RESUMEN
The pathogenesis of rheumatoid arthritis (RA) is incompletely understood. Human endogenous retroviruses (HERVs) and their superantigenic envelope protein (env) have been implicated in the pathogenesis of RA. In the present investigation, the arthritogenic potential of the superantigen staphylococcal enterotoxin A (SEA) has been investigated. In the present investigation, the bacterial superantigen staphylococcal enterotoxin A (SEA) was injected into the right knee joint of 15 Lewis rats. Further nine animals received saline. Animals were sacrificed one, five and 10 days after the injection, respectively. The antigens CD3, CD4, CD8, MHC class I, MHC class II, Pax5 and CD138 were investigated by immunohistochemistry on cryo-sections. After intra-articular SEA injection, the inflammation was initially dominated by CD8+ T cells. In the course of the investigation, the numbers of CD4+, Pax5+, CD138+ and MHC class II+ cells increased. CD3 was expressed in low numbers as compared to CD8. After saline injection, no similar inflammatory response has been detected. The arthritis induced by the superantigen SEA may be a novel model for inflammatory joint diseases, that is rheumatoid arthritis or juvenile idiopathic arthritis.
Asunto(s)
Artritis Experimental/inmunología , Artritis Experimental/patología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Enterotoxinas/inmunología , Superantígenos/inmunología , Animales , Artritis Reumatoide/patología , Linfocitos B/inmunología , Complejo CD3/metabolismo , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Modelos Animales de Enfermedad , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Masculino , Factor de Transcripción PAX5/metabolismo , Ratas , Ratas Endogámicas Lew , Sindecano-1/metabolismoRESUMEN
Acromegaly is a rare and severe condition, presenting with typical signs and symptoms. The diagnosis is often initially made years after the first manifestations of the disease. In more than 99% of patients the disease is caused by a benign pituitary tumor that secretes growth hormone (GH). The diagnosis is based on the presence of increased insulin-like growth factor 1 (IGF-1) levels and a lack of GH suppression in the oral glucose tolerance test. The standard imaging procedure for tumor detection is magnetic resonance imaging in the region of the sella turcica. Treatment includes surgical, drug and radiation therapy. Important factors are an intensive aftercare of the patient, controls for detection of tumor recurrence and pituitary insufficiency as well as assessment of various organ functions and risk constellations. Patient care should involve close cooperation between endocrinologists, neurosurgeons and general practitioners as well as other specialist disciplines.
Asunto(s)
Acromegalia/diagnóstico , Acromegalia/sangre , Acromegalia/terapia , Adenoma/diagnóstico , Adenoma/terapia , Comorbilidad , Diagnóstico Diferencial , Adenoma Hipofisario Secretor de Hormona del Crecimiento/diagnóstico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/terapia , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Comunicación Interdisciplinaria , Colaboración Intersectorial , Enfermedades RarasRESUMEN
Gastro-oesophageal reflux (GER) has a special meaning for patients with cystic fibrosis (CF). Twelve voluntary patients with CF up to the age of 25 underwent an oesophageal manometry and a 24-hour impedance-pH monitoring. These patients were without symptoms of GER. The examination proved an acid GER in 42â%. In the total population the frequency is ≤â10â%. In 11 of 12 patients a pathologically low pressure of the lower oesophageal sphincter (LES) was found. No significant correlations between the DeMeester score and the pressure of the LES, the reflux and respiratory symptomatology, the lung function as well as the quality of life could be proven. However, there was a significant correlation between the DeMeester score and the acid clearance time. 37â% of the registered cough pushes were related to a GER, of which 78â% were associated with an acid GER. Therefore, coughing in patients with CF must not necessarily be caused by the underlying disease. The timely detection of a pathological GER in patients with CF, but without symptoms of GER, and its prompt therapy could protect the lung function.
