RESUMEN
BACKGROUND: Gamma-heavy chain disease is a rare disease, described so far in approximately 150 cases. The aim of this work was laboratory dia-gnostics of immunoglobulin heavy chain disease. MATERIALS AND METHODS: A 60-year-old patient was referred to the University Hospital in Ostrava for suspected marginal zone lymphoma from gastric bio-psy. Staging examinations including bone marrow trepanobio-psy and PET/CT were added; special examinations required serum protein electrophoresis, immunofixation electrophoresis, determination of polyclonal immunoglobulins, free light chains, and immunoglobulin heavy/light chain pairs. Isoelectric focusing in agarose gel followed by affinity immunoblotting and SDS electrophoresis was added due to unclear findings. RESULTS: 0.1 % of plasma cells were found in the bone marrow, of which 87 % were clonal (pathological) plasma cells, followed by the cyt cytotype LAMBDA + CD38 + CD138 + CD45 + CD19 + CD56- CD27 + CD81- CD117-. Monoclonal heavy chains were found in the patients serum. No monoclonal immunoglobulin heavy or light chains were detected in urine. The PET/CT examination showed generalized lymphadenopathy, splenomegaly and inhomogeneous accumulation of fluorodeoxyglucose in axillary and appendicular skeleton, but without the presence of typical osteolytic lesions. CONCLUSION: Monoclonal heavy chains of immunoglobulins are a rare disease. In contrast to the detection of a complete paraprotein molecule, additional methods must be used to confirm them. The finding of monoclonal heavy chain gamma in the serum of the study patient is related to the presence of marginal zone lymphoma, which was proven from a gastric bio-psy. The study was supported by the project of MH CZ - DRO - FNOs /2017 (Biobank in Teaching Hospital Ostrava) The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Asunto(s)
Enfermedad de las Cadenas Pesadas/diagnóstico , Cadenas gamma de Inmunoglobulina/sangre , Enfermedad de las Cadenas Pesadas/sangre , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Protein biomarkers for epithelial ovarian cancer are critical for the early detection of the cancer to improve patient prognosis and for the clinical management of the disease to monitor treatment response and to detect recurrences. Unfortunately, the discovery of protein biomarkers is hampered by the limited availability of reliable and sensitive assays needed for the reproducible quantification of proteins in complex biological matrices such as blood plasma. In recent years, targeted mass spectrometry, exemplified by selected reaction monitoring (SRM) has emerged as a method, capable of overcoming this limitation. Here, we present a comprehensive SRM-based strategy for developing plasma-based protein biomarkers for epithelial ovarian cancer and illustrate how the SRM platform, when combined with rigorous experimental design and statistical analysis, can result in detection of predictive analytes.Our biomarker development strategy first involved a discovery-driven proteomic effort to derive potential N-glycoprotein biomarker candidates for plasma-based detection of human ovarian cancer from a genetically engineered mouse model of endometrioid ovarian cancer, which accurately recapitulates the human disease. Next, 65 candidate markers selected from proteins of different abundance in the discovery dataset were reproducibly quantified with SRM assays across a large cohort of over 200 plasma samples from ovarian cancer patients and healthy controls. Finally, these measurements were used to derive a 5-protein signature for distinguishing individuals with epithelial ovarian cancer from healthy controls. The sensitivity of the candidate biomarker signature in combination with CA125 ELISA-based measurements currently used in clinic, exceeded that of CA125 ELISA-based measurements alone. The SRM-based strategy in this study is broadly applicable. It can be used in any study that requires accurate and reproducible quantification of selected proteins in a high-throughput and multiplexed fashion.
Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma Epitelial de Ovario/sangre , Espectrometría de Masas/métodos , Neoplasias Ováricas/sangre , Proteómica/métodos , Animales , Antígenos de Neoplasias/sangre , Proteínas Sanguíneas/análisis , Antígeno Ca-125/sangre , Estudios de Casos y Controles , Estudios de Cohortes , Desmogleína 2/sangre , Femenino , Enfermedad de las Cadenas Pesadas/sangre , Humanos , Cadenas mu de Inmunoglobulina/sangre , Proteínas de la Membrana/sangre , Ratones Transgénicos , Molécula L1 de Adhesión de Célula Nerviosa/sangre , Sensibilidad y Especificidad , Trombospondina 1/sangreRESUMEN
Heavy-chain deposition disease (HCDD) is characterized by tissue deposits of a truncated monoclonal immunoglobulin heavy-chain (HC) on basement membranes. Diagnosis is usually made on kidney biopsy, showing nodular glomerulosclerosis with HC deposits which can be missed, resulting in delay in diagnosis. We report four γ1-HCDD patients presenting with cutis laxa, hypocomplementemia and hypoalbuminemia. In two patients, unsuspected HCDD was revealed by cutis laxa and diagnosis was made on skin biopsy. In all patients, serum albumin and complement represented surrogate markers for disease monitoring. In γ-HCDD, extrarenal manifestations such as cutis laxa may precede renal injury and are precious tools for an early diagnosis, which is crucial to avoid progression of irreversible renal and elastic tissue damage.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cutis Laxo/etiología , Enfermedad de las Cadenas Pesadas/diagnóstico , Hipoalbuminemia/diagnóstico , Insuficiencia Renal/etiología , Adulto , Anciano , Biopsia , Proteínas del Sistema Complemento/análisis , Femenino , Enfermedad de las Cadenas Pesadas/sangre , Enfermedad de las Cadenas Pesadas/complicaciones , Enfermedad de las Cadenas Pesadas/tratamiento farmacológico , Humanos , Hipoalbuminemia/sangre , Cadenas gamma de Inmunoglobulina , Riñón/patología , Masculino , Persona de Mediana Edad , Diálisis Renal , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/terapia , Piel/patología , Resultado del TratamientoAsunto(s)
Enfermedad de las Cadenas Pesadas/patología , Linfoma de Células B Grandes Difuso/patología , Células Plasmáticas/ultraestructura , Enfermedad de las Cadenas Pesadas/sangre , Humanos , Cadenas mu de Inmunoglobulina/sangre , Linfoma de Células B Grandes Difuso/sangre , Linfoma de Células B Grandes Difuso/química , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/sangre , Vacuolas/ultraestructuraRESUMEN
Gamma heavy-chain disease (gHCD) is defined as a lymphoplasmacytic neoplasm that produces an abnormally truncated immunoglobulin gamma heavy-chain protein that lacks associated light chains. There is scant information in the literature regarding the morphologic findings in this rare disorder, but cases have often been reported to resemble lymphoplasmacytic lymphoma (LPL). To clarify the spectrum of lymphoproliferative disorders that may be associated with gHCD, this study reports the clinical, morphologic, and phenotypic findings in 13 cases of gHCD involving lymph nodes (n=7), spleen (n=2), bone marrow (n=8), or other extranodal tissue biopsies (n=3). Clinically, patients showed a female predominance (85%) with frequent occurrence of autoimmune disease (69%). Histologically, 8 cases (61%) contained a morphologically similar neoplasm of small lymphocytes, plasmacytoid lymphocytes, and plasma cells that was difficult to classify with certainty, whereas the remaining 5 cases (39%) showed the typical features of one of several other well-defined entities in the 2008 WHO classification. This report demonstrates that gHCD is associated with a variety of underlying lymphoproliferative disorders but most often shows features that overlap with cases previously reported as "vaguely nodular, polymorphous" LPL. These findings also provide practical guidance for the routine evaluation of small B-cell neoplasms with plasmacytic differentiation that could represent a heavy-chain disease and give suggestions for an improved approach to the WHO classification of gHCD.
