Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification

Aziz Bousfiha 1 2, Leila Jeddane 3, Capucine Picard 4 5, Waleed Al-Herz 6, Fatima Ailal 7, Talal Chatila 8, Charlotte Cunningham-Rundles 9, Amos Etzioni 10, Jose Luis Franco 11, Steven M Holland 12, Christoph Klein 13, Tomohiro Morio 14, Hans D Ochs 15, Eric Oksenhendler 16, Jennifer Puck 17, Troy R Torgerson 15, Jean-Laurent Casanova 18 19 20 21, Kathleen E Sullivan 22, Stuart G Tangye 23 24

Affiliations

01 January 2020

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doi: 10.1007/s10875-020-00758-x

Abstract

Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.

Keywords: IUIS; autoinflammatory disorders; classification; immune dysregulation; inborn errors of immunity; primary immune deficiency.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1 Immunodeficiencies affecting cellular and humoral immunity. a Severe combined immunodeficiencies defined by T cell lymphopenia. b Combined immunodeficiencies. * T cell lymphopenia in SCID is defined by CD3+ T cells < 300/μL. AD autosomal dominant transmission, ADA adenosine deaminase, Adp adenopathies, Ag antigen, AR autosomal recessive transmission, β2m bêta-2 microglobulin, Bc B cells, CBC complete blood count, CD cluster of differentiation, CVID common variable immunodeficiency, def deficiency, EBV Epstein-Barr virus, Eo eosinophilia, GOF gain-of-function mutation, HHV8 human herpes virus 8, HIGM hyper IgM syndrome, HPV human papillomavirus, HSM hepatosplenomegaly, Ig immunoglobulins, MHC major histocompatibility complex, Nl normal, NK natural killer, SCID severe combined immunodeficiency, Tc T cells, TCR T cell receptor, Treg regulatory T cells, XL X-linked transmission

Fig. 1 Immunodeficiencies affecting cellular and humoral immunity. a Severe combined immunodeficiencies defined by T cell lymphopenia. b Combined immunodeficiencies. * T cell lymphopenia in SCID is defined by CD3+ T cells < 300/μL. AD autosomal dominant transmission, ADA adenosine deaminase, Adp adenopathies, Ag antigen, AR autosomal recessive transmission, β2m bêta-2 microglobulin, Bc B cells, CBC complete blood count, CD cluster of differentiation, CVID common variable immunodeficiency, def deficiency, EBV Epstein-Barr virus, Eo eosinophilia, GOF gain-of-function mutation, HHV8 human herpes virus 8, HIGM hyper IgM syndrome, HPV human papillomavirus, HSM hepatosplenomegaly, Ig immunoglobulins, MHC major histocompatibility complex, Nl normal, NK natural killer, SCID severe combined immunodeficiency, Tc T cells, TCR T cell receptor, Treg regulatory T cells, XL X-linked transmission

Fig. 1 Immunodeficiencies affecting cellular and humoral immunity. a Severe combined immunodeficiencies defined by T cell lymphopenia. b Combined immunodeficiencies. * T cell lymphopenia in SCID is defined by CD3+ T cells < 300/μL. AD autosomal dominant transmission, ADA adenosine deaminase, Adp adenopathies, Ag antigen, AR autosomal recessive transmission, β2m bêta-2 microglobulin, Bc B cells, CBC complete blood count, CD cluster of differentiation, CVID common variable immunodeficiency, def deficiency, EBV Epstein-Barr virus, Eo eosinophilia, GOF gain-of-function mutation, HHV8 human herpes virus 8, HIGM hyper IgM syndrome, HPV human papillomavirus, HSM hepatosplenomegaly, Ig immunoglobulins, MHC major histocompatibility complex, Nl normal, NK natural killer, SCID severe combined immunodeficiency, Tc T cells, TCR T cell receptor, Treg regulatory T cells, XL X-linked transmission

Fig. 1 Immunodeficiencies affecting cellular and humoral immunity. a Severe combined immunodeficiencies defined by T cell lymphopenia. b Combined immunodeficiencies. * T cell lymphopenia in SCID is defined by CD3+ T cells < 300/μL. AD autosomal dominant transmission, ADA adenosine deaminase, Adp adenopathies, Ag antigen, AR autosomal recessive transmission, β2m bêta-2 microglobulin, Bc B cells, CBC complete blood count, CD cluster of differentiation, CVID common variable immunodeficiency, def deficiency, EBV Epstein-Barr virus, Eo eosinophilia, GOF gain-of-function mutation, HHV8 human herpes virus 8, HIGM hyper IgM syndrome, HPV human papillomavirus, HSM hepatosplenomegaly, Ig immunoglobulins, MHC major histocompatibility complex, Nl normal, NK natural killer, SCID severe combined immunodeficiency, Tc T cells, TCR T cell receptor, Treg regulatory T cells, XL X-linked transmission

Fig. 2 a, b CID with associated or syndromic features. Ab antibody, AD autosomal dominant transmission, AD DN autosomal dominant transmission with dominant negative effect, ANA anti-nuclear antibodies, ANCA anti-neutrophil cytoplasm antibodies, AR autosomal recessive transmission, Bc B cells, BCG bacillus Calmette-Guerin, BCR B cell receptor, CD cluster of differentiation, CID combined immunodeficiency of T and B cells, CMV cytomegalovirus, CNS central nervous system, def deficiency, DNA deoxyribonucleic acid, EBV Epstein-Barr virus, EDA anhidrotic ectodermal dysplasia, GOF gain-of-function, HIES hyper IgE syndrome, FILS facial dysmorphism, immunodeficiency, livedo and short stature, ID immunodeficiency, Ig immunoglobulins, IL-6 interleukin-6, IUGR intrauterine growth retardation, LOF loss-of-function, MCC mucocutaneous candidiasis, Nl normal, NK natural killer, PHA phytohemagglutinin, PPS polysaccharides, SCID severe combined immunodeficiency, sd syndrome, Tc T cells, TCR T cell receptor, TREC T cell receptor excision circle, XL X-linked transmission

