Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells
Alexia CarréFatoumata SamassaZhicheng ZhouJavier Perez-HernandezChristiana LekkaAnthony ManganaroMasaya OshimaHanqing LiaoRobert ParkerAnnalisa NicastriBarbara BrandaoMáikel L. ColliDécio L. EizirikJahnavi AluriDeep PatelMarcus GöranssonOrlando Burgos‐MoralesA. AndersonLaurie G. LandryFarah KobaisiRaphaël ScharfmannLorella MarselliPiero MarchettiSylvaine YouMaki NakayamaSine Reker HadrupSally C. KentSarah J. RichardsonNicola TernetteRoberto Mallone
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Abstract:
Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but the effect of IFN-α on the antigen repertoire of HLA Class I (HLA-I) in pancreatic β-cells is unknown. Here we characterize the HLA-I antigen presentation in resting and IFN-α-exposed β-cells and find that IFN-α increases HLA-I expression and expands peptide repertoire to those derived from alternative mRNA splicing, protein cis-splicing and post-translational modifications. While the resting β-cell immunopeptidome is dominated by HLA-A-restricted peptides, IFN-α largely favors HLA-B and only marginally upregulates HLA-A, translating into increased HLA-B-restricted peptide presentation and activation of HLA-B-restricted CD8+ T cells. Lastly, islets of patients with T1D show preferential HLA-B hyper-expression when compared with non-diabetic donors, and islet-infiltrating CD8+ T cells reactive to HLA-B-restricted granule peptides are found in T1D donors. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward alternative epitopes presented by HLA-B, hence recruiting T cells with a distinct repertoire that may be relevant to T1D pathogenesis.I. The Properties of Interferon. The Formation and Action of Interferon Induced in Cell Cultures and Chick Embryos.- 1. The Principal Properties of Interferon.- 1.1. Physicochemical properties.- 1.2. Species specificity.- 1.3. Antigenic properties.- 1.4. Conclusion.- 2. The Formation of Interferon in Cell Cultures and Chick Embryos.- 2.1. The interferon-inducing activity of viruses.- 2.1.1. The interferon-inducing action of poxviruses.- 2.1.2. The interferon-inducing activity of myxoviruses.- 2.1.3. The interferon-inducing activity of rhabdoviruses.- 2.1.4. The interferon-inducing activity of herpes viruses.- 2.1.5. The interferon-inducing activity of arboviruses.- 2.1.6. The interferon-inducing activity of other viruses.- 2.2. Nonviral induction of interferon in cell cultures.- 2.3. Factors influencing the intensity of interferon production.- 2.4. Comparative study of the induction of interferon by viruses in different cell cultures.- 2.5. Dynamics of formation and liberation of interferon in cell cultures.- 2.6. Blocking of the formation and action of interferon by viruses.- 2.7. Conclusion.- 3. The Action of Interferon in Cell Cultures.- 3.1. The sensitivity of viruses and cells to inferferon.- 3.2. Methods of indication and assay of interferon.- 3.3. Studies of the sensitivity of some virus-cell systems to interferon.- 3.4. Conclusion.- 4. Interferon Production by Human and Animal Leukocytes.- 4.1. Interferon production by rabbit and mouse blood leukocytes.- 4.2. Interferon production by monkey blood leukocytes.- 4.3. Interferon production by suspensions of human leukocytes.- 4.3.1. Importance of the blood group.- 4.3.2. Effect of incubation medium for leukocytes with virus on quantity of interferon formed.- 4.3.3. Effect of leukocyte concentration in suspension on interferon production.- 4.3.4. Effect of reaction of the medium.- 4.3.5. Effect of incubation temperature.- 4.3.6. Importance of the species of inducing virus and the multiplicity of infection.- 4.3.7. Dynamics of interferon production by human leukocytes.- 4.3.8. The properties of leukocytic interferon.- 4.4. Interferon production in growing cultures of human leukocytes.- 4.5. Conclusion.- II. Effect of Exogenous Interferon and Stimulators of Endogenous Interferon on Virus Infections.- 5. Effect of Exogenous Interferon on Virus Infections.- 5.1. Action of exogenous interferon on experimental virus infections.- 5.2. Clinical trials of exogenous interferon.- 5.3. Conclusion.- 6. Effect of Stimulators of Endogenous Interferon on Experimental Virus Infections.- 6.1. Stimulation of endogenous interferon by intravenous and other methods of injection of inducers of virus origin.- 6.2. Effect of virus inducers of interferon formation on experimental virus infections.- 6.3. Stimulation of endogenous interferon by double-stranded RNAs and their effect on virus infection.- 6.4. Stimulation of endogenous interferon by other nonviral inducers and its effect on experimental virus infection.