Asunto(s)
Enfermedades Autoinmunes/diagnóstico , Enfermedad de las Cadenas Pesadas/diagnóstico , Cadenas gamma de Inmunoglobulina/sangre , Tejido Linfoide/patología , Linfoma de Células B/diagnóstico , Macroglobulinemia de Waldenström/diagnóstico , Adulto , Anciano , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/metabolismo , Biomarcadores de Tumor/metabolismo , Células Clonales , Comorbilidad , Análisis Citogenético , Femenino , Enfermedad de las Cadenas Pesadas/sangre , Enfermedad de las Cadenas Pesadas/epidemiología , Enfermedad de las Cadenas Pesadas/genética , Humanos , Cadenas gamma de Inmunoglobulina/genética , Inmunofenotipificación , Hibridación Fluorescente in Situ , Linfocitos/metabolismo , Linfocitos/patología , Tejido Linfoide/metabolismo , Linfoma de Células B/epidemiología , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Masculino , Persona de Mediana Edad , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Factores Sexuales , Reino Unido/epidemiología , Estados Unidos/epidemiología , Macroglobulinemia de Waldenström/epidemiología , Macroglobulinemia de Waldenström/genética , Macroglobulinemia de Waldenström/metabolismoAsunto(s)
beta-Globulinas/análisis , Enfermedad de las Cadenas Pesadas/diagnóstico , Cadenas gamma de Inmunoglobulina/sangre , Anciano de 80 o más Años , Electroforesis de las Proteínas Sanguíneas , Neoplasias Óseas/complicaciones , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/secundario , Diagnóstico Diferencial , Reacciones Falso Positivas , Fracturas del Cuello Femoral/etiología , Enfermedad de las Cadenas Pesadas/sangre , Enfermedad de las Cadenas Pesadas/orina , Humanos , Inmunoelectroforesis , Inmunoglobulina G/sangre , Inmunoglobulina G/orina , Cadenas Ligeras de Inmunoglobulina/sangre , Cadenas Ligeras de Inmunoglobulina/orina , Masculino , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patologíaAsunto(s)
beta-Globulinas/análisis , Enfermedad de las Cadenas Pesadas/diagnóstico , Cadenas gamma de Inmunoglobulina/sangre , Electroforesis de las Proteínas Sanguíneas , Reacciones Falso Positivas , Enfermedad de las Cadenas Pesadas/sangre , Enfermedad de las Cadenas Pesadas/orina , Humanos , Inmunoelectroforesis , Cadenas Ligeras de Inmunoglobulina/sangre , Cadenas Ligeras de Inmunoglobulina/orinaAsunto(s)
beta-Globulinas/análisis , Enfermedad de las Cadenas Pesadas/diagnóstico , Cadenas gamma de Inmunoglobulina/sangre , Albuminuria/diagnóstico , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/secundario , Diagnóstico Diferencial , Reacciones Falso Positivas , Enfermedad de las Cadenas Pesadas/sangre , Enfermedad de las Cadenas Pesadas/orina , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/orina , Cadenas kappa de Inmunoglobulina/sangre , Cadenas kappa de Inmunoglobulina/orina , Masculino , Mieloma Múltiple/diagnóstico , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patologíaRESUMEN
Heavy chain diseases (HCDs) are rare B-cell lymphoproliferative neoplasias characterized by the production of a monoclonal component consisting of a truncated monoclonal Ig heavy chain without the associated light chain. Among them, patients with gamma-HCD are so rare that no more than 150 cases can be found in the literature. In this paper, we report one additional case: an 83-year-old man with a gamma-HCD, in whom a kappa light chain component was detected in the serum by using the serum free light-chain assessment and in addition monoclonal kappa cytoplasmic expression was detected in bone marrow plasma cells by flow cytometric analysis. In the work-up of the patient, the underlying anatomopathological lymphoproliferative disease corresponded to a lymphoplasmacytic lymphoma, as it is stated in the current World Health Organization classification (2008), with both lymphadenopathic and bone marrow infiltration. As in other cases, several autoimmune manifestations (antiphospholipidic syndrome and immune thrombocytopenia) were present during the course of the disease in this patient. This case report illustrates a new case of gamma-HCD, in which serum free light-chain analysis and flow cytometry represented a valuable tool for diagnosis, a finding that could be very important for the future management of these patients.
