Das Sjögren-Syndrom (SjS) stellt eine mögliche autoimmune Ursache einer interstitiellen Lungenerkrankung dar. Die Abklärung in Richtung SjS ist aber im Vergleich zu anderen systemischen Autoimmunerkrankungen bisher kaum standardisiert. Die subjektive Sicca-Symptomatik, die Anti-SS-A/Ro-Antikörper und selbst die ANA-Diagnostik als Suchtest haben alle relevante Einschränkungen in ihrer Sensitivität und/oder Spezifität. Vor diesem Hintergrund haben wir in einer interdisziplinären Diskussion einen Konsens für die SjS-Abklärung entwickelt, den wir hier für die breitere Diskussion vorstellen. Neben ANA sollten sowohl Anti-SS-A/Ro-Antikörper als auch Antikörper gegen α‑Fodrin bestimmt werden. Wichtig ist die Objektivierung der Trockenheit mittels Schirmer- und Saxon-Test und bei fehlenden typischen Autoantikörpern die Speicheldrüsenbiopsie. / Sjögren’s syndrome (SjS) is a possible autoimmune cause of interstitial lung disease. The diagnostic pathway for SjS, however, is largely undefined in comparison to other systemic autoimmune diseases. Subjective sicca symptoms, anti-SS-A/Ro antibodies and even ANA as screening tests all have relevant limitations in sensitivity and/or specificity. Against this background, in an interdisciplinary discussion we have developed a consensus for the clarification of SjS, which is presented here for broader discussion. In addition to ANA and anti-SS-A/Ro antibodies, antibodies against alpha-fodrin should be included. Objective measures of dryness, such a Schirmer and Saxon tests are important, as is a salivary gland biopsy in the absence of typical autoantibodies.

Le syndrome de Sjögren primitif (SSp) est une maladie auto-immune (MAI) systémique ayant des caractéristiques communes avec le lupus érythémateux. Ces caractéristiques incluent des mécanismes physiopathologiques et des facteurs de predispositions génétiques. Notre équipe et d’autres groupes ont pu mettre en evidence une signature interféron (IFN) dans les glandes salivaires et les PBMCs de patients ayant un SSp. Cette découverte a permis de mettre en évidence de nouvelles voies à explorer dans la pathogénie du SLE et SSp en permettant la focalisation des recherches sur le rôle de l’immunité innée et de la voie IFN.Nous avons confirmé le rôle de 2 gènes importants dans le SSp, impliqués dans les voies des IFN. Le premier est IRF5 sur la voie IFN de type I et STAT4 sur la voie IFN de type II. Nous avons pu mettre en évidence une fonctionnalité de l’allèle à risque d’IRF5 (Polymorphisme Indel situé dans le promoteur). Concernant STAT4, son expression n’était pas altérée par le SNP associé à la maladie. Toutefois, l’ARNm de STAT4 était corrélé à l’expression des gènes IFN de type I. Les dérégulations épigénétique pourraient jouer un rôle important dans la pathogénie de nombreuses MAI, en particulier la méthylation de l’ADN qui est hautement liée à l’extinction de l’expression des gènes. Nous avons étudié la méthylation du promoteur d’IRF5 et nous n’avons pas trouvé de régulation de ce promoteur par le méthylation. Une analyse de la méthylation avec une approche globale du méthylome est en cours dans notre équipe et permettra d’identifier de gènes cibles d’une dérégulation épigénétique pouvant être impliqués dans les MAI.Nous avons essayé de comprendre la relation entre STAT4 et gènes IFN de type I. Ainsi, nous rapportons que l’IL-12 induit spécifiquement l’IFN de type I par intéraction entre deux partenaires cellulaires, les lymphocytes T CD4+ et les cellules dendritiques plasmacytoïdes. Ces résultats pourraient expliquer l’implication des polymorphismes de STAT4 dans les MAI dépendantes de l’IFN de type I. Ces résultats suggèrent également que les MAI dépendantes des IFN de type I et II ne s’opposent pas. Elles seraient seulement le Yin et le Yang d’un facteur d’activation commun, STAT4, capable d’induire les IFNs de type I et II. / Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease (AID) that presents similar characteristics to systemic lupus erythematosus. These characteristics include pathophysiology and genetic factors. Our team and other groups have highlighted an interferon (IFN) signature in salivary glands and PBMCs from patients with Sjögren syndrome. This signature demonstrates new pathways in pSS and lupus, focusing research on innate immunity and in the IFN pathway.We have confirmed the implication of 2 genes in the pSS, and these genes are involved in the IFN pathway. The first gene is IRF5 which is in the type I IFN pathway and the second is STAT4 which is in the type II IFN pathway. We have shown a functional consequence of IRF5 at-risk allele. Regarding STAT4, the associated SNP did not altered STAT4 mRNA expression but was highly correlated with type I IFN genes expression.The epigenetic deregulation could play a triggering role in autoimmune diseases, particularly through DNA methylation which is highly implicated in the suppression of gene expression. We studied the methylation of IRF5 promoter and found no methylation. Our team is currently undertaking a global approach with methylome analysis. This methylome study will assess specific gene methylation patterns and will allow a better understanding of the role of these genes in autoimmune diseases.We further demonstrated that IL-12 specifically induces a type I IFN signature through a CD4+ T cells and pDCs crosstalk. These results could explain the implication of STAT4 polymorphism not only in type II IFN-dependent AIDs but also in type I IFN-dependent AIDs. Our data confirm that type I IFN- and type II IFN-mediated AIDs do not have to be opposed. They are only the yin and the yang of a common STAT4 activation which may induce secretion of both cytokines.

