Novel CXCL13 transgenic mouse: inflammation drives pathogenic effect of CXCL13 in experimental myasthenia gravis.

Abnormal overexpression of CXCL13 is observed in many inflamed tissues and in particular in autoimmune diseases. Myasthenia gravis (MG) is a neuromuscular disease mainly mediated by anti-acetylcholine receptor autoantibodies. Thymic hyperplasia characterized by ectopic germinal centers (GCs) is a common feature in MG and is correlated with high levels of anti-AChR antibodies. We previously showed that the B-cell chemoattractant, CXCL13 is overexpressed by thymic epithelial cells in MG patients. We hypothesized that abnormal CXCL13 expression by the thymic epithelium triggered B-cell recruitment in MG. We therefore created a novel transgenic (Tg) mouse with a keratin 5 driven CXCL13 expression. The thymus of Tg mice overexpressed CXCL13 but did not trigger B-cell recruitment. However, in inflammatory conditions, induced by Poly(I:C), B cells strongly migrated to the thymus. Tg mice were also more susceptible to experimental autoimmune MG (EAMG) with stronger clinical signs, higher titers of anti-AChR antibodies, increased thymic B cells, and the development of germinal center-like structures. Consequently, this mouse model finally mimics the thymic pathology observed in human MG. Our data also demonstrated that inflammation is mandatory to reveal CXCL13 ability to recruit B cells and to induce tertiary lymphoid organ development.

Thyrotoxic myopathy mimicking myasthenic syndrome associated with thymic hyperplasia.

A 41-year-old man with progressive limb weakness manifested fluctuating muscle weakness as seen in myasthenia gravis (MG). Laboratory investigations revealed hyperthyroidism without the complication of MG. Electrophysiological studies demonstrated abnormal features of neuromuscular transmissions resembling those of the Lambert-Eaton myasthenic syndrome rather than those of MG. A CT scan showed a mediastinal mass that suggested thymic hyperplasia which often complicates MG or hyperthyroidism. Medical treatment of hyperthyroidism resulted in resolution of MG-like symptoms and regression of thymic hyperplasia on CT concomitant with normalization of thyroid function. This case highlights the fact that careful investigations are needed to differentiate MG-like symptoms from genuine MG in cases of hyperthyroidism with thymic lesions.

Clinical features of patients with myasthenia gravis associated with autoimmune diseases.

We investigated the incidence and clinical features of patients with myasthenia gravis (MG) associated with autoimmune diseases. Associated autoimmune diseases were found in 28 of 142 consecutive Japanese MG patients (19.7%), amongst which Graves' disease (7.7%) and Hashimoto's thyroiditis (4.2%) were predominant. The clinical features of MG patients with Graves' disease were different from those of MG patients without autoimmune diseases in terms of age at onset of MG symptoms (35.5 +/- 4.0 years and 49.0 +/- 1.7 years; P < 0.05), positivity for the anti-acetylcholine receptor antibody (44.4% and 89.8%; P < 0.05), and association with thymic hyperplasia (72.7 and 17.9%; P < 0.05). The therapeutic outcome of MG patients with Graves' disease and that of those without autoimmune diseases were not significantly different. Further studies should be performed to investigate whether MG associated with Graves' disease is a distinct subtype of MG.

Raised prolactin levels in myasthenia gravis: two case reports and a study of two patient populations.

OBJECTIVES: To describe two patients with myasthenia gravis (MG) and prolactinoma and analyze the associations between MG and prolactin (PRL) levels. DESIGN: Two case reports and a case-control study of PRL levels in 192 patients with MG. PARTICIPANTS: The Immunological Research Laboratory, Center for Molecular Medicine, Department of Medicine and the Department of Neurology, Karolinska Institutet, Stockholm, Sweden; St Petersburg Medical Academy for Postgraduate Studies, and St Petersburg State Medical Pediatric Academy, Russia. RESULTS: Two women with MG and thymic hyperplasia accompanied by prolactinomas are described. The levels of plasma PRL were raised in 101 women with MG, but not in 91 men. There was an association between high PRL levels and high levels of autoantibodies against the acetylcholine receptor. CONCLUSIONS: There is an association of MG with raised levels of PRL in women. PRL has stimulating effects on immune activation and the increased levels might thus be implied in the pathophysiology of MG.

[Intestinal microbiocenosis in children with thymomegaly and acute lower respiratory tract infections and regimen of its correction].

