The ubiquitous ɣ-herpesvirus Epstein-Barr virus (EBV) infects B cells and modifies their differentiation programme leading to B cell activation and immortalization. Although different evidences support a link between EBV infection and rheumatoid arthritis (RA) and Sjogren’s syndrome (SS), the exact role of EBV in RA and SS pathogenesis remain elusive. Recently ectopic lymphoid structures (ELS) have been identified as preferential niches for EBV persistence and reactivation in patients with multiple sclerosis and myasthenia gravis. Independent studies demonstrated that around 50% of RA synovia and 30% of SS salivary glands are characterised by the development of functional ELS, capable to promote local differentiation of autoreactive plasma cells. In this PhD project I explored the potential role of EBV in RA and SS pathogenesis by analysing EBV infection in the RA synovium and SS salivary glands and its relationship with ELS, in situ autoreactive plasma cell differentiation, pathogenic autoantibodies production and cytotoxic immune response. In this work I demonstrated that: i) markers of EBV latent and lytic infection are consistently associated with the presence of ELS in the RA synovium and SS salivary glands; ii) latent EBV proteins are preferentially expressed by B cells, while viral reactivation occurs in plasma cells; iii) a large subset of autoreactive plasma cells is EBV lytically infected in the RA synovia and SS salivary glands; iv) antibodies specific for unmodified and citrullinated EBV peptides, known to cross-recognize ACPA, are produced within ectopic lymphoid structures as 8 demonstrated in vivo in human RA/SCID chimeras; v) SS salivary gland grafts transplanted into SCID mice release human IgG against EBV antigens, whose production correlates with the level of SS-associated auto-antibodies and vi) analysis of CD8+ and CD4+ T-cell localization and granzyme B expression indicated that EBV persistence in ELS-containing RA synovia and SS salivary glands may be favoured by exclusion of CD8+ T cells from B-cell follicles and impaired CD8-mediated cytotoxicity. Overall, these results redefine a novel and pathogenically relevant role for EBV in B-cell dysregulation and chronic inflammation in RA synovium and SS salivary glands.

Portadores de diabetes parecem ter mais queixas de olho seco do que o resto da população. Acredita-se que isto possa estar associado a uma forma de neuropatia diabética expressa por uma redução na sensibilidade corneana desses pacientes. Nossos principais objetivos neste estudo foram avaliar a influência da diabetes melito tipo 2 na sensibilidade corneana central e verificar se há uma associação entre a sensibilidade corneana central e a síndrome do olho seco em indivíduos com a doença. Assim, 62 portadores de diabetes tipo 2 foram submetidos a um exame oftalmológico de rotina, a uma ceratoestesiometria e a testes específicos para avaliar olho seco e polineuropatia distal simétrica. Num outro grupo, 20 voluntários saudáveis tiveram seus olhos avaliados da mesma forma, exceto pela não realização dos testes específicos para disfunção lacrimal. Entre os indivíduos diabéticos avaliados, foram observados 53.2% com hipoestesia corneana, 54.2% com retinopatia diabética, 45.9% com polineuropatia distal simétrica e 51.6% com a síndrome do olho seco. Entre os principais achados, observamos associações significativas envolvendo: diabetes tipo 2 e hipoestesia corneana central, síndrome do olho seco e hipoestesia corneana central, produção lacrimal reflexa (avaliada pelo teste de Schirmer II) e sensibilidade corneana central e retinopatia diabética proliferativa e sensibilidade corneana central. Uma possível associação foi encontrada envolvendo síndrome do olho seco retinopatia diabética proliferativa. Os autores discutem os resultados obtidos e os mecanismos envolvidos. / Diabetes bearers seem to have more complaints of dry eye than the rest of the population. It`s believed that this fact might be associated to a kind of diabetes neuropathy wich is represented by a reduction in corneal sensibility of these patients. Our main target in this study was to evaluate the influence of type 2 diabetes mellitus in central corneal sensibility and to determine if there is an association among central corneal sensibility and the dry eye syndrome in individuals suffering of this disease. Therefore, 62 type 2 diabetic patients were submitted to an ophthalmological routine examination, to corneal esthesiometry and to specific tests to evaluate dry eye and peripheral polineurophaty. In other group, 20 healthy volunteers had their eyes evaluated in the same way, except for the non accomplishment of the specific tests for dry eye. Among the examined diabetic individuals, 53.2% had corneal hypoesthesia, 54.2% presented diabetic retinopathy, 45.9% presented periferal polineuropathy and 51.6% presented the dry eye syndrome. Among the main findings, we observed associations between: type 2 diabetes and central corneal hypoesthesia, dry eye syndrome and central corneal hypoesthesia, reflex tear production (evaluated by Schirmer 2 test) and central corneal esthesiometry and also between proliferative diabetic retinopathy and central corneal sensibility. A possible association was found involving dry eye syndrome and proliferative diabetic retinophaty. The authors discuss the results obtained and the involved mechanisms.