Asunto(s)
Fibrosis Quística/diagnóstico , Fibrosis Quística/fisiopatología , Unión Esofagogástrica/fisiopatología , Esófago/química , Esófago/fisiopatología , Reflujo Gastroesofágico/diagnóstico , Reflujo Gastroesofágico/fisiopatología , Adulto , Fibrosis Quística/complicaciones , Monitorización del pH Esofágico , Femenino , Determinación de la Acidez Gástrica , Reflujo Gastroesofágico/etiología , Humanos , Concentración de Iones de Hidrógeno , Masculino , Manometría , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Ectopic pancreas is a rare congenital anomaly. It is usually asymptomatic, or presents with non specific gastrointestinal symptoms. We describe here a case of ectopic pancreas in the gastric antrum, with pseudocyst and pseudoaneurysm formation. This entity has not been reported previously in the literature.
Asunto(s)
Aneurisma Falso/diagnóstico por imagen , Coristoma/diagnóstico por imagen , Páncreas , Seudoquiste Pancreático/diagnóstico por imagen , Gastropatías/diagnóstico por imagen , Diagnóstico Diferencial , Femenino , Humanos , Recién Nacido , Antro Pilórico/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Ultrasonografía Doppler en Color/métodosRESUMEN
PURPOSE: Risk stratification of metastatic and relapsed Ewing's tumors (ETs) has been a matter of debate during the last decade. Patients with bone or bone marrow metastases or early or multiple relapses constitute the worst risk group in ET and have a poorer prognosis than patients with primary lung metastases or late relapses. In this article, the results of the present Meta European Intergroup Cooperative Ewing Sarcoma Study (MetaEICESS) (tandem melphalan/etoposide [TandemME]) were compared with the result of the previous study (hyper melphalan/etoposide [HyperME]), both at 5 years, in a patient population within the same high-risk stratum to determine toxicity. PATIENTS AND METHODS: Among 54 eligible patients, 26 were treated according to the HyperME protocol, and 28 were treated according to TandemME protocol. Patients received six cycles of the Cooperative Ewing Sarcoma Study treatment in HyperME and six cycles of the EICESS treatment in TandemME as induction chemotherapy. Patients also received involved-compartment irradiation for local intensification and myeloablative systemic intensification consolidation with hyperfractionated total-body irradiation (TBI) combined with melphalan/etoposide in HyperME or two times the melphalan/etoposide in TandemME followed by autologous stem-cell transplantation. RESULTS: The event-free survival (EFS) rate +/- SD in HyperME and TandemME was 22% +/- 8% and 29% +/- 9%, respectively. The dead of complication rate was 23% in HyperME and 4% in TandemME. CONCLUSION: TandemME offers a decent, albeit still not satisfactory, rate of long-term remissions in most advanced ETs (AETs), with short-term treatment and acceptable toxicity. TBI was not required to maintain EFS level in this setting but was associated with a high rate of toxic death. Future prospective studies in unselected patients are warranted to evaluate high-dose therapy in an unselected group of patients with AET.
Asunto(s)
Sarcoma de Ewing/tratamiento farmacológico , Irradiación Corporal Total , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Médula Ósea/secundario , Neoplasias Óseas/secundario , Niño , Preescolar , Terapia Combinada , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Femenino , Humanos , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Sarcoma de Ewing/radioterapia , Análisis de Supervivencia , Irradiación Corporal Total/efectos adversosRESUMEN
BACKGROUND: The influence of physical strain on the esophageal motility has already been examined in a number of studies. It was found that high physical strain compromises the sufficient contractility of the esophagus. However, it needs more examinations to verify these findings. METHODS: To validate these results healthy volunteers were examined using gas-perfusion manometrie. Bicycle ergometry was performed to generate an exactly defined physical exercise. After a pilot study, the changing of the contraction amplitude was determined as the main variable to evaluate the esophageal motility, and the sample size was calculated. Eight subjects without esophageal diseases or symptoms were examined by simultaneous gas-perfusion esophageal manometry and bicycle ergometry. KEY RESULTS: The results showed that high physical strain during bicycle ergometry can induce a significant decrease of the contraction amplitude (α = 5%, ß = 10%). The 95% confidence interval of the quotient of contraction amplitude at rest and under physical strain is (1.074; 1.576). This effect is more pronounced in liquid acts of swallowing than in dry and is also more obvious at the middle measuring point (7.8 cm above the lower esophageal sphincter) than at the distal and proximal point (2.8 and 12.8 cm). Furthermore, a decreasing tendency of the contraction duration could be found. CONCLUSIONS & INTERFERENCES: Gas-perfusion manometry is an inexpensive examination method, which enables the evaluation of the esophageal motility in moving test subjects under conditions of physical strain. It could be proved that physical strain negatively influences the esophageal motility by a decrease of the contraction amplitude.