A Síndrome Metabólica (SM) tem sido descrita nas doenças autoimunes. No entanto, existem poucos dados na literatura sobre a síndrome metabólica e o perfil de adipocitocinas na síndrome de Sjögren primária (SSp). Setenta e um pacientes do sexo feminino com SSp com idades entre 18-65 anos (Critérios do Consenso Euramericano, 2002) e 71 mulheres saudáveis pareadas por idade e raça foram incluídas neste estudo caso-controle. Os dados clínicos foram coletados por meio de um protocolo padronizado. Os níveis sanguíneos de glicose, colesterol total, LDL-colesterol (LDL-C), HDL-colesterol (HDL-C), triglicérides, interleucina-1 beta (IL-1 beta)/ IL-6, fator de ativação das células B (BAFF), insulina e leptina/ adiponectina/ visfatina/ resistina foram determinados. Os pacientes e os controles foram comparáveis com relação ao índice de massa corporal (IMC), tabagismo, sedentarismo e menopausa (p > 0,05). A síndrome metabólica (39,4 vs. 16,9%, p= 0,005), hipertensão (p= 0,004) e a dislipidemia (p= 0,002) foram mais frequentes nos pacientes do que nos controles. Os níveis de IL-1 beta, IL-6, BAFF, resistina e adiponectina foram mais elevados nos pacientes do que nos controles (p < 0,05). Os pacientes com SSp com SM (n= 28) apresentaram maiores valores de IMC, circunferência abdominal, colesterol total, LDL-C, triglicérides, insulina, leptina e HOMA-IR, além de maiores taxas de hipertensão e diabetes do que os pacientes com SSp sem SM (n= 43) (p < 0,05). O uso atual e/ou prévio de prednisona (75,0 vs. 62,8%, p = 0,313), a dose atual (3,0 ± 4,5 vs. 1,6 ± 3,2 mg/dia, p= 0,299) e a dose cumulativa de prednisona (p= 0,495) foram semelhantes em ambos os grupos. Entretanto, os níveis de IL-1 beta foram maiores em pacientes com SM do que nos pacientes sem SM (p= 0,012). Este achado foi confirmado por análise multivariada (p= 0,048) com ajustes para idade, etnia, uso de prednisona, doses cumulativas e atuais de prednisona e ainda duração do uso da mesma. Nós identificamos elevada frequência de síndrome metabólica e um perfil anormal de adipocitocinas em pacientes com SSp. A associação da síndrome metabólica com elevados níveis de IL-1 beta sugere que a inflamação possa desempenhar um papel importante na sua patogênese / The metabolic syndrome (MetS) has been described in autoimmune diseases. However, there are few data in the literature on metabolic syndrome and adipocytokines profile in primary Sjögren\'s syndrome (pSS). Seventy-one female patients with pSS aged 18-65 years (criteria of the American European Consensus, 2002) and 71 healthy women matched for age and race were included in this case-control study. Clinical data were collected using a standardized protocol. Blood levels of glucose, total cholesterol, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triglycerides, interleukin-1 beta (IL-1 beta)/ IL-6, B-cell activating factor (BAFF), insulin and leptin/ adiponectin/ visfatin/ resistin were determined. Patients and controls were comparable with respect to body mass index (BMI), smoking, sedentary lifestyle and menopause (p > 0.05). The metabolic syndrome (39.4 vs. 16.9%, p= 0.005), hypertension (p= 0.004) and dyslipidemia (p= 0.002) were more frequent in patients than in controls. IL-1 beta, IL-6, BAFF, resistin and adiponectin levels were higher in patients than in controls (p < 0.05). pSS patients with MetS (n= 28) had higher BMI, waist circumference, total cholesterol, LDL-C, triglycerides, insulin, leptin and HOMA-IR, as well as higher rates of hypertension and diabetes than pSS patients without MetS (n= 43) (p < 0.05). The current and/or prior use of prednisone (75.0 vs. 62.8%, p= 0.313), the current dose (3.0 ± 4.5 vs. 1.6 ± 3.2 mg/day p= 0.299) and cumulative dose of prednisone (p= 0.495) were similar in both groups. However, IL-1 beta levels were higher in pSS patients with MetS than in pSS patients without MetS (p= 0.012). This finding was confirmed by multivariate analysis (p= 0.048) with adjustments for age, ethnicity, use of prednisone, current and cumulative doses of prednisone and even duration of use. We have identified high frequency of metabolic syndrome and an abnormal profile of adipocytokines in pSS patients. The association of metabolic syndrome with elevated IL-1 beta levels suggests that inflammation may play an important role in its pathogenesis

