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

PLoS One. 2015 Jul 17;10(7):e0133220. doi: 10.1371/journal.pone.0133220. eCollection 2015.

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.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • CD4-Positive T-Lymphocytes / immunology
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Female
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Immunologic Deficiency Syndromes / diagnosis
  • Immunologic Deficiency Syndromes / genetics*
  • Lipopolysaccharides / immunology
  • Mutation*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Lipopolysaccharides
  • Nuclear Proteins
  • RAG2 protein, human
  • RAG-1 protein

Grants and funding

Biomedizinische ForschungsgmbH provided no support in the form of salary for author Martha M. Eibl, and did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of the authors are articulated in the author contributions section.