Asunto(s)
Enfermedad de las Cadenas Pesadas/sangre , Enfermedad de las Cadenas Pesadas/diagnóstico , Cadenas gamma de Inmunoglobulina/sangre , Anciano de 80 o más Años , Citometría de Flujo , Humanos , MasculinoAsunto(s)
Neoplasias de la Mama/patología , Enfermedad de las Cadenas Pesadas/patología , Neoplasias Hepáticas/patología , Linfoma de Células B/patología , Linfoma de Células B Grandes Difuso/patología , Neoplasias del Bazo/patología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/secundario , Femenino , Enfermedad de las Cadenas Pesadas/sangre , Enfermedad de las Cadenas Pesadas/complicaciones , Enfermedad de las Cadenas Pesadas/tratamiento farmacológico , Humanos , Cadenas mu de Inmunoglobulina/metabolismo , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Linfoma de Células B/sangre , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/etiología , Linfoma de Células B Grandes Difuso/sangre , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/etiología , Persona de Mediana Edad , Neoplasias del Bazo/sangre , Neoplasias del Bazo/tratamiento farmacológico , Neoplasias del Bazo/secundarioRESUMEN
A 75-year-old woman with rheumatoid arthritis showed a discrepancy between the reduced level of serum gamma globulin on cellulose acetate electrophoresis and the normal level of serum IgG determined by laser nephelometry. Although no M-peak was detectable on cellulose acetate electrophoresis, immunoelectrophoresis of the patient's serum revealed a monoclonal protein reacting with anti-IgG antiserum but not with anti-kappa or anti-lambda light chain antiserum. Western blotting of the patient's serum showed abnormal low-molecular-weight gamma chains. Thus, the patient was diagnosed with gamma heavy chain disease. A comparison of gamma globulin levels determined by different methods may be useful when screening for this disease.
Asunto(s)
Enfermedad de las Cadenas Pesadas/sangre , Enfermedad de las Cadenas Pesadas/diagnóstico , gammaglobulinas/análisis , Anciano , Western Blotting , Errores Diagnósticos , Electroforesis en Acetato de Celulosa , Femenino , Humanos , Inmunoelectroforesis , Inmunoglobulina G/sangre , Tamizaje Masivo , Nefelometría y Turbidimetría , Estadística como AsuntoRESUMEN
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder characterized by a decrease or absence of glycosylphosphatidylinositol (GPI)-anchored molecules such as CD55 and CD59 from the surface of affected cells, resulting in intravascular hemolysis, cytopenia, and venous thrombosis. A PNH-like phenotype has been detected in various hematological disorders, mainly in aplastic anemia and myelodysplastic syndromes, but also in lymphoproliferative syndromes (LPSs). To the best of our knowledge, CD55- or CD59-deficient red cells have not been detected in plasma cell dyscrasias (PCDs). The aim of this study was the detection of CD55- and/or CD59-deficient red cell populations in patients with PCD. Seventy-seven patients were evaluated; 62 with multiple myeloma (MM), 7 with Waldenstrom macroglobulinemia (WM), 6 with monoclonal gammopathy of undetermined significance (MGUS), and 2 with heavy chain disease (HCD). The sephacryl gel microtyping system was applied; Ham and sucrose lysis tests were also performed on all samples with CD55- or CD59-negative populations. Red cells deficient in both molecules were detected in 10 (12.9%) of 77 patients with PCD: 2 (28.6%) of 7 with WM, 1 (16.6%) of 6 with MGUS, 6 (9.6%) of 62 with MM, and 1 of 2 patients with HCD. Isolated CD55 deficiency was found in 28.5% of all PCD patients, whereas isolated CD59 deficiency was not observed in any patients. These findings illustrate the existence of the PNH phenotype in the red cells of patients with PCD; further investigation is needed into the mechanisms and significance of this phenotype.