- 6.5. Tolerance or hyporeactivity in interferon production.- 6.6. Conclusion.- 7. Clinical Trials of Stimulators of Endogenous Interferon.- 7.1. Stimulation of endogenous interferon in man and its effect on virus infections.- 7.2. Interferon-inducing properties of living influenza vaccine virus.- 7.3. Interferon-inducing properties of partially UV-inactivated A2 influenza virus.- 7.4. Interferon-inducing properties of inactivated viruses.- 7.5. Effect of stimulators of endogenous interferon on survival of influenza vaccine virus.- 7.6. Conclusion.- III. Interferon Formation and Virus Infection.- 8. Interferon Formation in the Body during Virus Infections and Its Pathogenic Role.- 8.1. Interferon formation in virus infections of animals.- 8.2. Interferon formation in human virus infections.- 8.3. Effect of various factors on interferon production in vivo.- 8.4. Interferon production in the immune organism.- 8.5. The role of interferon in the pathogenesis of virus infections.- 8.6. A study of interferon formation in vivo and in vitro (by leukocytes) in experimental virus infections.- 8.6.1. Interferon formation in experimental influenza.- 8.6.2. Interferon formation in experimental ectromelia.- 8.6.3. Interferon formation in experimental Western equine encephalomyelitis (WEE).- 8.6.4. Interferon formation in vivo in animals of different ages.- 8.6.5. Individual differences in interferon formation.- 8.6.5.1. Individual differences in serum interferon production in noninbred and inbred mice.- 8.6.5.2. Individual interferon production in mice infected with WEE virus.- 8.6.5.3. Individual differences in serum interferon production in rabbits and guinea pigs.- 8.6.6. Effect of cooling, internal irradiation, and ACTH on production of serum interferon in mice.- 8.7. Relationship between interferon formation and sensitivity of animals to some virus infections.- 8.7.1. Relationship between interferon formation and reproduction of viruses in chick embryos of different ages.- 8.7.2. Relationship between the reproduction of WEE virus and interferon formation in the mouse brain.- 8.7.3. Relationship between individual interferon formation and susceptibility of animals to WEE virus and to fixed rabies virus.- 8.7.4. Relationship between individual interferon formation and skin reaction of rabbits to vaccinia virus.- 8.8 Relationship between the pathogenicity and interferon-inducing ability of strains of vaccinia virus.- 8.9. Conclusion.- 9. Interferon Formation in Man under Normal and Pathological Conditions.- 9.1. Interferon production by leukocytes of healthy persons of different ages. Detection of interferon in the urine and serum.- 9.2. Interferon production by the leukocytes of newborn infants.- 9.3. Production of leukocytic interferon by patients with leukemia.- 9.4. Production of leukocytic interferon in other internal diseases.- 9.5. Interferon formation in children vaccinated against smallpox.- 9.6. Interferon production in adults with influenza.- 9.7. Interferon production in children with acute respiratory virus infections and its correlation with the production of leukocytic interferon.- 9.8. Conclusion.- Mechanism of Formation and Action of Interferon.- Conclusions and Prospects.
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Background: Some antigens of H. pylori are excreted into the stool of infected people. These antigens can be used to detect the infection by immunoassays such as ELISA. Our aim was to identify these antigens by immunoblottin g and affinity chromatography techniques. Methods: Four different antigenic preparations, namely, whole cell sonicate (WCS), outer membrane proteins (OMPs), cytoplasmic antigens (CAs) and cell surface-associated antigens (CSAAs) were obtained from H. pylori . Rabbit antiserum against these preparations was used to detect them in fecal antigenic extracts (FAEs) of infected patients. Results: By immunoblotting, we were able to detect a 26 kDa band in the positive stool samples. Anti-OMPs acted more specifically, so, it was used to isolate the Helicobacter pylori diagnostic antigens (HpDAs) from the stool. More antigens (at least 4 antigens with the molecular weights of about 14, 26, 55 and 57 kDa) were isolated by affinity chromatography. But, the 26 kDa antigen had a higher concentration and was seen in almost all positive samples. Conclusion: Since the 26 kDa antigen is detectable by these two techniques in all positive samples, we are confident that this antigen is one of the major antigens of H. pylori, which is released into the stool and can be considered as a candidate diagnostic antigen to be used in diagnostic kit development. Iran J Med Sci 2007; 32(4): 198-204.
