Increased capacity for interleukin-2 synthesis parallels disease progression in mice infected with Leishmania major

Lymph node cells of BALB/c mice with progressive leishmaniasis produced sixfold more interleukin-2 (IL-2) in culture than those of healing C57BL/6 mice. IL-2 synthesis also increased in C57BL/6 mice made susceptible by IL-12 or gamma interferon deficiency. However, IL-2 mRNA levels in vivo did not reflect IL-2 production in vitro. Because IL-2 contributes to the pathogenesis of progressive leishmaniasis, the functional significance of these findings should be further explored.     

Macrophages in mice acutely infected with lymphocytic choriomeningitis virus are primed for nitric oxide synthesis

Following infection of adult mice with lymphocytic choriomeningitis virus (LCMV) there is a well documented suppression of T-cell and B-cell functions concurrent with the strong anti-LCMV immune response. Macrophages have been shown to be infected and activated during acute LCMV infection and there is some evidence to indicate that there is altered antigen presentation in acutely infected mice. We have examined nitric oxide (NO) production by splenic macrophages during acute infection of adult mice. Our results show that these macrophages are primed for production of NO, that the inducible production of NO parallels the immune suppression, and that NO production is dependent on the presence of IFN gamma. However, neither in vivo nor in vitro treatment with N-monomethyl-L-arginine (NMA), a specific inhibitor of nitric oxide synthase, altered the induction or maintenance of virus-induced immune suppression in mice acutely infected with LCMV.     

Trypanosoma cruzi-induced immunosuppression: blockade of costimulatory T-cell responses in infected hosts due to defective T-cell receptor-CD3 functioning

A model of experimental Trypanosoma cruzi murine infection with chemically induced metacyclic forms (opossum clone Dm28c) showed a marked state of T-cell unresponsiveness during acute phase, but lacked evidence of suppressor cell activity. Spleen cells from infected mice were suppressed in vitro in responses to T-cell activators concanavalin A, anti-Thy1 monoclonal antibody (MAb), and anti-CD3 MAb compared with spleen cells from control littermates. Activation with accessory cell-independent stimulus provided by immobilized anti-CD3 was defective in splenic CD4-positive T cells from infected mice, but not in such cells from control mice. No evidence of splenic suppressor cell activity was found in cell-mixing experiments using nylon-passed T cells from control and infected donors. Kinetic experiments showed that there was a discrete stage in infection when T cells were already suppressed in response to anti-CD3 but still responded to anti-CD69 MAb. In these T cells, immobilized anti-CD3 failed to enhance simultaneous CD69 responses, although anti-CD3 enhanced CD69 responses in control T cells from uninfected donors. These results demonstrate an intrinsic defect in T-cell receptor-mediated T-cell activation, which could be a mechanism generating T-cell suppression during infection by T. cruzi.     

Corneal transplantation in antibody-deficient hosts

PURPOSE: To examine the role of donor-specific antibodies, with or without complement, in rejection of orthotopic corneal transplants by using mice as recipients in which the genes for the heavy chain of immunoglobulin or the third complement component have been eliminated by homologous recombination. METHODS: BALB/c corneas were transplanted into eyes of B-cell-deficient (n=17) or wild-type control C57BL/6 (n=30) mice and into eyes of complement (C3)-deficient (n=15) or wild-type control 129-C57BL/6 (n=13) mice. After surgery all grafts were evaluated over 8 weeks in a masked manner by biomicroscopy for signs of rejection. RESULTS: The rates of corneal transplant rejection were similar among B-cell-deficient and C3-deficient mice compared with rejection rates in their respective wild-type control subjects. This similarity applied to the time course of rejection and to cumulative survival rates. CONCLUSIONS: Neither donor-specific antibody nor the third component of complement play essential roles in acute rejection of orthotopic corneal allografts in mice.     

