Dual role of the IL-12/IFN-gamma axis in the development of autoimmune myocarditis: induction by IL-12 and protection by IFN-gamma.

IL-12 and IFN-gamma positively regulate each other and type 1 inflammatory responses, which are believed to cause tissue damage in autoimmune diseases. We investigated the role of the IL-12/IFN-gamma (Th1) axis in the development of autoimmune myocarditis. IL-12p40-deficient mice on a susceptible background resisted myocarditis. In the absence of IL-12, autospecific CD4(+) T cells proliferated poorly and showed increased Th2 cytokine responses. However, IFN-gamma-deficient mice developed fatal autoimmune disease, and blockade of IL-4R signaling did not confer susceptibility to myocarditis in IL-12p40-deficient mice, demonstrating that IL-12 triggers autoimmunity by a mechanism independent of the effector cytokines IFN-gamma and IL-4. In conclusion, our results suggest that the IL-12/IFN-gamma axis is a double-edged sword for the development of autoimmune myocarditis. Although IL-12 mediates disease by induction/expansion of Th1-type cells, IFN-gamma production from these cells limits disease progression.

Human leukocyte antigen G up-regulation in lung cancer associates with high-grade histology, human leukocyte antigen class I loss and interleukin-10 production.

Immune evasion in lung cancer results from both structural and functional alterations of human leukocyte antigen (HLA) class I molecules and the local release of immunosuppressive cytokines. Recent data suggest that HLA-G, a nonclassical class Ib molecule, is involved in immune evasion by tumor cells. We sought to determine whether HLA-G could contribute to immunescape in lung cancer. All of 19 tumor specimens examined demonstrated detectable membrane-bound (HLA-G1), as well as soluble (HLA-G5) isoform transcription. Nine of 34 (26%) tumors were positive by immunohistochemistry using monoclonal antibody (mAb) 4H84, recognizing all denatured HLA-G isoforms, of which six were positive using mAb 16G1, recognizing soluble HLA-G. HLA-G immunoreactivity correlated with high-grade histology, with HLA-G being preferentially expressed on large-cell carcinomas. In these patients, loss of classical HLA class I molecules was observed to associate with HLA-G protein up-regulation. Moreover, we found interleukin-10 expressed in 15 of 34 (44%) tumors, and in most of the HLA-G-positive cases (7 of 9), suggesting up-modulation of HLA-G by interleukin-10. It is conceivable that HLA-G expression in lung cancer might be one of the ways how the tumor down-regulates host immune response, in addition to interleukin-10 production and HLA class I loss.

Lethal autoimmune myocarditis in interferon-gamma receptor-deficient mice: enhanced disease severity by impaired inducible nitric oxide synthase induction.

BACKGROUND: Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease. METHODS AND RESULTS: We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease. The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts. Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis. CONCLUSIONS: Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.

[Malignant lymphoma of the larynx: a case report and review of the literature]. / Das maligne Lymphom des Larynx: Fallbericht und Literaturübersicht.

BACKGROUND: Malignant lymphoma of the larynx are rare tumors and represent less than 1% of primary malignant laryngeal tumors. CASE REPORT: In this case report we present a case of a diffuse large B-cell lymphoma of the larynx. Clinical presentation, diagnostic approach, staging and differential diagnosis as well as therapy and prognosis are discussed in relation to the available literature. CONCLUSIONS: Lymphomas primary to the larynx are non-Hodgkin-lymphomas and are predominantly located in the supraglottic larynx. The presenting symptoms and signs include dysphagia, dysphonia, dyspnea which on occasion can be severe, and enlarged cervical lymphoma. B-symptoms are mostly not present. Indirect laryngoscopy reveals a globoid submucosal faintly pink tumor mass. The diagnosis rests on histological examination of a biopsy specimen. Benign tumors, squamous cell carcinoma and other lymphoproliferative diseases have to be excluded from the differential diagnosis. Extensive tumor staging is necessary before radiotherapy or chemotherapy. Surgery is not indicated, even in localized disease. Prognosis is good in the most often localized laryngeal non-Hodgkin-lymphomas (stage IE and IIE) and generalization is rare. Hence, supraglottic submucosal laryngeal tumors can represent non-Hodgkin-lymphomas. Biopsy and subsequent histological examination are essential for correct diagnosis.

Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model.

