Primary immunodeficiencies: A rapidly evolving story - 30/01/13

Doi : 10.1016/j.jaci.2012.11.051

Nima Parvaneh, MD ^a,^b,^⁎ , Jean-Laurent Casanova, MD, PhD ^c,^d, Luigi Daniele Notarangelo, MD, PhD ^e,^f, Mary Ellen Conley, MD ^g,^h
^a Pediatric Infectious Diseases Research Center, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
^b Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
^c St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY
^d Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, University Paris Descartes and INSERM U980, Paris, France
^e Division of Immunology, Children’s Hospital Boston, Harvard Medical School, Boston, Mass
^f Manton Center for Orphan Disease Research, Children’s Hospital Boston, Harvard Medical School, Boston, Mass
^g Department of Pediatrics, University of Tennessee College of Medicine, Memphis, Tenn
^h Le Bonheur Children’s Hospital, Memphis, Tenn

Corresponding author: Nima Parvaneh, MD, Pediatric Infectious Diseases Research Center, Children’s Medical Center, 62 Gharib St, 14194 Tehran, Iran.

Abstract

The characterization of primary immunodeficiencies (PIDs) in human subjects is crucial for a better understanding of the biology of the immune response. New achievements in this field have been possible in light of collaborative studies; attention paid to new phenotypes, infectious and otherwise; improved immunologic techniques; and use of exome sequencing technology. The International Union of Immunological Societies Expert Committee on PIDs recently reported on the updated classification of PIDs. However, new PIDs are being discovered at an ever-increasing rate. A series of 19 novel primary defects of immunity that have been discovered after release of the International Union of Immunological Societies report are discussed here. These new findings highlight the molecular pathways that are associated with clinical phenotypes and suggest potential therapies for affected patients.

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Key words : Primary immunodeficiencies, combined immunodeficiencies, well-defined syndromes with immunodeficiency, predominantly antibody defects, defects of immune dysregulation, congenital defects of phagocytes, defects in innate immunity, autoinflammatory disorders, mutation detection

Abbreviations used : ADAM17, BCR, EV, HHV6, HPS, HPV, HSE, HSV1, ICA, ICL, IL-36Ra, ISG15, IUIS, LCK, LRBA, MCM4, MSMD, MST, NEMO, NF-κB, NK, PI3K, PID, PLCγ2, RHOH, TBK1, TCR, TLR3, TRIF, UNC119, WASP, WIP

Plan

Combined immunodeficiencies

T-cell receptor ⍺ gene mutation: T-cell receptor ⍺β⁺ T-cell depletion

Ras homolog gene family member H deficiency: Loss of naive T cells and persistent human papilloma virus infections

MST1 deficiency: Loss of naive T cells

Lymphocyte-specific protein tyrosine kinase deficiency: T-cell deficiency with CD4⁺ lymphopenia

Uncoordinated 119 deficiency: Idiopathic CD4⁺ lymphopenia

Well-defined syndromes with immunodeficiency

Wiskott-Aldrich syndrome protein–interacting protein deficiency: Wiskott-Aldrich syndrome-like phenotype

Phospholipase Cγ2 gain-of-function mutations: Cold urticaria, immunodeficiency, and autoimmunity/autoinflammatory

Predominantly antibody defects

Defect in the p85⍺ subunit of phosphoinositide 3-kinase: Agammaglobulinemia and absent B cells

CD21 deficiency: Hypogammaglobulinemia

LPS-responsive beige-like anchor deficiency: Hypogammaglobulinemia with autoimmunity and early colitis

Defects of immune dysregulation

Pallidin deficiency: Hermansky-Pudlak syndrome type 9

CD27 deficiency: Immune dysregulation and persistent EBV infection

Congenital defects of phagocyte number, function, or both

Interferon-stimulated gene 15 deficiency: Mendelian susceptibility to mycobacterial diseases

Defects in innate immunity

NKX2-5 deficiency: Isolated congenital asplenia

Toll/IL-1 receptor domain–containing adaptor inducing IFN-β and TANK-binding kinase 1 deficiencies: Herpes simplex encephalitis

Minichromosome maintenance complex component 4 deficiency: NK cell deficiency associated with growth retardation and adrenal insufficiency

Autoinflammatory disorders

A disintegrin and metalloproteinase 17 deficiency: Inflammatory skin and bowel disease

IL-36 receptor antagonist deficiency: Generalized pustular psoriasis

Conclusion

Disclosure of potential conflict of interest: J.-L. Casanova has received grants from the National Institutes of Health (NIH); has been a consultant for Pfizer, GlaxoSmithKline, NovImmune, Biogenldec, Merck, and Sanofi-Aventis; and has grants/grants pending from Pfizer and Merck. L. D. Notarangelo is a board member for the Immune Disease Institute, is employed by Children’s Hospital Boston, has grants/grants pending with the NIH, the March of Dimes, and the Jeffrey Modell Foundation; and has received payment for lectures, including service on speakers’ bureaus for the WAS foundation. M. E. Conley is employed by the University of Tennessee, has received grants/grants pending from the NIH and the March of Dimes, has received payment for lectures from the Immune Deficiency Foundation, and is receiving royalties from the Southern Bio for monoclonal antibodies. N. Parvaneh declares no relevant conflicts of interest.

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Vol 131 - N° 2

P. 314-323 - février 2013 Retour au numéro

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Primary immunodeficiencies: A rapidly evolving story - 30/01/13

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