IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition characterised by elevated serum IgG4 and an abundance of IgG4 plasma cells in involved organs. The natural history of disease and pathogenic mechanisms are poorly understood, and are explored in this thesis. The diagnosis of IgG4-RD is a challenge. Evidence to support a serum IgG4 level of 2.8g/l in differentiating IgG4-RD from non-IgG4-RD conditions, a serum IgG1:IgG4 ratio of 0.24 in differentiating IgG4-sclerosing cholangitis from primary sclerosing cholangitis with elevated serum IgG4, and the role of serum IgE in those with a history of allergy and atopy is provided. Furthermore, observational data highlighting new environmental risk factors and disease associations are revealed. Despite being considered a benign corticosteroid-responsive condition, evidence for disease relapse, organ dysfunction and failure, malignancy and mortality in a prospective cohort is shown. Patterns of disease presentation and levels of serum IgG4 and IgE at diagnosis are used to identify those who relapse and develop multi-organ disease. A single antigen initiating disease has yet to be found. Polyclonal IgG4 responses to multiple environmental antigens in IgG4-RD are reported, and evidence against Helicobacter pylori plasminogen binding peptide as a microbial antigen is shown. Novel HLA class II associations, linked to disease susceptibility in a UK cohort provide support for immune-mediated pathogenesis. Gene expression analysis implicates cytokines in driving IgG4 switch and proliferation, chemokines in trafficking and homing of lymphocytes to end organs, complement proteins in the classical and lectin pathways, and members of the TGF-beta pathway as putative immune drivers of disease. Differences in the phenotype of IgG1 and IgG4 B cells in health and IgG4-RD are reported, including responses to complement activation and immune complexes. Finally, elevated IgE levels, the presence of IgE-positive mast cells in involved tissues, and up-regulation of the Fc-Epsilon receptor on the surface of IgG4 cells, support the role of an IgE-mediated response.

Submitted by Hiolanda Rêgo (hiolandar@gmail.com) on 2013-07-12T19:23:22Z No. of bitstreams: 1 Tese_ICS_ Joanemile Figueiredo.pdf: 10179633 bytes, checksum: 58c4b5620c6ef7bea0cc319ebb0cccb3 (MD5) / Made available in DSpace on 2013-07-12T19:23:23Z (GMT). No. of bitstreams: 1 Tese_ICS_ Joanemile Figueiredo.pdf: 10179633 bytes, checksum: 58c4b5620c6ef7bea0cc319ebb0cccb3 (MD5) / esquistossomose é uma doença de grande impacto na saúde pública dos países em desenvolvimento. As principais ações de controle da transmissão da doença são através da educação, melhorias no saneamento e campanhas de tratamento em massa. O desenvolvimento de vacina representa uma importante estratégia para o controle da mesma, entretanto, ainda não foi desenvolvida vacina que confira proteção adequada contra a infecção humana. Por outro lado, há evidências que infecções crônicas parasitárias, especialmente pelo S. mansoni, protegem contra as alergias. Com o objetivo de esclarecer o papel da IgE e IgG4 na indução de resistência/susceptibilidade à infecção pelo Schistosoma mansoni e no risco de desenvolvimento de asma foi avaliado, em uma grande casuística, indivíduos de área endêmica em esquistossomose do interior da Bahia. Foi observado que a razão entre IgE/IgG4 para antígeno solúvel de verme adulto do S. mansoni (SWAP) foi maior nos indivíduos não infectados ou com baixas cargas, quando comparado aos indivíduos altamente infectados. A carga parasitária de S. mansoni foi positivamente correlacionada com os níveis de IgE total, de IgG4 específico para SWAP e para o antígeno solúvel do ovo do S. mansoni (SEA). Os valores dos anticorpos e a razão entre eles, não interferiram, entretanto, no risco de reinfecção seis meses após o tratamento da parasitose. Adicionalmente, os indivíduos não infectados pelo S. mansoni, apresentaram níveis mais elevados de IgE específico e da razão IgE/IgG4 para antígeno 1 do Dermatophagoides pteronyssinus (Der p1), quando comparado aos infectados, enquanto que não foi observado diferença significativa nos níveis de IgG4 específico entre os dois grupos. Essas diferenças, no entanto, não foram observadas quando as análises foram ajustados para idade, gênero e grau de exposição à água contaminada. Estes resultados ressaltam o papel fundamental da IgG4 específica para antígenos do S. mansoni e da relação IgE/IgG4 na resistência/susceptibilidade à infecção por este helminto. Por outro lado, é possível que a infecção pelo S. mansoni proteja contra o desenvolvimento da asma, modulando negativamente a produção de anticorpos que participam da resposta inflamatória alérgica. O melhor entendimento do papel da resposta imune humoral na resistência à infecção pelo S. mansoni e no controle da asma pode auxiliar no desenvolvimento de novas estratégias de controle destas doenças. / Salvador

