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Monogenic autoimmune diseases are highly variable syndromes that usually have onset in the first year of life and are often fatal in early childhood. Identifying monogenic autoimmune diabetes is important as it can have implications for medical management of patients, informs families and clinicians of prognosis and recurrence risk, and gives insights into beta-cell autoimmunity and immune tolerance. The first section of this thesis introduces monogenic autoimmune disease, with focus on the conditions that have autoimmune endocrine disorders as part of their clinical phenotype. The following section details the methodologies used throughout this thesis. In chapter 1, we used a type 1 diabetes genetic risk score (T1D-GRS) based on the top 10 risk alleles for T1D to identify patients with monogenic autoimmunity from patients with early-onset polygenic diabetes and additional autoimmunity. We showed that the T1D-GRS was highly discriminatory of monogenic autoimmunity, especially when combined with age of onset (ROC-AUC 0.88). We also identified 16 families for gene discovery studies. Furthermore, this work shows that polygenic risk for the development of T1D does not affect the development of diabetes in monogenic autoimmunity. Chapter 2 describes the genetic and phenotypic information for the largest cohort of patients with IPEX syndrome, caused by hemizygous mutations in FOXP3, reported to date (n=48). We analysed this data to determine if there were any genotypic or clinical characteristics of IPEX syndrome that could predict prognosis. We did not find evidence of phenotype-genotype relationships and showed that presenting feature did not predict prognosis. Medical management of IPEX syndrome cannot, therefore, be based on genotype or presentation. In chapter 3 we employed whole exome sequencing to look for causal variant(s) in a patient with diabetes (diagnosed aged 7 weeks) and autoimmune lymphoproliferative disease. This identified recessively inherited causative variants in LRBA. We then used targeted next generation sequencing (NGS) to screen a large cohort of patients (n=169) and identified an additional 8 probands and an affected family member. This confirms the role of LRBA as a neonatal diabetes gene, bringing the total number of genes to 25. In chapter 4, we assessed if immunoglobulin E (IgE) could be useful to identify patients with early-onset multisystem autoimmune disease caused by gain of function (GOF) STAT3 mutations. We showed that serum IgE was below the lower limit of the normal reference range (2KU/L) in all patients with STAT3 GOF (n=6), giving this threshold a sensitivity of 100% (95% CI: 54.1 – 100) and specificity 97.2% (95% CI: 96.2-97.9). We also found that IgE in patients with IPEX (n=16) was significantly higher than those with STAT3 GOF (p=0.002) suggesting it could be useful to identify IPEX from STAT3 GOF in non-consanguineous males with early-onset autoimmunity. The final concluding section summarises the key findings of each chapter, the impact of these findings and suggests future avenues for research. Identifying monogenic autoimmunity has enabled prenatal diagnoses, given families and clinicians knowledge on recurrence risk, and could enable targeted therapies to be employed. This body of work will enable better discrimination of monogenic autoimmunity from polygenic clustering of early-onset autoimmunity, and gives insights into the factors that determine disease phenotype and clinical course in monogenic autoimmunity. Gene discovery on the remaining patients will give new insights into the mechanisms of beta-cell autoimmunity and the regulation of the adaptive immune system and maintenance of immune tolerance.

Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders causing immune dysfunction that manifest with increased susceptibility to infection. Some PID patients may also have autoimmune and autoinflammatory manifestations. In many cases, PIDs are monogenic disorders that follow Mendelian inheritance and mutations in more than 250 genes have been shown to cause PIDs. However, in the majority of PID patients the causative mutations remain unknown. Here I report a study of a patient from a consanguineous family who presented in infancy with colitis, autoimmune hepatitis, autoimmune anemia and thrombocytopenia. The patient also suffered recurrent respiratory infections leading to bronchiectasis and had several episodes of severe varicella zoster virus (VZV) infections, including pneumonia and meningitis. Immunologically, the patient had increased IgM and IgG levels, absent IgA, low specific antibodies and multiple auto-antibodies, including anti-Interferon- antibodies. Whole blood stimulation assays identified an increased production of the pro-inflammatory cytokine IL-6. Throughout his life the patient received immunosuppressive therapy. Whole exome sequencing of the patient discovered a homozygous frameshift mutation in the ZC3H12A gene that encodes the Regnase-1 protein also known as MCPIP1. Regnase-1 is a regulatory RNase that directly degrades mRNAs of several pro-inflammatory genes, e.g. mRNA of cytokine IL-6, thus curbing the immune activation. The presentation of the patient resembled the phenotype of the Regnase-1-knockout mice that developed spontaneous systemic inflammation, disorganisation of lymphoid organs, severe anaemia and hyperimmunoglobulinemia, with the increased production of IL-6. I studied expression of the mutant Regnase-1 protein using commercial antibodies; also a new custom-made antibody that detects the truncated mutant Regnase-1 protein was developed. Analysis of the patient-derived cells demonstrated absence of the full-length Regnase-1 protein. Cloning and forced expression of the truncated mutant protein showed that it is mislocalized inside the cells and is functionally impaired. Studies of the iPSC-derived macrophages, EBV-transformed B cells and primary fibroblasts of the patient demonstrated increased levels of the IL-6 mRNA in the resting cells. They also showed impaired regulation of the truncated mutant Regnase-1 protein and IL-6 mRNA levels after cell stimulation. Mutations in Regnase-1 have never been associated with human diseases previously. Therefore, this study describes a novel PID caused by the Regnase-1 deficiency.

