Matching Items (3)
Description
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by progressive autoimmune destruction of insulin-producing pancreatic β-cells. Genetic, immunological and environmental factors contribute to T1D development. The focus of this dissertation is to track the humoral immune response in T1D by profiling autoantibodies (AAbs) and anti-viral antibodies using an innovative protein array platform called Nucleic Acid Programmable Protein Array (NAPPA).
AAbs provide value in identifying individuals at risk, stratifying patients with different clinical courses, improving our understanding of autoimmune destructions, identifying antigens for cellular immune response and providing candidates for prevention trials in T1D. A two-stage serological AAb screening against 6,000 human proteins was performed. A dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) was validated with 36% sensitivity at 98% specificity by an orthogonal immunoassay. This is the first systematic screening for novel AAbs against large number of human proteins by protein arrays in T1D. A more comprehensive search for novel AAbs was performed using a knowledge-based approach by ELISA and a screening-based approach against 10,000 human proteins by NAPPA. Six AAbs were identified and validated with sensitivities ranged from 16% to 27% at 95% specificity. These two studies enriched the T1D “autoantigenome” and provided insights into T1D pathophysiology in an unprecedented breadth and width.
The rapid rise of T1D incidence suggests the potential involvement of environmental factors including viral infections. Sero-reactivity to 646 viral antigens was assessed in new-onset T1D patients. Antibody positive rate of EBV was significantly higher in cases than controls that suggested a potential role of EBV in T1D development. A high density-NAPPA platform was demonstrated with high reproducibility and sensitivity in profiling anti-viral antibodies.
This dissertation shows the power of a protein-array based immunoproteomics approach to characterize humoral immunoprofile against human and viral proteomes. The identification of novel T1D-specific AAbs and T1D-associated viruses will help to connect the nodes in T1D etiology and provide better understanding of T1D pathophysiology.
AAbs provide value in identifying individuals at risk, stratifying patients with different clinical courses, improving our understanding of autoimmune destructions, identifying antigens for cellular immune response and providing candidates for prevention trials in T1D. A two-stage serological AAb screening against 6,000 human proteins was performed. A dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) was validated with 36% sensitivity at 98% specificity by an orthogonal immunoassay. This is the first systematic screening for novel AAbs against large number of human proteins by protein arrays in T1D. A more comprehensive search for novel AAbs was performed using a knowledge-based approach by ELISA and a screening-based approach against 10,000 human proteins by NAPPA. Six AAbs were identified and validated with sensitivities ranged from 16% to 27% at 95% specificity. These two studies enriched the T1D “autoantigenome” and provided insights into T1D pathophysiology in an unprecedented breadth and width.
The rapid rise of T1D incidence suggests the potential involvement of environmental factors including viral infections. Sero-reactivity to 646 viral antigens was assessed in new-onset T1D patients. Antibody positive rate of EBV was significantly higher in cases than controls that suggested a potential role of EBV in T1D development. A high density-NAPPA platform was demonstrated with high reproducibility and sensitivity in profiling anti-viral antibodies.
This dissertation shows the power of a protein-array based immunoproteomics approach to characterize humoral immunoprofile against human and viral proteomes. The identification of novel T1D-specific AAbs and T1D-associated viruses will help to connect the nodes in T1D etiology and provide better understanding of T1D pathophysiology.