A Síndrome Metabólica (SM) tem sido descrita nas doenças autoimunes. No entanto, existem poucos dados na literatura sobre a síndrome metabólica e o perfil de adipocitocinas na síndrome de Sjögren primária (SSp). Setenta e um pacientes do sexo feminino com SSp com idades entre 18-65 anos (Critérios do Consenso Euramericano, 2002) e 71 mulheres saudáveis pareadas por idade e raça foram incluídas neste estudo caso-controle. Os dados clínicos foram coletados por meio de um protocolo padronizado. Os níveis sanguíneos de glicose, colesterol total, LDL-colesterol (LDL-C), HDL-colesterol (HDL-C), triglicérides, interleucina-1 beta (IL-1 beta)/ IL-6, fator de ativação das células B (BAFF), insulina e leptina/ adiponectina/ visfatina/ resistina foram determinados. Os pacientes e os controles foram comparáveis com relação ao índice de massa corporal (IMC), tabagismo, sedentarismo e menopausa (p > 0,05). A síndrome metabólica (39,4 vs. 16,9%, p= 0,005), hipertensão (p= 0,004) e a dislipidemia (p= 0,002) foram mais frequentes nos pacientes do que nos controles. Os níveis de IL-1 beta, IL-6, BAFF, resistina e adiponectina foram mais elevados nos pacientes do que nos controles (p < 0,05). Os pacientes com SSp com SM (n= 28) apresentaram maiores valores de IMC, circunferência abdominal, colesterol total, LDL-C, triglicérides, insulina, leptina e HOMA-IR, além de maiores taxas de hipertensão e diabetes do que os pacientes com SSp sem SM (n= 43) (p < 0,05). O uso atual e/ou prévio de prednisona (75,0 vs. 62,8%, p = 0,313), a dose atual (3,0 ± 4,5 vs. 1,6 ± 3,2 mg/dia, p= 0,299) e a dose cumulativa de prednisona (p= 0,495) foram semelhantes em ambos os grupos. Entretanto, os níveis de IL-1 beta foram maiores em pacientes com SM do que nos pacientes sem SM (p= 0,012). Este achado foi confirmado por análise multivariada (p= 0,048) com ajustes para idade, etnia, uso de prednisona, doses cumulativas e atuais de prednisona e ainda duração do uso da mesma. Nós identificamos elevada frequência de síndrome metabólica e um perfil anormal de adipocitocinas em pacientes com SSp. A associação da síndrome metabólica com elevados níveis de IL-1 beta sugere que a inflamação possa desempenhar um papel importante na sua patogênese / The metabolic syndrome (MetS) has been described in autoimmune diseases. However, there are few data in the literature on metabolic syndrome and adipocytokines profile in primary Sjögren\'s syndrome (pSS). Seventy-one female patients with pSS aged 18-65 years (criteria of the American European Consensus, 2002) and 71 healthy women matched for age and race were included in this case-control study. Clinical data were collected using a standardized protocol. Blood levels of glucose, total cholesterol, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triglycerides, interleukin-1 beta (IL-1 beta)/ IL-6, B-cell activating factor (BAFF), insulin and leptin/ adiponectin/ visfatin/ resistin were determined. Patients and controls were comparable with respect to body mass index (BMI), smoking, sedentary lifestyle and menopause (p > 0.05). The metabolic syndrome (39.4 vs. 16.9%, p= 0.005), hypertension (p= 0.004) and dyslipidemia (p= 0.002) were more frequent in patients than in controls. IL-1 beta, IL-6, BAFF, resistin and adiponectin levels were higher in patients than in controls (p < 0.05). pSS patients with MetS (n= 28) had higher BMI, waist circumference, total cholesterol, LDL-C, triglycerides, insulin, leptin and HOMA-IR, as well as higher rates of hypertension and diabetes than pSS patients without MetS (n= 43) (p < 0.05). The current and/or prior use of prednisone (75.0 vs. 62.8%, p= 0.313), the current dose (3.0 ± 4.5 vs. 1.6 ± 3.2 mg/day p= 0.299) and cumulative dose of prednisone (p= 0.495) were similar in both groups. However, IL-1 beta levels were higher in pSS patients with MetS than in pSS patients without MetS (p= 0.012). This finding was confirmed by multivariate analysis (p= 0.048) with adjustments for age, ethnicity, use of prednisone, current and cumulative doses of prednisone and even duration of use. We have identified high frequency of metabolic syndrome and an abnormal profile of adipocytokines in pSS patients. The association of metabolic syndrome with elevated IL-1 beta levels suggests that inflammation may play an important role in its pathogenesis

