Impaired Interferon Research Articles

Impaired interferon induction of human MxA protein in chronic hepatitis B virus infection

MxA protein is interferon inducible, and its role as an antiviral mediator is being studied in various viral diseases. Several cytokines, including type 1 interferons (alpha and beta), interleukins 2 and 12, and granulocyte, macrophage, and granulocyte-macrophage colony-stimulating factors, were tested for their ability to induce human MxA protein synthesis in peripheral blood mononuclear cells from 15 chronic hepatitis B virus-infected patients and 6 healthy subjects as controls. Constitutive MxA expression was scarce in patients and controls but increased significantly in response to type I interferons. MxA responsiveness to interferon alpha was diminished significantly in chronic hepatitis B patients, compared with healthy donors (P < 0.05); this effect was more marked in patients with high viremia levels. Interleukins 2 and 12, and none of the colony-stimulating factors tested, induced low, but detectable, MxA protein levels. These results indicate that chronic infection by hepatitis B virus may impair activation of the immune cells and their capacity to respond to type 1 interferons.

Impaired interferon induction of human MxA protein in chronic hepatitis B virus infection

Impaired interferon induction of human MxA protein in chronic hepatitis B virus infection

Impaired interferon production and natural killer cell activation in patients with the skin cancer-prone disorder, xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder with sun sensitivity, markedly increased skin cancer susceptibility, and defective DNA repair without consistently identified symptoms of immune deficiency. We examined natural killer (NK) cell activity and interferon production in peripheral blood lymphocytes (PBL) of eight XP patients who had multiple primary skin cancers. The XP patients had normal numbers of T cells and NK cells, as well as normal lymphokine-activated killer cell activity and normal tumor necrosis factor-alpha production. Unstimulated NK cell function was 40% of normal controls in five XP patients, but was normal in three other XP patients. However, PBL from all the XP patients tested showed no enhancement of NK activity by the interferon inducer, polyinosinic acid:polycytidilic acid (polyIC) but enhancement by interferon-alpha was normal, suggesting an impairment in interferon production. Parallel studies in non-XP skin cancer patients revealed that both unstimulated and polyIC-enhanced NK activity were normal. Further investigation using PBL from XP patients revealed that the production of interferon-gamma after stimulation with interferon inducers (polyIC, interleukin 2, or K562 tumor cells) was 13-43% of normals. These data indicate that XP lymphocytes have a defect in production of interferons and suggest that defective interferon production, as well as DNA repair defects, may play an important role in the susceptibility of XP patients to skin cancer.

Impaired interferon-? production in whole-blood cultures from bladder cancer patients

Interferon-alpha (IFN-alpha) production was investigated in whole-blood cultures of 66 bladder cancer patients and 65 control subjects. IFN synthesis was induced with Sendai virus, and IFN activity was assayed in FL cells challenged with vesicular stomatitis virus (VSV). The mean levels of the IFN-alpha produced were 5,724 +/- 2,288 IU/ml in the control subjects and 4,800 +/- 2,353 IU/ml in the bladder cancer patients. IFN-alpha production was significantly suppressed in the bladder cancer patients compared with that in the control subjects (P less than 0.05). The impairment in IFN-alpha production correlated with the tumor grade, and it was shown that the tendency toward decreased IFN-alpha production was closely associated with the advancement of the tumor stage. Our results suggested that the decreased IFN-alpha production may contribute to the disordered immunoregulation in bladder cancer patients.

Correlation of in vitro immune defects with impaired gamma interferon response in human-immunodeficiency-virus-infected individuals.

65 patients belonging to known acquired-immune-deficiency-syndrome (AIDS) risk groups were tested for mitogen responsiveness to pokeweed mitogen, concanavalin A and phytohemagglutinin, percentages of peripheral blood CD4, CD8 and Leu7 lymphocyte subsets, serum neopterin levels, and gamma-interferon (gamma-IFN) concentrations in cell culture supernatants. Patients with clinical symptoms of human-immunodeficiency-virus infection showed reduced gamma-IFN production in vitro. The IFN concentrations were correlated significantly with mitogen-induced blastogenesis. High serum neopterin levels and decreased CD4/CD8 ratios were associated with diminished gamma-IFN levels. The percentage of Leu7 lymphocytes was increased in a group of patients with strikingly elevated gamma-IFN levels.

Correlation of in vitro Immune Defects with Impaired Gamma Interferon Response in Human-Immunodeficiency-Virus-Infected Individuals

65 patients belonging to known acquired-immune-deficiency-syndrome (AIDS) risk groups were tested for mitogen responsiveness to pokeweed mitogen, concanavalin A and phytohemagglutinin, percentages of peripheral blood CD4, CD8 and Leu7 lymphocyte subsets, serum neopterin levels, and γ-interferon (γ-IFN) concentrations in cell culture supernatants. Patients with clinical symptoms of human-immunodeficiency-virus infection showed reduced γ-IFN production in vitro. The IFN concentrations were correlated significantly with mitogen-induced blastogenesis. High serum neopterin levels and decreased CD4/CD8 ratios were associated with diminished γ-IFN levels. The percentage of Leu7 lymphocytes was increased in a group of patients with strikingly elevated γ-IFN levels.

Impaired gamma interferon production by cells from patients with lymphoproliferative disorders of mature T and NK cells.