Pan-T antigens
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Aim To evaluate the anti-SARS-CoV effect of interferon-α,interferon-γ and the combination of interferon-α and interferon-γ at 5 different ratios in vitro.Methods The antiviral activity of interferon-αand interferon-γ was determined by MTT colorimetry.Results The TCID50 of SARS-CoV was 10-7.Interferon-α and interferon-γ had anti-SARS-CoV activity in vitro.The anti-SARS-CoV effect of Interferon-α was better than that of interferon-γ.And the anti-SARS-CoV effect of the combination of Interferon-α and interferon-γ was better than that of any single drug.Conclusion Interferon-α,interferon-γ and the combination of interferon-α and interferon-γ all have anti-SARS-CoV activity in vitro.This study has provided experimental evidence for the clinical use of antiviral treatment of the SARS-CoV infection.
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Summary The pre-treatment of mouse L cells with interferon or polyinosinic-polycytidylic acid potentiated the interferon response of these cells to subsequent stimulation with suboptimal doses of polyinosinic-polycytidylic acid. This potentiation was manifested as an earlier production of interferon, a faster attainment of maximum interferon production, and a greater yield of interferon. Pre-treatment of cells with either low (5 units/ml.) or high (1000 units/ml.) doses of interferon never caused a reduced interferon response to stimulation by polyinosinic-polycytidylic acid. Primary rabbit kidney cells which were pre-treated with interferon (500 units/ml.) responded to stimulation with polyinosinic-polycytidylic acid in the same manner as did mouse L cells. In contrast, under certain conditions mouse L cells pre-treated with interferon became resistant to stimulation with Newcastle disease virus. The extent of the reduced response depended on the pre-treatment dose of interferon and the stimulating dose of Newcastle disease virus. It was concluded that the presence of interferon and its virus resistant state were not directly correlated with hyporesponsiveness to repeated induction of interferon, at least by rI.rC.
Newcastle Disease
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The antiviral activity of interferon was found to be related to the amount of interferon that became cell-associated. Reduction in the amount of interferon uptake by cells by sulfhydryl-binding compounds (p-chloromercuribenzoate and N-ethylmaleimide) reduced the level of antiviral activity of the cells. Interferon, inactivated by heat or trypsin did not affect the ability of active interferon to induce an interferon uptake system. Trypsin-inactivated interferon was, however, shown to compete with active interferon for the interferon uptake system while heat-inactivated interferon was without effect.
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1) The effects of secondary injections of various soluble protein antigens, subsequent to disappearance from the circulating system of antibodies to a primary antigen, are described. 2) Secondary antigen injections do not elicit antibody responses to previously injected antigens, if the antigens are unrelated. 3) Quantitative levels of antibody response to secondary antigens are apparently unaffected by previous antigenic stimulations of the animal, if the antigens are unrelated.
Antibody response
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The response of serologically mature fowls to antigens having varying degrees of relationship to a previously injected antigen was studied by quantitative precipitin methods and absorption analyses. After successive injections with related antigens three major antibody populations were detected: (1) antibodies reacting only with the second antigen, equivalent in amount to those obtained in a primary response to that antigen; (2) antibodies reacting only with the first antigen, lower in amount than those obtained during a primary response to that antigen; and (3) antibodies reacting with both antigens, in much greater amount than after successive injections with a single antigen.
Successive immunization with unrelated antigens did not result in the formation of antibodies capable of reacting with the primary antigen.
Precipitin
Antibody response
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The production of antibodies in cell cultures from the draining lymph nodes of rabbits injected in the foot pads with two to four different protein antigens was studied. Antibodies against all of the immunizing antigens were produced simultaneously when aliquots of the cells were cultured 4 to 8 weeks after immunization in the absence of further antigen exposure. In vitro exposure to a single immunizing antigen always resulted in an anamnestic response to the added antigen and a general enhancement of antibody production against cross-reactive determinants on other immunizing antigens. However, antibody production against unrelated immunizing antigens was always significantly suppressed by this exposure. This suppression was not the result of antibody feedback and could not be induced unless the unrelated antigen had been used as a priming antigen.
Priming (agriculture)
Antibody response
Pan-T antigens
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