57 children with thymomegaly from 3 months to 3 years of age with acute lower respiratory tract infections were studied. Disturbances of gut microflora - changes in both obligate and potentially harmful symbionts were detected in 70.2% of cases. In 47,5% of cases increased quantity of enterococci was observed. Decreased quantities of bifidobacteria and lactobacilli were observed in all and 27.5% of studied patients respectively. Most diverse gut microflora has been observed in children with pneumonia and thymomegaly of II level. During treatment of children with thymomegaly changes in gut microflora should be considered along with changes in the immune system.

Abnormalities of Th1 function in non-IgE food allergy, celiac disease, and ileal lymphonodular hyperplasia: a new relationship?

BACKGROUND: Non-IgE mechanisms may also be involved food allergy (FA). Our group has been studying the immunopathogenesis clinical entities in children with gastro-intestinal symptoms and in whom biopsies of the terminal ileum show lymphoid tissue masses referred to as ileal lymphonodular hyperplasia. Our more recent studies have demonstrated Th1/Th2 cytokine profiles associated with non-IgE FA and other clinical entities. OBJECTIVE: We investigated 12 subjects with non-IgE FA (group 1) and 4 subjects with celiac disease (group 2). Cytokine profiles and immunologic studies of lymphocytes in peripheral blood and from gastro-intestinal biopsy tissues from patients in groups 1 and 2 were also evaluated. METHODS: Group 1 consisted of 12 children with clinical symptoms of anorexia, diarrhea, and abdominal pain. The diagnosis of non-IgE FA was established by positive double-blind, placebo-controlled food challenge and reduced or negative immediate-type skin testing and negative IgE radioallergosorbent tests. Group 2 consisted of four patients with celiac disease and three adult females with biopsy-proven clinical symptoms of celiac disease. RESULTS: In group 1, peripheral blood CD4 and CD8 lymphocyte distributions were normal, with a predominance of CD4+ cells with a decreased intracellular Th1 cytokine pattern and a normal Th2 intracellular cytokine pattern. In contrast, all four patients in group 2 not only displayed abnormal CD4 and CD8 peripheral blood lymphocyte distributions (CD8 > CD4), but also an abnormal predominance of CD4+ cells with an increased Th1 and a normal Th2 cytokine pattern. A similar abnormal pattern of CD4 > CD8 ratio was observed in intestinal biopsies. All 12 patients in group 1 showed lymphonodular hyperplasia in each of the biopsies and by ileoscopy. CONCLUSIONS: These studies suggest that abnormalities in Th1 function may not only play a role in some patients with non--IgE-mediated FA in whom decreased Th1 function is seen, but also in patients with celiac disease in whom an increased Th1 function is seen. The studies also suggest that lymphonodular hyperplasia may be a hallmark histologic lesion in patients with non--IgE-mediated FA.

[Advances in the research on immunopathogenesis of myasthenia gravis]. / Postepy w poznaniu immunopatogenezy miastenii.

Microscopic structure and immunologic function of the thymus gland are outlined, with an emphasis on its role in the process of T and B lymphocytes maturation. Other types of thymic cells are also described, including epithelial and myoid cells that presumably have a central role in initiation of an autoimmunologic process leading to myasthenic symptoms development. A detailed account is presented of issues concerning pathophysiology of myasthenia, the structure of nicotinic acetylcholine receptor (AchR) at neuromuscular junctions, and mechanisms underlying its destruction by autoantibodies. The role of T and B lymphocytes, of various cytokine types, of autoantibodies to various striated muscle antigens, as well as a possible role of genetic and bacterial factors in the development of myasthenia gravis are discussed. In conclusion it is stressed that since recent research findings go beyond the classic theory of myasthenia, a new consistent theory of the disease immunopathogenesis must be created in the future to place all the newly discovered phenomena in a logical conceptual structure.

[Combined effect of immobilization stress and gamma-irradiation on the blood-forming system in mice]. / Sochetannoe vliianie immobilizatsionnogo stressa i gamma-izlucheniia na krovetvornuiu sistemu myshei.

Experiments with mice BALB/C were aimed at studying effects of immobilization stress and consecutive total gamma-irradiation at the dose of 2.0 Gy. Disorders in the blood system were shown to be a function of phase of the general adaptation syndrome (GAS). Acute gamma-irradiation on the stage of GAS resistance inhibited adaptive and compensatory potentials of the blood-forming system, whereas chronic stress by itself increased the spontaneous rate of chromosomal aberrations in nucleus-containing bone marrow cells in experimental animals.

