RESUMO
CD8+ T cell-mediated immune response plays a major role in the clearance of virus-infected cells, including human papillomavirus (HPV). The effective treatment of women with normal cytology but persistent high risk-HPV infection or with low-grade intraepithelial lesions could take advantage of novel strategies based on vaccination with viral immunological targets with a wide spectrum of cross-protection. The helicase E1, expressed early during viral replication in HPV infection, is among the most conserved papillomavirus proteins, which makes it a good vaccine candidate. In the present study, we examined E1-specific CD8+ T cell and NK immune responses in a mouse model with α-galactosylceramide (α-GalCer) as an adjuvant. We found that mice immunized with E1 combined with α-GalCer elicited an E1-specific CD8+ T and NK cell cytotoxic responses, which correlated with growth inhibition of grafted melanoma B16-F0 cells expressing E1, both in prophylactic and therapeutic protocols.
Assuntos
Vacinas Anticâncer/imunologia , Citotoxicidade Imunológica , Galactosilceramidas/administração & dosagem , Proteínas Oncogênicas Virais/imunologia , Linfócitos T Citotóxicos/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Feminino , Galactosilceramidas/imunologia , Papillomavirus Humano 18 , Humanos , Células Matadoras Naturais/imunologia , Melanoma Experimental/prevenção & controle , Melanoma Experimental/terapia , Melanoma Experimental/virologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Oncogênicas Virais/administração & dosagem , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/terapia , Transplantes , Células Tumorais Cultivadas/imunologia , VacinaçãoRESUMO
BACKGROUND: Peroxisome proliferator activated receptor alpha (PPARα), a regulator of enzymes involved in ß oxidation, has been reported to influence lymphocyte activation. The purpose of this study was to determine whether PPARα plays a role in T cell-mediated hepatitis induced by Concanavalin A (ConA). METHODS: Wild type (wt) or PPARα-deficient (PPARα-/-) mice were treated with ConA (15 mg/kg) by intravenous injection 0, 10 or 24 h prior to sacrifice and serum and tissue collection for analysis of tissue injury, cytokine response, T cell activation and characterization. RESULTS: Ten and 24 h following ConA administration, wt mice had significant liver injury as demonstrated by serum transaminase levels, inflammatory cell infiltrate, hepatocyte apoptosis, and expression of several cytokines including interleukin 4 (IL4) and interferon gamma (IFNγ). In contrast, PPARα-/- mice were protected from ConA-induced liver injury with significant reductions in serum enzyme release, greatly reduced inflammatory cell infiltrate, hepatocellular apoptosis, and IFNγ expression, despite having similar levels of hepatic T cell activation and IL4 expression. This resistance to liver injury was correlated with reduced numbers of hepatic natural killer T (NKT) cells and their in vivo responsiveness to alpha-galactosylceramide. Interestingly, adoptive transfer of either wt or PPARα-/- splenocytes reconstituted ConA liver injury and cytokine production in lymphocyte-deficient, severe combined immunodeficient mice implicating PPARα within the liver, possibly through support of IL15 expression and/or suppression of IL12 production and not the lymphocyte as the key regulator of T cell activity and ConA-induced liver injury. CONCLUSION: Taken together, these data suggest that PPARα within the liver plays an important role in ConA-mediated liver injury through regulation of NKT cell recruitment and/or survival.
Assuntos
Citocinas/imunologia , Galactosilceramidas/imunologia , Hepatite Autoimune/etiologia , Macrolídeos/toxicidade , PPAR alfa/imunologia , Linfócitos T/imunologia , Animais , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Hepatite Autoimune/imunologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Abstract Background Peroxisome proliferator activated receptor alpha (PPARα), a regulator of enzymes involved in β oxidation, has been reported to influence lymphocyte activation. The purpose of this study was to determine whether PPARα plays a role in T cell-mediated hepatitis induced by Concanavalin A (ConA). Methods Wild type (wt) or PPARα-deficient (PPARα−/−) mice were treated with ConA (15 mg/kg) by intravenous injection 0, 10 or 24 h prior to sacrifice and serum and tissue collection for analysis of tissue injury, cytokine response, T cell activation and characterization. Results Ten and 24 h following ConA administration, wt mice had significant liver injury as demonstrated by serum transaminase levels, inflammatory cell infiltrate, hepatocyte apoptosis, and expression of several cytokines including interleukin 4 (IL4) and interferon gamma (IFNγ). In contrast, PPARα−/− mice were protected from ConA-induced liver injury with significant reductions in serum enzyme release, greatly reduced inflammatory cell infiltrate, hepatocellular apoptosis, and IFNγ expression, despite having similar levels of hepatic T cell activation and IL4 expression. This resistance to liver injury was correlated with reduced numbers of hepatic natural killer T (NKT) cells and their in vivo responsiveness to alpha-galactosylceramide. Interestingly, adoptive transfer of either wt or PPARα−/− splenocytes reconstituted ConA liver injury and cytokine production in lymphocyte-deficient, severe combined immunodeficient mice implicating PPARα within the liver, possibly through support of IL15 expression and/or suppression of IL12 production and not the lymphocyte as the key regulator of T cell activity and ConA-induced liver injury. Conclusion Taken together, these data suggest that PPARα within the liver plays an important role in ConA-mediated liver injury through regulation of NKT cell recruitment and/or survival.
