John Harley, MD, PhD, joins the Autoimmune Disease Prevention Network

An important research accomplishment has been the funding of U01AI130830 for the Autoimmune Disease Prevention Network and becoming the administrative site for the Infrastructure and Opportunities Fund for this initiative from the National Institute of Allergy and Infectious Diseases (NIAID). Indeed, this accomplishment makes Cincinnati Children's one of the premier institutions for autoimmune research and a collaborative member of the best investigative units in the country, led by investigators at the University of Colorado and Stanford University, to mention two of the other five members of this consortium.

Multiple Sclerosis funding awarded to first time R01 recipient, Matthew Weirauch, PhD

Another important accomplishment has been the funding of Dr. Matthew Weirauch's first R01 focused on Multiple Sclerosis (MS). Indeed, it is quite unusual for someone who has never published on this disease to be able to obtain National Institutes of Health R01 funding. This speaks to the importance of our preliminary data. We have found associations using the transcription factors made from the DNA of a virus with the genes that alter the risk of MS. These associations nominate molecular interactions that may show us how the virus causes MS. Work by others has led the community of investigators trying to solve the origins of MS to conclude the involvement of Epstein-Barr virus in causing MS. Our work holds great promise to reveal how this happens, thereby providing the insights and basic knowledge that will lead to new management and therapies for MS patients.

Kenneth Kaufman, PhD, made new discoveries regarding the pathogenesis of rheumatoid arthritis

Working with colleagues, Drs. John Harley, MD, PhD, and Matthew Weirauch, PhD, in the Center for Autoimmune Genomics and Etiology, and the University of Michigan, Dr. Kenneth Kaufman, PhD, has been studying viral infection in the fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis. Identification of viral DNA in the FLS from all rheumatoid arthritis and osteoarthritis samples tested was surprising. Currently, Dr. Kaufman is working on identifying the strain of the virus infecting these cells, characterizing the frequency of infection in the cells and studying the effect the virus has on human gene expression. Interestingly, Dr. Weirauch's work has shown that rheumatoid arthritis genetic risk loci are statistically enriched for specific viral transcription binding sites. These findings suggest that the effect of viral infection on human gene expression may differ based on the presence or absence of rheumatoid arthritis risk alleles and that these differences may play a role in the pathogenesis of rheumatoid arthritis.

Dr. Kaufman continues to work with many collaborators at Cincinnati Children's to utilize next-generation DNA sequencing and micro array technologies to identify polymorphisms that lead to disease. These studies cover a wide range of phenotypes and diseases including: eosinophilic esophagitis with Dr. Marc Rothenberg, PhD (Division of Allergy and Immunology), macrophage activation syndrome with Dr. Alexi Grom, MD (Division of Rheumatology), cardiomyopathy in patients with sickle cell anemia with Dr. Punam Malik, MD (Division of Experimental Hematology and Cancer Biology), tracheal ring deformity with Dr. Paul Kingma, MD, PhD (Divisions of Neonatology and Pulmonary Biology), and others.

Susan Thompson, PhD, performs ongoing JIA genetic studies

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children, and describes a group of clinically heterogeneous arthritides which begin before the age of 16 years, persist for at least six weeks and have an unknown cause. Genome-wide association (GWAS) and Immunochip studies led by the Thompson lab using high-density single nucleotide polymorphism (SNP) arrays have identified 35 associations to date between common genetic variations (minor allele frequency (MAF) > 5%) and JIA. Interestingly, while JIA patients share clinical and pathological features with adult rheumatoid arthritis (RA) patients, we have found that only about 1/2 of the genetic associations reported in JIA overlap with those reported in adult rheumatoid arthritis. Comparing adult and pediatric forms of arthritis has the potential to identify disease mechanisms and causes specific to the developing pediatric immune system. Fine mapping within the HLA has allowed us to classify subcategories of JIA and delineate differences from adult arthritis based on unique amino acids present in the antigen binding pocket of the class II HLA-DRB1 molecule. Genetic approaches application can assist in understanding response to medications. For example, methotrexate, is a drug that is widely used to treat arthritis in children, but it is only effective in ~30% of patients. Identification of genetic variation that will predict patient response to methotrexate and molecular markers of methotrexate metabolism is being used to generate genomic profiles that will help clinicians choose the most appropriate therapy for rapid and effective treatment of childhood arthritis.

Alexey Porollo, PhD, published results from pneumocystis pneumonia (PCP) pathogenesis R01

The study of pneumocystis pneumonia (PCP) pathogenesis in the mouse model has National Institutes of Health (NIH) funding for five years, R01HL119190. Dr. Alexey Porollo, PhD, has completed an RNA-seq analysis of the host, pathogen, and associated lung microbiome. The identified mouse genes perturbed through the progress of PCP, enabling the elucidation of biological pathways and cell types involved in combating the fungal infection. Functional genomics of the pathogenic fungus (pneumocystis murina), its metabolic strategies for acquiring nutrients and interaction with the revealation of the host. Directed supplementation experiments established a long term culture for the non-cultivable fungus. To perform a metatranscriptome analysis of the RNA-seq data containing a complex mixture of host, pathogen and bacterial transcripts, researchers developed a new computational workflow. Published results are in peer-reviewed journals, including mBio and Microbiome. The study lays the foundation for a formulation of the culture media permitting a long term cultivation of the parasitic fungus and for identifying new drug targets within the persistent opportunistic pathogen.