A doença do enxerto contra o hospedeiro (DECH) é uma das maiores causas de mortalidade e morbidade pós-transplante de células-tronco hematopoiéticas. A DECH, em sua manifestação crônica (DECHc), ainda não tem sua fisiopatologia totalmente esclarecida; entretanto, o envolvimento do sistema imunológico, por meio de respostas imunes inatas e adaptativas é bem estabelecido na literatura. A DECHc afeta múltiplos órgãos, incluindo as glândulas salivares, o que tem, como causa imediata, a xerostomia. Essas alterações são largamente desconhecidas e sub-relatadas. Assim, esse estudo indagou se o sintoma de xerostomia na DECHc é decorrente de alterações morfológicas e funcionais das glândulas salivares. Para responder essa pergunta analisamos de forma qualitativa e por meio da morfometria, espécimes de biopsias de glândulas salivares labiais de pacientes com DECHc e com sintoma de xerostomia. Foram utilizados como controles, espécimes de biopsias de glândulas salivares de pacientes diagnosticados com Síndrome de Sjögren (SSp) (que é um modelo clássico de xerostomia) e de pacientes com líquen plano oral (LPO) (cujas manifestações clínicas orais podem se assemelhar às da DECHc) e queixa de xerostomia. Também foram analisadas, por meio de ensaio multiplex, as citocinas relacionadas à resposta imune Th17 (importante via imunológica na patogenia da DECHc) na saliva de 21 pacientes de DECHc, 27 de SSp, 10 de LPO e 15 voluntários saudáveis. Os principais achados morfológicos nas glândulas salivares dos pacientes de DECHc foram a extensa fibrose, fibroplasia periductal, atrofia ductal e acinar; alterações vasculares representadas pela congestão e formação de trombos hialinos; e infiltrado inflamatório intersticial difuso de aspecto leve a moderado. As glândulas salivares de SSp, entretanto, apresentaram um infiltrado inflamatório na forma de focos de linfócitos ao redor dos ductos excretores de intensidade moderada a severa; os ductos excretores apresentaram-se atróficos, ectásicos, exibindo metaplasia oncocítica e fibroplasia periductal; as alterações vasculares, por sua vez, se apresentaram em maior proporção na forma de vasculite. No LPO as alterações teciduais foram menos intensas. Quando analisadas as concentrações das citocinas, na DECHc, foram encontradas maiores concentrações de IL-17A, IL-4, IL-17F e IL-10, em relação aos grupos controles, essas citocinas estão envolvidas em mecanismos prófibróticos, o que permitiu a correlação dessa expressão aos eventos escleróticos nas glândulas salivares dos pacientes de DECHc. Entre elas, a IL-17F apresentou uma tendência de aumento em relação a proporção da área de fibrose nas glândulas salivares destes pacientes. A CD40L, que também esteve presente em maior concentração nos pacientes de DECHc, é uma molécula de ligação capaz de amplificar a resposta imunológica no mecanismo de rejeição do enxerto no hospedeiro, além de regular o mecanismo de apoptose e ativar o endotélio para a formação de trombos. As citocinas IL-31, IL-23 e IL-22, também apresentaram relevância na saliva dos pacientes de DECHc, sendo participantes do mecanismo das alterações liquenóides no LPO. Através das análises comparativas foi possível correlacionar a presença de citocinas envolvidas na resposta Th17 com as alterações glandulares e consequente xerostomia nos pacientes de DECHc. / The graft versus host disease (GVHD) is one of the biggest causes of mortality and morbidity after hematopoietic stem cells transplantation. The pathophysiology in the chronical manifestation of the disease (cGVHD), is not entirely elucidated, however the involvement of the immunological system, by means of the innate and adaptive responses are depicted in the literature concerning the disease development. The cGVHD affects multiple organs, including the salivary glands, leading to xerostomia. These alterations are under reported and mostly unknown. Therefore, this study investigated if the symptom of xerostomia in cGVHD is triggered by functional e morphological changes in minor salivary glands. To answer this inquiry specimens of biopsied labial salivary glands from patients of cGVHD and