Interesting papers in PID

Articles review - March

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By Anna Villa

Dear ESID members,

I would like to invite you to focus your attention on three papers published in February.

1. The group directed by M. Lenardo has described a new primary immunodeficiency  named XMEN : X-linked immunodeficiency with Magnesium defect, Epstein-Barr virus infection and Neoplasias caused by mutations in a new gene encoding magnesium transporter (MAGT1).  Patients show CD4 lymphopenia, chronic elevated EBV levels, recurrent viral infections and/or EBV-associated B cell lymphomas.  B cells were moderately high, with increased transitional B cells and neutropenia, while some patients presented with autoimmune cytopenia. Patients show variable Immunoglobulin levels. Of note, many of the patients did not come to medical attention until EBV associated malignancies appeared.  (Li FY et al. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood2014 Feb 18)


This paper reveals the unexpected immune regulatory role of free intracellular Mg2+. The loss of MAGT1 activity has two effects on intracellular Mg2+:  abolition of a rapidly-induced transient TCR-induced free Mg flux required for T cell activation and the chronic decrease in the basal level of free Mg2+ which causes the lost of expression of NKG2D, a receptor on natural killer and cytotoxic T lymphocytes important for antiviral and antitumor cytotoxic activity.

2. Although not directly correlated with PID, I would like to draw your attention on an interesting paper published on NEJM describing a new gene involved in the pathogenesis of polyarteritis nodosa. Exome sequencing in patients from multiply affected families of Georgian and German ancestry has lead to the identification of CECR1 encoding adenosine deaminase 2 (ADA2), the major extracellular adenosine deaminase and an adenosine deaminase growth factor. In humans, adenosine is degraded to inosine and deoxyadenosine to deoxyinosine is catalyzed by intracellular ADA1 and extracellular ADA2.

Of note, while ADA1 mutations lead to the well-known severe combined immunodeficiency (ADA SCID), mutations in ADA 2 gene causes vasculitis with no gross immune deficiency.  Patients show a spectrum of clinical manifestations ranging from severe or fatal vasculitis, strokes or limited cutaneous manifestations. This paper is important since it highlights the complexity of the role of adenosine in the inflammatory response.

(Elkan P et al. Mutant Adenosine Deaminase 2 in a Polyarteritis Nodosa Vasculopathy. N.Engl J Med, 2014 Feb 19)


3. In childhood, acute lymphoblastic leukemia (ALL) is characterized by ETV6-RNUX1 fusion gene.  Peter Campbell and Mel Greaves show that RAG-mediated recombination is the driving mechanism in the progression of B-ALL, thus acting as the main actors of secondary events associated with leukemic transformation.  They performed genome and exome sequencing in 51 and 56 ETV6-RUNX1 positive cases. To determine the prevalence of off-target RAG activity, they resolved structural variations and identified Recombination signal sequences (RSS) in 12% of the structural variations, 40% of breakpoints contained RSS. Most of them were located in active promoter and enhancer regions. Interestingly, these RAG-mediated rearrangements are repetitive in space and time.

Overall, these data indicate RAG-mediated recombination as a novel mutation process driving leukemia progression and are instrumental for the design of novel vectors expressing RAG genes in gene therapy setting.

(Papaemmanuil E et al. RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. Nat Genet. 46:116-25, 2014.)