Asunto(s)
Esófago/fisiología , Motilidad Gastrointestinal , Esfuerzo Físico , Adulto , Esfínter Esofágico Inferior/fisiología , Ejercicio Físico , Prueba de Esfuerzo , Femenino , Voluntarios Sanos , Humanos , Masculino , Manometría , Contracción MuscularRESUMEN
To define the epitope(s) on human thyroid peroxidase (TPO) recognized by antibodies in the sera of patients with autoimmune thyroid disease, we constructed and screened a human TPO cDNA sublibrary containing 3.8 million random fragments of human TPO cDNA, each 200-500 basepairs in length. These fragments would code for TPO polypeptides of 66-166 amino acid residues. The validity of this approach was first tested with a murine monoclonal antibody against the denatured human thyroid microsomal antigen (TPO). Analysis of the nucleotide sequence of 14 clones selected from this library enabled molecular identification of the epitope recognized by this monoclonal antibody. In contrast to the data obtained with the monoclonal antibody, sera from patients with Hashimoto's thyroiditis containing polyclonal antimicrosomal/TPO antibodies did not recognize the TPO protein fragments generated by this library. These results differ from previous data obtained with recombinant human TPO fragments generated as bacterial fusion proteins. Our data suggest that, contrary to previous concepts, the natural B-cell epitope(s) on human TPO may be highly conformational (requiring a complex 3-dimensional structure) or may be discontinuous (formed by distant regions of the linear polypeptide chain being brought into apposition by protein folding).
Asunto(s)
Epítopos/inmunología , Yoduro Peroxidasa/inmunología , Proteínas de Unión a Hierro , Tiroiditis Autoinmune/inmunología , Secuencia de Aminoácidos , Anticuerpos Monoclonales/inmunología , Reacciones Antígeno-Anticuerpo , Autoantígenos/inmunología , Secuencia de Bases , ADN/aislamiento & purificación , Regulación Enzimológica de la Expresión Génica , Humanos , Yoduro Peroxidasa/genética , Datos de Secuencia Molecular , Fragmentos de Péptidos/inmunología , Reacción en Cadena de la Polimerasa , Conformación Proteica , Tiroiditis Autoinmune/sangre , Tiroiditis Autoinmune/genéticaRESUMEN
In a panel of 13 mouse monoclonal antibodies generated against native (nondenatured) human thyroid peroxidase (TPO), only 1 (monoclonal antibody 47) recognized TPO protein fragments expressed in a human TPO cDNA sublibrary. Determination of the nucleotide sequences of 18 clones recognized by monoclonal antibody 47 localized its epitope to 9 amino acids (residues 713-721) in the human TPO protein. On Western blot analysis, only TPO monoclonal antibody 47 recognized the 933-amino acid TPO molecule after denaturation and reduction of the latter, supporting the concept that the major part of the epitope is represented by a continuous portion of the TPO sequence. The binding of TPO monoclonal antibody 47 to native TPO is inhibited by immunoglobulin G in the serum of patients with autoimmune thyroid disease. The epitope for monoclonal antibody 47 defined in the present study is, therefore, part of or in the vicinity of an epitope for autoimmune thyroid disease-associated TPO antibodies.