xerostomia were analyzed qualitatively and through morphometry. Specimens of biopsied salivary glands from patients with Sjögren\'s Syndrome (SS) (which is a classic model of xerostomia) and from patients with oral lichen planus (OLP) (whose clinical oral manifestations resemble the cGVHD lesions) were used as controls. Also, the cytokines related to the immunological response Th17 (important immune pathway in cGVHD pathophysiology) in the saliva of 21 cGVHD patients, 27 of SS, 10 patients of OLP and 165 healthy individuals were analyzed using the multiplex assay. The major morphological findings revealed on the salivary glands of cGVHD patients were the extensive fibrosis, periductal fibrosis, ductal and acinar atrophy. Congestion and hyaline thrombi formation were the most important vascular changes shown among these specimens. A diffuse interstitial inflammatory infiltrate was observed, with varied intensity. The SS salivary glands, however, portrayed a focal inflammatory infiltrate, with moderate to severe intensity around the excretory ducts. These ducts exhibited atrophy, ectasia, periductal fibrosis and oncocytic metaplasia. The main vascular change presented in these patients was the manifestation of vasculitis. The salivary glands from the OLP patients showed a lesser amount of alterations. The multiplex assay revealed a higher concentration of the cytokines IL-17A, IL-4, IL-17F and IL-10 in the cGVHD samples, when compared to the other groups. These cytokines are involved within the promotion of fibrosis, which endorsed the association of these secretions with the salivary glands sclerotic mechanisms. The secretion of CD40L was higher in cGVHD samples; this membrane protein is capable of amplifying the immunological response in graft rejection, besides the capacity to regulate apoptosis and activate the endothelium in thrombi formation. The cytokines IL-31, IL-23 and IL-22, also presented a higher concentration in cGHVD patients\' saliva, these secretions are actively involved in the mechanisms of lichenoid lesions in OLP, corroborating the perceived morphological changes. The comparative analysis of the morphological and salivary changes in cGVHD confirmed the correlation of Th17 immunological response within the minor salivary glands injuries and consequent xerostomia in these patients.

<p>Patients with systemic lupus erythematosus (SLE) have an activated type I interferon (IFN) system with an ongoing IFN-α synthesis. This may be caused by circulating immune complexes, consisting of anti-DNA antibodies (Abs) and DNA, with IFN-α inducing capacity. Produced IFN-α may be crucial in the pathogenesis, because this cytokine can break tolerance and promote autoimmunity.</p><p>In the present thesis, possible mechanisms of the IFN-α production in SLE were studied. To investigate whether IFN-α inducing material could be derived from apoptotic cells, IgG from SLE patients (SLE-IgG) were combined with apoptotic cells. This combination induced high IFN-α production in normal peripheral blood mononuclear cells (PBMC). The IFN-α induction was associated to presence of anti-RNP Abs, but not to anti-dsDNA Abs, indicating that two inducers could be active in SLE, one containing DNA and the other RNA.</p><p>Apoptotic cells and SLE-IgG exclusively activated the natural interferon producing cells (NIPC) and the IFN-α response was enhanced by type I IFN and inhibited by IL-10 and TNF-α. The IFN-α induction was dependent on FcγRII, because blocking this receptor reduced IFN-α production and NIPC were found to express FcγRIIa.</p><p>To further elucidate the role of different autoantibodies in the IFN-α induction, sera from patients with Sjögren´s syndrome (SS), containing autoantibodies to RNA binding proteins (SSA, SSB, RNP and/or Sm) were investigated. The combination of SS or SLE sera and apoptotic or necrotic cell material induced high IFN-α production in PBMC. RNA, but not DNA, was required for IFN-α induction, indicating that RNA and Abs to RNA-binding proteins form potent IFN-α inducing complexes.</p><p>The findings in this thesis can explain central mechanisms for the activation of NIPC in SLE, and perhaps also other autoimmune diseases. This activation is mediated by interferogenic immune complexes, and modulating the NIPC activation may be a novel therapeutic approach in SLE.</p>

