Leaky RAG Deficiency in Adult Patients with Impaired Antibody Production against Bacterial Polysaccharide Antigens

Abstract

Loss of function mutations in the recombination activating genes RAG1 and RAG2 have been reported to cause a T-B-NK+ type of severe combined immunodeficiency. In addition identification of hypomorphic mutations in RAG1 and RAG2 has led to an expansion of the spectrum of disease to include Omenn syndrome, early onset autoimmunity, granuloma, chronic cytomegalovirus- or EBV-infection with expansion of gamma/delta T-cells, idiophatic CD4 lymphopenia and a phenotype resembling common variable immunodeficiency. Herein we describe a novel presentation of leaky RAG1 and RAG2 deficiency in two unrelated adult patients with impaired antibody production against bacterial polysaccharide antigens. Clinical manifestation included recurrent pneumonia, sinusitis, otitis media and in one patient recurrent cutaneous vasculitis. Both patients harbored a combination of a null mutation on one allele with a novel hypomorphic RAG1/2 mutation on the other allele. One of these novel mutations affected the start codon of RAG1 and resulted in an aberrant gene and protein expression. The second novel RAG2 mutation leads to a truncated RAG2 protein, lacking the C-terminus with intact core RAG2 and reduced VDJ recombination capacity as previously described in a mouse model. Both patients presented with severely decreased numbers of naïve CD4+ T cells and defective T independent IgG responses to bacterial polysaccharide antigens, while T cell-dependent IgG antibody formation e.g. after tetanus or TBEV vaccination was intact. In conclusion, hypomorphic mutations in genes responsible for SCID should be considered in adults with predominantly antibody deficiency.

Human RAG mutations: biochemistry and clinical implications

“…Following this description, several other cases of CID–G/AI with various auto immune manifestations (such as cytopaenias, vitiligo, psoriasis, myasthenia gravis and Guillain–Barré syndrome) have been reported 33–40 . Additional phenotypes that are associated with RAG deficiency include idiopathic CD4 + T cell lymphopaenia 41 , common variable immunodeficiency 40,42 , IgA deficiency 43,44 , selective deficiency of polysaccharide-specific antibody responses 44 , hyper-IgM syndrome 45 and sterile chronic multifocal osteomyelitis 46 . Overall, these observations have substantially broadened the clinical and immunological spectrum of human RAG deficiency and have identified immune dysregulation as a prominent manifestation of perturbed RAG function.…”

Characterization of T and B cell repertoire diversity in patients with RAG deficiency

“…Another form of LS with expansion of T cells expressing the γδ form of the TCR occurs especially in patients with cytomegalovirus infection (3, 4). More recently, hypomorphic RAG mutations were identified in patients with delayed-onset combined immunodeficiency associated with granulomas and/or autoimmunity (CID-G/AI) (5, 6), or in other, more rare, milder and atypical presentations, including CD4 lymphopenia (7), common variable immune deficiency (8), selective deficiency of anti-polysaccharide antibody responses (9), and pyoderma gangrenosum (10). These heterogeneous clinical phenotypes are associated with a broad spectrum of nonsense, frameshift, in-frame deletion or insertion, and missense mutations of the RAG1 and RAG2 genes that affect various domains of the respective proteins (11).…”

Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

“…3, 4 Hypomorphic RAG1/2 mutations with more preserved residual V(D)J recombination activity (5–30%) result in a distinct phenotype of combined immunodeficiency with granuloma and/or autoimmunity (CID-G/A). 1, 2, 5 Beyond CID, RAG deficiency has been found in patients with predominantly primary antibody deficiencies 6, 7 and naïve CD4 + T cell lymphopenia in most cases. Currently there is no published systematic evaluation for the presence of an underlying RAG deficiency in patients with primary antibody deficiencies.…”