One of the etiological theories of schizophrenia is dysregulation of the immune system. Autoantibodies specific for the α7 subunit of the nicotinic receptor could potentially contribute to the pathophysiology of the disease. In this study, positive antibodies specific for the receptor were found to exist in 23% of the patients diagnosed with schizophrenia (n = 21). On the average, levels for the antibody were elevated in the schizophrenia patient population than in controls. The data also suggests that there is a significant correlation between antibody titer and age, lending support to the neurodegenerative nature of the disease.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20611号 / 医博第4260号 / 新制||医||1023(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 椛島 健治, 教授 竹内 理, 教授 生田 宏一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Overall, the work presented in this thesis explored the impact of cigarette smoke on the immunopathogenesis of respiratory disease. This thesis highlighted the determinantal impact of cigarette smoke on (auto)antibody levels and pulmonary macrophage composition. Work completed by Steven P Cass 2016-2021. / Cigarette smoke is an insidious insult that is associated with a spectrum of respiratory diseases that range from cancer to obstructive diseases such as chronic obstructive pulmonary disease (COPD), to restrictive diseases such as idiopathic pulmonary fibrosis (IPF). In this thesis, we explore how cigarette smoke impacts immune components that contribute to respiratory disease. To begin, we assessed the impact of cigarette smoke on airway antibody and autoantibody levels. We assessed sputum, a non-invasive method to sample the lower airways, to directly assess the presence of antibodies and autoantibodies in COPD. Total immunoglobulin M (IgM), IgG and IgA were detectable in the sputum of subjects. Notably, in patients with mild to moderate COPD, current smoking status was associated with decreased IgM and IgG. Next, using a comprehensive autoantigen array, we measured matched sputum and serum autoantibodies in 224 individuals. Serum autoantibodies were more abundant than sputum autoantibodies and correlated strongly between two independent COPD cohorts. Overall, the autoantibody profile of a patient with COPD was the same as a control subject. A proportion of autoantibody specificities were differentially expressed in patients with COPD with anti-tissue autoantibodies weakly associated with measures of emphysema. Taken together, these data suggested chronic cigarette smoke exposure was associated with limited differential expression of autoantibodies, but these changes were not a reliable method to identify COPD status. In our third study, we assessed the impact of cigarette smoke exposure on the composition and function of pulmonary macrophage subpopulations. Macrophages perform a central role in respiratory host defence and are implicated in the pathobiology of several respiratory diseases. Using a mouse model of cigarette smoke exposure, we reported cigarette smoke-induced expansion of CD11b+ macrophage subpopulations including monocyte-derived alveolar macrophages and interstitial macrophages. The altered pulmonary macrophage composition following cigarette smoke exposure contributed to attenuated fibrogenesis in a model of bleomycin-induced lung injury. This study offered insight to pulmonary macrophage composition and function following cigarette smoke exposure. This thesis summarises the original contributions and work completed during the course of this Ph.D., aimed at understanding the impact of cigarette smoke exposure on immune components central to respiratory disease. In conclusion, these findings shed light on the presence of (auto)antibodies in patients with COPD and the composition of macrophage subpopulations following cigarette smoke exposure. / Thesis / Doctor of Philosophy (PhD) / Currently there are 1.3 billion people who use tobacco across the world. The most common method to consume tobacco is by smoking cigarettes. Cigarette smoking is well-known to cause disease; however, smoking rates are still increasing with more daily cigarette smokers in 2012 than there were in 1980. In this thesis, we explore the impact of cigarette smoke upon the immune system. We first assessed whether cigarette smoking impacts the levels of antibodies, proteins that are produced by the immune system to protect against foreign bodies, in healthy individuals, cigarette smokers without disease and patients with chronic obstructive pulmonary disease (COPD). We found that current smokers had decreased antibodies in the airways, thus predisposing cigarette smokers to increased damage. In our second study, we measured the presence of airway and blood autoantibodies. These are antibodies that target self and have the potential to inflict damage. We discovered that patients with COPD had minor changes in autoantibodies and these changes were weakly associated with emphysema. In our third study, we evaluated the impact of cigarette smoke on lung macrophages, cells that eat and destroy foreign bodies, in a mouse model of cigarette smoke exposure. Cigarette smoke increased the number of bone marrow-derived macrophages and this change in macrophage populations was associated with a reduced wound healing ability. Overall, these studies offer insight into how cigarette smoke impairs the function of the immune system and contributes to lung disease.