ContributorsBian, Xiaofang (Author) / LaBaer, Joshua (Thesis advisor) / Mandarino, Lawrence (Committee member) / Chang, Yung (Committee member) / Arizona State University (Publisher)
Created2015
Description
In rehabilitation settings, activity limitation can be a significant barrier to recovery. This study sought to examine the effects of state and trait level benefit finding, positive affect, and catastrophizing on activity limitation among individuals with a physician-confirmed diagnosis of either Osteoarthritis (OA), Fibromyalgia (FM), or a dual diagnosis of OA/FM. Participants (106 OA, 53 FM, and 101 OA/FM) who had no diagnosed autoimmune disorder, a pain rating above 20 on a 0-100 scale, and no involvement in litigation regarding their condition were recruited in the Phoenix metropolitan area for inclusion in the current study. After initial questionnaires were completed, participants were trained to complete daily diaries on a laptop computer and instructed to do so a half an hour before bed each night for 30 days. In each diary, participants rated their average daily pain, benefit finding, positive affect, catastrophizing, and activity limitation. A single item, "I thought about some of the good things that have come from living with my pain" was used to examine the broader construct of benefit finding. It was hypothesized that state and trait level benefit finding would have a direct relation with activity limitation and a partially mediated relationship, through positive affect. Multilevel modeling with SAS PROC MIXED revealed that benefit finding was not directly related to activity limitation. Increases in benefit finding were associated, however, with decreases in activity limitation through a significant mediated relationship with positive affect. Individuals who benefit find had a higher level of positive affect which was associated with decreased activity limitation. A suppression effect involving pain and benefit finding at the trait level was also found. Pain appeared to increase the predictive validity of the relation of benefit finding to activity limitation. These findings have important implications for rehabilitation psychologists and should embolden clinicians to encourage patients to increase positive affect by employing active approach-oriented coping strategies like benefit finding to reduce activity limitation.
ContributorsKinderdietz, Jeffrey Scott (Author) / Zautra, Alex (Thesis advisor) / Davis, Mary (Committee member) / Barrera, Manuel (Committee member) / Okun, Morris (Committee member) / Arizona State University (Publisher)
Created2012
Description
Autoimmunity develops when the immune system targets self-antigens within the body. Rheumatoid arthritis (RA) is a common autoimmune disease, and its progression is characterized by pro-inflammatory immune cells rapidly proliferating, migrating, and infiltrating joint tissue to provoke inflammation. In order to fulfill this taxing autoreactive response, an increase in energy metabolism is required by immune cells, such as dendritic cells (DCs). Therefore, a shift in DC energy reliance from the Krebs cycle toward glycolysis occurs. This metabolic shift phenotypically transitions DCs from anti-inflammatory properties toward an aggressive pro-inflammatory phenotype, in turn activating pro-inflammatory T cells and promoting RA pathogenesis. If the disease persists uncontrollably, further complications and eventual joint dysfunction can occur. Although, clinically approved drugs can prevent RA progression, they require frequent administration for temporary symptom relief. Furthermore, current approved biological products for RA are not known to have a direct modulatory effect on immunometabolism. Given that cellular metabolism controls immune cell function, this work aims to harness perturbations within RA immune cell energy metabolism and utilizes it as a therapeutic target by reprogramming immune cell metabolism via the delivery of metabolite-based particles. The two-time delivery of these particles reduced RA inflammation in a RA collagen-induced arthritis (CIA) mouse model and generated desired responses with long-term effects. Specifically, this work was achieved by:
Aim 1 – developing and delivering metabolite-based polymeric microparticles synthesized from the Krebs cycle metabolite, alpha-ketoglutarate (aKG; termed paKG MPs) to DCs to modulate their energy metabolism and promote anti-inflammatory properties (in context of RA).
Aim 2 – exploiting the encapsulation ability of paKG MPs to inhibit DC glycolysis in the presence of the CIA self-antigen (collagen type II (bc2)) for the treatment of RA in CIA mice. Herein, paKG MPs encapsulating a glycolytic inhibitor and bc2 induce an anti-inflammatory DC phenotype in vitro and generate suppressive bc2-specific T cell responses and reduce paw inflammation in CIA mice.
ContributorsMangal, Joslyn Lata (Author) / Acharya, Abhinav P (Thesis advisor) / Florsheim, Esther B (Committee member) / Wu, Hsin-Jung Joyce (Committee member) / Anderson, Karen (Committee member) / Arizona State University (Publisher)
Created2022