Research on exposure to animals and risk of type 1 diabetes (T1D) has had conflicting results with some researchers finding that animal exposure reduces the risk of T1D and others finding no association between animal exposure and T1D. Previously conducted studies on the association between animal exposure and T1D are case-control studies that have been limited by recall bias. The purpose of this study is to investigate the association between early life animal exposure and the risk of persistent, confirmed islet autoantibodies (IA) and T1D diagnosis among an eligible cohort of genetically high T1D risk participants enrolled in the international prospective cohort study, The Environmental Determinants of Diabetes in the Young (TEDDY). It is hypothesized that children who are exposed to animals in early life will have a lower risk of developing IA and T1D than children who are not exposed to animals in early life. A total of 7,432 TEDDY participants were included in the study. The associations between early life animal exposure and the outcomes of interest were explored using Cox proportional hazards models. In order to control for confounding, a propensity score analysis was applied by three different methods: adjustment for the propensity score variable in the Cox proportional hazards model, stratification on propensity score groups, and propensity score pair matching. Early life animal exposure was not associated with diabetes autoimmunity or T1D onset in this genetically high T1D risk population. These findings were consistent across all three propensity score analysis methods and when directly adjusting for HLA type. The hypothesis that children who are exposed to animals in early life will have a lower risk of developing IA and T1D than children who are not exposed to animals in early life is not supported by this study. The results of this study suggest that there is no association between early life animal exposure and development of T1D. Performing this analysis again after longer follow-up has been completed for the study population is recommended as it may elucidate the effect of animal exposure on T1D and IA risk. Further studies are also needed on animal exposure and T1D in different types of environments (e.g., high residential density) and the effect of different types of animal exposures (e.g., species, duration) on T1D and IA risk. Additionally, studies on differences in perceptions of pets across countries could also aid the interpretation of studies on animal exposure and health outcomes.

The main and most critical function of the immune system is to distinguish between self and non-self and react accordingly. Differentiating self-reactive immune cells as soon as they develop is the phenomenon of tolerance against self-antigens and is a highly regulated process. The development of autoantibodies is a sign of the breakdown of tolerance and may be the harbinger of the onset of an autoimmune disease. It is well-known fact that many systemic autoimmune diseases (AUIDs) first manifest in the oral cavity. If proven that oral infections trigger AUIDs, then improving oral health may be a potential therapeutic strategy to reduce autoimmune disease incidence. Although etiology and pathogenesis of specific AUIDs may vary, presentation in the oral cavity often involves oral lesions manifested at early stages of systemic inflammatory and autoimmune disease. Therefore regular dental and medical checkups may provide an opportunity for clinicians, in particular dentists, to contribute to earlier detection of AUIDs thereby improving long-term treatment options and overall patient prognosis. Mechanisms leading to the onset of autoimmune disease are still being considered. Epidemiological inquires and the increasing numbers of genome-wide association studies have analyzed the breakdown of tolerance and the causes behind autoimmunity. The role of the environment is crucial in the onset of autoimmunity via the breakdown of tolerance; through toll-like receptors that mediate innate immunity which in turn triggers the adaptive autoimmune response, T regulatory cells and Th17 differentiation, through changes in the spleen autoantibody production due to a change in the B cell count, and through self antigen and epigenetic deviations induced by environmental spurs. In spite of many research efforts and the accumulation of innovative data, there are still multiple gaps in knowledge pertaining to this subject matter. The autoimmune process begins with the activation of Tcells by antigen presenting cells (APC) and progresses to CD4+ CD25+ Tcells and forkhead box P3 (Foxp3), which stimulate Th1 and Th2 responses and finally B cell activation, which plays a role in autoimmune development. This paper will review the etiopathogenesis of autoimmune diseases and different cell players as well as transcription factors such as TGF–β, IL–6, IL–10, IL–17, Th–17, T reg cells, B reg cells, Th–1, Th–2, and INF–γ. This paper aims to review published evidence and further explore the etiopathology of individual autoimmune diseases such as Behcet's, Crohn's disease, Sjögren syndrome, systemic lupus erythematosus, and rheumatoid arthritis and the subsequent dental implications and therapeutic management. This review also aims to study the most relevant autoimmune, auto-inflammatory, and systemic chronic inflammatory diseases, as well as mechanisms of autoimmune manifestation with respect to oral health.

