Lessons learned from the study of human inborn errors of innate immunity
2018; Elsevier BV; Volume: 143; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2018.07.013
ISSN1097-6825
AutoresGiorgia Bucciol, Leen Moens, Barbara Bosch, Xavier Bossuyt, Jean‐Laurent Casanova, Anne Puel, Isabelle Meyts,
Tópico(s)Parvovirus B19 Infection Studies
ResumoInnate immunity contributes to host defense through all cell types and relies on their shared germline genetic background, whereas adaptive immunity operates through only 3 main cell types, αβ T cells, γδ T cells, and B cells, and relies on their somatic genetic diversification of antigen-specific responses. Human inborn errors of innate immunity often underlie infectious diseases. The range and nature of infections depend on the mutated gene, the deleteriousness of the mutation, and other ill-defined factors. Most known inborn errors of innate immunity to infection disrupt the development or function of leukocytes other than T and B cells, but a growing number of inborn errors affect cells other than circulating and tissue leukocytes. Here we review inborn errors of innate immunity that have been recently discovered or clarified. We highlight the immunologic implications of these errors. Innate immunity contributes to host defense through all cell types and relies on their shared germline genetic background, whereas adaptive immunity operates through only 3 main cell types, αβ T cells, γδ T cells, and B cells, and relies on their somatic genetic diversification of antigen-specific responses. Human inborn errors of innate immunity often underlie infectious diseases. The range and nature of infections depend on the mutated gene, the deleteriousness of the mutation, and other ill-defined factors. Most known inborn errors of innate immunity to infection disrupt the development or function of leukocytes other than T and B cells, but a growing number of inborn errors affect cells other than circulating and tissue leukocytes. Here we review inborn errors of innate immunity that have been recently discovered or clarified. We highlight the immunologic implications of these errors. Innate immunity is a germline-encoded system that enables eukaryotes to defend themselves against infection.1Beutler B.A. TLRs and innate immunity.Blood. 2009; 113: 1399-1407Crossref PubMed Scopus (463) Google Scholar, 2Ronald P. Beutler B. Plant and animal sensors of conserved microbial signatures.Science. 2010; 330: 1061-1064Crossref PubMed Scopus (156) Google Scholar It consists of 3 main components: (1) anatomic barriers, such as the physical barrier of intact skin and the chemical barrier of low gastric pH; (2) soluble proteins secreted onto mucosal surfaces or into the bloodstream, such as complement factors; and (3) a cellular compartment composed of both hematopoietic and nonhematopoietic cells. Antigen-presenting cells (APCs), such as dendritic cells (DCs); phagocytes, such as neutrophils; cytotoxic/cytolytic cells, such as natural killer (NK) cells; and other innate lymphoid cells (ILCs), together with nonhematopoietic cells, such as fibroblasts, keratinocytes, epithelial cells, and neurons, harbor pathways that allow an adequate response to infection. Pathogens are first detected through innate immune sensors or receptors. Several classes of microbial receptors have been described: Toll-like receptors (TLRs), retinoic acid–inducible protein 1 (RIG-I)–like receptors (RLRs), Nod-like receptors, C-type lectin receptors (CLRs), and DNA sensors.3Kaisho T. Akira S. Toll-like receptor function and signaling.J Allergy Clin Immunol. 2006; 117: 979-987Abstract Full Text Full Text PDF PubMed Scopus (571) Google Scholar, 4Sancho-Shimizu V. Perez de Diego R. Jouanguy E. Zhang S.Y. Casanova J.L. 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Intrinsic immunity: a front-line defense against viral attack.Nat Immunol. 