Assuntos
Animais , Masculino , Camundongos , Linfócitos T/imunologia , Citocinas/imunologia , Macrolídeos/toxicidade , Hepatite Autoimune/etiologia , PPAR alfa/imunologia , Galactosilceramidas/imunologia , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Hepatite Autoimune/imunologia , Modelos Animais de Doenças , Reação em Cadeia da Polimerase em Tempo Real , Camundongos Endogâmicos C57BLRESUMO
Common variable immunodeficiency (CVID) is a syndrome with predominantly defective B cell function. However, abnormalities in the number and function of other lymphocyte subpopulations in peripheral blood (PB) have been described in most patients. We have analysed the distribution of iNKT cell subpopulations in the PB of CVID patients and the ability of these cells to provide in vitro cognate B cell help. The total of iNKT cells was reduced in the PB of CVID patients, especially CD4+, CD4-/CD8- and CCR5+/CXCR3+. These findings were associated with an enrichment of memory-like and a tendency towards a reduction in TNF-α-expressing effector iNKT cells in the peripheral blood mononuclear cells (PBMC) of CVID patients. Moreover, an accumulation of follicular helper iNKT cells in the PB of CVID patients was demonstrated. CVID αGalCer-pulsed iNKT cells are not able to induce autologous B cell proliferation although they do induce proliferation to healthy donor B cells. Interestingly, autologous and heterologous co-cultures did not differ in the amount of immunoglobulin secreted by B cells in vitro. Finally, reduced intracellular SAP expression in iNKT cells and other lymphocytes in the blood from CVID patients was observed. These results provide further insights into the immunological mechanisms underlying the iNKT cell defects and the potential targets to improve B cell help in CVID.
Assuntos
Linfócitos B/imunologia , Comunicação Celular , Imunodeficiência de Variável Comum/imunologia , Células T Matadoras Naturais/imunologia , Saposinas/metabolismo , Adolescente , Adulto , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Feminino , Galactosilceramidas/imunologia , Humanos , Imunoglobulinas/metabolismo , Memória Imunológica , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Receptores CCR5/metabolismo , Receptores CXCR3/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto JovemRESUMO
An 11-year-old girl had a painless oculomotor nerve palsy confined to the inferior division. Anti-galactocerebroside and anti-GM1 antibodies were elevated during the acute phase and decreased to normal limits with clinical improvement, suggesting a possible autoimmune basis for this mononeuropathy.
Assuntos
Gangliosídeo G(M1)/imunologia , Galactosilceramidas/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Doenças do Nervo Oculomotor/imunologia , Criança , Feminino , HumanosRESUMO
Increasing evidence suggests that in Chagas' disease chronic-phase pathology is autoimmune in nature. There are at least two nonexclusive explanations for the generation of autoimmunity in Chagas disease: a) infection with the parasite perturbs immunoregulation, leading to loss of tolerance for self-antigens; b) immune recognition of T. cruzi antigens is crossreactive with selected mammalian antigens, leading to autoimmunity (molecular mimicry). Through this latter mechanism, T. cruzi antigens that share epitopes with mammalian nervous tissue may drive autoreactive B- or T-cell clones to expand and cause autoimmune lesions in chronic chagasic patients. Several different antigens sharing this characteristic have been studied, as for example the 160-kDa flagellum-associated surface protein (Fl-160), which has a nervous tissue crossreactive epitope composed by twelve amino acids. Additionally, it has been demonstrated that a trypomastigote stage-specific 85kDa surface glycoprotein (Gp85) has terminal galactosyl(alpha 1-3)galactose terminal residues, which are reactive with chronic chagasic sera. Common glycolipid antigens have also been reported, as for example galactocerebroside, sulfogalactocerebroside and sulfoglucuronylcerebroside, all of them specifically present at high concentrations in mammalian nervous system and in T. cruzi trypomastigotes. Chronic chagasic patients produce elevated levels of antibodies against these three glycolipid antigens. They also do against terminal galactosyl(alpha 1-3)galactose residues present on several acid and neutral glycolipids common either to nervous system or parasite. These antibodies are powerful lytic for circulating T. cruzi trypomastigotes. Another common strongly immunogenic residues are galactosyl(alpha 1-2)galactose, galactosyl(alpha 1-6)galactose and galactofuranosyl(beta 1-3)mannose residues present on several glycoinositolphospholipids (GIPL), against which chronic chagasic patients have elevated levels of specific antibodies. In brief, very specific host-parasite relationships existing only in Chagas' disease may explain the particular peripheral nervous tissue damage seen in acute or chronic stages of this disease. This specificity could depend either on invasion of autonomic ganglia by T. cruzi trypomastigotes and modification of nervous cell surface structures by some of the several mechanisms of acquired molecular mimicry.
