transforming-growth-factor-beta and Paraproteinemias

Monoclonal gammopathy of renal significance (MGRS) is characterized by the nephrotoxic monoclonal immunoglobulin secreted by an otherwise asymptomatic or indolent B cell or plasma cell clone, without hematologic criteria for treatment. These MGRS-associated diseases can involve one or more renal compartments, including glomeruli, tubules, and vessels. Hydrophobic residue replacement, N-glycosylated, increase in isoelectric point in monoclonal immunoglobulin (MIg) causes it to transform from soluble form to tissue deposition, and consequently resulting in glomerular damage. In addition to MIg deposition, complement deposition is also found in C3 glomerulopathy with monoclonal glomerulopathy, which is caused by an abnormality of the alternative pathway and may involve multiple factors including complement component 3 nephritic factor, anti-complement factor auto-antibodies, or MIg which directly cleaves C3. Furthermore, inflammatory factors, growth factors, and virus infection may also participate in the development of the diseases. In this review, for the first time, we discussed current highlights in the mechanism of MGRS-related lesions.

Topics: Antibodies, Monoclonal; Autoantibodies; Complement C3; Complement C3 Nephritic Factor; Complement C3-C5 Convertases; Complement Pathway, Alternative; Cryoglobulinemia; Glycosylation; Humans; Immunoglobulin Light-chain Amyloidosis; Inflammation Mediators; Kidney Diseases; Kidney Glomerulus; Neoplasm Proteins; Paraproteinemias; Paraproteins; Protein Processing, Post-Translational; Transforming Growth Factor beta

Plasma cell dyscrasias (PCDs) are disorders of plasma cells having in common the production of a monoclonal M-protein. They include a spectrum of conditions that may represent a natural progression of the same disease from monoclonal gammopathy of unknown significance to asymptomatic and symptomatic multiple myeloma, plasma cell leukemia, and Waldenström's macroglobulinemia. In PCDs, the immune system is actively suppressed through the secretion of suppressive factors and the recruitment of immune suppressive subpopulations. In this study, we examined the expression of two subpopulations of cells with immunosuppressive activity, monocytic myeloid-derived suppressor cells (MDSCs) and monocytes expressing latency-associated peptide (LAP), in patients with different PCDs and in healthy volunteers.. A total of 27 consecutive patients with PCDs were included in this study. Nineteen healthy volunteers served as controls.. We observed a hierarchical correlation between disease activity and the presence of monocytes with immunosuppressive activity.. These results suggest that MDSCs and monocytes expressing LAP have diverging roles in PCDs and may perhaps serve as biomarkers of tumor activity and bulk.. Amaç: Plazma hücreli diskrazi (PHD), monoklonal M-proteinin üretimine sahip olan plazma hücrelerinin bozukluklarıdır. Aynı hastalığın, önemi bilinmeyen monoklonal gammopatiden, asemptomatik ve semptomatik multipl myeloma, plazma hücreli lösemi ve Waldenström makroglobulinemiye doğru doğal ilerlemesini temsil edebilen bir dizi spektrum içerir. PHD’lerde, baskılayıcı faktörlerin salgılanması ve bağışıklık baskılayıcı alt popülasyonların katılımı ile bağışıklık sistemi aktif olarak baskılanır. Bu çalışmada, PHD’lerin ve sağlıklı gönüllülerin, immün baskılayıcı aktiviteye sahip iki alt popülasyonundaki; monositik myeloid kökenli baskılayıcı hücreler (MKBH) ve latent asosiye peptit (LAP) eksprese eden monositlerin, ekspresyonunu incelenmiştir. Gereç ve Yöntemler: Bu çalışmaya PHD’li toplam 27 hasta dahil edildi. On dokuz sağlıklı gönüllü, kontrol olarak kullanılmıştır. Bulgular: Hastalık aktivitesi ile immünosüpresif aktivitesi olan monositler arasında hiyerarşik bir ilişki gözlenmiştir. Sonuç: Bu sonuçlar LAP anlatımı gösteren MKBH’lerin ve monositlerin, PHD’lerde farklı rollere sahip olduğunu ve tümör aktivitesi ve kitle biyobelirteçleri olarak kullanılabileceğini düşündürmektedir.

