The peripheral immune system plays a role in delayed neural injury after stroke. This response originates from the spleen as splenectomy prior to middle cerebral artery occlusion (MCAO) in rats significantly reduces infarct volume in the brain. This research is based on the hypothesis that inhibiting the splenic response will reduce neurodegeneration after stroke. Studies in animals have implicated lymphocytes as the immune cell type that is detrimental following MCAO. Interferon gamma (IFNγ) has been identified as a pro-inflammatory cytokine that is also detrimental following stroke. IFNγ is important because it activates microglia and macrophages in a pro-inflammatory nature that increases neural injury following stroke. Therefore IFNγ was examined in the brain and the spleen following MCAO. IFNγ protein was elevated at 24 h in the spleen and at 72 h in the brain post MCAO. Microglia/macrophages become maximally activated at 72 h in the brain after MCAO. Splenectomy decreases the levels of IFNγ in the brain following MCAO. Systemic administration of IFNγ reversed the protective effects of splenectomy. The cellular response to MCAO was examined next because of the difference in time between the spike in IFNγ in the spleen and the delayed increase in the brain. The cellular response from the spleen was studied by labeling splenocytes five days prior to MCAO with a fluorescein dye. Tissues were examined 48 and 96 h post MCAO or sham MCAO for fluorescence. These cells were released from the spleen into circulation at 48 h post MCAO and migrated to the brain where the cells produced IFNγ at 96 h post MCAO. IFNγ appears to play a role in the splenic response to stroke. One protein that is up regulated by cells that have been activated by IFNγ, interferon-inducible protein 10 (IP-10) is part of the inflammatory cycle driven by IFNγ. IP-10 recruits more IFNγ producing T helper (Th) cells to the site of injury. IP-10 has the unique ability to attract Th1 cells, the pro-inflammatory Th cells, and inhibit Th2 cells, the anti-inflammatory Th cells. This leads to more IFNγ production as IFNγ is the signature cytokine of a Th1 response. IP-10 is significantly increased in the brain at 72 h post MCAO, similar to IFNγ expression. In the spleen IP-10 increased at 24 h and remained elevated out to 96 h following MCAO. IFNγ signaling was inhibited by utilizing an IFNγ neutralizing antibody administered beginning 24 h post MCAO. The IFNγ antibody treated group had decreased infarct volumes, IP-10 levels in the brain, and appeared to have decreased T cells in the ipsilateral hemisphere at 96 h post MCAO. Following ischemic stroke splenocytes are released into circulation and migrate to the brain. They release IFNγ to activate microglia/macrophages in a proinflammatory phenotype causing an increase in IP-10 levels. IP-10 then potentiates the Th1 driven inflammation which inhibits the Th2 response. The elevated levels of IFNγ increase neural injury following MCAO. Blocking IFNγ selectively blocks the inflammatory facet of the immune response to reduce stroke induced neurodegeneration. This leaves the other immune responses intact and able to contribute to tissue repair, regeneration, and able to respond to infections. Selectively inhibiting IFNγ signaling is a promising stroke therapeutic.