[Hypophyseal-adreno-gonadal system function in myasthenia patients with tumorous and nontumorous pathology of the thymus]. / Sostoianie gipofizarno-adrenogonadnoi sistemy u bol'nykh miasteniei pri opukholevoi i neopukholevoi patologii vilochkovoi zhelezy.

Overall twenty-five patients (all women) who ranged from 16 to 56 years old were examined. They were divided into two groups: group I was formed of subjects with hyperplasia of the thymus gland, group II--thymoma. Blood serum levels of prolactin, progesterone, estriol, estradiol, testosterone hydrocortisone. All patients showed a significant increase in average blood plasma levels of estrogens, testosterone and prolactin. Average levels of progesterone and hydrocortisone in patients with thymus hypertrophy were lower than in controls, while in thymoma patients these were much higher. The data submitted are indicative of substantial differences in the endocrine status of myasthenia patients depending on tumor or nontumor lesion of the thymus gland, which fact may suggest different pathogenetic mechanisms of development of the condition.

Timectomía y miastenia gravis / Thymectomy and myasthenia gravis

La miastenia gravis es una enfermedad autoinmune que se caracteriza por presentar fatiga y debilidad muscular progresiva. La alteración esencial es la disminución del número de receptores de la acetilcolina a nivel de las uniones neuromusculares, debido a la presencia de anticuerpos contra los receptores para la acetilcolina. Actualmente, se han demostrado alteraciones de la histología del timo que va de la hiperplasia tímica a la presencia de timoma. En el presente trabajo se reporta una serie de 43 casos que fueron sometidos a timectomía como parte del tratamiento de la miastenia gravis y los resultados obtenidos después del procedimiento, 38 (88.3 por ciento) mujeres y 5 (11.6 por ciento) hombres, respectivamente, con un promedio de edad de 32.4 años y rango de 17-58 años. Con un promedio de evolución del padecimiento de 22.33 meses. El diagnóstico histopatológico fue hiperplasia tímica en 34 (79 por ciento) casos, timo en involución en 2 (5 por ciento) casos, timoma maligno en 3 (7 por ciento) casos y timoma benigno en 4 (9 por ciento) casos. Todos los casos fueron valorados con telerradiografía de tórax, tomografía lineal en 3 casos (20.1 por ciento), tomografía axial computada y resonancia magnética nuclear. La dosis de piridostigmina se redujo en un promedio de 187.5 mg que equivale a un 76.84 por ciento de la dosis preoperatoria, demostrando que fue estadísticamente significativa p = < 0.0001. El volumen corriente mejoró el 21 por ciento en relación del volumen corriente preoperatorio posterior a la cirugía, estadísticamente significativo, p = < 0.0001. Hubo mejoría de la capacidad vital en un 9.73 por ciento, lo cual equivale a un 15.15 por ciento de mejoría en relación al nivel preoperatorio, mostrándose estadísticamente significativo p = < 0.0001. La fuerza inspiratoria postquirúrgica mejoró en relación a la cifra basal, siendo estadísticamente significativa p = < 0.0001. En un solo caso operado, se observó la no respuesta a la terapia con bromuro de piridostigmina

Hiperplasia tímica como causa de dificultad respiratoria en el neonato / Thymic hiperplasia how caused of respiratory distress syndrome in newborn