Patients with systemic lupus erythematosus (SLE) have an activated type I interferon (IFN) system with an ongoing IFN-α synthesis. This may be caused by circulating immune complexes, consisting of anti-DNA antibodies (Abs) and DNA, with IFN-α inducing capacity. Produced IFN-α may be crucial in the pathogenesis, because this cytokine can break tolerance and promote autoimmunity. In the present thesis, possible mechanisms of the IFN-α production in SLE were studied. To investigate whether IFN-α inducing material could be derived from apoptotic cells, IgG from SLE patients (SLE-IgG) were combined with apoptotic cells. This combination induced high IFN-α production in normal peripheral blood mononuclear cells (PBMC). The IFN-α induction was associated to presence of anti-RNP Abs, but not to anti-dsDNA Abs, indicating that two inducers could be active in SLE, one containing DNA and the other RNA. Apoptotic cells and SLE-IgG exclusively activated the natural interferon producing cells (NIPC) and the IFN-α response was enhanced by type I IFN and inhibited by IL-10 and TNF-α. The IFN-α induction was dependent on FcγRII, because blocking this receptor reduced IFN-α production and NIPC were found to express FcγRIIa. To further elucidate the role of different autoantibodies in the IFN-α induction, sera from patients with Sjögren´s syndrome (SS), containing autoantibodies to RNA binding proteins (SSA, SSB, RNP and/or Sm) were investigated. The combination of SS or SLE sera and apoptotic or necrotic cell material induced high IFN-α production in PBMC. RNA, but not DNA, was required for IFN-α induction, indicating that RNA and Abs to RNA-binding proteins form potent IFN-α inducing complexes. The findings in this thesis can explain central mechanisms for the activation of NIPC in SLE, and perhaps also other autoimmune diseases. This activation is mediated by interferogenic immune complexes, and modulating the NIPC activation may be a novel therapeutic approach in SLE.

A doença do enxerto contra o hospedeiro (DECH) é uma das maiores causas de mortalidade e morbidade pós-transplante de células-tronco hematopoiéticas. A DECH, em sua manifestação crônica (DECHc), ainda não tem sua fisiopatologia totalmente esclarecida; entretanto, o envolvimento do sistema imunológico, por meio de respostas imunes inatas e adaptativas é bem estabelecido na literatura. A DECHc afeta múltiplos órgãos, incluindo as glândulas salivares, o que tem, como causa imediata, a xerostomia. Essas alterações são largamente desconhecidas e sub-relatadas. Assim, esse estudo indagou se o sintoma de xerostomia na DECHc é decorrente de alterações morfológicas e funcionais das glândulas salivares. Para responder essa pergunta analisamos de forma qualitativa e por meio da morfometria, espécimes de biopsias de glândulas salivares labiais de pacientes com DECHc e com sintoma de xerostomia. Foram utilizados como controles, espécimes de biopsias de glândulas salivares de pacientes diagnosticados com Síndrome de Sjögren (SSp) (que é um modelo clássico de xerostomia) e de pacientes com líquen plano oral (LPO) (cujas manifestações clínicas orais podem se assemelhar às da DECHc) e queixa de xerostomia. Também foram analisadas, por meio de ensaio multiplex, as citocinas relacionadas à resposta imune Th17 (importante via imunológica na patogenia da DECHc) na saliva de 21 pacientes de DECHc, 27 de SSp, 10 de LPO e 15 voluntários saudáveis. Os principais achados morfológicos nas glândulas salivares dos pacientes de DECHc foram a extensa fibrose, fibroplasia periductal, atrofia ductal e acinar; alterações vasculares representadas pela congestão e formação de trombos hialinos; e infiltrado inflamatório intersticial difuso de aspecto leve a moderado. As glândulas salivares de SSp, entretanto, apresentaram um infiltrado inflamatório na forma de focos de linfócitos ao redor dos ductos excretores de intensidade moderada a severa; os ductos excretores apresentaram-se atróficos, ectásicos, exibindo metaplasia oncocítica e fibroplasia periductal; as alterações vasculares, por sua vez, se apresentaram em maior proporção na forma de vasculite. No LPO as alterações teciduais foram menos intensas. Quando