Influenza A viruses can cause a highly contagious respiratory illness in humans. Immediately after virus infection the innate immune response is initiated by binding of viral RNA species to RIG-I that leads to activation of IRF3 and NF-κB transcription factors and activation of interferon (IFN) transcription. LGP2 is a member of the RIG-I like receptor (RLR) family and is induced after virus infection. The role of LGP2 in virus infection is controversial: it has been reported to either positively or negatively affect RIG-I mediated signaling. The goal of this study was to determine whether LGP2 has a role during infection with influenza A viruses that have circulated in humans. We focused on two viruses expressing NS1 proteins that differ in their ability to inhibit IRF3 activation and IFN transcription; a H1N1 virus (Tx91) that inhibits IRF3 activation and a H3N2 virus (Ud) that does not. This study revealed that LGP2 has strikingly different roles during infection of mouse embryonic fibroblasts and human cells with these viruses. Specifically, LGP2 has no detectable role in H1N1 virus-infected cells, whereas it downregulates IFN synthesis in H3N2 virus-infected cells. Our results indicate that LGP2 acts as a negative regulator of the IFN response in influenza A viruses that activate IRF3. The NS1 protein also binds the 30kDa-subunit of the cleavage and polyadenylation specificity factor-CPSF30, a protein required for 3′-end processing of cellular pre-mRNAs, thereby inhibiting production of mature IFN-β mRNA. The NS1 proteins of pathogenic 1997 H5N1 viruses lack two highly conserved residues (F103 and M106) that are needed to stabilize the NS1-CPSF30 complex. Instead their NS1 proteins have L at 103 and I at 106, resulting in non-optimal CPSF30 binding in infected cells. We demonstrated that strengthening CPSF30 binding by changing L and I to the consensus residues (F and M respectively) leads to a dramatic (300-fold) increase in lethality of the virus in mice. This increased virulence is associated with faster systemic spread of the virus. Microarray analyses revealed increased cytokine levels in extrapulmonary tissues, particularly the brain. These results highlight the importance of NS1:CPSF30 binding in modulating virulence in H5N1 viruses. / text

Interferon (IFN) is activated in response to virus infections and upregulates interferon-stimulated genes (ISGs) resulting in the expression of hundreds of proteins, many of which have direct or indirect antiviral activity. Parainfluenza virus 5 (PIV5) of the Paramyxoviridae family is a non-segmented negative sense single-stranded RNA virus with seven genes encoding eight proteins. Here we present that IFN induces alterations in the pattern of both virus transcription and translation and that ISG56 is primarily responsible for these effects. We report that when cells were treated with IFN post-infection, virus protein synthesis was inhibited while virus transcription levels were increased. These results suggest that ISG56 selectively inhibits the translation of viral mRNAs. In addition, the relationship of various PIV5 isolates was analysed by next generation sequencing. Four areas with a high degree of single nucleotide polymorphisms (SNPs) were identified and mapped to the intergenic regions of NP-V/P, M-F and HN-L, as well as the entire SH gene. Three of the isolates, the porcine strain SER and the canine strains CPI+ and CPI-, did not express an SH protein due to the lack of a start codon. A low degree of variation was found in the amino acid sequence of the HN glycoprotein suggesting that PIV5 may be less pressured to evolve in order to evade immune responses, such as neutralising antibodies.

Diss. (sammanfattning) Stockholm : Karol inst., 2004. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Cutaneous lupus erythematosus (CLE) is an autoimmune disease that resolves with or without permanent scars depending on the subtype. Interferons (IFNs), including the skin specific IFNλ mainly activate STAT1, which results in inflammation in CLE and may play a significant role in scar formation in chronic discoid CLE. IL-22 activates STAT3 and it is emerging as a mediator with significant impact on normal wound repair, epidermal hyperproliferation and prevention of fibrosis. This work focussed on understanding the regulation and functional impact of IL-22 and IFNλ on skin cells. The counter-regulatory effect of IL-22 on the activities of IFNλ was assessed through downstream interferon stimulated genes (ISGs) expression in healthy and CLE keratinocytes. Cell proliferation and gap closure were investigated in skin resident cells using cell trace dye and scratch assay. Dermal fibroblasts were assessed for the presence of IFNλR1 and IL-22R1, downstream activities of the receptors. Results showed that IL-22 accelerated “scratch” closure in keratinocytes while IFNλ caused a delay in closure. IL-22 significantly downregulated IFNλ-induced chemokines expression in healthy, but not CLE keratinocytes. Reduced IL-22R1 expression and “STAT3 signature genes” was observed in CLE keratinocytes. A key finding of this project is that dermal fibroblasts respond to both IFNλ and IL-22. This work shows that IL-22 can reduce the damaging effect of IFNs in inflamed skin and also identifies dermal fibroblasts as important cells in skin immune responses. In conclusion, IL-10 family members can have both beneficial and destructive effects on the skin organ depending on the micro milieu and cell-type involved. Manipulating the balance of IL-10 family members in the skin may offer new therapeutic approach for both psoriasis and CLE.