We investigated interferon (IFN) production by peripheral blood mononuclear cells from four patients with chronic OKT4 T-lymphocytic leukaemia and three patients with abnormal expansions of granular lymphocytes. No spontaneous production of IFN-gamma was found in supernatants of cultures from both patients and normal controls. However, whereas the enzyme galactose oxidase or staphylococcal enterotoxin B was able to induce IFN-gamma production by normal cells, no production could be obtained in the cells under study. The possibility that this lack of production might have been attributed to an excess of N-acetylneuraminic acid masking galactose residues or to a defect of monocyte accessory cells was ruled out either by pre-treating the cells with neuraminidase or by adding normal adherent cells to the cultures, both of which resulted in a lack of production. On the contrary, the calcium ionophore A23187 (considered to act as a second specific step, following oxidation of galactose residues, toward genetic derepression of IFN-gamma) induced considerable IFN-gamma production in all the three tested patients. It can be concluded that, although in rare cases, as previously reported by other authors, cells from patients with T or NK lymphoproliferative disorders may spontaneously produce IFN-gamma, this is not a general mechanism that underlies the disease. In fact, in all our cases a defect of IFN-gamma production was found. This defect seems due to an alteration at the membrane level of the galactose-containing glycoproteins and can be restored by induction with a calcium ionophore.

Interferon-α regulation of lymphocyte function in systemic lupus erythematosus

Interferon (IFN) production and responsiveness are abnormal in some patients with systemic lupus erythematosus (SLE). The present investigation was designed to further delineate these abnormalities of IFN response. The response to IFN-α was determined in peripheral blood mononuclear cells (PBMC) using the natural killer (NK) cell assay, the concanavalin A (Con A)-induced T-cell proliferation assay, and the pokeweed mitogen (PWM) blastogensis system. The average NK cell activity was impaired in SLE patients ( 19.7 ± 3.8 LU 10 7 cells ; n = 22 ) compared to 24 normal controls ( 45.6 ± 7.2 LU 10 7 cells ; n = 24 ) ( P < 0.05). In addition, the response to IFN in the NK cell system was impaired in SLE (110.0 ± 38.0% enhancement) compared to controls (320.0 ± 94.0% enhancement; ±SD P < 0.05). In contrast to the impaired IFN response of the NK cell in SLE, the effect of IFN on Con A- and PWM-induced blastogenesis in SLE was normal ( P > 0.1). Thus, the defect in IFN response in SLE appeared to be confined to the NK cell system, but was not present in the other assay systems. To determine if the impaired IFN response might be secondary to impaired release of natural killer cytotoxic factor (NKCF) induced by IFN, NKCF was generated from PBMC in the presence of IFN. IFN-induced NKCF release was markedly impaired in SLE (8.9 ± 11.7%) relative to normal controls (22.3 ± 11.2%) ( P < 0.05). IFN-induced release of NKCF in SLE also closely correlated with IFN-induced NK enhancement ( r = .83, P < 0.05). No depletion of NK cells was noted using the monoclonal antibody HNK-1. Thus, this study demonstrates for the first time that the insensitivity to IFN in SLE is not a universal lymphocyte defect but appears to be isolated to the NK cell which is functionally abnormal.

Stress, cortisol, interferon and “stress” diseases: I. Cortisol as the cause of “stress” diseases

An attempt is made to define a biochemical formula for stress, as an overproduction of cortisol ± impaired interferon response. The behavior Type A individual under stress, would exhibit elevated levels of cortisol with normal interferon response, whereas the Type C individual, would exhibit elevated levels of cortisol and impaired interferon responses. Evidence is presented that elevated levels of cortisol manufactured chronically under the affect of stress, and regardless of the type of individual affected, are a cause or the cause of chronic diseases, and not the result of same. This evidence would show that: 1. 1. Elevated levels of cortisol precede certain diseases, and do not follow them, when cortisol is checked out for this purpose in pre-disease conditions. 2. 2. When elevations of cortisol levels are induced through long-term corticosteroids therapy, in patients suffering of diseases requiring this type of treatment, conditions mimicking chronic diseases, would appear. 3. 3. When corticosteroids therapy would be discontinued, the “chronic diseases” mentioned above would disappear. 4. 4. When pharmaceuticals with potential cortisol antagonistic capabilities, were used in diseases totally unrelated, but having in common, elevated levels of cortisol, alleviation of symptoms and/or diseases would occur.

Interferon production by peripheral lymphocytes in HBsAg-positive liver diseases.

Interferon production by lymphocytes was normal in HBsAg carriers with normal liver function tests and normal liver histology, whereas it was significantly decreased in HBsAg–positive patients with chronic active hepatitis and cirrhosis. It is possible that an impaired interferon system is causally related to the development of chronic liver disease in hepatitis B virus infection.

Lack of correlation between impaired interferon production and natural killer activity of lymphocytes in multiple sclerosis.

The ability of lymphocytes from patients with multiple sclerosis (MS) to produce Interferon (IFN-alpha) in response to Newcastle Disease Virus (NDV) was studied in vitro. The correlation between individual IFN-alpha titers and natural killer (NK) cell activity and the presence of HLA system antigens associated with MS (B-7 and DRW-2) was also investigated. Lymphocytes from MS patients showed a significantly impaired capacity to synthesize IFN-alpha in vitro when compared to lymphocytes from healthy donors (mean titers: 85.9 I.U. and 268.2 I.U., respectively). Marked differences in IFN-alpha titers were observed in the group of MS patients. The production of IFN-alpha by the patients' lymphocytes did not correlate with either the activity of NK cells or with their stimulation by exogenous IFN-alpha. There was also no correlation between IFN-alpha production by lymphocytes from MS patients and the presence or absence of B-7 and DRW-2 antigens.