Fig. 2 a, b CID with associated or syndromic features. Ab antibody, AD autosomal dominant transmission, AD DN autosomal dominant transmission with dominant negative effect, ANA anti-nuclear antibodies, ANCA anti-neutrophil cytoplasm antibodies, AR autosomal recessive transmission, Bc B cells, BCG bacillus Calmette-Guerin, BCR B cell receptor, CD cluster of differentiation, CID combined immunodeficiency of T and B cells, CMV cytomegalovirus, CNS central nervous system, def deficiency, DNA deoxyribonucleic acid, EBV Epstein-Barr virus, EDA anhidrotic ectodermal dysplasia, GOF gain-of-function, HIES hyper IgE syndrome, FILS facial dysmorphism, immunodeficiency, livedo and short stature, ID immunodeficiency, Ig immunoglobulins, IL-6 interleukin-6, IUGR intrauterine growth retardation, LOF loss-of-function, MCC mucocutaneous candidiasis, Nl normal, NK natural killer, PHA phytohemagglutinin, PPS polysaccharides, SCID severe combined immunodeficiency, sd syndrome, Tc T cells, TCR T cell receptor, TREC T cell receptor excision circle, XL X-linked transmission

Fig. 2 a, b CID with associated or syndromic features. Ab antibody, AD autosomal dominant transmission, AD DN autosomal dominant transmission with dominant negative effect, ANA anti-nuclear antibodies, ANCA anti-neutrophil cytoplasm antibodies, AR autosomal recessive transmission, Bc B cells, BCG bacillus Calmette-Guerin, BCR B cell receptor, CD cluster of differentiation, CID combined immunodeficiency of T and B cells, CMV cytomegalovirus, CNS central nervous system, def deficiency, DNA deoxyribonucleic acid, EBV Epstein-Barr virus, EDA anhidrotic ectodermal dysplasia, GOF gain-of-function, HIES hyper IgE syndrome, FILS facial dysmorphism, immunodeficiency, livedo and short stature, ID immunodeficiency, Ig immunoglobulins, IL-6 interleukin-6, IUGR intrauterine growth retardation, LOF loss-of-function, MCC mucocutaneous candidiasis, Nl normal, NK natural killer, PHA phytohemagglutinin, PPS polysaccharides, SCID severe combined immunodeficiency, sd syndrome, Tc T cells, TCR T cell receptor, TREC T cell receptor excision circle, XL X-linked transmission

Fig. 2 a, b CID with associated or syndromic features. Ab antibody, AD autosomal dominant transmission, AD DN autosomal dominant transmission with dominant negative effect, ANA anti-nuclear antibodies, ANCA anti-neutrophil cytoplasm antibodies, AR autosomal recessive transmission, Bc B cells, BCG bacillus Calmette-Guerin, BCR B cell receptor, CD cluster of differentiation, CID combined immunodeficiency of T and B cells, CMV cytomegalovirus, CNS central nervous system, def deficiency, DNA deoxyribonucleic acid, EBV Epstein-Barr virus, EDA anhidrotic ectodermal dysplasia, GOF gain-of-function, HIES hyper IgE syndrome, FILS facial dysmorphism, immunodeficiency, livedo and short stature, ID immunodeficiency, Ig immunoglobulins, IL-6 interleukin-6, IUGR intrauterine growth retardation, LOF loss-of-function, MCC mucocutaneous candidiasis, Nl normal, NK natural killer, PHA phytohemagglutinin, PPS polysaccharides, SCID severe combined immunodeficiency, sd syndrome, Tc T cells, TCR T cell receptor, TREC T cell receptor excision circle, XL X-linked transmission

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References

  1.  
    1. Tangye SG, Al-Herz W, Bousfiha A,Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol (2020). 10.1007/s10875-019-00737-x - PMC - PubMed
  2.  
    1. Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N, Casanova JL, Abel L. Primary immunodeficiency diseases worldwide: more common than generally thought. J Clin Immunol. 2013;33(1):1–7. doi: 10.1007/s10875-012-9751-7. - DOI - PubMed
  3.  
    1. Bousfiha A, Jeddane L, Picard C, Ailal F, Gaspar HB, Al-Herz W, et al. The 2017 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol. 2018;38(1):129–143. doi: 10.1007/s10875-017-0465-8. - DOI - PMC - PubMed
  4.  
    1. Jeddane L, Ouair H, Benhsaien I, El Bakkouri J, Bousfiha AA. Primary immunodeficiency classification on smartphone. J Clin Immunol. 2017;37(1):1–2. doi: 10.1007/s10875-016-0354-6. - DOI - PubMed
  5.  
    1. Shearer WT, Dunn E, Notarangelo LD, Dvorak CC, Puck JM, Logan BR, et al. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the primary immune deficiency treatment consortium experience. J Allergy Clin Immunol. 2014;133(4):1092–8. - PMC - PubMed

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