Primary immunodeficiencies: A rapidly evolving story

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Presentation transcript:

Primary immunodeficiencies: A rapidly evolving story Nima Parvaneh, MD, Jean-Laurent Casanova, MD, PhD, Luigi Daniele Notarangelo, MD, PhD, Mary Ellen Conley, MD Journal of Allergy and Clinical Immunology Volume 131, Issue 2, Pages 314-323 (February 2013) DOI: 10.1016/j.jaci.2012.11.051 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 TCR signaling. Multiple signal transduction pathways are stimulated through the TCR. These pathways collectively activate transcription factors that organize T-cell survival, proliferation, differentiation, homeostasis, and migration. Mutant molecules in patients with TCR-related defects are indicated in red. AP1, Activator protein 1; BCL10, B-cell lymphoma/leukemia 10; CARMA, CARD-containing MAGUK protein; DAG, diacylglycerol; ER, endoplasmic reticulum; FOXO, forkhead box O; GAD, GRB2-related adaptor protein; IKK, IκB kinase; IP3, inositol trisphosphate; IP3R, inositol trisphosphate receptor; LAT, linker of activated T cells; MALT, mucosa-associated lymphoid tissue lymphoma translocation protein; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NCK, noncatalytic region of tyrosine kinase adaptor protein; NFAT, nuclear factor of activated T cells; PDK, phosphoinositide-dependent kinase; PIP2, phosphatidyl inositol bisphosphate; PKB, protein kinase B; PKCθ, protein kinase C θ; RASGRP, RAS guanyl nucleotide–releasing protein; SLP-76, SH2 domain–containing leukocyte protein of 76 kDa; STIM1, stromal interaction molecule 1; ZAP70, ζ-chain associated protein kinase of 70 kDa. Journal of Allergy and Clinical Immunology 2013 131, 314-323DOI: (10.1016/j.jaci.2012.11.051) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Cross-talk between monocyte/macrophage cells and T/NK lymphocytes. Genes in the IL-12/IFN-γ pathway are particularly important for protection against mycobacterial disease. IRF8 is an IFN-γ–inducible transcription factor required for the induction of various target genes, including IL-12. The NF-κB essential modulator (NEMO) mutations in the LZ domain impair CD40-NEMO–dependent pathways. Some gp91phox mutations specifically abolish the respiratory burst in monocyte-derived macrophages. ISG15 is secreted by neutrophils and potentiates IFN-γ production by NK/T cells. Genetic defects that preclude monocyte development (eg, GATA2) can also predispose to mycobacterial infections (not shown). Mutant molecules in patients with unusual susceptibility to infection are indicated in red. IFNγR, IFN-γ receptor; IL-12R, IL-12 receptor; MB, mycobacterium; STAT, signal transducer and activator of transcription; TYK2, tyrosine kinase 2. Journal of Allergy and Clinical Immunology 2013 131, 314-323DOI: (10.1016/j.jaci.2012.11.051) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions