Heide Christine Patterson - Academia.edu (original) (raw)

Papers by Heide Christine Patterson

Proceedings of the National Academy of Sciences, 2016

Proceedings of the National Academy of Sciences, 2017

SignificanceImmune-mediated diseases are prevalent, debilitating, and costly. Unfortunately, curr... more SignificanceImmune-mediated diseases are prevalent, debilitating, and costly. Unfortunately, current treatments rely on nonspecific immunosuppression, which also shuts down a protective immune response. To circumvent this, we exploited the noninflammatory natural means of clearance of red blood cells (RBCs), in combination with sortase-mediated RBC surface modification to display disease-associated autoantigens as RBCs’ own antigens. We found that this strategy holds promise for prophylaxis and therapy, as shown in a mouse model of multiple sclerosis and of type 1 diabetes.

Proceedings of the National Academy of Sciences of the United States of America, Jan 5, 2015

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) govern cellular homeostasis by ind... more Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) govern cellular homeostasis by inducing signaling. H2O2 modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H2O2 signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H2O2 signaling colocalize as H2O2 induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in th...

Blood, Jan 18, 2014

Global nuclear condensation, culminating in enucleation during terminal erythropoiesis, is poorly... more Global nuclear condensation, culminating in enucleation during terminal erythropoiesis, is poorly understood. Proteomic examination of extruded erythroid nuclei from fetal liver revealed a striking depletion of most nuclear proteins, suggesting that nuclear protein export had occurred. Expression of the nuclear export protein, Exportin 7 (Xpo7), is highly erythroid-specific, induced during erythropoiesis, and abundant in very late erythroblasts. Knockdown of Xpo7 in primary mouse fetal liver erythroblasts resulted in severe inhibition of chromatin condensation and enucleation but otherwise had little effect on erythroid differentiation, including hemoglobin accumulation. Nuclei in Xpo7-knockdown cells were larger and less dense than normal and accumulated most nuclear proteins as measured by mass spectrometry. Strikingly,many DNA binding proteins such as histones H2A and H3 were found to have migrated into the cytoplasm of normal late erythroblasts prior to and during enucleation, b...

Diabetes, 2014

Brown adipose tissue (BAT) is specialized to burn lipids for heat generation as a natural defense... more Brown adipose tissue (BAT) is specialized to burn lipids for heat generation as a natural defense against cold and obesity. Previous studies established microRNAs (miRNAs) as essential regulators of brown adipocyte differentiation, but whether miRNAs are required for the feature maintenance of mature brown adipocytes remains unknown. To address this question, we ablated Dgcr8, a key regulator of the miRNA biogenesis pathway, in mature brown as well as in white adipocytes. Adipose tissue-specific Dgcr8 knockout mice displayed enlarged but pale interscapular brown fat with decreased expression of genes characteristic of brown fat and were intolerant to cold exposure. Primary brown adipocyte cultures in vitro confirmed that miRNAs are required for marker gene expression in mature brown adipocytes. We also demonstrated that miRNAs are essential for the browning of subcutaneous white adipocytes in vitro and in vivo. Using this animal model, we performed miRNA expression profiling analysi...

Transfusion Medicine, 2010

Proceedings of the National Academy of Sciences, 2012

The effects of adiponectin on hepatic glucose and lipid metabolism at transcriptional level are l... more The effects of adiponectin on hepatic glucose and lipid metabolism at transcriptional level are largely unknown. We profiled hepatic gene expression in adiponectin knockout (KO) and wild-type (WT) mice by RNA sequencing. Compared with WT mice, adiponectin KO mice fed a chow diet exhibited decreased mRNA expression of rate-limiting enzymes in several important glucose and lipid metabolic pathways, including glycolysis, tricarboxylic acid cycle, fatty-acid activation and synthesis, triglyceride synthesis, and cholesterol synthesis. In addition, binding of the transcription factor Hnf4a to DNAs encoding several key metabolic enzymes was reduced in KO mice, suggesting that adiponectin might regulate hepatic gene expression via Hnf4a. Phenotypically, adiponectin KO mice possessed smaller epididymal fat pads and showed reduced body weight compared with WT mice. When fed a high-fat diet, adiponectin KO mice showed significantly reduced lipid accumulation in the liver. These lipogenic defec...

Proceedings of the National Academy of Sciences, 2013

SignificanceThe host immune system provides diverse defense mechanisms to fight harmful bacteria ... more SignificanceThe host immune system provides diverse defense mechanisms to fight harmful bacteria and viruses. One of these mechanisms is the production of antibodies targeting infectious agents. However, the production of antibodies has to be tightly controlled. Insufficient control of the immune system may result in the development of autoimmune diseases, including lupus. Lupus is characterized by the production of antibodies attacking the kidneys, leading to life-threatening kidney failure if untreated. In this study, we show that microRNA-155, one member of a family of regulatory molecules, promotes the production of antibodies. By deleting microRNA-155, we can prevent the production of harmful antibodies and alleviate lupus-like disease in mice. Our results suggest the possibility of targeting microRNA-155 to treat autoimmune diseases.

Nature Immunology, 2008

The genomic region encoding the miR-17−92 microRNA (miRNA) cluster is often amplified in lymphoma... more The genomic region encoding the miR-17−92 microRNA (miRNA) cluster is often amplified in lymphoma and other cancers, and miRNAs within this cluster are expressed in high amounts in cancer cells carrying this amplification. Retroviral expression of miR-17−92 accelerates cMyc-induced lymphoma development, but precisely how elevated miR-17−92 expression promotes lymphomagenesis remains unclear. Here we generated mice with elevated miR-17−92 expression in lymphocytes. These mice developed lymphoproliferative disease and autoimmunity, and died prematurely. Lymphocytes from these mice showed increased proliferation and reduced activationinduced cell death. miR-17−92 miRNAs suppressed expression of the tumor suppressor Pten and the pro-apoptotic protein Bim. This mechanism likely contributed to the lymphoproliferative disease and autoimmunity observed in miR-17−92 transgenic mice, and to lymphoma development in patients carrying amplifications of the miR-17−92 coding region.