Arterial inflammatory responses are thought to be a significant component of atherosclerotic disease. We describe here, using a transgenic approach, the mutual perpetuation of immune-mediated arterial inflammation and cholesterol-induced atherosclerosis. Mice expressing the bacterial transgene beta-galactosidase exclusively in cardiomyocytes and in smooth muscle cells in lung arteries and the aorta (SM-LacZ), and hypercholesterolemic apolipoprotein E-deficient SM-LacZ mice (SM-LacZ/apoE(-/-)) developed myocarditis and arteritis after immunization with dendritic cells presenting a beta-galactosidase-derived immunogenic peptide. Hypercholesterolemia amplified acute arteritis and perpetuated chronic arterial inflammation in SM-LacZ/apoE(-/-) mice, but had no major impact on acute myocarditis or the subsequent development of dilated cardiomyopathy. Conversely, arteritis significantly accelerated cholesterol-induced atherosclerosis. Taken together, these data demonstrate that the linkage of immune-mediated arteritis and hypercholesterolemia favors initiation and maintenance of atherosclerotic lesion formation. Therapeutic strategies to prevent or disrupt such self-perpetuating vicious circles may be crucial for the successful treatment of atherosclerosis.

[Diagnosis and course of myocarditis: a survey in the medical clinics of Zurich University Hospital 1980 to 1998]. / Diagnose und Verlauf bei Myokarditis: eine Erhebung in den Medizinischen Kliniken des Universitätsspitals Zürich im Zeitraum von 1980 bis 1998.

The clinical picture of myocarditis/myopericarditis is of importance in differential diagnosis, especially in younger patients with suspected myocardial infarction. Myocarditis/myopericarditis commonly presents with chest pain, and the diagnosis is usually established on clinical grounds. However, endomyocardial biopsy is necessary to confirm the diagnosis. We evaluated the characteristics of acute myocarditis over the years 1980-1998 in 54 patients of the Department of Medicine of the University Hospital, Zurich. Two to 6 patients per year were hospitalised with this diagnosis. In most cases the diagnosis was established by a combination of criteria, such as a preceding infection of the upper respiratory tract, thoracic pain, ST segment elevations in different precordial leads followed by T wave inversions, arrhythmias, elevation of cardiac enzymes, reversible hypokinesia by echocardiography and normal coronary arteries. At least 3 of 5 criteria were requested. In a first step we analysed retrospectively all patients with acute myocarditis/myopericarditis in the years 1980-1993. Among 30 cases of acute myocarditis/myopericarditis the following causes could be identified: one influenza B, one Toxoplasma gondii infection, 2 Epstein-Barr infections and one bacterial myocarditis with gram-negative rods. The aetiology of the other 25 cases remained unknown. The majority of myocarditis/myopericarditis healed without complications. One patient with Epstein-Barr myocarditis and one with Toxoplasma gondii infection died. Two patients developed dilated cardiomyopathy. In a second phase we analysed prospectively all cases with acute myocarditis/myopericarditis over the period 1994-1998: 24 patients with acute myocarditis/myopericarditis were hospitalised. At that time coronary angiography and endomyocardial biopsies were performed more frequently. We found 2 patients with giant cell myocarditis and 2 with Toxoplasma gondii infection and HIV, all of whom died. In addition, there were 2 patients with eosinophilic myocarditis, one with Lyme carditis, one with Epstein-Barr myocarditis, one with myopericarditis after Campylobacter enteritis and one histologically proven myocarditis after pneumonia with Haemophilus influenzae. The aetiology of the remaining 13 cases with myocarditis/myopericarditis could not be established. Three patients with probable viral myocarditis developed cardiogenic shock requiring intraaortic balloon pump, and fully recovered. The patient with Lyme carditis manifested with total atrioventricular block and was treated with a temporary pacemaker. One patient with lymphocytic myocarditis required heart transplantation because of terminal heart failure and one female patient with histologically proven diffuse lympho-monocytic myocarditis died of cardiogenic shock. All the other cases healed without complications. Serologies are of little diagnostic value and should be restricted to serologies with therapeutic implications. We believe that the apparent increase in myocarditis/myopericarditis in recent years is a result of better diagnostic tools, such as more specific cardiac enzyme tests, coronary angiography and endomyocardial biopsies. In most cases the therapy remains symptomatic. In elected, severe cases steroids and other immunosuppressive drugs are sometimes used.