Submitted by TULIO MORANDIN FERRISSE null (tuliomferrisse@gmail.com) on 2016-05-30T18:50:25Z No. of bitstreams: 1 DISSERTAÇÃO - FINAL.doc: 8888832 bytes, checksum: ca99c5983969f9477ae1a74714d6d280 (MD5) / Rejected by Ana Paula Grisoto (grisotoana@reitoria.unesp.br), reason: Solicitamos que realize uma nova submissão seguindo as orientações abaixo: A versão final da dissertação/tese deve ser submetida no formato PDF (Portable Document Format). O arquivo PDF não deve estar protegido e a dissertação/tese deve estar em um único arquivo, inclusive os apêndices e anexos, se houver. Por favor, corrija o formato do arquivo e realize uma nova submissão. Agradecemos a compreensão. on 2016-05-31T17:11:40Z (GMT) / Submitted by TULIO MORANDIN FERRISSE null (tuliomferrisse@gmail.com) on 2016-06-02T18:27:31Z No. of bitstreams: 2 DISSERTAÇÃO - FINAL.doc: 8888832 bytes, checksum: ca99c5983969f9477ae1a74714d6d280 (MD5) DISSERTAÇÃO_Mestrado_24_05_2016.pdf: 2063661 bytes, checksum: 945e0429ad165f9d8b64a9f65b91534a (MD5) / Approved for entry into archive by Ana Paula Grisoto (grisotoana@reitoria.unesp.br) on 2016-06-02T19:56:03Z (GMT) No. of bitstreams: 1 ferrisse_tm_me_arafo.pdf: 2063661 bytes, checksum: 945e0429ad165f9d8b64a9f65b91534a (MD5) / Made available in DSpace on 2016-06-02T19:56:03Z (GMT). No. of bitstreams: 1 ferrisse_tm_me_arafo.pdf: 2063661 bytes, checksum: 945e0429ad165f9d8b64a9f65b91534a (MD5) Previous issue date: 2016-03-31 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O conceito de reação liquenóide ou interface liquenóide foi introduzido na dermatologia para definir diversas doenças inflamatórias da pele que apresentam características histopatológicas similares. Assim como a pele, a mucosa oral é afetada por uma variedade de lesões liquenóides orais (LLOs). As LLOs foram classificadas em: lesão liquenóide de contato; lesão liquenóide a medicamento; doença do enxerto-versus-hospedeiro e lesões liquenóides não classificáveis de aspecto liquen plano-like, como a estomatite ulcerativa crônica (EUC) recentemente descrita. Além da sobreposição de características entres as lesões que compõem este grupo, o líquen plano oral (LPO) representa o principal diagnóstico diferencial. Tradicionalmente, o diagnóstico das LLOs e do LPO depende da associação clínica e histopatológica, mas em vários casos, esta abordagem não oferece um diagnóstico confiável. As realizações de estudos clínicos e laboratoriais podem auxiliar no entendimento da etiopatogenia destas doenças e refinar a capacidade de diferenciar as LLOs. Diante disto, os objetivos específicos deste estudo foram: (1) Realizar uma revisão sistemática sobre EUC com ênfase específica nas características clínicas, histopatológicas e imunopatológicas desta condição recentemente descrita; e (2) Realizar um estudo prospectivo para avaliar as características clínicas e histopatológicas das LLOs. / The concept of lichenoid reaction or lichenoid interface was introduced in dermatology to define various inflammatory diseases of the skin that have similar histopathological features. Just as the skin and oral mucosa is affected by a variety of oral lichenoid lesions (OLLs). OLLs were classified as contact Lichenoides injury; drug Lichenoides injury; chronic graft versus host and not classifiable lichenoid lesions aspect lichen planus-like, such as chronic ulcerative stomatitis (CUS) recently described. Besides the overlapping features among injuries that make up this group, oral lichen planus (OLP) is the main differential diagnosis. Traditionally, the diagnosis of OLLs and the OLP depends on the clinical and histopathological association, but in many cases, this approach does not provide a confident diagnosis. The achievement of clinical and laboratory studies may help to understand the pathogenesis of these diseases and refine the ability to differentiate OLLs. Thus, the specific objectives of this study were: (1) conduct a systematic review of CUS with particular emphasis on clinical, histopathological and immunopathological of this newly described condition; and (2) Conducting a prospective study to evaluate the clinical and histopathological characteristics of OLLs.