Immunologic phenotype of hosts orally immunized with corneal alloantigens

PURPOSE: To evaluate the immunologic phenotype of hosts tolerized by oral administration of corneal alloantigens. METHODS: CB6F1 mice were tolerized by oral administration of allogeneic C3H/Hej corneal epithelial and endothelial cells before receiving heterotopic C3H/Hej corneal allografts. C3H-specific cytotoxic T-lymphocyte (CTL), delayed-type hypersensitivity (DTH), and mixed-lymphocyte responses were evaluated in orally tolerized and control mice. Cytokine profiles of Peyer's patch cells from orally tolerized mice were determined by enzyme-linked immunosorbent assay and mink lung cell culture bioassay. RESULTS: Oral administration of corneal cells produced a profound inhibition of allospecific CTL, DTH, and mixed-lymphocyte responses. Conjugation with the B subunit of cholera toxin markedly increased the tolerizing activity of corneal endothelial cells, so that a single dose of cholera toxin-conjugated corneal cells inhibited alloimmune responses to the same degree as 10 doses of corneal cells unconjugated with cholera toxin. Peyer's patch cells from orally tolerized mice produced reduced quantities of interferon-gamma and interleukin-2 but produced increased amounts of transforming growth factor-beta and interleukin-10 compared with concentrations in normal control animals. CONCLUSIONS: Oral administration of cholera toxin-conjugated corneal cells produces a dose-dependent inhibition of allospecific CTL, DTH, and mixed-lymphocyte responses. Orally induced inhibition of cell-mediated immune responses to corneal alloantigens is correlated with a sharp increase in the secretion of transforming growth factor-beta and interleukin-10 and a concomitant suppression of interleukin-2 and interferon-gamma. The well-recognized immunosuppressive characteristics of transforming growth factor-beta and interleukin-10 are suggestive that orally induced tolerance to corneal alloantigens is mediated by these cytokines.     

Lymphohematopoietic engraftment in minimally myeloablated hosts

Interferons (IFNs) are now in use worldwide for the treatment of chronic viral hepatitis. Unfortunately, various side effects of IFNs have been reported. Because cytokines, which include IFNs, can affect endocrine function, endocrinological abnormalities are sometimes observed in patients treated with IFNs. We examined the effects of IFN-beta on peripheral levels of pituitary and adrenal hormones and cytokines. Six million international units of IFN-beta dissolved in glucose solution was injected for 30 min. As a control study, glucose solution without IFN-beta was injected. Pituitary hormones (ACTH, GH, TSH, prolactin (PRL), LH, FSH, and arginine-vasopressin (AVP)), cortisol, and cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF), and interleukin-1 receptor antagonist (IL-1ra) were measured before and after IFN-beta injection. The study was carried out on 14 patients with chronic hepatitis type C who were under treatment with IFN-beta. All studies were performed when the patients were afebrile. None of the patients had any endocrine or autoimmune diseases. Plasma ACTH levels increased significantly at 60-120 min after IFN-beta injection compared with the levels before IFN-beta injection and in the control study using glucose injection. Plasma cortisol levels increased after IFN-beta injection, in parallel with plasma ACTH elevation. Serum GH levels increased significantly at 120 min after IFN-beta injection. All the increased hormones including ACTH, cortisol, and GH, were decreased at the end of the study-180 min after IFN-beta injection. Serum levels of TSH, PRL, LH, FSH, and AVP were not changed significantly by IFN-beta injection. Plasma IL-1 and TNF levels did not change after IFN-beta injection, while IL-6 and IL-1ra were elevated significantly. The increases in IL-6 and IL-1ra were gradual, reaching their peak levels at 180 min after IFN-beta injection. However there were no correlations between the hormones measured in this study and the levels of IL-6 or IL-1ra. It would seem that IFN-beta has direct or indirect stimulatory effects for ACTH and GH without mediation of the cytokines. These in vivo results are important for investigating the relationship between endocrine and cytokine systems in humans.     

Nail changes in patients infected with human immunodeficiency virus. A prospective controlled study

OBJECTIVES: To study the frequency of nail changes in a population of human immunodeficiency virus (HIV)-infected patients and to evaluate the specificity of these findings by comparison with HIV-negative control subjects. DESIGN: Prospective controlled study. Nail changes were recorded by a standardized clinical examination (curvature, nail plate, color, onychomycosis). In case of clinical diagnosis of onychomycosis, mycological culture was performed. SETTING: Primary care university hospital. PATIENTS: A total of 155 HIV-1-positive patients and 103 healthy HIV-negative control subjects of comparable age and sex ratio. INTERVENTION: None. MAIN OUTCOME MEASURE: Clinical examination findings. RESULTS: Nail symptoms were present in 67.7% of HIV-positive patients vs 34.0% of controls (P < .001). The following symptoms were significantly more frequent in the HIV group: clubbing (5.8%) (P < .05), transverse lines (7.1%) (P < .01), onychoschizia (7.1%) (P < .05), leukonychia (14.3%) (P < .001), and longitudinal melanonychia (14.8%) (P < .01). The main finding was onychomycosis in 30.3% of patients vs 12.6% of controls (P < .001). Trichophyton rubrum was present in 48% of onychomycoses and unusual Candida species were also recorded. Multiple fungi were frequently cultured in a single patient. The mean CD4+ cell count was lower in patients with onychomycosis and the frequency of onychomycosis increased in advanced stages of HIV disease. Acquired total leukonychia of the 20 nails was present in 4% of patients. CONCLUSION: Nail symptoms are much more frequent in patients with HIV than in healthy controls, and some of them could be linked to the level of immunosuppression.     