Les patients admis en réanimation semblent pouvoir présenter des infections sévères à CMV, en dehors de tout traitement immunosuppresseur, mais l’incidence exacte de ces infections est difficile à évaluer. Nous avons réalisé un dépistage systématique du CMV chez 242 patients consécutifs, considérés non immunodéprimés avant leur admission en réanimation. Nous avons ainsi identifié que 16% des patients développaient au cours de leur séjour en réanimation une infection à CMV. La mortalité des patients ayant présenté une infection à CMV était supérieure à ceux n’ayant pas présenté l’infection. La physiopathologie des réactivations à CMV chez ces patients est incomprise. Nous avons sélectionné les patients de réanimation non-immunodéprimés et séropositif pour le CMV à l’admission, et nous avons comparé le statut des NK circulants de 15 patients ayant présenté une réactivation CMV dépistée par antigénémie circulante (les cas) à celui de 15 patients contrôles appariés aux premiers pour l’âge, le sexe, et la gravité à l’admission. Dans la période précédant la réactivation CMV, alors que les capacités de cytotoxicité sont comparables, nous mettons en évidence une déficience NK en termes de capacité de production d’interféron gamma chez les cas en comparaison des contrôles, et également de témoins sains. Le sepsis, cad le tableau clinique résultant de la réponse à toute infection, est dans sa forme la plus sévère, l’une des principales causes d’admission en service de réanimation. Nous avons réalisé un « immunomonitoring » complet des NK circulantes à la phase initiale d’états pro-inflammatoires chez 42 patients admis en réanimation pour des motifs infectieux (sepsis sévère ou choc septique) ou des tableaux de SIRS non infectieux. Les patients septiques présentaient une capacité réduite de dégranulation en comparaison des patients non-septique (SIRS). Ils présentaient également une réduction de la sécrétion d’interféron-, toujours en comparaison des patients SIRS. / Patients admitted to the intensive care unit (ICU) seem to have severe infections with CMV, without any immunosuppressive therapy, but the exact incidence of these infections is difficult to assess. We conducted a systematic screening of CMV in 242 consecutive patients non-immunosuppressed before ICU admission. We identified that 16% of patients developed CMV infection during their stay in ICU. The mortality of patients with CMV infection was higher than those without such infection. The pathophysiology of CMV reactivation occurring in critically ill patients with no previous immunosuppression is misunderstood. We selected non-immunocompromised ICU patients, CMV seropositive at admission, and we compared the status of circulating NK of 15 patients with CMV reactivation detected by antigenemia (cases) to 15 controls matched for age, gender, and severity on admission. In the period preceding the CMV reactivation, whereas capabilities cytotoxicity (degranulation) are comparable, we show impaired NK in terms of production of gamma interferon in cases compared to controls, and also healthy. Levels of IL-10 were significantly higher in cases with a strong correlation between the levels of this cytokine and severity of CMV reactivation as measured by the number of cells positive antigenemia. Sepsis, the clinical picture resulting from the response to any infection, in its severest form, is one of the main causes of admission in ICU. We conducted a complete immunomonitoring of circulating NK in the initial phase of pro-inflammatory state in 42 patients admitted to intensive care for reasons of infection (severe sepsis or septic shock) or of non-infectious SIRS (systemic inflammatory response syndrome). Septic patients showed a reduced ability of degranulation compared with non-septic patients (SIRS). They also showed a reduction in the secretion of gamma interferon, compared with patients with SIRS.

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2012-11-27T17:22:07Z No. of bitstreams: 1 Andréa Mendes Pereira Ativação de celulas... 2006.pdf: 40276494 bytes, checksum: 9f4656b98e4c74bae9c81e7797e85988 (MD5) / Made available in DSpace on 2012-11-27T17:22:07Z (GMT). No. of bitstreams: 1 Andréa Mendes Pereira Ativação de celulas... 2006.pdf: 40276494 bytes, checksum: 9f4656b98e4c74bae9c81e7797e85988 (MD5) Previous issue date: 2006 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, Bahia, Brasil / Visando avaliar futuramente o potencial de citocinas na indução de resposta imune celular específica do tipo ThI quando associadas a antígeno(s) recombinante(s) de Leishmania chagasi/infantum no cão, a combinação de IL-2 e IL-12 caninas recombinantes é analisada no presente trabalho. Aqui, descrevemos a clonagem do DNA complementar (cDNA) e, pela primeira vez, a expressão de IL-2 canina recombinante biologicamente ativa em Escherichia coli e por células de mamífero. Para expressão em E. coli, utilizou-se a construção pRSET-calL- 2, anteriormente gerada por nosso grupo. Para expressão em células de mamíferos, foi