Clinical immunology and immunopathology最新文献

The effects of cocaine exposure upon the host's immune response is equivocal since a variety of studies have generated conflicting conclusions, often as the result of differences betweenin vitroand/or animal models and the actual conditions experienced in humans who are acutely abusing this drug. To further address this issue, we have studied a group of patients who were positive for cocaine or cocaine metabolites and we evaluated a variety of functional parameters of T-lymphocytes and other peripheral lymphoid cell populations, as well as immunophenotypic characteristics of these cells. When compared to normal controls and patients who were negative for cocaine, we found that the cocaine-positive patients had T-cell functional assays which were essentially normal, with the exception of a slight depression in PHA stimulation. Likewise, the immunophenotype of the peripheral blood lymphocytic populations showed normal percentages and numbers of their T cell subsets (CD4, CD8), NK cells, and B cells. Multicolor flow cytometry analysis revealed no difference in T cell subpopulations positive for the “memory” marker, CD62L. No correlation could be established between levels of cocaine or cocaine metabolites and any phenotypic, demographic, or functional parameter. In summary, these results demonstrate that individuals acutely exposed to cocaine do not show markedly altered T cell function or fluctuations in phenotypically identified cell populations. These studies imply that acute cocaine exposure does not predispose individuals to grossly apparent immunosuppression. However, the possibility that subtle, transient, or more specific changes in the immune system may be incurred by use of cocaine, particularly with chronic exposure, remains to be determined.

Many different autoantibodies which react with a variety of different nuclear and cytoplasmic antigens have been described. Detection of some these antibodies has been shown to be clinically useful in a number of different autoimmune diseases. For many years, the detection of most of the clinically relevant antibodies was done with by immunofluorescence on tissue substrates and human cultured cell lines. Within the past few years, a number of technical advances has now made it possible to convert to enzyme immunoassay. The paper reviews the clinically relevant antibodies and discusses the variety of new methods which are now available for ANA detection in diagnostic laboratories.

The interleukin-15 receptor (IL-15R) is composed of at least three chains, namely γ_c, IL-2Rβ, and the recently identified IL-15Rα, while the IL-9R complex consists of γ_cand a subunit designated IL-9Rα. Our previous work and that of others have shown that human neutrophils express γ_cand IL-2Rβ (two components shared with IL-2R) but not IL-2Rα and that IL-15 is a neutrophil agonist, whereas IL-2 is not. In this study, using flow cytometry with a specific anti-human IL-15Rα, we show for the first time that human neutrophils express surface IL-15Rα. Although we previously found that IL-15 is a neutrophil agonist, our present work shows that IL-15 does not trigger superoxide production nor cell spreading onto glass. In addition, we report that human neutrophils do not respond to IL-9 with respect to the functions/responses studied, namely, superoxide production, spreading onto glass, cell shape changes, phagocytosis, RNA synthesis, and apoptosis. Further, our results show that neutrophils do not express IL-9Rα as assessed by flow cytometry with a specific anti-human IL-9Rα antibody that stains the transfected cell line BW-h9R used as positive control. Finally, our results indicate that γ_cexpression was not modulated and remained stable for up to 24 h when neutrophils were stimulated with all currently known “γ_cusers,” namely, IL-2, IL-4, IL-7, IL-9, and IL-15. We conclude that human neutrophils express all IL-15R components on their surface, including IL-15Rα, that IL-15 activates human neutrophils (as the IL-4 neutrophil agonist) by a mechanism which does not involve upregulation of γ_ccell surface expression, and that IL-9 is not a neutrophil agonist as demonstrated by the inability to modulate the tested functions/responses that correlate with lack of the IL-9R component, namely, IL-9Rα.

Oral administration of antigen modulates subsequent immune responses raised by conventional subcutaneous priming. If experimental autoantigens are administered, subsequent induction of autoimmune diseases may be inhibited. However, feeding autoantigens after priming or disease induction is more clinically relevant, but the trials have been less successful. Using therapeutic feeding of peptides to inhibit experimental autoimmune uveoretinitis (EAU) induced in LEW rats by bovine S-Ag peptides, we found that only mild disease could be inhibited if feeding was delayed until after immunization, and relatively high feeding doses were required. In recipients with more severe EAU, the clinical efficacy of therapeutic feeding was minimal despite concurrent down-regulation ofin vitroantigen-specific lymphocyte proliferation and serum antibody responses. No further inhibition of EAU was found by increasing the feeding dose. Feeding the same peptides prior to immunization produced resistance to moderate to severe disease induction. Unlike prophylactic feeding protocols, conditions were found such that feeding after immunization with low doses of antigen led to worsening of mild disease, raising a note of caution.