Asunto(s)
Antígenos CD55/análisis , Antígenos CD59/análisis , Membrana Eritrocítica/química , Paraproteinemias/sangre , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Enfermedad de las Cadenas Pesadas/sangre , Pruebas de Hemaglutinación , Hemoglobinuria Paroxística/sangre , Hemólisis , Humanos , Inmunofenotipificación/métodos , Masculino , Microquímica , Persona de Mediana Edad , Mieloma Múltiple/sangre , Macroglobulinemia de Waldenström/sangreAsunto(s)
Enfermedad de las Cadenas Pesadas/diagnóstico , Linfoma no Hodgkin/diagnóstico , Paraproteínas/análisis , Células Plasmáticas/patología , Anciano , Enfermedad de las Cadenas Pesadas/sangre , Enfermedad de las Cadenas Pesadas/complicaciones , Humanos , Inmunoelectroforesis Bidimensional , Cadenas Pesadas de Inmunoglobulina , Linfoma no Hodgkin/sangre , Linfoma no Hodgkin/complicaciones , MasculinoRESUMEN
This report describes a new case of gamma-1-heavy chain disease found in a woman with malignant lymphoproliferative disease. The patient's serum and urine containing gamma-1-heavy chains were analyzed using different electrophoretic approaches, especially two-dimensional electrophoresis and immunoblotting analysis. In a serum sample, five sets of gamma-1-heavy chain spots differing in molecular weight with acidic pI values and one set of more basic gamma-1-heavy chain spots were found. The major group of spots exhibited molecular weight in the range from 29 to 39 kDa. Examination of urine sample proved the presence of the more basic set of gamma-1-heavy chain spots and two acidic groups, including 29 to 39 kDa set.
Asunto(s)
Enfermedad de las Cadenas Pesadas/sangre , Enfermedad de las Cadenas Pesadas/orina , Anciano , Western Blotting , Electroforesis en Gel Bidimensional , Femenino , Humanos , Cadenas gamma de Inmunoglobulina/sangre , Cadenas gamma de Inmunoglobulina/orinaRESUMEN
Capillary electrophoresis (CE) has been used in our teaching hospital clinical laboratory to assay approximately 13 000 specimens for serum protein electrophoresis (SPE) in 4 1/2 years. During that period we have found several unusual samples, five of which are discussed here. These samples are from separate patients with IgD myeloma, IgG heavy chain disease, a triple IgG(Kappa) monoclonal band, a rapidly changing abnormal/monoclonal band and a mixed type-11 cryoglobulinaemia. Albumin has been used to calibrate the 50-microm fused silica capillary, the quantity of the monoclonal bands being calculated by the software of either the Applied Biosystems 270A-HT or BioFocus instrument. We have found CE for the initial SPE to be a robust, labour-saving, cost effective technique, which is able to determine less than 1 g/l of monoclonal protein. However, because of the expense and time required for immunosubtraction, we prefer isoelectric focusing (IEF) for typing of paraproteins. The only samples which need care in handling are serum containing large amounts of cryoglobulin protein.
