, Francisco A. Bonilla4, Mikko Seppänen5, Esther de Vries6, 7, Ahmed Aziz Bousfiha8, 9, Jennifer Puck10 and Jordan Orange11
(1)
Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
(2)
Department of Immunology and Biology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
(3)
Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
(4)
Division of Immunology, Children’s Hospital Boston, Boston, MA, USA
(5)
Adult Primary Immunodeficiency Unit, Rare Disease Center, Infectious Diseases, Inflammation Center, Helsinki University Hospital (HUH), Helsinki, Finland
(6)
Department of Pediatrics & Jeroen Bosch Academy, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands
(7)
Tilburg University, Tilburg, The Netherlands
(8)
Clinical Immunology Unit, Casablanca Children Hospital Ibn Rushd, Casablanca, Morocco
(9)
Faculty of Medicine and Pharmacy, King Hassan II University, Casablanca, Morocco
(10)
Department of Pediatrics, University of California-San Francisco, San Francisco, CA, USA
(11)
Department of Immunology, Allergy and Rheumatology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA
Keywords
Primary immunodeficiency diseasesInfectionsAutoimmunityMalignancies1.1 Definition
1.1.1 Background
The immune system is a complex network of cells and organs which cooperate to protect individual against infectious microorganisms, as well as internally-derived threats such as cancers. The immune system specializes in identifying danger, containing and ultimately eradicating it. It is composed of highly specialized cells, proteins, tissues, and organs. B- and T- lymphocytes, phagocytic cells and soluble factors such as complement are some of the major components of the immune system, and have specific critical functions in immune defense.
When part of the immune system is missing or does not work correctly, immunodeficiency occurs; it may be either congenital (primary) or acquired (secondary). Secondary immunodeficiency diseases are caused by environmental factors such as infection with HIV, chemotherapy, irradiation, malnutrition, and others; while primary immunodeficiency diseases (PIDs) are hereditary disorders, caused by mutations of specific genes.
Primary immunodeficiency diseases are a heterogeneous group of inherited disorders with defects in one or more components of the immune system. These diseases have a wide spectrum of clinical manifestations and laboratory findings; however, in the vast majority of cases, they result in an unusually increased susceptibility to infections and a predisposition to autoimmune diseases and malignancies [44, 82, 83, 120, 214, 218, 251, 278]. Primary immunodeficiencies constitute a large group of diseases, including more than conservatively defined hereditary disorders [14, 120, 218, 278], affecting development of the immune system, its function, or both [24]. The number of known PIDs has been increased considerably over the last two decades, through two lines of research: the genetic dissection of known clinical phenotypes and the investigation of new clinical phenotypes [41, 64, 89, 239, 284]. Some of these clinical phenotypes are more common than traditional PID phenotypes. In particular, new PIDs conferring a specific predisposition to infections with one or a few pathogens have been described [61], including genetic predisposition to EBV [294], Neisseria [142], papillomavirus [228], Streptococcus pneumonia [236], weakly virulent mycobacteria [24, 146], herpes simplex virus [64], and Candida albicans [118]. Mendelian predisposition to tuberculosis has even been reported [114, 296]. In addition, various non-infectious phenotypes, as diverse as allergy, angioedema, hemophagocytosis, autoinflammation, autoimmunity, thrombotic microangiopathy and cancer, have been shown to result from inborn errors of immunity, in at least some patients [61]. Although the number of patients diagnosed with PIDs is growing, many physicians still know little about these disorders. Thus, many patients are diagnosed late; many cases suffer from complications by chronic infections, irretrievable end-organ damage, or even death before the definitive diagnosis is made. Timely diagnosis and appropriate treatment remain the keys to the successful management of patients with PIDs [68, 136, 246].
1.1.2 History
The birth of the primary immunodeficiency field is attributed to Col. Ogden Bruton in 1952, who reported a male patient with early onset recurrent infections and an absent gammaglobulin peak on serum protein electrophoresis. This child had an excellent response to immunoglobulin replacement therapy [53]; later, the condition ultimately became known as X-linked agammaglobulinemia (XLA) or Btk (Bruton’s tyrosine kinase) deficiency. However, several patients with characteristic clinical manifestations of immunodeficiency disorders had been reported before 1950; e.g. Ataxia-telangiectasia (AT) in 1926 [283], chronic mucocutaneous candidiasis (CMCC) in 1929 [288], and Wiskott-Aldrich syndrome (WAS) in 1937 [315]. The first patient with cellular deficiency was initially reported in 1950 [124], the first case of a phagocytic defect (severe congenital neutropenia: SCN) was reported in 1956 [155], and the first case of complement deficiency (C2 deficiency) was initially reported in 1966 [154].