analisadas as concentrações das citocinas, na DECHc, foram encontradas maiores concentrações de IL-17A, IL-4, IL-17F e IL-10, em relação aos grupos controles, essas citocinas estão envolvidas em mecanismos prófibróticos, o que permitiu a correlação dessa expressão aos eventos escleróticos nas glândulas salivares dos pacientes de DECHc. Entre elas, a IL-17F apresentou uma tendência de aumento em relação a proporção da área de fibrose nas glândulas salivares destes pacientes. A CD40L, que também esteve presente em maior concentração nos pacientes de DECHc, é uma molécula de ligação capaz de amplificar a resposta imunológica no mecanismo de rejeição do enxerto no hospedeiro, além de regular o mecanismo de apoptose e ativar o endotélio para a formação de trombos. As citocinas IL-31, IL-23 e IL-22, também apresentaram relevância na saliva dos pacientes de DECHc, sendo participantes do mecanismo das alterações liquenóides no LPO. Através das análises comparativas foi possível correlacionar a presença de citocinas envolvidas na resposta Th17 com as alterações glandulares e consequente xerostomia nos pacientes de DECHc. / The graft versus host disease (GVHD) is one of the biggest causes of mortality and morbidity after hematopoietic stem cells transplantation. The pathophysiology in the chronical manifestation of the disease (cGVHD), is not entirely elucidated, however the involvement of the immunological system, by means of the innate and adaptive responses are depicted in the literature concerning the disease development. The cGVHD affects multiple organs, including the salivary glands, leading to xerostomia. These alterations are under reported and mostly unknown. Therefore, this study investigated if the symptom of xerostomia in cGVHD is triggered by functional e morphological changes in minor salivary glands. To answer this inquiry specimens of biopsied labial salivary glands from patients of cGVHD and xerostomia were analyzed qualitatively and through morphometry. Specimens of biopsied salivary glands from patients with Sjögren\'s Syndrome (SS) (which is a classic model of xerostomia) and from patients with oral lichen planus (OLP) (whose clinical oral manifestations resemble the cGVHD lesions) were used as controls. Also, the cytokines related to the immunological response Th17 (important immune pathway in cGVHD pathophysiology) in the saliva of 21 cGVHD patients, 27 of SS, 10 patients of OLP and 165 healthy individuals were analyzed using the multiplex assay. The major morphological findings revealed on the salivary glands of cGVHD patients were the extensive fibrosis, periductal fibrosis, ductal and acinar atrophy. Congestion and hyaline thrombi formation were the most important vascular changes shown among these specimens. A diffuse interstitial inflammatory infiltrate was observed, with varied intensity. The SS salivary glands, however, portrayed a focal inflammatory infiltrate, with moderate to severe intensity around the excretory ducts. These ducts exhibited atrophy, ectasia, periductal fibrosis and oncocytic metaplasia. The main vascular change presented in these patients was the manifestation of vasculitis. The salivary glands from the OLP patients showed a lesser amount of alterations. The multiplex assay revealed a higher concentration of the cytokines IL-17A, IL-4, IL-17F and IL-10 in the cGVHD samples, when compared to the other groups. These cytokines are involved within the promotion of fibrosis, which endorsed the association of these secretions with the salivary glands sclerotic mechanisms. The secretion of CD40L was higher in cGVHD samples; this membrane protein is capable of amplifying the immunological response in graft rejection, besides the capacity to regulate apoptosis and activate the endothelium in thrombi formation. The cytokines IL-31, IL-23 and IL-22, also presented a higher concentration in cGHVD patients\' saliva, these secretions are actively involved in the mechanisms of lichenoid lesions in OLP, corroborating the perceived morphological changes. The comparative analysis of the morphological and salivary changes in cGVHD confirmed the correlation of Th17 immunological response within the minor salivary glands injuries and consequent xerostomia in these patients.