Background: Allergic diseases are characterised by dysregulated immune responses. The first manifestation of the atopic phenotype is often food allergy, with symptoms like eczema. Food allergy in children is generally outgrown before 3 years of age, but a temporary food elimination diet is often advocated. The prevalence of allergic diseases has increased in affluent countries during the last decades, possibly as a consequence of a changed lifestyle leading to decreased microbial load. Aim: To investigate humoral, mucosal and cell-mediated immunity in association to allergy and allergy development in young children and relate this to environmental factors. Subjects: Two cohorts of children were investigated; 1) Children from countries with high (Sweden) and low (Estonia) prevalence of allergy that were followed prospectively from birth to 5 years of age. 2) Infants with eczema and suspected food allergy that were followed prospectively to 4 ½ years of age. Methods: Endotoxin levels were analysed in house dust samples. Antibodies were measured in serum and saliva samples with ELISA. Food allergen induced cytokine responses were analysed in mononuclear cells. Results: The microbial load, delineated as endotoxin levels, was higher in house dust from Estonia than Sweden and was, in Swedish children, inversely associated with sensitisation and clinical symptoms of allergy. The decreased microbial load in Sweden may have an impact on mucosal immune responses as different IgA antibody patterns were observed in Sweden and Estonian children with much lower secretory (S)IgA antibody levels and high proportion of non-SIgA, i.e. IgA antibodies lacking the secretory component, in the Swedish children. Moreover, low levels of SIgA were associated with clinical symptoms in sensitised children. High IgG4 antibody levels to food allergens during infancy were associated with faster tolerance development in food allergic children. Cytokine responses by mononuclear cells after allergen stimulation was upregulated with age in children with prolonged food allergy, but not in children who develop tolerance before 4 ½ years of age, possibly because of the prolonged elimination diet in the former group. Summary: Reduced microbial exposure in affluent countries may affect the mucosal immune responses during infancy, possibly resulting in an increased risk of developing allergic disease. High levels of IgG4 antibodies during infancy are associated with faster achievement of tolerance in food allergic children. Allergen elimination during infancy may result in a dysfunctional cytokine response.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18861号 / 医博第3972号 / 新制||医||1008(附属図書館) / 31812 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 野田 亮, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

© 2017, © 2017 American Federation for Medical Research. A middle-aged man presents with acute pancreatitis of unknown etiology and is found to have a presentation consistent with the diagnosis of type 2 autoimmune pancreatitis (AIP). AIP is a group of rare heterogeneous diseases that are challenging to diagnose. There are 2 types of AIP. Type 1 disease is the more common worldwide than type 2 AIP. While type 1 AIP is associated with IgG4-positive antibodies, type 2 AIP is IgG4 antibody negative. Both types of AIP are responsive to corticosteroid treatment. Although type 1 AIP has more extrapancreatic manifestations and more commonly relapses, this is a case of a patient with type 2 AIP with inflammatory bowel disease and relapsing course.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18873号 / 医博第3984号 / 新制||医||1008(附属図書館) / 31824 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 三森 経世, 教授 山田 亮 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24528号 / 医博第4970号 / 新制||医||1065(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊藤 能永, 教授 羽賀 博典, 教授 河本 宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Patients with primary Sjögren’s syndrome (pSS) are at increased risk of developing malignant lymphoma. The studies in this thesis aim at broadening our understanding of the association between these two conditions. Germinal centre (GC)-like structures were found in minor salivary gland biopsies taken at the time of pSS diagnosis in 25% of 175 studied patients. Lymphoma development was observed in 86% of the GC-positive pSS patients and 14% of the GC-negative patients. GC-like structures in salivary gland biopsies at pSS diagnosis might identify pSS patients at high risk for later lymphoma development. We used the National Patient Register and the Cancer Register to identify pSS patients with lymphoid malignancy for the following studies. The lymphoma tissues were reviewed and classified according to the WHO classification. In a study of 79 patients with available lymphoma tissues, we identified histopathological and clinical features compatible with IgG4-related disease (IgG4-RD) in one patient (1.3%). Histological features of IgG4-RD in lymphoma tissue in patients with an initial pSS diagnosis seem to be rare but, if present, may indicate underlying IgG4-RD. We identified and compared pSS patients with (n=18/17%) and without (n=87) pre-existing lymphoma at pSS diagnosis and found similar pSS characteristics in both groups. Mucosa-associated lymphoid tissue (MALT) lymphoma in salivary glands was more common in patients with pre-existing lymphoma. The findings support the removal of pre-existing lymphoma as a general exclusion criterion for a pSS diagnosis in classification criteria. Further, the findings suggest an investigation for pSS in patients presenting with MALT lymphoma in salivary glands. We compared the distribution of lymphoma subtypes with a general population reference. Both diffuse large B-cell lymphoma (DLBCL) (32%) and marginal zone lymphoma (MZL) (31%) were common, but only MZL (MALT lymphomas) occurred at an increased relative frequency compared to the general population. Men constituted 15% of 105 pSS patients with lymphoma. Men had a shorter time between the pSS and lymphoma diagnoses and more often had lymphoma in the salivary glands compared with women. Increased awareness of signs of lymphoma in salivary glands already during the first years after pSS diagnosis is justified in men with pSS.

Onchocerca volvulus is a filarial parasite transmitted to humans by female Simulium spp. black flies. Infection with this parasite can cause blindness and severe skin disease among humans in Africa and the Americas. Enzyme-linked Immunosorbent Assay serological testing of OV-16 antigen is a diagnostic tool for determining effective elimination of the parasite. Programs typically rely on OV–16 ELISA to evaluate the progress towards interruption and/or elimination of disease by mass drug distribution of ivermectin and vector larvicidal control efforts. As elimination grows closer, monoclonal antibody positive controls for OV-16 ELISA become important to develop for Onchocerca testing due to the limited availability of pooled sera positive controls. Recent evaluation of laboratory designed OV-16 ELISA coating antigen by the Unnasch Lab (University of South Florida) showed that polymorphisms occurred which may alter the ability of the humanized monoclonal antibody to recognize the cognate antigen. With this development, it was important to evaluate these polymorphisms and isolate them for further testing against the standardized monoclonal antibody and positive sera to determine the effects antigenic polymorphisms could have on diagnostic testing. Upon evaluation, the polymorphisms did influence signaling when testing the monoclonal antibody. However, little effect on the recognition of the antigen was seen when different isoforms were evaluated against sera from O. volvulus infected individuals. Data suggest that the epitope recognized by the synthetically produced monoclonal antibody is not immuno-dominant in infected individuals.

No description available.