Asunto(s)
Linfocitos B/inmunología , Epítopos/genética , Yoduro Peroxidasa/inmunología , Tiroiditis Autoinmune/genética , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/inmunología , Secuencia de Bases , Western Blotting , Células Cultivadas , Cricetinae , Cricetulus , Epítopos/inmunología , Femenino , Humanos , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Datos de Secuencia Molecular , Ovario/citología , Ovario/enzimología , Pruebas de Precipitina , Tiroiditis Autoinmune/enzimologíaRESUMEN
The prevalence of TSI in Graves' disease was investigated with a radioligand receptor assay using human thyroid membranes and highly purified labeled porcine TSH or bovine TSH in 110 patients before treatment and in 39 patients after successful treatment with antithyroid drugs. In 11 patients, the assay was performed before, during, and after therapy. The results in the radioligand receptor assay were compared to thyroid function tests (TRH test, free T4 index, serum %3 level, and thyroid suppression test). Normal IgG inhibits nonspecifically, but dose dependently, the binding of [125I]TSH to thyroid membranes. IgG samples from patients were only considered to be positive if they reduced the binding of the labeled hormone below the mean value minus 2 SD of the controls. TSI activity was found in 50% of the patients with untreated diffuse toxic goiter, in 3 out of 27 cases who regained suppressible thyroid function, and in 5 out of 12 cases who were off therapy for more than 6 weeks and showed normal TRH tests and normal hormone levels but in whom the suppression test was not performed. Our data cannot prove the hypothesis that only humoral antibodies are responsible for the thyroid stimulation in Graves' disease, but of course they cannot exclude it; furthermore, they suggest the existence of antibodies which bind to the human thyroid cell membrane without necessarily stimulating thyroid cellular activity.
Asunto(s)
Enfermedad de Graves/inmunología , Inmunoglobulinas/análisis , Glándula Tiroides/inmunología , Complejo Antígeno-Anticuerpo , Enfermedad de Graves/metabolismo , Humanos , Ensayo de Unión Radioligante , Receptores de Superficie Celular/metabolismo , Receptores de Tirotropina , Glándula Tiroides/metabolismo , Tirotropina/inmunología , Tirotropina/metabolismoRESUMEN
Several methodological aspects concerning the measurement of thyroid-stimulating antibodies (TSAb) were examined using a 5000-g particulate fraction from human thyroid tissue. TSH displayed maximal stimulation at 32 C. An ATP-regenerating system had no influence at ATP concentrations greater than 0.67 mM. Theophylline did not influence cAMP concentrations in the incubation medium after stimulation with increasing dosages of TSH, suggesting the absence of active phosphodiesterases in the membrane preparations. Sera dialyzed against Tris-HCl were as suitable as immunoglobulin G preparations for determination of TSAb. One hundred and nineteen patients with ophthalmic Graves' disease, 42 of whom were hyperthyroid at the time of study, were investigated for TSH binding-inhibiting antibodies ( TBIAb ) and TSAb. In 76% of these patients, concordance between the presence and absence of both activities was found independent of whether they were untreated, treated, or in remission. When gradations of potency in the two systems were compared, linear regression revealed a correlation coefficient of 0.59. The coefficient correlation increased when TBIAb and TSAb were each determined in a single assay using identical thyroid membrane preparations. In four other patients, both TSAb and TBIAb were measured repeatedly during the course of the disease. In three patients, both activities were parallel, whereas in one patient, dissociation of the two activities was found. The data suggest the presence of antibodies with varying stimulating and binding-inhibiting properties. However, in hyperthyroidism of Graves' disease, both activities usually were present in similar quantities.