Nan Shen, MD, PhD, identified a functional genetic variant causing amino acid replacement in neutrophil cystolic factor 1

Working with colleagues at the Medical University of South Carolina and Shanghai Jiao Tong University, Dr. Shen’s group has identified a functional genetic variant causing amino acid replacement in neutrophil cystolic factor 1 (NCF1), leading to a lower capacity of inducing oxidative burst, that is strongly associated with several common autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis, and Sjögren's syndrome among different ethnic patients’ cohorts. The published study is found in Nature Genetics. The data provide an elegant strategy to define the genetic causal variant located at a complex genomic region missed by a conventional genome wide association study (GWAS) approach and highlight the pathogenic role of reduced reactive oxygen species in autoimmune disease development.

Improved understanding of lupus and psoriatic arthritis etiology; Iouri Chepelev, PhD

In studies funded by the Lupus Research Institute, Arthritis National Research Foundation and National Psoriasis Foundation, Iouri Chepelev, PhD, has been investigating genetic and molecular mechanisms of regulation of some genes implicated in the pathogenesis of systemic lupus erythematosus and psoriatic arthritis. His laboratory has mapped out detailed 3-dimensional structures of human genome in immune cells to better understand the regulation of these genes. The data generated in these studies will reveal some genetic interactions involved in the etiology of lupus, and psoriatic arthritis, and will provide a strong foundation for his future studies on the genetic basis of these diseases.

Natural killer cells in cytomegalovirus vaccination; new findings by Stephen Waggoner, PhD

In this Center for Clinical & Translational Science & Training (CCTST) funded study, Dr. Stephen Waggoner, PhD, and colleagues, evaluated the functionality and inducibility of unique subsets of human natural killer cells associated with cytomegalovirus infection. The goal was to determine whether subsets of natural killer cells normally present only in cytomegalovirus infected individuals, can develop if stimulated following administration of a cytomegalovirus vaccine. A secondary goal was to determine the functional contribution of these cells as a means to ascertain the value of intentionally triggering the development of these cells during immunization. The study involved a collaboration with Drs. David Bernstein, MD, MA (Division of Infectious Diseases) and Yenan Bryceson, PhD (Karolinska Institute), and made use of a unique set of longitudinal blood samples collected from adolescent cytomegalovirus-negative women receiving an experiment cytomegalovirus vaccine. The results reveal important functions of these natural killer cells, and remarkably demonstrate the appearance of the natural killer subset in cytomegalovirus-negative individuals at time points after vaccine administration. These findings will be important in the design of next generation vaccines to prevent diseases associated with congenital cytomegalovirus infection.

Bahram Namjou, MD, continues to uncover genetic associations of NAFLD, appendicitis and early onset migraine

In this National Human Genome Research Institute (NHGRI) funded study (U01HG008666; PI Harley), Bahram Namjou-Khales, MD, and colleagues from the Electronic Medical Records and Genomics (eMERGE) Network developed NLP phenotype algorithms, identified and obtained cases and controls from the Cincinnati Biobank, and genotyped new subjects for eMERGE Network-wide GWAS and PheWAS studies. The goal of these projects is to expand the genetic knowledgebase for different phenotypes, specifically those important in pediatrics. In FY 17, finalization of phenotype algorithms for non-alcoholic fatty liver condition (NAFLD/NASH), appendicitis and early onset migraine occurred.

Ongoing genomic discovery in the laboratory of Leah Kottyan, PhD

The Kottyan lab continues their work elucidating the genetic causal variants at the risk loci associated with systemic lupus erythematosus and eosinophilic esophagitis. Through collaboration, the lab is also participating in functional genomic projects to understand preterm birth, autoimmune liver disease, and response to therapy in patients with attention deficit hyperactivity disease (ADHD).

Halima Moncrieffe, PhD, transcriptional profiles of JIA patient blood with subsequent poor response to methotrexate

Dr. Halima Moncrieffe, PhD, and colleagues, performed a multi-site study to identify a gene expression profile that associates with response to methotrexate in children with juvenile idiopathic arthritis (JIA). Methotrexate remains the first line disease-modifying anti-rheumatic drugs (DMARD) therapy for patients with JIA,; with a good response seen in less than half of patients. The first signs of a good response are not usually seen until at least six-eight weeks into the treatment, and it may take several months to achieve the full benefit of this treatment. To our knowledge, this is the first demonstration that suggests a cell-type specific signature associated with MTX non-response in patients with JIA. This method of identifying gene expression patterns specific to cell populations may be a valuable tool in understanding the complex mechanisms of drug response and enable greater precision in treatment selection for patients with JIA.