realizada a clonagem do cDNA de IL-2, sintetizado por reação de transcrição reversa seguida de reação da polimerase em cadeia (RT-PCR) a partir do RNA total de células mononucleares do sangue periférico (CMSP) de cão estimuladas com concanavalina A (Con-A), no vetor pcDNAS.l, gerando a construção pcDNA3.1-caIL-2. O sucesso da clonagem em ambos os vetores de expressão foi confirmado a partir do sequenciamento de DNA e comparação dos resíduos de nucleotídeos com a seqüência de IL-2 canina previamente descrita por outro grupo de investigadores. A IL-2 canina recombinante (rcaIL-2) foi obtida como proteína de fiisão contendo cauda de histidina a partir da transformação de E. coli BL21(DE3)pLysS com pRSET- caIL-2, purificada por cromatografia de afinidade e renaturada por diálise. Além disso, a forma nativa de rcaIL-2 foi secretada no sobrenadante de cultura de células COS-7 transfectadas com a construção pcDNA3.1-caIL-2. A atividade proliferativa de rcaIL-2 sobre células CTLL-2 foi demonstrada em concentrações de até 220 pg/mL da citocina purificada a partir da expressão em E. coli e até a diluição de 1:256 do sobrenadante de COS-7 contendo rcaIL-2. A proteína biologicamente ativa foi capaz de manter a proliferação de CMSP de cães sadios por até 12 dias de cultivo quando as células foram tratadas com 50 ng/mL de IL-2 canina obtida de E. coli e por 10 dias com diluições de até 1:200 do sobrenadante de COS-7 contendo a citocina, na ausência de estímulo prévio ou concomitante. A proliferação foi dose-dependente, com ponto máximo ocorrendo no 8° dia de cultivo. A produção de interferon gama (IFN-y) por CMSP de cães sadios estimuladas com sobrenadante de COS-7 contendo IL-2 ou contendo IL-12 não foi significantemente maior que a produção basal. No entanto, um efeito sinérgico sobre a produção in vitro de IFN-y ocorreu quando concentrações subótimas de ambas as citocinas foram associadas. Diante dos resultados obtidos, a construção pcDNA3.1-caIL-2 e ambas as formas de IL-2 canina recombinante obtidas, assim como as condições experimentais aqui descritas, poderão ser utilizadas no futuro para o estudo do potencial de IL-2, associada ou não a IL-12, como modulador da resposta imune in vitro e in vivo de cães, durante o desenvolvimento de uma vacina ou imunoterapia para leishmaniose visceral canina. / Aiming to study in the fiiture the role of cytokines in inducing specific ThI cellular immune response when associated to Leishmania chagasi/infantum recombinant antigen(s) in dogs, the combination of recombinant canine IL-2 and IL-12 is analysed in the present study. Herein, we describe complementary DNA (cDNA) cloning and, for the first time, the expression of biologically active recombinant canine IL-2 in Escherichia coli and mammal cells. The construction pRSET-caIL-2, previously generated by our group, was used for E. coli expression. For mammalian expression, canine IL-2 cDNA was synthesized by reverse transcription followed by polymerase chain reaction (RT-PCR), using cDNA from a healthy dog’s peripheral blood mononuclear cells (PBMC) stimulated with concanavalin A (Con-A) and cloned into pcDNA3.1, generating the construction pcDNA3.1-caIL-2. Success in canine IL-2 cDNA cloning was accessed in both expression vectors by DNA sequencing and was confirmed by comparing nucleotides residues with canine IL-2 sequence previously described by other investigators. Recombinant canine IL-2 (rcaIL-2) was expressed as His-tag fiision protein after E. coli BL21(DE3)pLysS transformation with pRSET-caIL-2, purified by affinity chromatography and renatured through dialysis. In addition, the native form was secreted in culture supematants of pcDNA3.1-caIL-2 transfected COS-7 cells. A proliferative activity was demonstrated in CTLL-2 cells when the recombinant protein was diluted at 220 pg/mL of purified cytokine from E. coli expression or when COS-7 supernatant was diluted at 1:256. The biologically active protein was able to induce proliferation of PBMC of six healthy dogs until 12 days of culture when cells were treated with 50 ng/mL of E. coli expressed-IL-2 or until 10 days when treated with 1:200 COS-7 supernatant dilution containing the cytokine, without previous or concomitant stimulus. The proliferative effect was dose-dependent and maximum at 8th day of culture. Interferon-gamma (IFN-y) production by PBMC of eight healthy dogs induced by COS-7 IL-2 or IL-12-containing supematants was not significantly higher than the baseline production. However, the association of suboptimal concentrations of both cytokines induced synergistic effect upon in vitro IFN-y production by PBMC. Based on the presented results, the construction pcDNA3.1-caIL-2 or both recombinant protein forms obtained, as well as the experimental conditions described here, can be used in the future to evaluate the potential role of IL-2, associated or not to canine IL-12, as a modulator of in vitro and in vivo immune response of dogs during the development of a vaccine or immunotherapy for canine visceral leishmaniasis.