Malakoplakia of the colon in an infant with severe combined immunodeficiency (SCID) and charge association.

We report on malakoplakia of the colon observed in a six month old girl in a setting of severe combined immunodeficiency (SCID) and a malformational syndrome termed CHARGE association. By the age of six months, hemorrhagic diarrhea had developed, and multiple ulcers were seen at colonoscopy. The biopsy specimen showed ulcerating malakoplakia. Immunodeficiency was primarily reflected by deprivation of CD4 cells in the peripheral blood, and CT scans failed to detect structures consistent with a normal thymus. There were also polylymphadenopathy and chronic erythroderma. The lymph node showed extreme hypoplasia of the follicular cortex and marked expansion of the paracortex. B cell counts progressively declined, and plasma cells were absent both in intact mucosa of the colon and in a lymph node. The patient died at eighteen months of respiratory failure following recurrent airway infections. Pediatric malakoplakia of the colon, though rare, may be regarded as an example of opportunistic bacterial infection in an immunocompromised host. Combined immunodeficiency (CID) has to be considered in such instances, in particular when malformational syndromes coexist affecting the development of the thymus.

Primary cutaneous T-cell-rich B-cell lymphoma and Hodgkin's disease in a patient with Gardner's syndrome.

A 50-year-old patient, suffering from familial polyposis (Gardner's syndrome), initially presented with several nodules on his left arm. Histological examination revealed primary cutaneous T-cell-rich B-cell lymphoma (TCRBCL). Staging procedures failed to detect any systemic involvement. Three years after total excision of the tumours, the patient presented with a non-specific dermatitis, enlarged axillary lymph nodes and splenomegaly. Histological and immunohistochemical examination of lymph node and spleen biopsy specimens resulted in the diagnosis of Hodgkin's disease (HD) of the nodular sclerosis type. Sequence analysis of single cells micromanipulated from skin and from lymph node lesions indicated that both lymphoma infiltrates were derived from the same precursor germinal centre B-cell clone. This is a case showing a clonal relationship between TCRBCL and HD, providing support to the B-cell origin of Hodgkin and Reed-Sternberg cells.

Assessment of peritoneal tolerance of a new MR blood pool contrast agent in rabbits.

OBJECTIVE: Fast 3D MR angiography in conjunction with a new blood pool contrast agent (iron oxide crystals) is a recently described method for detection and localization of intra-abdominal bleeding sites with high sensitivity and specificity. However, peritoneal reactions to the contrast agent have not yet been investigated. The purpose of this study was to assess the peritoneal tolerance of the contrast agent in an animal experiment. METHODS: Eleven rabbits were intraperitoneally injected with 5 mL diluted NC100150 Injection; two rabbits were used as the control group. Rabbits injected with NC100150 Injection were imaged in pairs at 12, 24, and 48 hours and 3 weeks, and a single rabbit was imaged at 72 hours and 1 and 2 weeks after the intraperitoneal administration of the agent. Immediately after imaging, the rabbits were killed and an autopsy was performed. Samples of peritoneal surfaces and intra-abdominal organs were harvested for histology. MR imaging, gross pathology, and histology were evaluated. RESULTS: MR imaging and gross pathology demonstrated the presence of intraperitoneal contrast agent up to 24 hours after administration. Histology revealed a considerable amount of iron in the peritoneum, mesenteric fat, and lymph nodes within the first 24 hours. In most cases, iron was rapidly cleared from these sites within 2 days; in one animal, however, iron was detectable up to 1 week. No signs of inflammation or fibrosis were detected. CONCLUSIONS: This study shows no evidence of inflammatory reactions or signs of fibrosis after the intraperitoneal application of NC100150 Injection.

Selection and immunomagnetic purging of peripheral blood CD34+ cells for autologous transplantation in B-cell non-Hodgkin's lymphomas.