This essay aims to understand how meaning and materiality work in four picture books from the 00s and 10s; Gittan och gråvargarna by Pija Lindenbaum, I skogen by Eva Lindström, Vem ser Dim? by Maria Nilsson Thore and Vi blåste bort ibland by Viveka Sjögren. The essay uses two theoretical works about picture books: Bilderbokens pusselbitar by Maria Nikolajeva and Modernismens bilder – Den moderna bilderboken i Norden by Elina Druker. Questions to lead the analysis are: How can text and picture be understood as materiality? How can meaning be understood as a material-discursive phenomenon? How can reading and meaning be understood as performative processes? The chapter “Diffractions: Differences, Contingencies, and Entanglements That Matter” from Karen Barad’s book Meeting the Universe Halfway – Quantum Physics and the Entanglement of Matter and Meaning provides help to understand diffraction as a metaphor and methodological attitude. Eve Kosofsky Sedgwick’s understanding of knowledge as performative in the book Touching Feeling – Affect, Pedagogy, Performativity is used to understand the picture book as an act of knowledge and meaning, and reading as a performative process where human involvement cannot be overlooked. The essay problematizes the theoretical texts about picture books by taking on different parts of the picture book’s form and drawing examples from the four chosen picture books. Parts that are examined are divisions of signs in semiotics (and in the picture book theory), the picture book’s limits between for instance framework and content, fiction and reality, and book and reader, mimesis and the analytical problems with looking for truth, the impact of the picture book’s size and shape, and lastly illustration techniques and the influence that illustrator, materiality and reader have on the book. The essay shows how different involvements affect the meaning that is created in the picture book, how solid delimitations of different kinds can be problematic, and how words such as picture, text, paratext and content should be treated gently and consciously. Different ways of breaking with methods and thoughts of habit are presented, for instance by using Barad’s concept of diffraction. The essay ends by emphasizing the complexity that follows meaning, materiality and reading, the responsibility it demands of us and how picture book theory sometimes simplifies analysis. This essay stresses the importance of questioning how the methods and words we use affect what is possible to understand, but not in the sense that we should read in a paranoid and closed way, but rather open minded and with room for failures, reconsiderations and other ways forward. / Syftet med denna uppsats är att förstå hur mening och materialitet hänger ihop i fyra bilderböcker från 00- och 10-tal; Gittan och gråvargarna av Pija Lindenbaum, I skogen av Eva Lindström, Vem ser Dim? av Maria Nilsson Thore och Vi blåste bort ibland av Viveka Sjögren. Uppsatsen går i dialog med de bilderboksteoretiska verken Bilderbokens pusselbitar av Maria Nikolajeva och Modernismens bilder – Den moderna bilderboken i Norden av Elina Druker. Frågor för att leda undersökningen är som följer: På vilket sätt är text och bild materialitet? Hur kan mening förstås som materiellt-diskursivt fenomen i bilderböckerna? Hur kan läsning och mening förstås som performativa processer? Avsnittet ”Diffractions: Differences, Contingencies, and Entanglements That Matter” ur Karen Barads verk Meeting the Universe Halfway – Quantum Physics and the Entanglement of Matter and Meaning fungerar som hjälp för att förstå diffraktion som metafor och metodologisk hållning. Eve Kosofsky Sedgwicks förståelse av kunskap som performativ i verket Touching Feeling – Affect, Pedagogy, Performativity används för att förstå bilderboken som ett görande, och läsningen som en performativ process där mänsklig inblandning inte kan förbises. Uppsatsen problematiserar de bilderboksteoretiska verken genom att ta sig an olika aspekter av bilderbokens form samt exemplifiera detta med hjälp av det skönlitterära materialet. Områden som vidrörs är semiotikens (och bilderboksteoretikernas) indelning av tecken, bilderbokens gränser mellan bland annat ramar och innehåll, fiktion och verklighet samt verk och läsare, mimesis och sanningssökandets analytiska problem, bilderbokens påverkan av storlek och format, samt slutligen illustrationstekniker och den inverkan illustratör, materialitet och läsare har på verket. Uppsatsen visar på hur olika inblandningar påverkar den mening som skapas i bilderboken, hur fasta gränsdragningar av olika slag kan anses problematiska, samt hur begrepp som till exempel bild, text, paratext och innehåll bör behandlas varsamt och medvetet. Olika sätt att komma runt upptrampade metodologiska tillvägagångssätt och tankespår presenteras, bland annat med hjälp av Barads diffraktionsbegrepp. Uppsatsen avslutas med att betona den komplexitet som följer med mening, materialitet och läsning, det ansvar detta avkräver oss och hur bilderboksteorin ibland fungerar förenklande i analyser. Denna uppsats lyfter vikten av att ifrågasätta vad de metoder och ord vi använder egentligen gör med vad som är möjligt att förstå, men inte i den mening att vi bör läsa misstänksamt och stängt, utan snarare öppensinnat och med utrymme för misslyckanden, omprövningar och andra vägar vidare.