Assuntos
Antígenos de Protozoários/química , Autoantígenos/química , Doença de Chagas/parasitologia , Proteínas do Tecido Nervoso/imunologia , Trypanosoma cruzi/fisiologia , Sequência de Aminoácidos , Animais , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/etiologia , Sequência de Carboidratos , Doença de Chagas/complicações , Doença de Chagas/imunologia , Doença Crônica , Reações Cruzadas , Galactose/imunologia , Galactosilceramidas/imunologia , Glucose/imunologia , Glicosilfosfatidilinositóis/imunologia , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/química , Proteínas de Protozoários/química , Proteínas de Protozoários/imunologia , Sulfoglicoesfingolipídeos/imunologiaRESUMO
Increasing evidence suggests that in Chagas' disease chronic-phase pathology is autoimmune in nature. There are at least two nonexclusive explanations for the generation of autoimmunity in Chagas disease: a) infection with the parasite perturbs immunoregulation, leading to loss of tolerance for self-antigens; b) immune recognition of T. cruzi antigens is crossreactive with selected mammalian antigens, leading to autoimmunity (molecular mimicry). Through this latter mechanism, T. cruzi antigens that share epitopes with mammalian nervous tissue may drive autoreactive B- or T-cell clones to expand and cause autoimmune lesions in chronic chagasic patients. Several different antigens sharing this characteristic have been studied, as for example the 160-kDa flagellum-associated surface protein (Fl-160), which has a nervous tissue crossreactive epitope composed by twelve amino acids. Additionally, it has been demonstrated that a trypomastigote stage-specific 85kDa surface glycoprotein (Gp85) has terminal galactosyl(alpha 1-3)galactose terminal residues, which are reactive with chronic chagasic sera. Common glycolipid antigens have also been reported, as for example galactocerebroside, sulfogalactocerebroside and sulfoglucuronylcerebroside, all of them specifically present at high concentrations in mammalian nervous system and in T. cruzi trypomastigotes. Chronic chagasic patients produce elevated levels of antibodies against these three glycolipid antigens. They also do against terminal galactosyl(alpha 1-3)galactose residues present on several acid and neutral glycolipids common either to nervous system or parasite. These antibodies are powerful lytic for circulating T. cruzi trypomastigotes. Another common strongly immunogenic residues are galactosyl(alpha 1-2)galactose, galactosyl(alpha 1-6)galactose and galactofuranosyl(beta 1-3)mannose residues present on several glycoinositolphospholipids (GIPL), against which chronic chagasic patients have elevated levels of specific antibodies. In brief, very specific host-parasite relationships existing only in Chagas' disease may explain the particular peripheral nervous tissue damage seen in acute or chronic stages of this disease. This specificity could depend either on invasion of autonomic ganglia by T. cruzi trypomastigotes and modification of nervous cell surface structures by some of the several mechanisms of acquired molecular mimicry
Assuntos
Animais , Antígenos de Protozoários/química , Autoantígenos/química , Doença de Chagas/parasitologia , Proteínas do Tecido Nervoso/imunologia , Trypanosoma cruzi/fisiologia , Sequência de Aminoácidos , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/etiologia , Sequência de Carboidratos , Doença Crônica , Reações Cruzadas , Doença de Chagas/complicações , Doença de Chagas/imunologia , Galactose/imunologia , Galactosilceramidas/imunologiaRESUMO
In an attempt to find a serological marker for neuropsychiatric manifestations (NPM) of SLE, sera from 66 patients (classified in three groups, according to their NPM-defined, probable and without NPM) were analysed by ELISA for IgG and IgM anticardiolipin, antigangliosides and antigalactocerebrosides antibodies. A strong correlation was found between IgM antigangliosides and antigalactocerebrosides antibodies and NPM, but not with IgG class. IgM and IgG antibodies anticardiolipin were not correlated with NPM in this study. Both IgM antigangliosides and antigalactocerebrosides antibodies disappeared in seven patients with definite but clinically inactive NPM. The analysis of these autoantibodies showed an important role predictive for NPM in SLE; the negative test decreases the chance of the NPM.
Assuntos
Anticorpos/análise , Cardiolipinas/imunologia , Galactosilceramidas/imunologia , Gangliosídeos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Transtornos Mentais/imunologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Masculino , Transtornos Mentais/diagnóstico , Transtornos Mentais/etiologia , Testes SorológicosRESUMO
Os autores avaliam a presença de anticorpos antifraçöes lipídicas (cardiolipina, gangliosídios e galactocerebrosídios) em 13 pacientes com doença de Behcet. Anticorpos séricos anticardiolipina do isotipo IgG foram detectados em 30// dos casos, 50// do isotipo IgM. Em nenhum dos pacientes foi observada presença de isotipo IgA. Antigalactocerebrosídio foram detectados em apenas dois (15//) dos pacientes. Com relaçäo às manifestaçöes clínicas, observou-se que a presença de anticorpos anticardiolipina configura fator de risco para o desenvolvimento do acometimento neurológico