The anticardiolipin antibody syndrome is relatively uncommon. It should be suspected mostly in young people with unexplained embolic or thrombotic events. A young patient with an abnormal prothrombin time, partial thromboplastin time, or venereal disease research lab test with one of the above noted vascular events would be a suspect for this disorder. Though an antibody test that will qualitatively and quantitatively measure antiphospholipid antibodies is available, its clinical application is not entirely clear. The presence of the antibody will support a diagnosis but cannot be used alone for diagnosis or treatment.

Digital full-text not provided.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24991号 / 医博第5025号 / 新制||医||1069(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 生田 宏一, 教授 椛島 健治, 教授 上野 英樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introduction: Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by a platelet count less than 100 x 109/L. Platelet-bound autoantibodies are detected in the peripheral blood of only 40-50% of ITP patients. The subset of ITP patients who do not have detectable autoantibodies may truly be seropositive, but autoantibodies may not be detected due to limitations of the assays. Studies have also suggested that autoantibodies might be sequestered in the bone marrow where autoantibodies may impair platelet production. In addition, detecting autoreactive antibody-secreting B cells using the Enzyme-linked Immunospot (ELISPOT) assay was shown to be highly sensitive. In this study, the bone marrow and the peripheral blood compartments of ITP patients were tested for the presence of anti-GPIIbIIIa and anti-GPIbIX IgG autoantibodies and autoreactive B cells. Methods: Bone marrow aspirate and peripheral blood samples were collected from ITP patients (n=12), non-immune thrombocytopenic patient controls (n=3), and healthy controls (n=5). Mononuclear cells were isolated and tested for the presence of anti-GPIIbIIIa and anti-GPIbIX IgG autoreactive B cells before stimulation and after stimulation with R848 and IL-2 using the ELISPOT assay. Anti-GPIIbIIIa and anti-GPIbIX IgG autoantibodies were detected in the bone marrow and the peripheral blood using the direct antigen capture assay. Results: In our study, we detected autoantibodies and autoreactive B cells of known specificity in the bone marrow of a subset of ITP patients. Detecting anti-GPIIbIIIa and anti-GPIbIX autoantibodies in the bone marrow or the peripheral blood had a sensitivity of 42% and testing both compartments increased the sensitivity to 58%, while maintaining 100% specificity. Autoreactive B cells were detected at low frequencies with low specificity in the bone marrow and the peripheral blood of a subset of ITP patients. The majority of the ITP patients without detectable autoantibodies in the peripheral blood did not have autoantibodies in the bone marrow, and autoreactive B cells were not detected in either compartment. Conclusion: Examining both the bone marrow and the peripheral blood compartments for autoantibodies or autoreactive B cells increased the sensitivity. Furthermore, detecting autoantibodies using the antigen capture assay is more sensitive and specific than detecting autoreactive B cells using the ELISPOT assay. / Thesis / Master of Science (MSc)

O anticorpo anti-proteína P ribossomal é um dos marcadores sorológicos do lúpus eritematoso sistêmico, previamente associado a glomerulonefrite lúpica classe V (ISN-RPS). Neste trabalho foi avaliado o prognóstico renal em pacientes que possuem positividade para este anticorpo. Sessenta pacientes foram avaliados para parâmetros de sobrevida renal. Onze pacientes (18%) apresentaram positividade sorológica exclusiva para anticorpo anti-P ribossomal e vinte e oito pacientes (47%) para anti-dsDNA. Ao final do período de seguimento, foi observado que os pacientes anti-P positivos apresentaram uma maior sobrevida renal (11,0 ± 4,5 vs. 9,2 ± 4,5 anos, p=0,03) quando comparados aqueles anti-P negativos, assim como menor frequência de necessidade de terapia substitutiva renal (0 vs. 35% p = 0,025). Pacientes anti-P positivos apresentaram também maior frequência de classe V (91% vs. 31%, p < 0.001) e menor incidência de alterações proliferativas (45% vs. 82%, p = 0,021) na avaliação da biópsia renal quando comparados aos pacientes sem a positividade para este anticorpo. Os dados reforçam a hipótese de que o anticorpo anti-P é um marcador útil de um melhor prognóstico renal em pacientes portadores de lúpus eritematoso sistêmico / Antibodies to ribossomal P proteins are one of the serologic markers of systemic lupus erythematosus, previously described as associated to class V lupus glomerulonephritis (ISN-RPS). Our study assessed renal prognosis in patients with anti-P antibodies. Sixty consecutive SLE patients with biopsyproven nephritis (2004 ISN/RPS) were evaluated for renal survival parameters. Eleven patients (18%) had exclusive anti-P positivity and 28 (47%) patients anti-dsDNA. The post-biopsy follow-up analysis demonstrated that anti-P positive patients disclosed better renal survival (11.0 ± 4.5 vs. 9.2 ± 4.5 years, p = 0.03) as well as lower frequency of patients requiring dialysis (0 vs. 35% p = 0.025). The frequency of class V nephritis was higher in anti-P positive patients (91% vs. 31%, p < 0.001) and the occurrence of proliferative lesions at biopsy was lower in these patients (45% vs. 82%, p=0.021). Our data supports the notion that anti-P antibody is a valuable marker to predict a better long-term renal outcome in lupus patients