Asunto(s)
Anticuerpos/análisis , Enfermedad de Graves/inmunología , Inmunoglobulina G/análisis , Tirotropina/inmunología , Adenilil Ciclasas/metabolismo , Adulto , Femenino , Humanos , Inmunoglobulinas Estimulantes de la Tiroides , Técnicas In Vitro , Masculino , Ensayo de Unión Radioligante , Glándula Tiroides/enzimologíaRESUMEN
This study reports the development of a highly sensitive and reproducible RIA for the measurement of 3,5-diiodothyronine (3,5-T2) in human serum and tissue. The RIA employs 3-bromo-5-[125I]iodo-L-thyronine (3-Br-5-[125I]T1) as tracer, which was synthesized carrier free by an interhalogen exchange from 3,5-dibromo-L-thyronine (3,5-Br2T0). The detection limits were 1.0 fmol/g and 0.8 pmol/L in human brain tissue and serum, respectively. T3, diiodothyroacetic acid, and 3-monoiodothyronine cross-reacted with a 3,5-T2 antibody to the extent of 0.06%, 0.13%, and 0.65%, respectively. Serum concentrations of 3,5-T2 were measured in 62 healthy controls and 4 groups of patients with nonthyroidal illness, i.e. patients with sepsis (n = 24), liver diseases (n = 23), head and/or brain injury n = 15), and brain tumors (n = 21). The mean serum level of 3,5-T2 in the healthy subjects was 16.2 +/- 6.4 pmol/L. Concentrations of 3,5-T2 were significantly elevated in patients with sepsis (46.7 +/- 48.8 pmol/L; P < 0.01), liver diseases (24.8 +/- 14.9 pmol/L; P < 0.01), head and/or brain injury (24.1 +/- 11.3 pmol/L; P < 0.05), and brain tumors (21.6 +/- 4.8 pmol/L; P < 0.01). In all 4 patient groups, serum levels of T3 were significantly reduced, confirming the existence of a low T3 syndrome in these diseases. Serum concentrations of 3,5-T2 were significantly elevated in patients with hyperthyroidism (n = 9) and were reduced in patients with hypothyroidism (n = 8). The levels of T4, T3, and 3,5-T2 were measured in normal human tissue samples from the pituitary gland and various brain regions and in brain tumors. In normal brain tissue, the concentrations of 3,5-T2 ranged between 70-150 fmol/g, and the ratio of T3 to 3,5-T2 was approximately 20:1. In brain tumors, however, T3 levels were markedly lower, resulting in a ratio of T3 to 3,5-T2 of approximately 1:1. Recent findings suggest a physiological, thyromimetic role of 3,5-T2, possibly stimulating mitochondrial respiratory chain activity. Should this prove to be correct, then the increased availability of 3,5-T2 in nonthyroidal illness may be one factor involved in maintaining clinical euthyroidism in patients with reduced serum levels of T3 during nonthyroidal illness.
Asunto(s)
Neoplasias Encefálicas/sangre , Diyodotironinas/sangre , Radioinmunoensayo/métodos , Astrocitoma/metabolismo , Lesiones Encefálicas/sangre , Neoplasias Encefálicas/metabolismo , Traumatismos Craneocerebrales/sangre , Diyodotironinas/análisis , Glioblastoma/metabolismo , Humanos , Hepatopatías/sangre , Radioinmunoensayo/estadística & datos numéricos , Valores de Referencia , Sensibilidad y Especificidad , Sepsis/sangre , Tiroxina/sangre , Triyodotironina/análisis , Triyodotironina/sangreRESUMEN
The genetic susceptibility to Graves' disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves' disease, 293 patients with IDDM, and 325 controls. Patients with Graves' disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 x 10(-4). The phenotypic frequency of Ala-positive patients (73%) was significantly higher than of controls (58%; P = 10(-4); relative risk = 2). Patients with IDDM also had significantly more Ala alleles as homozygotes (19%) or heterozygotes (50%; P = 0.01). In conclusion, an alanine at codon 17 of CTLA4 is associated with genetic susceptibility to Graves' disease as well as to IDDM.