Human cytomegalovirus inhibits cellular DNA synthesis and arrests productively infected cells in late G1

Human embryonic lung fibroblasts (LU) can be productively infected with human cytomegalovirus (HCMV). During the course of productive infection, the virus elicits a number of responses that resemble certain aspects of G1 cell cycle progression. The virus activates cyclin E/Cdk2 kinase in both subconfluent, serum-arrested, and density-arrested cultures. Activation of cyclin E-dependent kinase is due, in part, to induction of cyclin E and, in part, to inhibition of the cyclin kinase inhibitors, Cip1 and Kip1. However, G1 progression is incomplete in HCMV-infected cells. Neither cyclin A nor cyclin D is induced, and cellular DNA synthesis does not occur if one takes care to avoid addition of fresh serum to serum-starved cultures. The data indicate that the virus induces a state of late G1 arrest, in which cyclin E/Cdk2 activates nucleotide metabolism and other biosynthetic processes that are necessary for viral replication. Failure to activate host cell DNA synthesis ensures that the virus will have uncompleted access to such precursors.     

Hematopoietic remodeling in interferon-gamma-deficient mice infected with mycobacteria

Control of intracellular bacterial infections requires interferon-gamma (IFN-gamma) both for establishing a Th1 T-cell response and for activating macrophages to kill the bacteria. Exposure of mice deficient in IFN-gamma to mycobacterial infection produces an immune response characterized by a Th2 T-cell phenotype, florid bacterial growth, and death. We report here that IFN-gamma-deficient mice infected with mycobacteria also undergo a dramatic remodeling of the hematopoietic system. Myeloid cell proliferation proceeds unchecked throughout the course of mycobacterial infection, resulting in a transition to extramedullary hematopoiesis. The splenic architecture of infected IFN-gamma-deficient mice is completely effaced by expansion of macrophages, granulocytes, and extramedullary hematopoietic tissue. These features coincide with splenomegaly, an increase in splenic myeloid colony-forming activity, and marked granulocytosis in the peripheral blood. Systemic levels of cytokines are elevated, particularly interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF). These results suggest that in addition to its central role in cellular immunity, IFN-gamma may be a key cytokine in coordinate regulation of immune effector cells and myelopoiesis. This model should be valuable for deciphering the cross-talk between the immune response and hematopoiesis during bacterial infection and for improving our understanding of the mechanisms that control chronic infections.     

Anti-liver antibody in rabbits infected with Schistosoma japonicum

Anti-liver antibody has been demonstrated in the sera of Schistosoma japonicum-infected rabbits. By the 8th week after exposure to cercariae, perceptible levels of autoantibody were present and appeared to be direct predominantly determinants located in the cell membrane of the hepatocyte.     

Epstein-Barr virus-associated dural leiomyosarcoma in a man infected with human immunodeficiency virus. Case report

A 35-year-old man infected with human immunodeficiency virus presented with cervical myelopathy of 2 months duration. Clinical and radiographic evaluation revealed a discrete, subdural mass at C-6. At surgery, the mass proved to have a dural attachment and thus clinically, radiographically, and grossly, it resembled meningioma. Histopathological analysis revealed a leiomyosarcoma that stained diffusely for muscle-specific actin. Electron microscopy revealed basal lamina surrounding the tumor cells and intracytoplasmic bundles of myofilaments. Epstein-Barr virus (EBV) was demonstrated within tumor cell nuclei by in situ hybridization for EBER1 messenger RNA and immunohistochemical staining for EBNA2 protein. Epstein-Barr virus latent membrane protein (LMP1) was not detected. This is the first documentation of an EBV-associated smooth-muscle tumor of the dura, and the first demonstration that tumors in this location contain EBV in an unusual form of latency not seen in lymphoid cell lines. With increasing numbers of individuals being afflicted with long-term immunosuppression, EBV-associated dural leiomyoma and leiomyosarcoma may be encountered more frequently in the future.     