O anticorpo anti-proteína P ribossomal é um dos marcadores sorológicos do lúpus eritematoso sistêmico, previamente associado a glomerulonefrite lúpica classe V (ISN-RPS). Neste trabalho foi avaliado o prognóstico renal em pacientes que possuem positividade para este anticorpo. Sessenta pacientes foram avaliados para parâmetros de sobrevida renal. Onze pacientes (18%) apresentaram positividade sorológica exclusiva para anticorpo anti-P ribossomal e vinte e oito pacientes (47%) para anti-dsDNA. Ao final do período de seguimento, foi observado que os pacientes anti-P positivos apresentaram uma maior sobrevida renal (11,0 ± 4,5 vs. 9,2 ± 4,5 anos, p=0,03) quando comparados aqueles anti-P negativos, assim como menor frequência de necessidade de terapia substitutiva renal (0 vs. 35% p = 0,025). Pacientes anti-P positivos apresentaram também maior frequência de classe V (91% vs. 31%, p < 0.001) e menor incidência de alterações proliferativas (45% vs. 82%, p = 0,021) na avaliação da biópsia renal quando comparados aos pacientes sem a positividade para este anticorpo. Os dados reforçam a hipótese de que o anticorpo anti-P é um marcador útil de um melhor prognóstico renal em pacientes portadores de lúpus eritematoso sistêmico / Antibodies to ribossomal P proteins are one of the serologic markers of systemic lupus erythematosus, previously described as associated to class V lupus glomerulonephritis (ISN-RPS). Our study assessed renal prognosis in patients with anti-P antibodies. Sixty consecutive SLE patients with biopsyproven nephritis (2004 ISN/RPS) were evaluated for renal survival parameters. Eleven patients (18%) had exclusive anti-P positivity and 28 (47%) patients anti-dsDNA. The post-biopsy follow-up analysis demonstrated that anti-P positive patients disclosed better renal survival (11.0 ± 4.5 vs. 9.2 ± 4.5 years, p = 0.03) as well as lower frequency of patients requiring dialysis (0 vs. 35% p = 0.025). The frequency of class V nephritis was higher in anti-P positive patients (91% vs. 31%, p < 0.001) and the occurrence of proliferative lesions at biopsy was lower in these patients (45% vs. 82%, p=0.021). Our data supports the notion that anti-P antibody is a valuable marker to predict a better long-term renal outcome in lupus patients

Objective: Type 1 diabetes is associated with autoantibodies to different organs that include the gut. The objective of the study was to determine the risk of developing gastric parietal cell autoimmunity in relation to other autoimmunity in individuals with a family history of type 1 diabetes. Methods: Autoantibodies to the parietal cell autoantigen, H+/K+ ATPase subunit A (ATP4A) was measured in 2218 first-degree relatives of patients with type 1 diabetes, who were prospectively followed from birth for a median of 14.5 years. All were also tested regularly for the development of islet autoantibodies, transglutaminase autoantibodies, and thyroid peroxidase autoantibodies. Results: The cumulative risk to develop ATP4A autoantibodies was 8.1% (95% CI, 6.6–9.6) by age 20 years with a maximum incidence observed at age 2 years. Risk was increased in females (HR, 1.9; 95% CI, 1.3–2.8; p = 0.0004), relatives with the HLA DR4-DQ8/DR4-DQ8 genotype (HR, 3.4; 95% CI, 1.9–5.9; p < 0.0001) and in participants who also had thyroid peroxidase autoantibodies (HR, 3.7; 95% CI, 2.5– 5.5; p < 0.0001). Risk for at least one of ATP4A-, islet-, transglutaminase-, or thyroid peroxidase-autoantibodies was 24.7% (95% CI, 22.6–26.7) by age 20 years and was 47.3% (95% CI, 41.3–53.3) in relatives who had an HLA DR3/DR4-DQ8, DR4-DQ8/ DR4-DQ8, or DR3/DR3 genotype (p < 0.0001 vs. other genotypes). Conclusions: Relatives of patients with type 1 diabetes who have risk genotypes are at very high risk for the development of autoimmunity against gastric and other organs.