BACKGROUND: Clonogenic tumor cells in the hematopoietic progenitor cell harvest may contribute to relapse after high dose therapy for B-cell malignancies. Purging of the HPC harvest requires large amounts of anti-B-cell antibodies, whereas CD34-selection enriches self renewing HPC's but malignant cells are still detectable in many CD34+ fractions. PATIENTS AND METHODS: We examined the feasibility and safety of a CD34-selection followed by purging with anti B-cell antibodies in 11 patients with B-cell non-Hodgkin's lymphomas undergoing high-dose therapy with cyclophosphamide, BCNU and etoposide with retransfusion of autologous HPC's. RESULTS: A mean number of 340 x 10(8) mononuclear cells was used for CD34-selection and immunomagnetic purging. CD34+ cells were enriched from a mean of 1.7% (range 0.2%-4.5%) to a mean of 68% (range 49%-87%) with a mean recovery of 27% (range 15%-43%). The mean number of retransfused CD34+ cells was 1.2 x 10(6)/kg (range 0.6-2.2 x 10(6)/kg) body weight with a median of 11 days (range 10-13 days) to neutrophil recovery of 0.5 x 10(9)/l and 17 days (range 13-25 days) to platelet recovery of 50 x 10(9)/l. Mean number of intravenous antibodies and inpatient days were 8 (range 0-14) and 22 (range 19-26) respectively. Major toxicity consisted in four septicemias. CONCLUSIONS: CD34-selected and purged HPC's are safe and mediate rapid hematological recovery after high dose therapy for B-cell non-Hodgkin's lymphomas.

T helper 2 (Th2) T cells induce acute pancreatitis and diabetes in immune-compromised nonobese diabetic (NOD) mice.

Autoimmune diabetes is caused by the CD4(+), T helper 1 (Th1) cell-mediated apoptosis of insulin-producing beta cells. We have previously shown that Th2 T cells bearing the same T cell receptor (TCR) as the diabetogenic Th1 T cells invade islets in neonatal nonobese diabetic (NOD) mice but fail to cause disease. Moreover, when mixed in excess and cotransferred with Th1 T cells, Th2 T cells could not protect NOD neonates from Th1-mediated diabetes. We have now found, to our great surprise, the same Th2 T cells that produced a harmless insulitis in neonatal NOD mice produced intense and generalized pancreatitis and insulitis associated with islet cell necrosis, abscess formation, and subsequent diabetes when transferred into immunocompromised NOD.scid mice. These lesions resembled allergic inflamation and contained a large eosinophilic infiltrate. Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4. These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease. Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants.

Beta cell apoptosis in T cell-mediated autoimmune diabetes.

Insulin-dependent diabetes mellitus results from T cell-mediated destruction of insulin-producing, pancreatic islet beta cells. How this destruction takes place has remained elusive--largely due to the slow kinetics of disease progression. By crossing a transgenic mouse carrying a beta cell-specific T cell receptor onto the NOD.scid background, we produced a simplified but robust and accelerated model of diabetes. This mouse produces CD4+ T cells bearing transgenic T cell receptor but is devoid of CD8+ T cells and B cells. More importantly, this mouse develops a rapid diabetes, which has allowed us to record and quantify beta cell death. We have determined that beta cells within the inflamed islets die by apoptosis.

Congenital pancreatic pseudocyst: report of two cases.

Pancreatic pseudocysts have not been reported to occur in the fetus or newborn. The authors report two cases of histologically proven pancreatic pseudocysts in neonates, which were detected using prenatal ultrasonography. Surgical management included external marsupialization followed by internal drainage in one case, and excision in the other. Both patients ultimately did well. The etiology of these lesions remains unclear.

Magnetic resonance imaging and intraoperative frozen sections in intratemporal facial schwannomas.

Seven cases of intratemporal facial schwannoma were assessed by preoperative magnetic resonance imaging (MRI) and intraoperative frozen sections to determine tumor boundaries. These results were then analyzed with respect to gross tumor appearance, under the operating microscope, and final histopathologic diagnosis, with immunostains. Gadolinium-enhanced MRI was helpful in planning the surgical and approach and in defining the extent of tumor involvement relative to the facial nerve. Frozen sections on the other hand were often unreliable in confirming the completeness of resection, frequently overestimating tumor infiltration. Ultimately, tumor-nerve interface, especially in the proximal facial segments, is best judged by its gross intraoperative appearance under high magnification, with the aid of MRI. The difficulty in establishing tumor infiltration in the presence of organized neutral fibers and artifacts is emphasized. Immunohistochemical assays are essential in this regard. Complete tumor removal was achieved in all seven cases, with acceptable functional outcome in those with sufficiently long follow-up.