic conditions in which the diagnosis is... (Review)
Review
Monoclonal gammopathy of undetermined significance (MGUS) is, in many ways, a unique hematologic entity. Unlike most hematologic conditions in which the diagnosis is intentional and credited to hematologists, the discovery of MGUS is most often incidental and made by nonhematologists. MGUS is considered an obligate precursor to several lymphoplasmacytic malignancies, including immunoglobulin light-chain amyloidosis, multiple myeloma, and Waldenström macroglobulinemia. Therefore, long-term follow-up is generally recommended. Despite its high prevalence, there is surprisingly limited evidence to inform best clinical practice both at the time of diagnosis and during follow-up. We present 7 vignettes to illustrate common clinical management questions that arise during the course of MGUS. Where evidence is present, we provide a concise summary of the literature and clear recommendations on management. Where evidence is lacking, we describe how we practice and provide a rationale for our approach. We also discuss the potential harms associated with MGUS diagnosis, a topic that is rarely, if ever, broached between patients and providers, or even considered in academic debate.
Topics: Aged; Bone Marrow; Bone and Bones; Disease Management; Disease Progression; Female; Humans; Male; Middle Aged; Paraproteinemias
PubMed: 29183887
DOI: 10.1182/blood-2017-09-807560 -
Journal of the Peripheral Nervous... Jun 2024Monoclonal gammopathy-related peripheral neuropathies encompass a spectrum of clinical presentations in which the monoclonal protein directly damages the tissues,... (Review)
Review
Monoclonal gammopathy-related peripheral neuropathies encompass a spectrum of clinical presentations in which the monoclonal protein directly damages the tissues, including the peripheral nervous system. Given the prevalence of both peripheral neuropathy and monoclonal gammopathy in the general population, these conditions may overlap in clinical practice, posing a challenge for clinicians in determining causality. Therefore, a comprehensive understanding of primary clinical syndromes and their neurophysiological patterns is of great importance for accurate differential diagnoses and effective treatment strategies. In this article, we examine the main forms of monoclonal gammopathies that affect the peripheral nerve. We explore the clinical and electrophysiological aspects and their correlation with each syndrome's corresponding monoclonal protein type. This knowledge is essential for healthcare professionals to diagnose better and manage patients presenting with monoclonal gammopathy-related peripheral nervous system involvement.
Topics: Humans; Paraproteinemias; Peripheral Nervous System Diseases
PubMed: 38873841
DOI: 10.1111/jns.12638