An Emerging Phenotype of Partial RAG 1/2 Deficiency Among Young Children with Autoimmunity and Viral Infections
Poster Dec 12, 2017
B. Patel, B. Ujhazi, K. Csomos, J.E. Walter
The recombination-activating gene 1 (RAG1) and RAG2 proteins initiate the combinatorial joining of the variable (V), diversity (D) and joining (J) gene segments that diversifies T and B cell receptor repertoire. Functionally null RAG1/2 mutations result in full absence of T and B cells and Severe Combined Immunodeficiency (SCID). Whereas partial RAG1/2 proteins with variable recombinase activity result in a broad phenotype including combined immunodeficiency (CID) with autoimmunity and inflammatory complications. Phenotypic variability of the same mutations indicates additional epigenetic factors, such as viral infections shaping the clinical presentation.
We describe the natural history of a cohort of 12 patients with confirmed partial RAG1/2 mutations and autoimmunity at a young age. We were seeking the link between viral infections and autoimmunity and tested candidate biomarkers that may reflect the underlying RAG1/2 protein deficiency.
A retrospective chart review was completed. Patients were enrolled through national and international collaborative effort. Autoantibody profiling was performed by microarray, Bioplex 23 and/or ELISA.
Onset of viral infection ranged from 6 to 30 month of age. Out of 12 patients, 5 patients had complicated vaccine associated varicella infections, 4 patients had cytomegalovirus infections and 2 patients had adenovirus with combination of herpes virus. All patient developed autoimmune complications preceded by viral infections. Autoimmunity was mainly cytopenias including autoimmune hemolytic anemia (66%), immune thrombocytopenia (25%), and autoimmune neutropenia (25%) confirmed by serology in the majority of the cases. Other autoimmune complications included severe vasculitis and thyroid disease. Autoantibody profiling confirmed the presence of a specific panel of anti-cytokine autoantibodies targeting IFNaIFNwand IL-12 (8 of 9 patients tested). RAG deficiency was confirmed long after onset of autoimmunity and in one case post-mortem. Homozygous or compound heterozygous RAG1/2 mutations are fully characterized in 11 of 12 patients with average recombinase activity level ranging from 4-50% as measured by an in vitro recombinase assay (Lee JACI 2013). 11 of 12 patients underwent bone marrow transplantation with high survival rate (1 of 11 deceased).
As an emerging new phenotype. partial RAG1/2 deficiency may present with features of complicated viral infections and autoimmunity, most commonly autoimmune cytopenias. A specific signature of anti-cytokine antibodies may assist the clinician to identify an underlying immunodeficiency, and initiate early definitive treatment with bone marrow transplantation.
Characterization of a Type 2 diabetes-associated islet-specific enhancer cluster in STARD10 by genome editing of EndoC-βH1 cellsPoster
Genome-wide association studies (GWAS) have identified more than 100 genetic loci associated with type 2 diabetes. The majority of these are located in the intergenic or intragenic regions suggesting that the implicated variants may alter chromatin conformation. This, in turn, is likely to influence the expression of nearby or more remotely located genes to alter beta cell function. At present, however, detailed molecular and functional analyses are still lacking for most of these variants. We recently analysed one of these loci and mapped five causal variants in an islet-specific enhancer cluster within the STARD10 gene locus. Here, we aimed to understand how these causal variants influence b-cell function by alteration of the chromatin structure of enhancer clusterREAD MORE
P450 Induction in Cryopreserved Hepatocytes from PXR and CAR Nuclear Receptor Knock-out RatsPoster
The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of phase I (cytochrome P450s), phase II metabolizing enzymes and transporter genes in response to xenobiotics, including prescription drugs.READ MORE
Psychiatric Risk Gene Cacna1c and Early Life Stress: Potential Gene-Environment interactions?Poster
Early life stress (ELS) is highly associated with development of psychopathology
and mood disorders in adulthood. Genetic studies have identified variation in the gene calcium voltage-gated channel subunit alpha1C (CACNA1C) to increase risk for several psychiatric disorders. This poster assessed the expression of Cacna1c following prepubertal stress.