Cell-mediated Immunity to Human Tamm-Horsfall Glycoprotein in Autoimmune Liver Disease with Renal Tubular Acidosis

Cell-mediated immune responses to Tamm-Horsfall glycoprotein isolated from human urine were investigated using the leucocyte migration test. Abnormal responses were found in 91% of patients with active chronic hepatitis or primary biliary cirrhosis with an associated renal tubular acidosis (R.T.A.) but in only 19% of those without R.T.A. In nearly all of a group of patients without autoimmune liver disease and in a control group of normal subjects results were within normal limits. In addition, using an immunofluorescent technique with rabbit antibody to human Tamm-Horsfall glycoprotein, it was possible to show the presence in human liver cell membrane of material reacting immunologically as Tamm-Horsfall. These findings suggest that the development of an immune response to this glycoprotein, initiated by release of cross-reacting antigens from damaged hepatocytes, could be the mechanism underlying the occurrence of R.T.A. in some patients with autoimmune liver disease.     

Cell-mediated Immunity in Herpesvirus hominis Infections

The cell-mediated and antibody responses to Herpesvirus hominis type 1 were investigated in patients with primary and recurrent herpetic infections. Stimulation of lymphocyte transformation with the virus and the complement fixing antibody titre did not differ significantly between patients and controls. However, macrophage migration inhibition and lymphocyte cytotoxicity were impaired in patients. The defects were specific to H. hominis, as Candida oblicans, which was used as an unrelated antigen, failed to show a similar abnormality. These results and preliminary sequential studies suggest that the susceptibility to recurrent herpesvirus infection may be due to an impaired production of macrophage migration inhibition factor and lymphocyte cytotoxicity in the presence of intact lymphocyte sensitization and antibody formation.     

Cell Interactions in Humoral and Cell-mediated Immunity

THYMUS-derived lymphocytes (T-cells) play an important role in the initiation of both humoral and cell-mediated immunity^1–3. We have investigated whether the helper function and the cell-mediated killer function of lymphocyte populations are performed by the same cells, by assaying thymus-derived lymphocytes both for their capacity to cooperate in vitro with bone marrow-derived lymphocytes (B-cells) in the induction of plaque-forming cells and for their capacity to cause in vitro complement independent lysis of target cells.     

Rosette-forming T Lymphocytes and Cell-mediated Immunity in Malnutrition

The frequency of rosette-forming thymus-dependent lymphocytes was reduced in the peripheral blood of malnourished infants and children. The reduced frequency parallelled the impairment of delayed hypersensitivity response to 2, 4-dinitrochlorobenzene and decreased DNA synthesis by lymphocytes challenged with phytohaemagglutinin. The abnormalities were reversed on nutritional improvement.     

Cell-mediated Immunity in Patients Positive for Hepatitis-associated Antigen

Cell-mediated immunity to antigens prepared from both serum and liver of patients positive for hepatitis-associated antigen (H.A.A.) was measured by using the leucocyte migration test. Altogether, 43 patients with H.A.A.-positive acute and chronic liver disease, eight with serum antibody to H.A.A., and 13 controls were studied. The cell-mediated immunity detected was specific for H.A.A. or other antigenic determinants of the associated infective agent and could be found only in patients with evidence of previous contact with H.A.A.Cell-mediated immunity to the H.A.A.-positive test antigens was found in all but one of the patients with acute hepatitis, in about half of the patients with chronic aggressive hepatitis or cirrhosis, rarely in those with chronic persistent hepatitis, and in none of the apparently healthy carriers.Our results support the hypothesis that the cellular immune response plays an important part in the clearance of the infective agent from H.A.A.-positive patients and in the pathogenesis of the associated liver cell injury.     

Postoperative Depression of Tumour-directed Cell-mediated Immunity in Patients with Malignant Disease

Leucocytes from 46 melanoma patients, 45 breast carcinoma patients, and 95 control donors were tested by the leucocyte migration test against the supernatants of homogenates of malignant melanomas, breast carcinomas, simple breast tumours, and breasts showing simple cystic disease. By comparison with controls inhibition of migration occurred significantly more frequently when tumour patients'' leucocytes were exposed to extracts of histogenetically similar tumours.Cell-mediated immunity to tumour-associated antigens was measured in 12 patients with breast carcinoma and 12 with malignant melanoma immediately before surgical operation and in the postoperative period. All patients tested before operation showed significant inhibition of migration on contact with extracts of histogenetically similar tumours. Postoperatively the degree of leucocyte migration inhibition was reduced in all patients with melanoma and breast carcinoma. Significant inhibition of leucocyte migration returned in most patients 6-22 days after operation.     

Implication of PMLIV in Both Intrinsic and Innate Immunity

PML/TRIM19, the organizer of nuclear bodies (NBs), has been implicated in the antiviral response to diverse RNA and DNA viruses. Several PML isoforms generated from a single PML gene by alternative splicing, share the same N-terminal region containing the RBCC/tripartite motif but differ in their C-terminal sequences. Recent studies of all the PML isoforms reveal the specific functions of each. The knockout of PML renders mice more sensitive to vesicular stomatitis virus (VSV). Here we report that among PML isoforms (PMLI to PMLVIIb), only PMLIII and PMLIV confer resistance to VSV. Unlike PMLIII, whose anti-VSV activity is IFN-independent, PMLIV can act at two stages: it confers viral resistance directly in an IFN-independent manner and also specifically enhances IFN-β production via a higher activation of IRF3, thus protecting yet uninfected cells from oncoming infection. PMLIV SUMOylation is required for both activities. This demonstrates for the first time that PMLIV is implicated in innate immune response through enhanced IFN-β synthesis. Depletion of IRF3 further demonstrates the dual activity of PMLIV, since it abrogated PMLIV-induced IFN synthesis but not PMLIV-induced inhibition of viral proteins. Mechanistically, PMLIV enhances IFN-β synthesis by regulating the cellular distribution of Pin1 (peptidyl-prolyl cis/trans isomerase), inducing its recruitment to PML NBs where both proteins colocalize. The interaction of SUMOylated PMLIV with endogenous Pin1 and its recruitment within PML NBs prevents the degradation of activated IRF3, and thus potentiates IRF3-dependent production of IFN-β. Whereas the intrinsic antiviral activity of PMLIV is specific to VSV, its effect on IFN-β synthesis is much broader, since it affects a key actor of innate immune pathways. Our results show that, in addition to its intrinsic anti-VSV activity, PMLIV positively regulates IFN-β synthesis in response to different inducers, thus adding PML/TRIM19 to the growing list of TRIM proteins implicated in both intrinsic and innate immunity.     

Intrinsic Immunity Shapes Viral Resistance of Stem Cells

1. Download high-res image (223KB)
2. Download full-size image

     

Depression of Cellular Immunity in Pregnancy due to a Serum Factor

Lymphocytes from pregnant women and non-pregnant individuals were cultured under the stimulus of phytohaemagglutinin in the presence of their own and heterologous (allogeneic) sera. The results indicate that heterologous sera have an inhibitory effect on the lymphocyte transformation rate and suggest that the inhibitory property is more powerful in pregnant and fetal sera. Conversely, the addition of heterologous non-pregnant sera to cultures of pregnant lymphocytes increases their transformation rate. These findings suggest that there is a serum inhibitor in pregnancy and this finding may be relevant to the survival of the fetal allograft.