La hiperplasia tímica es una entidad clínica rara que puede tener distintos grados de agrandamiento tímico con o sin sintomatología presente. La sintomatología de la hiperplasia tímica en el neonato o lactante generalmente es leve, puede presentarse con taquipnea, estridor laríngeo, cianosis ocasional o alteraciones del ritmo cardíaco de evolución benigna. La hiperplasia tímica se diagnostica radiológicamente por exclusión en casos de dificultad respiratoria, cianosisi o alteraciones del ritmo cardiaco en lactantes y menos frecuente en neonatos. Con la administración de esteroides mejora o desaparece la sintomatología, así como en la radiología se observa disminución de la sombra tímica. El caso que presentamos se trata de un producto femenino a término macrosómico que nació por cesárea con líquido amniótico levemente teñido de meconio sin asfixia al nacimiento. A las dos horas de vida se detectó taquipnea que se manejó con un casco de oxigeno al 40 por ciento. A la exploración física, presentaba como único dato relevante la taquipnea. Se descartó sepsis y se encontró una pequeña fuga de aire en mediastino del lado izquierdo. Además se observó el mediastino ensanchado. A las 48 horas de vida, la fuga de aire estaba casi resuelta, pero el medistino permanecía ensanchado. Clínicamente estable, pero persistía la taquipnea con frecuencias respiratoria entre 90 y 100 por minuto. Al tercer día de vida continuaba clínicamente sin cambios, se repitió la radiografía de tórax encontrándose el parénqima pulmonar sin patología y el mediastino ensanchado. Se consideró el diagnóstico de hiperplasia tímica. Se inició tratamiento con esteroides. Al quinto día de vida y segundo de uso del esteroide, desapareció la taquipnea así como la imagen ensanchada del mediastino en la radiografía de tórax. Al octavo día de vida, se dio de alta completamente asintomático y con una radiografía de tórax normal. La hiperplasia tímica consideramos que debiera ser incluida en el diagnóstico diferencial de el síndrome de dificultad respiratoria del neonato.

Thymus hyperplasia, differential diagnosis in the wheezing infant

La hiperplasia del timo no es rara en la infancia, pero generalmente se considera que no causa síntomas. Presentamos en esta revisión una serie de 11 niños vistos en el Instituto Nacional de Pediatría, (INP) que sí tienen sintomatología respiratoria secundaria a hiperplasia del timo. Las primeras manifestaciones respiratorias se presentaron generalmente al nacimiento, pero la edad mediana a la cual acudieron al INP fue de seis meses, con crisis respiratorias y enfermedades respiratorias de repetición. Se realizó toracotomía en cinco niños y lobectomía pulmonar derecha fue necesaria en uno dado los cambios irreversibles del tejido pulmonar secundarias a compresión crónica. En otro paciente se realizó lobectomía tímica derecha, para aliviar la compresión extrínseca del bronquio superior derecho, causa de atelectasias recurrentes. Las cinco biopsias mostraron tejido tímico normal, hiperplásico o en involución, sin datos de malignidad. La evolución fue favorable en todos. En conclusión: la hiperplasia del timo forma parte del diagnóstico diferencial de un lactante con síntomas respiratorios

Hyperplasia of thymic gland.

Hyperplasia of the thymus is the most common anterior mediastinal mass in infants. It is however exceedingly difficult to evaluate by the weight of the gland as it continues to grow after birth until puberty and thereafter undergoes progressive atrophy. It normally maintains most of the radiographic characteristics of the normal thymus. Massive thymic hyperplasia, a rare variant of true thymic hyperplasia is extremely rare during the first two decades of life and clinically can cause mediastinal compression or acute and recurrent pulmonary infection. Two such cases are reported and the clinico-pathology is briefly described and discussed.

L-selectin and alpha 4 beta 7 integrin homing receptor pathways mediate peripheral lymphocyte traffic to AKR mouse hyperplastic thymus.

Before the development of thymic lymphoma, AKR mice undergo a striking lymphoid hyperplasia of the thymic medulla. We have previously shown that there is a marked increase in traffic of B and T lymphocytes from the periphery into the preneoplastic, hyperplastic thymuses of these mice, in contrast to the scant traffic of such cells to normal thymuses. The traffic of lymphocytes to lymph nodes and Peyer's patches is controlled in part by the interaction of lymphocyte adhesion molecules called homing receptors with their tissue-selective endothelial ligands known as vascular addressins. We have investigated the roles of homing receptors and vascular addressins in the traffic of lymphocytes to the AKR hyperplastic thymus. We demonstrate that development of hyperplasia is accompanied by an increase in the number of thymic medullary blood vessels with high endothelial venule morphology and expression of the peripheral node addressin (PNAd) and the mucosal addressin (MAdCAM-1). In vitro and in vivo functional assays show that the addressin/homing receptor pairs PNAd/L-selectin and MAdCAM-1/alpha 4 beta 7 are involved in lymphocyte traffic to the hyperplastic thymus. These results indicate that molecular adhesion mechanisms involved in tissue-selective migration of lymphocytes to peripheral lymph node and to mucosal lymphoid tissues play a role in the recruitment of B and T lymphocytes to the AKR thymus and thus in the pathogenesis of thymic hyperplasia.