Multiple immunoregulatory abnormalities characterize systemic lupus erythematosus. Abnormalities of the antigen receptor-mediated early signal transduction biochemical events underscore the diverse cellular aberrations. Fresh peripheral T and B cells and T cell lines from patients with systemic lupus erythematosus display increased Ca²⁺responses that are preceded by enhanced antigen receptor-initiated cytosolic protein tyrosine phosphorylation. To further dissect the aberrant signaling events of lupus T cells we studied the early anti-CD3 mAb-induced signaling events in autoantigen-specific T cells from lupus patients. We report herein that a lupus snRNP-specific T cell clone, but not other T cells, displays increased Ca²⁺fluxes and enhanced production of tyrosine-phosphorylated proteins following TCR/CD3 stimulation.

Cell-mediated immunity participates in host defense against mycobacterial infection. Both interleukin 12 (IL-12) and interferon-γ-inducing factor (IGIF/IL-18), produced mainly by macrophages, play a critical role in expression of cell-mediated immunity. To investigate the role of IL-12 and IGIF/IL-18in vivo,we examined cytokine profile, bacterial growth, and the potential benefit of cytokine therapy in susceptible and resistant mice infected withMycobacterium leprae.The early expression of IL-12 p40 and IGIF/IL-18 at the site of inoculation was found in resistant mice 3–72 h after the infection, but not in susceptible mice. Both strains of mice did not show expression of IFN-γ and IL-4. IL-12 administration resulted in a significant reduction of bacterial counts in mice with establishedM. lepraeinfection. The results imply that susceptible mice exhibit decreased expression of type 1 helper T (Th1) response without reciprocal increased Th2 response and show responsiveness to exogenous IL-12. IL-12 therapy may be a possible rationale for treatment ofM. lepraeinfection.

We previously reported that blind T cell homeostasis, in which the total T cell count is maintained but the CD4⁺and CD8⁺subset composition of the T cells can vary, fails approximately 1.5 to 2.5 years before the onset of AIDS. The present study was premised on the hypothesis that if failure of T cell homeostasis (i.e., a decline in total T cell counts) is important in the pathogenesis of AIDS, it should be a significant predictor of AIDS after controlling for the CD4⁺lymphocyte count. Data from 1556 homosexual men with sufficient sequential T cell subset measurements were evaluated, representing 11,988 person-visits in men with known clinical outcomes over a period of more than 10 years. Using regression models that incorporated CD4⁺lymphocyte count and HIV-related symptoms (fever, thrush), it was determined that a yearly decline of more than 300 T cells/μl of peripheral blood was an independent predictor of the onset of AIDS for subjects with CD4⁺lymphocyte counts of <500 cells/μl. The results support an important role for failure of T cell homeostasis in the pathogenesis of AIDS.

Guillain–Barré syndrome (GBS) is an immune-mediated demyelinating disease of peripheral nerves that is often preceded by an infection and is usually self-restricted. The Th1 cytokine interferon-γ (IFN-γ) is thought to be disease-promoting in organ-specific autoimmune diseases. We report the spontaneous induction of IFN-γ and a mechanism involving the generation of neutralizing autoantibodies (Aabs) to IFN-γ that may regulate the disease. Numbers of cells spontaneously secreting IFN-γ in peripheral blood were augmented in GBS, in particular at the peak of clinical disease, and decreased during recovery. This decrease was associated with elevated serum concentrations of IgG Aabs to IFN-γ. These Aabs specifically bound to IFN-γ and neutralized its effects in a biological assay. Aabs to IFN-γ are proposed to be another important regulatory mechanism in IFN-γ-driven GBS.

Thymoma is a thymic epithelial tumor which often contains a large number of immature T cells. Although the metastatic lesions are also associated with abundant lymphocytes, their characteristics have not been assessed in detail. In this study, the phenotype was analyzed and compared with those in their primary lesions. Nine metastatic thymomas were obtained from seven patients. In the metastatic lesions, CD1a⁺cells and CD4⁺CD8⁺cells accounted for 77.7 ± 10.6 and 52.3 ± 15.8% of all the lymphocytes, respectively. In five primary lesions and their metastatic lesions, CD3⁻CD4⁺CD8⁻cells accounted for 23.9 ± 16.9 and 45.2 ± 15.5% of the CD4⁺CD8⁻cells, respectively. CD69 was expressed on 70.9 ± 9.5 and 53.1 ± 11.8% of the CD4⁺CD8⁻cells, respectively. These results indicate that the metastatic lesions of thymoma are associated with abundant immature T cells which are phenotypically less mature than those in their primary lesions.