Asunto(s)
Alanina/genética , Antígenos de Diferenciación/genética , Diabetes Mellitus Tipo 1/genética , Predisposición Genética a la Enfermedad , Enfermedad de Graves/genética , Inmunoconjugados , Abatacept , Adolescente , Adulto , Alelos , Antígenos CD , Antígeno CTLA-4 , Niño , Preescolar , Cromosomas Humanos Par 2 , Exones , Femenino , Antígenos HLA-DQ/genética , Cadenas alfa de HLA-DQ , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
Endocrine autoimmune disorders share susceptibility and resistance factors of the human leukocyte antigen system on the short arm of chromosome 6, but other gene loci also contribute to predisposition and protection. Because the cytotoxic T lymphocyte antigen 4 (CTLA4) alanine-17 encoded by the CTLA4 gene on chromosome 2q33 confers susceptibility to Graves' disease, as well as to type 1 (insulin-dependent) diabetes mellitus, we investigated this dimorphism in the other endocrine autoimmune disorders: Hashimoto's thyroiditis and Addison's disease. We analyzed the CTLA4 exon 1 polymorphism (49 A/G) in 73 patients with Hashimoto's thyroiditis, 76 with Addison's disease, and 466 healthy controls. This dimorphism corresponds to an aminoacid exchange (Thr/Ala) in the leader peptide of the expressed protein. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism analysis, and restriction fragment length polymorphism analysis using BbvI. Patients with Hashimoto's thyroiditis had significantly more Ala alleles than controls, both as homozygotes (22% vs. 15%) and heterozygotes (53% vs. 46%), and less Thr than controls as homozygotes (25% vs. 39%), P < 0.04. The phenotypic frequency for Ala was significantly higher in patients (75%), compared with controls (61%), P < 0.03. Patients with Addison's disease did not differ significantly from controls, but those carrying the suceptibility marker, human leukocyte antigen DQA1*0501, were significantly more CTLA4 Ala17 positive than controls with the same DQA1 allele (P < 0.05). In conclusion, an alanine at codon 17 of CTLA4 confers genetic susceptibility to Hashimoto's thyroiditis, whereas this applies only to the subgroup of DQA1*0501+ patients with Addison's disease.
Asunto(s)
Enfermedad de Addison/inmunología , Antígenos de Diferenciación/genética , Codón/genética , Inmunoconjugados , Polimorfismo Genético/genética , Tiroiditis Autoinmune/inmunología , Abatacept , Adolescente , Adulto , Alelos , Antígenos CD , Antígeno CTLA-4 , Exones/genética , Frecuencia de los Genes , Antígenos HLA-DQ/genética , Humanos , Valores de ReferenciaRESUMEN
One hundred fifty patients with toxic and scintigraphically diffuse goiter were HLA typed (A, B, C, DR). One group consisted of 101 patients with concomitant Graves' ophthalmopathy and/or TSH-binding inhibiting antibodies (TBIAb). Forty nine patients had neither ophthalmopathy nor TBIAb. The former group showed a higher prevalence of HLA-B8 and DR3 compared to a normal control group. The latter group showed a higher frequency of HLA-DR5, whereas the HLA-B8 and DR3 antigens were slightly below normal prevalence. These data indicate an immunogenetic heterogeneity in patients with toxic diffuse goiter. A group of 47 hyperthyroid patients with single autonomous thyroid adenoma had no increased prevalence of any HLA-antigens. Patients with long term remission did not show an altered prevalence of any of the HLA antigens compared to controls. In contrast, patients with Graves' ophthalmopathy and/or TBIAb activity who relapsed had a significantly higher prevalence of HLA-B8 DR3, whereas patients without TBIAb and eye signs who relapsed had a significantly higher prevalence of HLA-DR5 than the control group.
Asunto(s)
Enfermedad de Graves/inmunología , Antígenos de Histocompatibilidad Clase II/análisis , Enfermedad de Graves/genética , Antígenos HLA/análisis , Antígeno HLA-B8 , Antígeno HLA-DR3 , Antígeno HLA-DR5 , Humanos , Inmunoglobulina G/análisis , Inmunoglobulinas Estimulantes de la TiroidesRESUMEN
The current literature contains reports of sarcoidosis with polyclonal increases in immunoglobulins. There are also reports of lymphoma in patients with pre-existing sarcoidosis. This is believed to be the first report of a patient in whom a monoclonal IgM kappa paraproteinemia developed after the diagnosis of sarcoidosis. This paraproteinemia was linked with a histologically proved non-Hodgkin's lymphoma. The possible relationships between the two disease entities are discussed.