Cytokine regulation on the synthesis of nitric oxide in vivo by chronically infected human polymorphonuclear leucocytes

1 We tested the hypothesis that lowering antioxidant protection through dietary vitamin E deprivation would alter active and passive mechanical properties in resistance arteries of the rat. Specifically, we hypothesized that vascular tone in isolated mesenteric arteries of the vitamin E-deprived rats would be altered due to impaired endothelial influences of nitric oxide and/or prostaglandins. 2 Lumen diameter and wall thickness were measured in pressurized arteries (approximately 250 microm diameter) from control (n=9) and vitamin E deprived (n=9) Sprague-Dawley female rats by use of a dimension analysing system. 3 Treatment with a cyclo-oxygenase inhibitor (meclofenamate) did not affect the basal vascular tone in either group. Treatment with a nitric oxide synthase inhibitor (NG-methyl-L-arginine) caused a significant increase in basal tone only in the vitamin E-deprived rats (% tone: 6.2+/-1.1 vs 1.2+/-0.3%; P<0.05). When tone was induced to 25% of the initial diameter with phenylephrine, treatment with the nitric oxide synthase inhibitor resulted in a greater potentiated tone in the vitamin E-deprived rats compared to the controls (26.5+/-2.7 vs 16.4+/-3.4%; P<0.05); suggesting a greater nitric oxide affect in the vessels from the vitamin E-deprived rats. Meclofenamate treatment in the induced tone arteries significantly relaxed (-17.4+/-4.0%; P<0.05) only the arteries from the vitamin E-deprived rats, indicating that a vasoconstrictor was modifying tone. The passive characteristics of distensibility and stress-strain relationship were not different between the two groups of rats. 4 In summary, vitamin E deprivation in the rat enhanced the modulation of vascular tone by both the nitric oxide and cyclo-oxygenase pathways but did not alter passive characteristics of mesenteric arteries.     

Prevalence and incidence of cytomegalovirus infection in patients infected with HIV-1. SEROCO group

OBJECTIVES: To study prevalence of the cytomegalovirus (CMV) infection as well as incidence of the CMV seroconversions in HIV-infected subjects enrolled in the French multicentric cohort SEROCO. METHOD: Prevalence of CMV infection at inclusion in the cohort was estimated from 1504 HIV-infected subjects. Incidence of the CMV seroconversion was estimated from 184 subjects CMV seronegative at inclusion. Cox model was used to identify independent factors related to CMV seroconversion. RESULTS: CMV prevalence was high (87.2%) mainly in homosexual men. The incidence of the CMV seroconversions was also high (9, 18/100 person-years), particularly in homosexual men, in subjects declaring sexual intercourse with occasional partner, and in those declaring a sexually transmitted disease during the follow-up. CONCLUSION: The risk to develop serious disease related to CMV in subjects with AIDS being particularly high when the CMV primary infection occurs during the course of the HIV infection, the prevention of CMV primary infections is thus a major element in the counselling of HIV-infected subjects.     

Nitric oxide synthesis is depressed in Bos indicus cattle infected with Trypanosoma congolense and Trypanosoma vivax and does not mediate T-cell suppression

Infection with African trypanosomes causes the diseases sleeping sickness in humans and nagana in cattle in sub-Saharan Africa. Suppression of cellular immune responses is a feature of trypanosomiasis in bovine, human, and murine hosts. Some aspects of immunosuppression in the murine model are mediated by nitric oxide (NO) produced by gamma interferon (IFN-gamma)-activated macrophages. We have investigated whether a similar mechanism is responsible for T-cell unresponsiveness in bovine trypanosomiasis. Bovine monocytes and macrophages from uninfected cattle and activated in vitro with IFN-gamma produced NO; however, this response was down-regulated in infected cattle. Similarly, the expression of inducible NO synthase messenger RNA was depressed in macrophages of infected cattle. Proliferation of mononuclear cells of trypanosome-infected cattle cultured with mitogen or trypanosome antigens was unchanged by the addition of an NO synthase inhibitor. Lymphocytes of infected cattle secreted interleukins with T-cell growth factor activity after in vitro activation with mitogens but not after activation with trypanosome antigens. Although lymph node cells secreted IFN-gamma after in vitro activation, ex vivo expression of mRNA was depressed. In contrast, the level of expression of interleukin 10 mRNA was higher during infection. We conclude that NO is not involved in the loss of T-cell proliferative function associated with trypanosomiasis in cattle and that, in contrast to the mouse model, the capacity of monocytes and macrophages to produce NO is actually down-regulated in infected cattle.     

Electron microscopy of surface structures of Blastocystis sp. from different hosts

Samples of Blastocystis sp. obtained from humans, monkeys, pigs and chickens were examined by scanning electron microscopy and transmission electron microscopy to compare surface structures. The surface coat of Blastocystis sp. cells from each host species showed some morphological variations, but these were not sufficiently different to allow judgement to be made on speciation. The surface structure morphology appeared similar for samples of Blastocystis sp. from the same host species. The surface coat of the cultured human isolate of B. hominis was much thinner than that of cells from fresh human faecal material, and the cell surface appeared to be smoother and without the small projections seen in the fresh forms. Bacteria were frequently found in association with the surface coat of Blastocystis sp. from all fresh faecal material. Possible functions of the surface coat, especially in relation to protection against osmotic shock, are discussed.