Portadores de diabetes parecem ter mais queixas de olho seco do que o resto da população. Acredita-se que isto possa estar associado a uma forma de neuropatia diabética expressa por uma redução na sensibilidade corneana desses pacientes. Nossos principais objetivos neste estudo foram avaliar a influência da diabetes melito tipo 2 na sensibilidade corneana central e verificar se há uma associação entre a sensibilidade corneana central e a síndrome do olho seco em indivíduos com a doença. Assim, 62 portadores de diabetes tipo 2 foram submetidos a um exame oftalmológico de rotina, a uma ceratoestesiometria e a testes específicos para avaliar olho seco e polineuropatia distal simétrica. Num outro grupo, 20 voluntários saudáveis tiveram seus olhos avaliados da mesma forma, exceto pela não realização dos testes específicos para disfunção lacrimal. Entre os indivíduos diabéticos avaliados, foram observados 53.2% com hipoestesia corneana, 54.2% com retinopatia diabética, 45.9% com polineuropatia distal simétrica e 51.6% com a síndrome do olho seco. Entre os principais achados, observamos associações significativas envolvendo: diabetes tipo 2 e hipoestesia corneana central, síndrome do olho seco e hipoestesia corneana central, produção lacrimal reflexa (avaliada pelo teste de Schirmer II) e sensibilidade corneana central e retinopatia diabética proliferativa e sensibilidade corneana central. Uma possível associação foi encontrada envolvendo síndrome do olho seco retinopatia diabética proliferativa. Os autores discutem os resultados obtidos e os mecanismos envolvidos. / Diabetes bearers seem to have more complaints of dry eye than the rest of the population. It`s believed that this fact might be associated to a kind of diabetes neuropathy wich is represented by a reduction in corneal sensibility of these patients. Our main target in this study was to evaluate the influence of type 2 diabetes mellitus in central corneal sensibility and to determine if there is an association among central corneal sensibility and the dry eye syndrome in individuals suffering of this disease. Therefore, 62 type 2 diabetic patients were submitted to an ophthalmological routine examination, to corneal esthesiometry and to specific tests to evaluate dry eye and peripheral polineurophaty. In other group, 20 healthy volunteers had their eyes evaluated in the same way, except for the non accomplishment of the specific tests for dry eye. Among the examined diabetic individuals, 53.2% had corneal hypoesthesia, 54.2% presented diabetic retinopathy, 45.9% presented periferal polineuropathy and 51.6% presented the dry eye syndrome. Among the main findings, we observed associations between: type 2 diabetes and central corneal hypoesthesia, dry eye syndrome and central corneal hypoesthesia, reflex tear production (evaluated by Schirmer 2 test) and central corneal esthesiometry and also between proliferative diabetic retinopathy and central corneal sensibility. A possible association was found involving dry eye syndrome and proliferative diabetic retinophaty. The authors discuss the results obtained and the involved mechanisms.

Portadores de diabetes parecem ter mais queixas de olho seco do que o resto da população. Acredita-se que isto possa estar associado a uma forma de neuropatia diabética expressa por uma redução na sensibilidade corneana desses pacientes. Nossos principais objetivos neste estudo foram avaliar a influência da diabetes melito tipo 2 na sensibilidade corneana central e verificar se há uma associação entre a sensibilidade corneana central e a síndrome do olho seco em indivíduos com a doença. Assim, 62 portadores de diabetes tipo 2 foram submetidos a um exame oftalmológico de rotina, a uma ceratoestesiometria e a testes específicos para avaliar olho seco e polineuropatia distal simétrica. Num outro grupo, 20 voluntários saudáveis tiveram seus olhos avaliados da mesma forma, exceto pela não realização dos testes específicos para disfunção lacrimal. Entre os indivíduos diabéticos avaliados, foram observados 53.2% com hipoestesia corneana, 54.2% com retinopatia diabética, 45.9% com polineuropatia distal simétrica e 51.6% com a síndrome do olho seco. Entre os principais achados, observamos associações significativas envolvendo: diabetes tipo 2 e hipoestesia corneana central, síndrome do olho seco e hipoestesia corneana central, produção lacrimal reflexa (avaliada pelo teste de Schirmer II) e sensibilidade corneana central e retinopatia diabética proliferativa e sensibilidade corneana central. Uma possível associação foi encontrada envolvendo síndrome do olho seco retinopatia diabética proliferativa. Os autores discutem os resultados obtidos e os mecanismos envolvidos. / Diabetes bearers seem to have more complaints of dry eye than the rest of the population. It`s believed that this fact might be associated to a kind of diabetes neuropathy wich is represented by a reduction in corneal sensibility of these patients. Our main target in this study was to evaluate the influence of type 2 diabetes mellitus in central corneal sensibility and to determine if there is an association among central corneal sensibility and the dry eye syndrome in individuals suffering of this disease. Therefore, 62 type 2 diabetic patients were submitted to an ophthalmological routine examination, to corneal esthesiometry and to specific tests to evaluate dry eye and peripheral polineurophaty. In other group, 20 healthy volunteers had their eyes evaluated in the same way, except for the non accomplishment of the specific tests for dry eye. Among the examined diabetic individuals, 53.2% had corneal hypoesthesia, 54.2% presented diabetic retinopathy, 45.9% presented periferal polineuropathy and 51.6% presented the dry eye syndrome. Among the main findings, we observed associations between: type 2 diabetes and central corneal hypoesthesia, dry eye syndrome and central corneal hypoesthesia, reflex tear production (evaluated by Schirmer 2 test) and central corneal esthesiometry and also between proliferative diabetic retinopathy and central corneal sensibility. A possible association was found involving dry eye syndrome and proliferative diabetic retinophaty. The authors discuss the results obtained and the involved mechanisms.