Asunto(s)
Enfermedades Pulmonares/patología , Linfoma/patología , Sarcoidosis/patología , Biopsia , Granuloma/patología , Humanos , Cadenas kappa de Inmunoglobulina/análisis , Enfermedades Pulmonares/complicaciones , Ganglios Linfáticos/patología , Linfoma/complicaciones , Masculino , Persona de Mediana Edad , Paraproteinemias/etiología , Paraproteinemias/patología , Sarcoidosis/complicacionesRESUMEN
Carboxyl terminal truncation of membrane-associated human thyroid peroxidase (hTPO), with the elimination of its single membrane-spanning and short intracytoplasmic regions, generates a soluble, secreted, enzymatically active protein (amino acids 1-848). In order to determine the effects of further carboxyl terminal deletions on the expression of hTPO, Chinese hamster ovary cells were stably transfected with plasmids constructed to express amino acids 1-771, 1-636, 1-539 and 1-382 of the 933 amino acid TPO protein, respectively. Unlike hTPO1-848, the more severely truncated TPO mutant proteins could not be detected in conditioned media by polyclonal anti-TPO antibodies. Using detergent-solubilized microsomal proteins from these cells, very low levels of hTPO1-771 (approximately 90 kDa), but not the more extensive deletion mutations, were detected by these anti-TPO antibodies. Confirmation of the loss of efficient expression of more severely truncated hTPO was obtained using a anti-hTPO monoclonal antibody with an epitope near the amino terminus and which recognizes only the denatured protein. The mRNA for all hTPO mutants was detected in the stably-transfected Chinese hamster ovary cells. In summary, the present study indicates that a largely intact extracellular portion of hTPO is required for expression in eukaryotic cells.
Asunto(s)
Regulación de la Expresión Génica/genética , Yoduro Peroxidasa/biosíntesis , Animales , Secuencia de Bases , Western Blotting , Cricetinae , Femenino , Humanos , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Plásmidos , Reacción en Cadena de la Polimerasa , Pruebas de Precipitina , ARN Mensajero/análisis , TransfecciónRESUMEN
Transformation of peripheral blood lymphocytes (PBL) in response to solubilized TSH receptor and to human thyroglobulin (hTG) was carried out in patients with Graves' disease (GD). Mean stimulation index (SI) in response to solubilized TSH receptor was significantly increased only in hyperthyroid GD patients (SI = 3.0 +/- 1.8 SD, n = 13, p less than 0.025) when compared to normal subjects (SI = 1.5 +/- 0.8 SD,n = 14). All other subgroups of GD patients (i.e., euthyroid GD patients after treatment as well as those with/without ophthalmopathy or TSH-displacing antibody [TDA]) showed a tendency to elevated mean SI, which, however, was never significantly increased. In contrast, patients who were suspected of having a "disseminated autonomy" showed a tendency to decreased mean SI compared to GD patients. The mitogenic response of PBLs induced by solubilized TSH receptor could be suppressed by incubation of antigen and PBLs with bTSH. Control experiments with purified protein derivate of tuberculin(PPD) as stimulating antigen revealed, however, that bTSH itself suppresses the mitogenic response of PBLs and that the decrease of SI in this experiment is not due to blockage of the antigenic determinants of the TSH receptor protein. Human thyroglobulin (hTG) produced no significant increase in the SI of PBLs. Only 9 out of 47 GD patients showed an SI higher than the mean of normals + 2 SD. All those patients, however, who showed an elevated SI ( greater than 2.0) also revealed an increased SI with solubilized TSH receptor.
