Clinical immunology and immunopathology最新文献

Following a hemorrhagic event, damage to the highly metabolic intestinal tissue induces loss of barrier function leading to bacterial escape and LPS contamination of the host. Orally administered IL-6 restores intestinal barrier function following hemorrhage in both rat and mouse models. IL-6 prevents apoptosis in a variety of lymphoid cells and lines, through the activation of the proto-oncogenebcl-2.This communication elucidates the role of the IL-6–bcl-2interaction in intestinal apoptosis following hemorrhagic shock. Terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) and p53 immunohistochemical staining were used to examine intestines from mice hemorrhaged and fed saline or IL-6 and enterocytes (IEC-6) exposed to hypoxia and LPS alone or LPS and IL-6in vitro. In situhybridization forbcl-2expression was performed on intestines or enterocytes. Intestinal sections from mice hemorrhaged and fed IL-6 showed reduction in apoptosis and increases inbcl-2gene expression relative to sections taken from mice hemorrhaged and fed saline. IEC-6 cells exposed to hypoxia and LPS had high numbers of TUNEL staining cells. Subsequent exposure to IL-6 after hypoxia and LPS reduced apoptotic cell numbers and increasedbcl-2gene expression. The data show that exposure of intestinal epithelial cells to IL-6 either by oral administration in hemorrhaged mice or by coculture following hypoxia and LPS treatment results in increasedbcl-2gene expression and reduced damage from apoptosis.

Characterization of gastric Na⁺/I⁻symporter (NIS) of the rat was carried out. Sequencing of the open reading frame of gastric NIS mRNA showed only three nucleotide changes when compared with FRTL-5 NIS cDNA, and two of these changes led to amino acid changes. The results of Northern blot analysis showed that abundant NIS mRNA was expressed in the stomach when compared with other organs. Western blot analysis using gastric mucosa and FRTL-5 lysates detected the difference in molecular weight between FRTL-5 and gastric mucosa lysates, suggesting abnormal posttranslational modification of gastric NIS protein. Immunohistochemically, gastric NIS protein was located in the cornification layer of the stratified squamous epithelium of the pars proventricularis and in parietal cells and on the apical border of surface epithelial cells of the pars glandularis. Gastric NIS protein was present in tubulovesicular structures and lysosomes in parietal cells by immunoelectron microscopy. Gastric NIS protein exists to trap I⁻from the gastric lumen, except in parietal cells. Results indicated that a very large amount of gastric NIS mRNA is expressed to be translated, whereas only a small amount of immature gastric NIS protein is detected. This may indicate that immature gastric NIS protein rapidly degrades to peptides.

Macrophage Fcγ receptors (FcγRs) are critical for host defense against infection and have an important role in immune cytopenias. Modulation of macrophage FcγRs expression is a potential therapeutic approach to immune disorders. Glucocorticoids and synthetic progesterone analogues decrease macrophage FcγRs expression. We assessed the effect of treatment with commonly employed progestins on the expression of macrophage FcγRs using an experimental model in the guinea pig. Eight clinically available progesterones, medroxyprogesterone acetate (P3), megestrol acetate (P4), medrogestone (P5), alylestrenol (P6), linestrenol (P7), didrogesterone (P8), norethisterone (P9), and gestonorone caproate (P10) and two endogenous progesterones, progesterone (P1) and 17 α-hydroxyprogesterone (P2), were studied. Followingin vivotreatment of guinea pigs, we determined the clearance of IgG-sensitized erythrocytesin vivo,the binding of IgG-sensitized erythrocytes by isolated splenic macrophages, and splenic macrophage Fcγ receptor cell surface expression. All progesterones impaired the clearance of IgG-sensitized erythrocytes by decreasing splenic macrophage Fcγ receptor expression. P5, P6, P7, and P8 were less effective. Flow cytometry and fluorescence microscopy with monoclonal antibodies demonstrated that progesterones decreased the cell surface expression of FcγR2 more than that of FcγR1,2. Clinically employed progestins impair the clearance of IgG-coated cells by decreasing splenic macrophage FcγRs expression. Thus, progesterones are candidate drugs for the treatment of immune disorders.

The effects of cocaine infusion (40 mg) on interferon-γ (IFN-γ) and interleukin-10 (IL-10) cytokine secretion were examined in 15 cocaine-dependent subjects. Pre- and postcocaine infusion peripheral blood mononuclear cells (PBMC), stimulated with phytohemagglutinin A, were cultured for 48 h and the cytokines in the supernatant measured by enzyme-linked immunosorbent assay. Cocaine infusion, but not saline infusion, increased IFN-γ secretion and decreased IL-10 secretion, while, in PBMC collected simultaneously from control subjects, secretion of these cytokines was unaltered. Baseline IFN-γ levels were lower and IL-10 levels higher in addicted subjects compared to those in control subjects. White blood cell and lymphocyte number and CD4⁺and CD8⁺counts were all increased following cocaine infusion.In vitrococaine treatment of PBMC from addicted subjects suppressed both IL-10 and IFN-γ secretion. These data suggest that acute cocaine administration, via both central and peripheral effects, may enhance Th1-type immune responses and inhibit Th2-type responses.