Journal of Biological Chemistry, 2013

Background: PAPA syndrome is an autoinflammatory disease linked to mutations in the PSTPIP1 gene.... more Background: PAPA syndrome is an autoinflammatory disease linked to mutations in the PSTPIP1 gene. Results: Ectopic expression of mutant PSTPIP1 leads to elevated level of circulating proinflammatory cytokines. Conclusion: Ectopic expression of mutant PSTPIP1 in mice partially recapitulates symptoms in human PAPA syndrome patients. Significance: These observations provide the first genetic analysis elucidating the pathophysiological function of PSTPIP1. Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne Syndrome (PAPA syndrome) is an autoinflammatory disease caused by aberrant production of the proinflammatory cytokine interleukin-1. Mutations in the gene encoding proline serine threonine phosphatase-interacting protein-1 (PSTPIP1) have been linked to PAPA syndrome. PSTPIP1 is an adaptor protein that interacts with PYRIN, the protein encoded by the Mediterranean Fever (MEFV) gene whose mutations cause Familial Mediterranean Fever (FMF). However, the pathophysiological function of PSTPIP1 remains to be elucidated. We have generated mouse strains that either are PSTPIP1 deficient or ectopically express mutant PSTPIP1. Results from analyzing these mice suggested that PSTPIP1 is not an essential regulator of the Nlrp3, Aim2, or Nlrc4 inflammasomes. Although common features of human PAPA syndrome such as pyogenic arthritis and skin inflammation were not recapitulated in the mouse model, ectopic expression of the mutant but not the wild type PSTPIP1 in mice lead to partial embryonic lethality, growth retardation, and elevated level of circulating proinflammatory cytokines.

Immunity, 2006

In addition to the tyrosines of the Iga and b immunoreceptor tyrosine-based activation motifs (IT... more In addition to the tyrosines of the Iga and b immunoreceptor tyrosine-based activation motifs (ITAMs), the evolutionarily conserved Iga non-ITAM tyrosine 204 becomes phosphorylated upon antigen recognition by the B cell receptor (BCR). Here we demonstrate that splenic B cells from mice with a targeted mutation of Iga Y204 exhibited an isolated defect in T cell-independent B cell activation, proliferation, and antibody response upon BCR engagement, yet normal BCR capping, antigen internalization, antigen presentation, and T cell-dependent antibody production. Mutant B cells, present in normal numbers, exhibited unimpaired BCR-induced spleen tyrosine kinase (Syk) phosphorylation but reduced B cell linker protein (BLNK) phosphorylation, calcium flux, and nuclear factor kB (NFkB), c-jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) activation. These results suggest that Iga non-ITAM tyrosine 204 promotes a distinct cellular response, namely T-independent B cell proliferation and differentiation via phosphorylation of the adaptor BLNK.

Genes & Development, 2012

Genome-wide association studies (GWASs) have identified a genetic variant of moderate effect size... more Genome-wide association studies (GWASs) have identified a genetic variant of moderate effect size at 6p21.1 associated with erythrocyte traits in humans. We show that this variant affects an erythroid-specific enhancer of CCND3. A Ccnd3 knockout mouse phenocopies these erythroid phenotypes, with a dramatic increase in erythrocyte size and a concomitant decrease in erythrocyte number. By examining human and mouse primary erythroid cells, we demonstrate that the CCND3 gene product cyclin D3 regulates the number of cell divisions that erythroid precursors undergo during terminal differentiation, thereby controlling erythrocyte size and number. We illustrate how cell type-specific specialization can occur for general cell cycle components—a finding resulting from the biological follow-up of unbiased human genetic studies.

Cell, 2007

MiR-150 is a microRNA (miRNA) specifically expressed in mature lymphocytes, but not their progeni... more MiR-150 is a microRNA (miRNA) specifically expressed in mature lymphocytes, but not their progenitors. A top predicted target of miR-150 is c-Myb, a transcription factor controlling multiple steps of lymphocyte development. Combining loss-and gain-of-function gene targeting approaches for miR-150 with conditional and partial ablation of c-Myb, we show that miR-150 indeed controls c-Myb expression in vivo in a dose-dependent manner over a narrow range of miRNA and c-Myb concentrations and that this dramatically affects lymphocyte development and response. Our results identify a key transcription factor as a critical target of a stage-specifically expressed miRNA in lymphocytes and suggest that this and perhaps other miRNAs have evolved to control the expression of just a few critical target proteins in particular cellular contexts.

The Journal of Immunology, 2011

Igα serine 191 and 197 and threonine 203, which are located in proximity of the Igα ITAM, dampen ... more Igα serine 191 and 197 and threonine 203, which are located in proximity of the Igα ITAM, dampen Igα ITAM tyrosine phosphorylation. In this study, we show that mice with targeted mutations of Igα S191, 197, and T203 displayed elevated serum IgG2c and IgG2b concentrations and had elevated numbers of IgG2c- and IgG2b-secreting cells in the bone marrow. BCR-induced Igα tyrosine phosphorylation was slightly increased in splenic B cells. Our results suggest that Igα serine/threonines limit formation of IgG2c- and IgG2b-secreting bone marrow plasma cells, possibly by fine-tuning Igα tyrosine-mediated BCR signaling.