Asunto(s)
Enfermedad de Graves/inmunología , Activación de Linfocitos , Mitógenos/farmacología , Receptores de Superficie Celular/inmunología , Membrana Celular/inmunología , Oftalmopatías/inmunología , Humanos , Hipertiroidismo/inmunología , Receptores de Tirotropina , Tiroglobulina/farmacología , Glándula Tiroides/citología , Tuberculina/inmunologíaRESUMEN
It is unknown whether in chronic lymphocytic thyroiditis the goitrous (Hashimoto's thyroiditis) and atrophic forms (primary myxedema) are variants of the same disease or different pathogenic entities. Conventional thyroid-related autoimmune parameters are unable to separate both diseases serologically. It is assumed that cellular and humoral cytotoxic events induce gland atrophy and thus should be detectable more often in non-goitrous than goitrous autoimmune thyroiditis. We determined antibody-dependent cell-mediated cytotoxicity in 67 patients with autoimmune thyroiditis, using a 51chromium-release assay against human thyroid cells. Thyroid volume had been measured by ultrasonography. Other thyroid-specific antibodies, like TSH binding-inhibiting antibodies, TSH function-blocking antibodies, thyroglobulin antibodies and thyroid peroxidase antibodies, were determined. Cytotoxic antibody activity was 20.5% (median, range 0-54.5%) in patients with autoimmune thyroiditis and 8.3% (median, range 0-18.4%) in controls (p < 0.0001). Analysis of cytotoxicity regarding thyroid size showed a high incidence of cytotoxic antibodies in atrophic disease (median thyroid volume 6 ml), where cytotoxic antibodies were detectable in 80% versus 39% (x2 = 9.6; p < 0.0001) in goitrous disease (median thyroid volume 36 ml). The specific lysis of 30% (median; 95% confidence limit 23.9-32.9) in non-goitrous thyroiditis patients was significantly higher than in goitrous patients (16.9%; 95% confidence limit 13.2-20.4) (p = 0.0006).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos , Enfermedades Autoinmunes/inmunología , Bocio/inmunología , Glándula Tiroides/diagnóstico por imagen , Glándula Tiroides/inmunología , Tiroiditis/inmunología , Adolescente , Adulto , Anciano , Atrofia , Femenino , Humanos , Masculino , Persona de Mediana Edad , UltrasonografíaRESUMEN
OBJECTIVE: TGPO autoantibodies (aAbs) that bind simultaneously to thyroglobulin (Tg) and thyroperoxidase (TPO) are present in the serum of patients with autoimmune thyroid diseases (AITD) and have been found to differ from monospecific Tg and TPO aAbs. To obtain further insights on the prevalence defined as the rate of occurrence and significance of TGPO aAbs in a large population, we carried out a collaborative study involving 15 European teams. METHODS: Serum samples from 3122 patients with various thyroid and non-thyroid diseases and normal subjects were assayed using a novel TGPO aAb detection kit. This test was designed so that TGPO aAbs are trapped between the Tg-coated solid phase and the soluble TPO labeled with a radioiodinated monoclonal antibody. RESULTS: Only three out of the 220 normal subjects (prevalence of 1.4%) were found to have positive TGPO aAb levels, which were mainly observed in the patients with AITD: the group of patients suffering from Hashimoto's thyroiditis had a TGPO aAb prevalence of 40.5% (n=437 patients), those with Graves' disease, a prevalence of 34.6% (n=645) and those with post-partum thyroiditis, 16.0% (n=243). Among the non-AITD patients with positive TGPO aAb levels, the TGPO aAb prevalence ranged from 20.7% among those with thyroid cancer (n=246) to 0% among those with toxic thyroid nodules (n=47). Among the patients with non-thyroid diseases, the TGPO aAb prevalence ranged from 9.8% in the case of Biermer's pernicious anemia (n=78) to 0% in that of premature ovarian failure (n=44). It is worth noting that the groups showing the highest TGPO aAb prevalence also contained the patients with the highest TGPO aAb titers. Statistical comparisons between the TGPO aAb prevalences in the various groups showed that TGPO aAb could be used as a parameter to distinguish between the groups of Hashimoto's and Graves' patients and between the women with post-partum thyroiditis and the post-partum women with only Tg and/or TPO aAb established during early pregnancy. Unexpectedly, the correlations between TGPO aAbs and Tg and TPO aAbs were found to depend mainly on the assay kit used. CONCLUSION: High TGPO aAb titers are consistently associated with AITD but the reverse was not found to be true. TGPO aAbs are a potentially useful tool, however, for establishing Hashimoto's diagnosis, and would be worth testing in this respect with a view to using them for routine AITD investigations.