2004; 5: 1109-1115Crossref PubMed Scopus (310) Google Scholar The study of inborn errors of immunity was long dominated by the concept of "conventional" primary immunodeficiencies (PIDs), in which rare Mendelian traits confer susceptibility to infection with a multitude of pathogens in a completely penetrant manner and with a measurable effect on immune cell number or function. The prototype of such PIDs is X-linked (XL) agammaglobulinemia, which is caused by deleterious mutations in the Bruton tyrosine kinase gene (BTK). Bruton tyrosine kinase is expressed in hematopoietic cells, and defects of this protein render the host susceptible for life to recurrent life-threatening infections with various microbes and result in a detectable immunologic phenotype (little or absent immunoglobulin production and few or absent B lymphocytes). 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Primary immunodeficiencies suggest redundancy within the human immune system.Sci Immunol. 2016; 1Crossref PubMed Google Scholar However, dichotomous classifications making distinctions between adaptive and innate immunity, not to mention cell-intrinsic immunity, represent an oversimplification and prove difficult to apply to inborn errors of immunity. In fact, inborn errors of innate immunity can result in the absence or impaired production of cytokines essential for the development, survival, proliferation, or function of B or T cells and can lead to allergy and autoimmunity, indications of adaptive immune dysregulation. In this review we explore a set of inborn errors affecting "primarily" innate immunity, acknowledging their effect on the adaptive immune response. We focus on recently described gene defects in the cellular compartment of the innate immune response or on new insights into the pathogenesis of previously described defects (Table I).15Della Mina E. Borghesi A. Zhou H. 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For the recently described CD55 deficiency, we refer to the original publication.65Ozen A. Comrie W.A. Ardy R.C. Dominguez Conde C. Dalgic B. Beser O.F. et al.CD55 deficiency, early-onset protein-losing enteropathy, and thrombosis.N Engl J Med. 2017; 377: 52-61Crossref PubMed Scopus (23) Google ScholarTable IOverview of recently described inborn errors of innate immunity to infectionProteinGeneOMIM no. gene/diseaseInheritance and penetranceCells, where expressed (mRNA and/or protein)Cells, where testedResultsImmunologic phenotypeInfectious phenotypeNoninfectious phenotypeAutoinflammationNo. of reported patientsTherapyYear of genetic reportUpstream defects of the TLR and/or IL-1R signaling pathway IRAK1IRAK1300283XLUbiquitousFibroblasts, PBMCs, EBV-B cellsTLR responses: impaired in fibroblasts and EBV-B cells, normal in PBMCsNormal responses to IL-1β in fibroblasts and PBMCsNANANA (MECP2 deletion sdr)No1NA201715Della Mina E. Borghesi A. Zhou H. Bougarn S. Boughorbel S. Israel L. et al.Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts.Proc Natl Acad Sci U S A. 2017; 114: E514-E523Crossref PubMed Scopus (2) Google Scholar TIRAPTIRAP606252AR-IPUbiquitousFibroblasts, PBMCs, granulocytesImpaired responses to TLR2 and TLR4 stimulationNASevere staphylococcal infectionNANo8NA201716Israel L. Wang Y. Bulek K. Della Mina E. Zhang Z. Pedergnana V. et al.Human adaptive immunity rescues an inborn error of innate immunity.Cell. 2017; 168: 789-800Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarInborn errors of the CBM complex CARD9CARD9607212/212050AR-CPGranulocytesPBMCs, monocyte-derived DCs, macrophagesImpaired T cell−dependent IL-17 production Defective cytokine and chemokine production on fungal stimulationImpaired neutrophil killing, impaired neutrophil recruitment to the site of infectionEosinophilia, high IgE levelSuperficial (eg, CMC) and invasive (eg, meningoencephalitis) fungal infectionsNANo58HSCTGM-CSFG-CSF200917Glocker E. Hennigs A. Nabavi M. Schäffer A.A. Woellner C. Salzer U. et al.A homozygous CARD9 mutation in a family with susceptibility to fungal infections.N Engl J Med. 2009; 361: 1727-1735Crossref PubMed Scopus (455) Google ScholarInborn errors of LUBAC HOIL-1HOIL1 (RBCK1)610924AR-CPUbiquitousFibroblasts, EBV-B cells, PBMCsImpaired NF-κB responses in fibroblasts and EBV-B cellsEnhanced response to IL-1β in monocytesImpaired vaccine responsesInvasive bacterial infectionsChronic autoinflammation, muscular amylopectinosisYes3NA201218Boisson B. Laplantine E. Prando C. Giliani S. Israelsson E. Xu Z. et al.Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency.Nat Immunol. 2012; 13: 1178-1186Crossref PubMed Scopus (185) Google Scholar HOIPHOIP (RNF31)612487AR-CPUbiquitousFibroblasts,EBV-B cells,PBMCsImpaired linear ubiquitination and NF-κB activation in fibroblasts Impaired CD40 activation in B cells. Enhanced response to IL-1β in monocytes.Lymphopenia, antibody deficiency and impaired distribution and function of T lymphocytesRecurrent viral and bacterial infectionsMultiorgan autoinflammation, chronic diarrhea, subclinical amylopectinosis, systemic lymphangiectasiaYes1NA201519Boisson B. Laplantine E. Dobbs K. Cobat A. Tarantino N. Hazen M. et al.Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia.J Exp Med. 2015; 212: 939-951Crossref PubMed Scopus (64) Google ScholarDefects of phagocytes VPS45 (SCN5)VPS45610035/615285AR-CPBroadly expressedLymphoblasts, fibroblasts, platelets, neutrophils, bone marrow myeloid cellsImpaired cell migration, increased apoptosis, loss of lysosomesLoss of α-granules in plateletsSCN, G-CSF treatment resistantPlatelet dysfunction, thrombocytopenia, progressive anemiaInvasive pyogenic bacterial and fungal infections of airways, skin, and urinary tract; sepsisExtramedullar hematopoiesis, bone marrow fibrosis, nephromegaly, hepatosplenomegaly, neurological involvementNo13HSCT201320Vilboux T. Lev A. Malicdan M.C. Simon A.J. Jarvinen P. Racek T. et al.A congenital neutrophil defect syndrome associated with mutations in VPS45.N Engl J Med. 2013; 369: 54-65Crossref PubMed Scopus (50) Google Scholar, 21Stepensky P. Saada A. Cowan M. Tabib A. Fischer U. Berkun Y. et al.The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy.Blood. 2013; 121: 5078-5087Crossref PubMed Scopus (0) Google Scholar JAGN1 (SCN6)JAGN1616012/616022AR-CPUbiquitousNeutrophilsUltrastructural defects, few granules, aberrant glycosylation of G-CSF receptor, increased apoptosisSCN, mostly G-CSF treatment resistantPyogenic bacterial infections of airways and skin; sepsisMyeloid maturation arrest, osteopenia, teeth abnormalities, facial dysmorphisms, short stature, pancreatic insufficiencyNo16G-CSFHSCT201422Boztug K. Jarvinen P.M. Salzer E. Racek T. Monch S. Garncarz W. et al.JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia.Nat Genet. 2014; 46: 1021-1027Crossref PubMed Scopus (43) Google Scholar G-CSF receptor (SCN7)CSF3R138971/617014AR-CPGranulocytes, placenta, and other tissuesPBMCsImpaired glycosylation, expression at the cell surface, and functionSCN, G-CSF treatment resistantPyogenic bacterial infections of airways, skin, and urinary tractNANo5GM-CSF201423Triot A. Jarvinen P.M. Arostegui J.I. Murugan D. Kohistani N. Dapena Diaz J.L. et al.Inherited biallelic CSF3R mutations in severe congenital neutropenia.Blood. 2014; 123: 3811-3817Crossref PubMed Scopus (26) Google Scholar SMARCD2 (SGD2)SMARCD2601736/617475AR-CPHematopoietic progenitor cellsHematopoietic progenitor cellsMyeloid differentiation defects, defect of granulopoiesis, and neutrophil granule scarcityNeutropenia, neutrophil-specific granule deficiency, granulocyte maturation arrestSevere recurrent bacterial infections, sepsis, and parasitic infectionsDevelopmental delay, skeletal anomalies, dysmorphic features, delayed separation of umbilical cord, progressive myelofibrosis and MDS, chronic diarrheaNo4HSCT201724Witzel M. Petersheim D. Fan Y. Bahrami E. Racek T. 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