Browsing by Subject "Autoimmune Diseases"

Now showing 1 - 5 of 5

Open Access
Alternative splicing in multiple sclerosis and other autoimmune diseases.
(RNA Biol, 2010-07) Evsyukova, Irina; Somarelli, Jason A; Gregory, Simon G; Garcia-Blanco, Mariano A
Alternative splicing is a general mechanism for regulating gene expression that affects the RNA products of more than 90% of human genes. Not surprisingly, alternative splicing is observed among gene products of metazoan immune systems, which have evolved to efficiently recognize pathogens and discriminate between "self" and "non-self", and thus need to be both diverse and flexible. In this review we focus on the specific interface between alternative splicing and autoimmune diseases, which result from a malfunctioning of the immune system and are characterized by the inappropriate reaction to self-antigens. Despite the widespread recognition of alternative splicing as one of the major regulators of gene expression, the connections between alternative splicing and autoimmunity have not been apparent. We summarize recent findings connecting splicing and autoimmune disease, and attempt to find common patterns of splicing regulation that may advance our understanding of autoimmune diseases and open new avenues for therapy.
Open Access
Association between cell-mediated demyelination and astrocyte stimulation.
(Prog Brain Res, 1992) Smith, ME; Sommer, MA
Open Access
Skewing of the population balance of lymphoid and myeloid cells by secreted and intracellular osteopontin.
(Nature immunology, 2017-09) Kanayama, Masashi; Xu, Shengjie; Danzaki, Keiko; Gibson, Jason R; Inoue, Makoto; Gregory, Simon G; Shinohara, Mari L
The balance of myeloid populations and lymphoid populations must be well controlled. Here we found that osteopontin (OPN) skewed this balance during pathogenic conditions such as infection and autoimmunity. Notably, two isoforms of OPN exerted distinct effects in shifting this balance through cell-type-specific regulation of apoptosis. Intracellular OPN (iOPN) diminished the population size of myeloid progenitor cells and myeloid cells, and secreted OPN (sOPN) increase the population size of lymphoid cells. The total effect of OPN on skewing the leukocyte population balance was observed as host sensitivity to early systemic infection with Candida albicans and T cell-mediated colitis. Our study suggests previously unknown detrimental roles for two OPN isoforms in causing the imbalance of leukocyte populations.
Open Access
The Hematopoietic Cell Transplant Comorbidity Index predicts survival after allogeneic transplant for nonmalignant diseases.
(Blood, 2019-02) Thakar, Monica S; Broglie, Larisa; Logan, Brent; Artz, Andrew; Bunin, Nancy; Burroughs, Lauri M; Fretham, Caitrin; Jacobsohn, David A; Loren, Alison W; Kurtzberg, Joanne; Martinez, Caridad A; Mineishi, Shin; Nelson, Adam S; Woolfrey, Ann; Pasquini, Marcelo C; Sorror, Mohamed L
Despite improvements, mortality after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases remains a significant problem. We evaluated whether pre-HCT conditions defined by the HCT Comorbidity Index (HCT-CI) predict probability of posttransplant survival. Using the Center for International Blood and Marrow Transplant Research database, we identified 4083 patients with nonmalignant diseases transplanted between 2007 and 2014. Primary outcome was overall survival (OS) using the Kaplan-Meier method. Hazard ratios (HRs) were estimated by multivariable Cox regression models. Increasing HCT-CI scores translated to decreased 2-year OS of 82.7%, 80.3%, 74%, and 55.8% for patients with HCT-CI scores of 0, 1 to 2, 3 to 4, and ≥5, respectively, regardless of conditioning intensity. HCT-CI scores of 1 to 2 did not differ relative to scores of 0 (HR, 1.12 [95% CI, 0.93-1.34]), but HCT-CI of 3 to 4 and ≥5 posed significantly greater risks of mortality (HR, 1.33 [95% CI, 1.09-1.63]; and HR, 2.31 [95% CI, 1.79-2.96], respectively). The effect of HCT-CI differed by disease indication. Patients with acquired aplastic anemia, primary immune deficiencies, and congenital bone marrow failure syndromes with scores ≥3 had increased risk of death after HCT. However, higher HCT-CI scores among hemoglobinopathy patients did not increase mortality risk. In conclusion, this is the largest study to date reporting on patients with nonmalignant diseases demonstrating HCT-CI scores ≥3 that had inferior survival after HCT, except for patients with hemoglobinopathies. Our findings suggest that using the HCT-CI score, in addition to disease-specific factors, could be useful when developing treatment plans for nonmalignant diseases.
Open Access
TNF is a potential therapeutic target to suppress prostatic inflammation and hyperplasia in autoimmune disease.
(Nature communications, 2022-04) Vickman, Renee E; Aaron-Brooks, LaTayia; Zhang, Renyuan; Lanman, Nadia A; Lapin, Brittany; Gil, Victoria; Greenberg, Max; Sasaki, Takeshi; Cresswell, Gregory M; Broman, Meaghan M; Paez, J Sebastian; Petkewicz, Jacqueline; Talaty, Pooja; Helfand, Brian T; Glaser, Alexander P; Wang, Chi-Hsiung; Franco, Omar E; Ratliff, Timothy L; Nastiuk, Kent L; Crawford, Susan E; Hayward, Simon W
Autoimmune (AI) diseases can affect many organs; however, the prostate has not been considered to be a primary target of these systemic inflammatory processes. Here, we utilize medical record data, patient samples, and in vivo models to evaluate the impact of inflammation, as seen in AI diseases, on prostate tissue. Human and mouse tissues are used to examine whether systemic targeting of inflammation limits prostatic inflammation and hyperplasia. Evaluation of 112,152 medical records indicates that benign prostatic hyperplasia (BPH) prevalence is significantly higher among patients with AI diseases. Furthermore, treating these patients with tumor necrosis factor (TNF)-antagonists significantly decreases BPH incidence. Single-cell RNA-seq and in vitro assays suggest that macrophage-derived TNF stimulates BPH-derived fibroblast proliferation. TNF blockade significantly reduces epithelial hyperplasia, NFκB activation, and macrophage-mediated inflammation within prostate tissues. Together, these studies show that patients with AI diseases have a heightened susceptibility to BPH and that reducing inflammation with a therapeutic agent can suppress BPH.