The availability of recombinant autoantigens allows the experimental study of the relationships between primary biliary cirrhosis (PBC) and mitochondrial antigens. We took advantage of these recombinant autoantigens and attempted to induce autoimmune cholangitis by immunizing neonatally thymectomized (NTx) lipopolysaccharide (LPS)-treated A/J mice, known to be prone to organ-specific autoimmune diseases. We employed a recombinant protein containing a dual-headed molecule that coexpresses the immunodominant epitope of the E2 subunits of the pyruvate dehydrogenase complex and the branched-chain keto-acid dehydrogenase complex. We report herein that an immune-mediated cholangiohepatitis was induced by such immunization and the concurrent injection of LPS into NTx mice. The incidence of cholangitis was 79% in the NTx, immunized, LPS group compared to 14% in the NTx, nonimmunized, LPS group. The histopathology ranged from mild to severe and included bile duct damage, focal hepatic necrosis, and endotheliitis, but no granulomas. Moreover, almost all such lesions persisted for 12 weeks after the discontinuation of immunization and LPS injections in the NTx mice. Interestingly, we were successful (89%) in transferring the cholangiohepatitis by injection of liver infiltrating mononuclear cells from the NTx, immunized, LPS mice into congenic nonimmunized NTx mice; such lesions could not be transferred with spleen cells. Although the pathology is not typical of PBC, this model offers a unique venue for the study of immune-mediated hepatobiliary injury.

Effector functions are acquired by mature CD4 T lymphocytes in an exquisitely antigen-specific and antigen-dependent fashion. T cell receptor recognition of the processed antigen presented on the major histocompatibility complex molecule by antigen-presenting cells dictates the specificity of the T cell clones that will be expanded. A complex array of further coreceptor and lymphokine-mediated interactions determines whether activation or inhibition will follow and which effector phenotype will be acquired by the lymphocytes. On the basis of a first antigen encounter, CD4 T cells are functionally defined as naive or memory/effector cells. In memory/effector T cells, the pattern of cytokine production permits further classification as Th1 or Th2 cells. Th1 cells mainly produce IFN-γ, whereas Th2 cells mainly produce IL-4. The functional properties of these cell subsets derive from the biological activities of these (and the related) lymphokines they produce. An established body of data supports the view that the migration of T lymphocytes is distinctively different in naive and memory/effector T cells. Both CD4 and CD8 memory/effector T cells selectively migrate into nonlymphoid organs, such as the skin, the gut, and the lung through the peripheral extravascular route, whereas naive T cells migrate through the high endothelial venules and enter lymphoid tissues, such as lymph nodes, Peyers' patches, and tonsils. Furthermore, the acquisition of a Th1 or Th2 profile further implies the coordinated expression of a relatively selective array of receptors capable of rerouting them differentially. These events have a dramatic effect on the outcome of an immune response and determine whether it will be protective or not. New therapeutic strategies can be envisaged that interfere with the key molecular processes taking place during these coordinated differentiation events.

The lacrimal glands of patients with Sjögren's syndrome develop extensive lymphocytic infiltration, but also contain a large number of seemingly healthy looking acinar and ductal cells. Despite this, the secretory function of this tissue is impaired, leading to aqueous tear-deficient dry eye. This raises the possibility that there is a defect in the neural innervation of the remaining portion of the lacrimal gland. To test for this possibility, we used antibodies specific to various markers of the parasympathetic, sympathetic, and sensory nerves and performed immunohistochemical analyses of lacrimal glands from a murine model of Sjögren's syndrome, the MRL/Mp-Fas-lpr/lpr(MRL/lpr) and the control mice MRL/Mp−+/+ (MRL/+). Our results show that the MRL/lpr, but not the MRL/+, lacrimal glands become infiltrated with lymphocytes starting at 8 weeks of age which worsens by 12 and 18 weeks. The density and the pattern of parasympathetic, sympathetic, and sensory innervation of the noninflamed acinar tissue of MRL/lpr lacrimal glands, at 4, 8, 12, and 18 weeks, is indistinguishable from that of age-matched control MRL/+ lacrimal glands. We conclude that the loss of the secretory function in Sjögren's syndrome lacrimal glands is not due to a loss or decrease of its innervation.