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An Emerging Phenotype of Partial RAG 1/2 Deficiency Among Young Children with Autoimmunity and Viral Infections

An Emerging Phenotype of Partial RAG 1/2 Deficiency Among Young Children with Autoimmunity and Viral Infections content piece image
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 IFNaIFNwand 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.