[Role of the thymus in the physiopathology of myasthenia]. / Rôle du thymus dans la physiopathologie de la myasthénie.

In myasthenia gravis (MG), the frequency of histologic abnormalities (hyperplasia in young patients, thymoma in older cases) and clinical improvement after thymectomy indicate involvement of the thymus in the pathophysiology of the disease. MG patient thymuses are characterized by the following features: increased amount of B cells (in hyperplasia) and functional abnormalities, mainly activation of B, T and epithelial cells. Moreover, thymic lymphocytes are sensitized to acetylcholine receptor (AChR): first, AChR specific T and B lines can be grown from MG thymus cultures, second, cultured thymic lymphocytes proliferate in the presence of AChR and produce anti-AChR antibodies. AChR molecules are expressed in thymic myoid cells and AChR-like molecules could be displayed at the surface of other cell types. Thus, autosensitization conditions are combined in MG thymus, and potential mechanisms are discussed. It could be a primary event, autosensitization of lymphocytes to AChR taking place initially in the thymus. Or it could be a secondary process, lymphocytes sensitized to AChR in the periphery could be trapped by myoid cells and restimulated in the thymus. In thymoma, autoimmunization occurs differently: the autoimmune process could be initiated by the tumor epithelial cells which express an AChR-like protein. The possible role of severe architectural disturbance in MG thymus (particularly in thymoma), altering thymic lymphocyte selection and maturation is also discussed.

[Diffuse thymus hyperplasia following chemotherapy for nodular sclerosing Hodgkin lymphoma]. / Diffuse Thymushyperplasie nach Chemotherapie eines nodulär-sklerosierenden Hodgkin-Lymphoms.

A persistent or new mass in the anterior mediastinum after chemotherapy for mediastinal lymphoma poses a major differential diagnostic problem. Misinterpretation as a persistent or recurrent tumor may lead to additional unnecessary and potentially harmful therapy. Benign mediastinal tumors, albeit very rare, need confirmation by biopsy since they cannot be distinguished by radiological methods from persistence or relapse of lymphoma. We present a case report of a patient with diffuse thymic hyperplasia following successful chemotherapy for nodular sclerosing Hodgkin's disease, with a review of the literature.

Tests for juvenile myasthenia gravis: comparative diagnostic yield and prediction of outcome.

The clinical picture, family history, laboratory data, treatment modalities, and outcome in 27 juvenile myasthenics seen over a 25-year period are presented. Onset was after 10 years of age in the majority of patients. Half presented with ocular signs, the other half with generalized-onset myasthenia. Half of those with ocular-onset myasthenia progressed to generalized myasthenia. The female-to-male ratio was 3.5:1. Myasthenia gravis was reported in the mother of one patient. Ptosis was the most common presenting sign. It was unilateral at onset in 33% of patients and remained unilateral in 11%. Pharmacologic tests (neostigmine methylsulfate and edrophonium chloride) were positive in 92% of patients. Serology was positive in 63%, whereas repetitive nerve stimulation was positive in 33% when distal nerves were stimulated and in 66% when proximal and distal nerves were stimulated. Seropositivity tended to increase with generalization of the myasthenic process. No statistically significant difference in seropositivity was noted between males and females. Anti-striated muscle antibodies were detected in two patients, neither of whom had thymoma. The yield of repetitive stimulation increased with generalization of the myasthenic process and when proximal nerves were stimulated. No statistically significant difference was noted in the decremental response between seropositive and seronegative patients. The majority of ocular myasthenics were treated with pyridostigmine bromide monotherapy. With generalization of the myasthenic process, other modes of medical and surgical therapies were needed. All patients given corticosteroids ultimately underwent thymectomy. The mean age at presentation and the duration of symptoms at presentation were longer in thymectomized patients than in those without thymectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

[Characteristics of hormonal homeostasis in children with thymus enlargement syndrome]. / Osobennosti gormonal'nogo gomeostaza u detei s sindromom uvelicheniia vilochkovoi zhelezy.

Hormonal homeostasis was examined in 104 children aged 1 to 14 years with thymus enlargement. There was a significant growth of somatotropic hormone in children of the first 3 years of life, characterized by thyroid dysfunction and hypofunction increase with age, by a tendency towards ACTH and hydrocortisone lowering under 6 years of age, and a significant decrease of those parameters in children over 6 years. The children with thymus enlargement also showed other disorders of hormonal homeostasis.