Asunto(s)
Proteínas Sanguíneas/análisis , Electroforesis Capilar/métodos , Anciano , Anticuerpos Monoclonales/sangre , Proteína de Bence Jones/análisis , Crioglobulinemia/sangre , Crioglobulinas/análisis , Femenino , Enfermedad de las Cadenas Pesadas/sangre , Humanos , Inmunoglobulina G/sangre , Focalización Isoeléctrica , Masculino , Persona de Mediana Edad , Proteínas de Mieloma/análisis , Proteinuria/sangreRESUMEN
We report here for the first time a patient with mu heavy-chain disease (HCD), hyperimmunoglobulinemia, and a positive direct antiglobulin test (DAT, Coombs test). The heavy-chain diseases involve the proliferation of lymphoplasma cells of B cell origin and are characterized by the production of incomplete heavy chains devoid of light chains. The association of mu heavy-chain disease with either hyperglobulinemia or a positive DAT has not been reported in the literature to date. In this patient, immunofixation of serum proteins with monospecific antisera to alpha-, gamma-, mu,- or delta-chains and to kappa- and lambda-chains revealed a precipitation band with antibody to IgM, but not with kappa and lambda light-chain antibodies, indicating mu heavy-chain disease. Hyperglobulinemia was present, which is very uncommon for HCD. A DAT of the patient's red blood cells (RBC) was found to be strongly positive for anti-IgG but negative for anti-IgM, -IgA, -C3c, and -C3d. However, when the eluate from the patient's red blood cells was investigated with nephelometry, it was found to contain antigens reactive with anti-y as well with anti-mu-antiserum. When a DAT was performed with a randomly chosen test cell incubated with the eluate, the antibody-containing eluate was shown to react with anti-IgG as well as with anti-IgM-antiserum. In summary, the eluate from the patient's RBCs contained IgG and an immunoglobulin structure reactive with anti-IgM in an RBC agglutination assay as well as with anti-mu antiserum in a nephelometric investigation. Whether this IgM on the patient's erythrocytes is penta- or oligomeric, complete IgM, or the heavy chain cannot be concluded from these observations.
Asunto(s)
Anemia/complicaciones , Enfermedad de las Cadenas Pesadas/complicaciones , Hipergammaglobulinemia/complicaciones , Anciano , Anemia/sangre , Anemia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Autoanticuerpos/sangre , Tipificación y Pruebas Cruzadas Sanguíneas , Prueba de Coombs , Ciclofosfamida/administración & dosificación , Eritrocitos/inmunología , Enfermedad de las Cadenas Pesadas/sangre , Enfermedad de las Cadenas Pesadas/tratamiento farmacológico , Humanos , Hipergammaglobulinemia/sangre , Lactante , Masculino , Prednisona/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
The NH2-terminal structure of serum abnormal protein, as well as the sequence of the corresponding mRNA, were determined in a new case of alpha heavy chain disease. The patient presented with typical clinical features of the disease. Intestinal and mesenteric lymphoplasmic infiltration was monoclonal as assessed by the study of the configuration of heavy and light chain genes. The serum abnormal alpha chains included two molecular species: one starting at the beginning of the hinge region and the other being two amino acids shorter, missing the two first amino acids of the hinge region. The sequence of the mRNA displayed a leader exon, a 93 bp sequence of unknown origin and the second and third constant exons of human alpha 1 chain. These data are discussed in the light of previously reported molecular studies in heavy chain diseases.
Asunto(s)
ADN/ultraestructura , Enfermedad de las Cadenas Pesadas , Cadenas alfa de Inmunoglobulina/ultraestructura , ARN Mensajero/ultraestructura , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Elementos Transponibles de ADN , Eliminación de Gen , Reordenamiento Génico , Enfermedad de las Cadenas Pesadas/sangre , Enfermedad de las Cadenas Pesadas/genética , Humanos , Masculino , Datos de Secuencia MolecularRESUMEN
We describe a 61-year-old patient suffering from gamma-1-heavy-chain disease (gamma 1-HCD) associated with Bence-Jones-lambda proteinemia and proteinuria. The analysis of the patients gamma 1-HCD protein (WIN) shows a deletion of the complete Fd fragment. The N-terminal seven amino-acid residue does not resemble any of the known immunoglobulin-heavy-chain variable regions. Unexpectedly, in PBL-DNA and in DNA from EBV-immortalized cells we found in addition to the expected predominantly rearranged Ig-lambda-light-chain gene a predominant rearrangement of an Ig-kappa gene. These findings show that the gamma-1-heavy-chain disease of the patient involves a defective regulation of Ig-light-chain-gene activation as well.