Orientador: Ramon Kaneno / Banca: Elaine Guadelupe Rodrigues / Banca: Daniela B. Kaneno / Resumo: O interferon alfa (IFN-α), um IFN do tipo I, se apresenta como uma citocina com grande potencial terapêutico, pois atua no combate direto às células tumorais, além de agir sobre a maturação de células dendríticas (DCs), que são células apresentadoras de antígenos profissionais e peças chave na elaboração da uma resposta antitumoral. Entretanto, a administração sistêmica de citocinas pode produzir toxicidade importante nos pacientes, de modo que a indução de sua produção in situ poderia representar uma forma de imunomodulação mais adequada. Assim, o objetivo deste estudo é verificar a ação de vetores lentivirais carregando o gene do IFN-α para transdução de células tumorais, permitindo assim a produção localizada de IFN-α, a fim de explorar, in vitro, seu potencial lítico e imunomodulatório sobre DCs. Vetores lentivirais carregando o gene do IFN-α humano (Lego-IFN) ou GFP (Lego-GFP) foram utilizados para a transdução in vitro de células de câncer colorretal. A transdução foi feita com diferentes multiplicidades de infecção (MOIs - 0.3, 1.0, 2.0, 4.0) para avaliarmos o efeito dose-dependente, seguido de co-cultura com DCs derivadas de monócitos de doadores saudáveis (DC-0.3, DC-1.0, DC-2.0, DC-4.0). Após 48h de co-cultura, as DCs foram avaliadas fenotípica e funcionalmente, através da análise dos marcadores de membrana por citometria de fluxo, capacidade de aloestimulação e de indução de linfócitos T citotóxicos (CTLs). Nós observamos que a transdução com Lego-GFP, mas não com Lego-IFN, aumentou a imunogenicidade das células tumorais, com aumento de expressão de CD54 e HLA-DR. A co-cultura de DCs com células tumorais transduzidas com Lego-IFN aumentou discretamente seu perfil de ativação, mas não seu potencial aloestimulatório in vitro. Observamos que linfócitos cultivados com DC-2.0 produziram níveis mais altos de IFN-γ, sugerindo a indução de um perfil Th1, enquanto que... / Abstract: Interferon alpha (IFN-α) is a type I IFN with great therapeutic potential, since it is able to directly fight tumor cells and enhance the maturation of dendritic cells (DCs), the main antigen-presenting cells, required for an effective antitumor response. However, the systemic administration of cytokines can induce severe collateral effects. Therefore, the induction of cytokine secretion in situ should represent a more adequate approach for cytokine-based immunotherapy. Thus, the goal of this study was to induce IFN-α secretion by colon cancer cells by transduction with a lentivirus vector carrying the human IFN-α gene, followed by analysis of its immunomodulatory potential over DCs. Transduction was made with different multiplicities of infection (MOIs - 0.3, 1.0, 2.0 and 4.0) to evaluate the dose-dependent effects. Such cells were co-cultured with monocyte-derived DCs from healthy donors (DC-0.3, DC-1.0, DC-2.0 and DC-4.0). Forty-eight hours later, DCs were evaluated for their phenotype (surface activation/maturation markers) by flow cytometry, their ability to induce allogeneic response in a mixed leukocyte reaction (MLR) and effectiveness to induce cytotoxic T cells. We observed that transduction with Lego-GFP, but not Lego-IFN, increased tumor cells' immunogenicity with up-regulation of the markers CD54 and HLA-DR. Co-culture of Lego-IFN-transduced tumor cells with DCs slightly enhanced their activation phenotype but not their potential to stimulate T cell proliferation in vitro. Furthermore, we observed that lymphocytes cultured with DC-2.0 produced higher levels of IFN-γ, suggesting an induction of Th1 profile on T cells, while DC-GFP induced more IL-10 and IL-4. Additionally, DC-4.0 was more efficient in generating cytotoxic T lymphocytes (CTLs) that the control DC, however DC-GFP induced even more CD8+T cell proliferation. The enhancement of tumor cell immunogenicity and the superior induction of CLTs ... / Mestre

