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The cup runneth over: lessons from the ever-expanding pool of primary immunodeficiency diseases

Nature Reviews Immunology volume 13, pages 635–648 (2013)Cite this article

Subjects

Key Points

  • The study of the genetics and the pathophysiology of immunodeficiencies has a long history of improving our understanding of basic immunological pathways.

  • Recent advances in laboratory diagnostics and sequencing have led to substantial advances in new aetiologies and pathways of immune diseases; some of these diseases have previously been described but others are newly identified.

  • Hypomorphic mutations in immune-related genes in humans result in disease phenotypes that are not predicted by null mutations in mice. Such findings highlight the differences between the mouse and human immune systems. These hypomorphic mutations also enable the study of the function of certain proteins in cell lineages that are normally absent in mice that have null mutations.

  • One example of the results of such investigations can be found in patients who have gene deficiencies that impair their immunity to Epstein–Barr virus. The study of such individuals led to the discovery of a role for magnesium as a second messenger in lymphocytes.

  • The study of a cohort of patients with familial cold urticaria led to the identification of phospholipase Cγ2 mutations, which could render cellular signalling hyporesponsive at body temperature but spontaneously active in the cold.

  • Patients with familial myelodysplasia and acute myeloid leukaemia, as well as patients who show increased susceptibility to a wide-range of infections, carry heterogeneous mutations in the transcription factor GATA-binding protein 2. These individuals provide an opportunity to study this transcription factor in the context of infection and oncogenesis.

Abstract

A recent surge in newly described primary immunodeficiencies (PIDs) has highlighted new physiological and pathophysiological pathways that affect the immune system. Furthermore, the study of individuals with PIDs has substantially improved our understanding of basic cellular and signalling pathways in host defence and immune regulation. Single-gene defects can lead to disease manifestations that range from extremely narrow infectious phenotypes to remarkably broad multisystem effects. Hypomorphic or hypermorphic gene mutations often occur in human diseases; when coupled with the fact that humans are exposed to naturally encountered antigens and pathogens, this helps to make the case that the study of immunological diseases in humans should be at the forefront of basic immunological research.

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Figure 1: Recently identified defects that impair T cell functions.
Figure 2: Recently identified defects that impair B cell functions.
Figure 3: New immunodeficiencies affecting the innate immune system.
Figure 4: Defects in immunity to Candida albicans.

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Acknowledgements

This work has been supported by the Division of Intramural Research, US National Institute of Allergy and Infectious Diseases, National Institutes of Health.

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Authors and Affiliations

  1. Allergic Inflammation Unit, Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Joshua D. Milner

  2. Laboratory of Clinical Infectious Diseases, Clinical Research Center B3-4141, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 208921684, Maryland, USA

    Steven M. Holland

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  1. Joshua D. Milner
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Correspondence to Joshua D. Milner or Steven M. Holland.

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The authors declare no competing financial interests.

PowerPoint slides

Glossary

T cell receptor excision circles

(TRECs). DNA episomes that are normally produced during the thymic maturation of T cells, specifically during recombination of the T cell receptor genes.

Wiskott–Aldrich syndrome protein

(WASP). An actin regulator that is involved in the formation of the immunological synapse. Mutations in WASP cause a life-threatening X-linked immunodeficiency that is characterized by thrombocytopaenia with small platelets, eczema, recurrent infections and an increased incidence of autoimmune manifestations and malignancies.

Recombinase activating gene 1

(RAG1). RAG1 and RAG2 encode the RAG proteins, which are involved in creating the double-stranded DNA breaks that are required to produce the rearranged gene segments encoding the complete protein chains of B cell and T cell receptors.

Mycobacterium avium complex

A complex of mycobacterial species that are ubiquitous in the environment and that can cause disease in immunocompromised individuals.

Immunoscope assays

Techniques used to assess the diversity of the T cell receptor (TCR) repertoire in a population of T cells. They use a reverse transcription PCR-based approach to assess the length of the complementarity determining region 3 of the variable genes encoding the TCR.

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Milner, J., Holland, S. The cup runneth over: lessons from the ever-expanding pool of primary immunodeficiency diseases. Nat Rev Immunol 13, 635–648 (2013). https://doi.org/10.1038/nri3493

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