Topics: Aged; Aged, 80 and over; Cohort Studies; Female; Humans; Immune Tolerance; Male; Middle Aged; Monocytes; Myeloid-Derived Suppressor Cells; Paraproteinemias; Peptides; Protein Precursors; Transforming Growth Factor beta

Systemic plasma cell dyscrasias have diverse manifestations in the skin and include an inflammatory paraneoplastic process. We encountered cases of scleroderma and eosinophilic fasciitis in the setting of an underlying plasma cell dyscrasia.. Ten cases of scleroderma-like tissue reactions in the setting of an underlying plasma cell dyscrasia were encountered. The biopsies were stained for Transforming growth factor (Transforming growth factor) beta, IgG4, kappa, and lambda.. Patients presented with a sclerodermoid reaction represented by eosinophilic fasciitis (5 cases), morphea (3 cases), and systemic scleroderma (2 cases). The mean age of presentation was 70 years with a striking female predominance (4:1). Acral accentuation was noted in 8 cases. In 6 of the cases, the cutaneous sclerosis antedated (4 cases) by weeks to 2 years or occurred concurrently (2 cases) with the initial diagnosis of the plasma cell. The biopsies showed changes typical of eosinophilic fasciitis and/or scleroderma. In 5 cases, light chain-restricted plasma cells were present on the biopsy. There was staining of the plasma cells for Transforming growth factor beta in 3 out of 5 cases tested.. In any older patient presenting with a sudden onset of eosinophilic fasciitis or scleroderma especially with acral accentuation, investigations should be conducted in regards to an underlying plasma cell dyscrasia.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Biopsy; Eosinophilia; Fasciitis; Female; Humans; Immunoglobulin G; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Immunohistochemistry; Male; Middle Aged; Paraneoplastic Syndromes; Paraproteinemias; Prognosis; Scleroderma, Localized; Scleroderma, Systemic; Skin; Transforming Growth Factor beta

An atypical case of late-onset lattice corneal dystrophy is described in a 61-year-old man without a family history of eye disease. Mutational analysis of the TGFBI gene excluded any pathogenic sequence variants. However, 2 years later, renal impairment and nephrotic syndrome were diagnosed, resulting in a diagnosis of systemic heavy-chain amyloidosis.. Slit-lamp examination, corneal photography, and in vivo confocal microscopy were performed. General systemic evaluation included blood and urine assessment, bone marrow and renal biopsies, and cardiologic evaluation. A DNA sample underwent initial mutational analysis of TGFBI and, subsequently, gelsolin. The renal biopsy sample was subject to direct protein sequencing by mass spectrometry.. A bilateral, atypical, fine, midperipheral lattice corneal dystrophy with minor central subepithelial scarring was clinically characterized. Subsequently, abnormal renal functions with proteinuria, IgG lambda paraproteinemia, extensive deposition of amyloid in renal glomeruli, and increased plasma cells in bone marrow were identified. No pathogenic sequence mutations were identified in TGFBI or the gelsolin genes. Direct protein sequencing by mass spectrometry showed amyloid to be heavy-chain deposition rather than the more usual light-chain deposition.. Atypical midperipheral lattice corneal dystrophy presenting with adult onset and negative family history should arouse suspicion for an association with paraproteinemias or amyloidosis. Exclusion of TGFBI mutations should alert the clinician to the possibility of potentially life-threatening conditions, with referral for careful systemic evaluation.

Topics: Amyloid; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Corneal Dystrophies, Hereditary; Dexamethasone; DNA Mutational Analysis; Extracellular Matrix Proteins; Gelsolin; Glucocorticoids; Humans; Immunoglobulin Heavy Chains; Male; Mass Spectrometry; Melphalan; Microscopy, Confocal; Middle Aged; Mutation; Nephrotic Syndrome; Paraproteinemias; Pyrazines; Sequence Analysis, Protein; Transforming Growth Factor beta

The purpose of this study was to report the association of phenotypic features characteristic of lattice corneal dystrophy (LCD) with a monoclonal gammopathy of undetermined significance (MGUS) after exclusion of a coding region mutation in transforming growth factor beta-induced (TGFBI) gene.. Case report.. Slit-lamp examination and collection of DNA for TGFBI screening were performed. A systemic evaluation was also performed to evaluate for conditions associated with systemic amyloidosis.. A 65-year-old man demonstrated bilateral linear branching corneal stromal opacities characteristic of classic LCD. No mutations were found in any of the 17 exons of TGFBI or in the intron-exon boundary regions. Four previously described single nucleotide polymorphisms were identified: c.698C>G (p.Leu217Leu; rs1442), c.1028A>G (p.Val327Val; rs1054124), c.1416C>T (p.Leu472Leu; rs1133170), and c.1667T>C (p.Phe540Phe; rs4669). Serum protein electrophoresis revealed the presence of a monoclonal spike, and based on the results of additional investigations, the patient was diagnosed with MGUS.. Although the presence of bilateral thin branching lattice lines in the corneal stroma is characteristic of classic LCD, this distinctive phenotype may not be associated with a TGFBI coding region mutation but instead with a myeloproliferative disorder such as MGUS. Therefore, appropriate genetic and serologic testing should be performed in patients with a late-onset LCD phenotype in the absence of a positive family history.

Topics: Aged; Blood Proteins; Corneal Dystrophies, Hereditary; Corneal Opacity; Corneal Stroma; Electrophoresis; Exons; Extracellular Matrix Proteins; Genetic Testing; Humans; Male; Mutation; Paraproteinemias; Phenotype; Polymorphism, Single Nucleotide; Transforming Growth Factor beta