Submitted by Marcelo Andrade Silva (marcelo.andradesilva@ufpe.br) on 2015-03-09T14:28:37Z No. of bitstreams: 2 DISSERTAÇÃO Joelma Carvalho Santos.pdf: 2064030 bytes, checksum: 9d9c233bec668a94294f6d19471cb844 (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) / Made available in DSpace on 2015-03-09T14:28:37Z (GMT). No. of bitstreams: 2 DISSERTAÇÃO Joelma Carvalho Santos.pdf: 2064030 bytes, checksum: 9d9c233bec668a94294f6d19471cb844 (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Previous issue date: 2014 / A presença de polimorfismos de único nucleotídeo (SNPs) e a expressão variante dos genes das citocinas IFN-α1, IFN-γ e do receptor IFN-α r1 em pacientes com infecção crônica pelo vírus da hepatite B (HBV), podem ser considerados fatores etiopatogênicos relacionados aos níveis séricos do HBV, resultando em complicações da doença. Desta forma, o presente estudo teve como objetivo verificar a associação entre as frequências genotípicas e proporções alélicas dos genes IFNG, IFNA1, IFNAR1 em relação aos níveis de expressão desses genes e à carga viral do HBV, em pacientes com infecção crônica pelo HBV sem tratamento antiviral. Foi realizado um estudo de caso-controle com amostras de sangue total de 208 indivíduos (94 pacientes com infecção crônica e 114 indivíduos imunes ao HBV) no período de outubro de 2012 a agosto de 2013, no ambulatório de hepatologia do Hospital das Clínicas da Universidade Federal de Pernambuco (HC/UFPE) e no Hospital Escola Dr. Helvio Auto da Universidade Estadual de Ciências da Saúde de Alagoas (HEHA/UNCISAL). Para a identificação dos polimorfismos foi utilizada a PCR em tempo real (qPCR) de acordo com técnica de alta resolução de melting (HRM). A quantificação da carga viral e a expressão absoluta dos genes IFNG (-5 A>G), IFNA1 (-2 C>T), IFNAR1 (-97 T>C) foram realizadas por qPCR. Em todos os pacientes com infecção crônica pelo HBV os níveis de expressão foram menores para o gene IFNA1 (mediana=2,56x10-1ηg/μL), em relação aos genes IFNG (mediana=4,54x105ηg/μL) e IFNAR1 (mediana=6,92x109ηg/μL), e a média de carga viral foi de 3,2 log10. Pacientes com genótipo heterozigoto IFNA1(-2) CT e alelo polimórfico IFNA1 (-2) T apresentaram maiores chances de desenvolver proteção pelo HBV quando comparados a indivíduos imunes com genótipo IFNA1(-2) CC e alelo tipo selvagem C, respectivamente (IFNA1 CT/CC: OR=0,45; p=0,01 e IFNA T/C: OR=0,54; p<0,01). Em pacientes com infecção crônica e genótipo tipo selvagem TT do IFNAR1, os baixos níveis de expressão do gene desse receptor, quando comparado aos outros genótipos, explicam em 40% os altos níveis de carga viral desses pacientes (r2=0,40 | p=0,04) conferindo um risco para o desenvolvimento da cronicidade. Para o genes IFNG(-5) não foi observada diferença estatisticamente significante entre os níveis de expressão e os genótipos. Assim, a presença da variante polimórfica do gene IFNA1 (-2) em pacientes com infecção crônica, pode estar associada à proteção da cronicidade quando comparada ao grupo controle. Os altos níveis de expressão do gene IFNAR1 e baixos níveis de IFNA1 podem contribuir para a cronicidade nestes indivíduos. Os pacientes que com genótipo polimórfico IFNA1 (-2) CT e alelo T apresentaram maior proteção para a cronicidade pelo HBV.