The discovery of PIDs and characterization of these diseases led to crucial contributions to understanding the functional organization of the immune system and molecular biology. Thus, the study of PIDs has contributed to progress in immunological and molecular diagnostic techniques. These advances enabled increased recognition and characterization of new types of PIDs, and identification of about 300 different types of PIDs in the ensuing years (Tables 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, and 1.8) [235].
Diseases | Inheritance | Genetic defects | |
|---|---|---|---|
T-B+ Severe combined immunodeficiency | γc deficiency | XL | IL-2 receptor gamma (IL2RG) |
JAK3 deficiency | AR | Janus-associated kinase 3 (JAK3) | |
IL7–Rα deficiency | AR | IL-7 receptor (IL7–R) alpha | |
CD45 deficiency | AR | Leukocyte-common antigen (LCA) or CD45 | |
CD3γ deficiency | AR | T-cell antigen receptor, Gamma subunit of T3 (CD3G) | |
CD3δ deficiency | AR | T-cell antigen receptor, Delta subunit of T3 (CD3D) | |
CD3ε deficiency | AR | T-cell antigen receptor, Epsilon subunit of T3 (CD3E) | |
CD3ξ deficiency | AR | T-cell antigen receptor, Zeta subunit of T3 (CD3Z) or CD247 | |
Coronin–1A deficiency | AR | Coronin 1A (CORO1A) | |
T-B− Severe combined immunodeficiency | RAG 1 deficiency | AR | Recombination-activating gene 1 (RAG1) |
RAG 2 deficiency | AR | Recombination-activating gene 2 (RAG2) | |
Artemis deficiency | AR | Artemis or DNA cross-link repair protein 1C (DCLRE1C) | |
DNA PKcs deficiency | AR | Protein kinase, DNA-activated catalytic subunit (PRKDC) | |
DNA ligase IV deficiency | AR | DNA ligase IV (LIG4) | |
Cernunnos/XLF deficiency | AR | Nonhomologous end-joining 1 (NHEJ1) or CERNUNNOS | |
Omenn syndrome | AR | RAG1/2, DCLRE1C, LIG4, IL2RG, IL7–R, ADA, AK2, RMRP | |
Purine salvage pathway defects | ADA deficiency | AR | Adenosine deaminase (ADA) |
Purine nucleoside phosphorylase (PNP) deficiency | AR | Purine nucleoside phosphorylase (PNP) | |
Reticular dysgenesis | AK2 deficiency | AR | Adenylate kinase 2 (AK2) |
DOCK2 deficiency | AR | Dedicator of Cytokinesis 2 (DOCK2) | |
Immunoglobulin class switch recombination deficiencies affecting CD40-CD40L | CD40 ligand deficiency | XL | Tumor necrosis factor ligand superfamily, member 5 (TNFS5B) or CD40 antigen ligand (CD40L) |
CD40 deficiency | AR | Tumor necrosis factor receptor superfamily, member 5 (TNFRSF5) | |
Complete DiGeorge syndrome | De novo, AD | 22q.11.2 deletion, T-box 1 (TBX1) | |
CHARGE syndrome | CHD7 deficiency | AD | Chromodomain helicase DNA-binding protein 7 (CHD7) |
SEMA3E deficiency | AD | Semaphorin 3E (SEMA3E) | |
Combined immunodeficiency with alopecia totalis | WHN deficiency | AR | Winged-helix-nude (WHN) or Forkhead box N1 (FoxN1) |
Immuno-osseous dysplasias | Schimke syndrome | AR | SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A-like (SMARCAL1) |
Cartilage hair hypoplasia | AR | RNA component of mitochondrial RNA-processing endoribonuclease (RMRP) | |
Combined immunodeficiency with intestinal atresias | TTC7A deficiency | AR | Tetratricopeptide repeat domain.containing protein 7A (TTC7A) |
MHC class II deficiency | CIITA deficiency | AR | Class II transactivator (CIITA) |
RFX5 deficiency | AR | MHCII promoter X box regulatory factor 5 (RFX5) | |
RFXAP deficiency | AR | Regulatory factor X-associated protein (RFXAP) | |
RFXANK deficiency | AR | Ankyrin repeat containing regulatory factor X-associated protein (RFXANK) | |
MHC class I deficiency | TAP1 deficiency | AR | Transporter associated with antigen processing 1 (TAP1) |
TAP2 deficiency | AR | Transporter associated with antigen processing 2 (TAP2) | |
TAPBP deficiency | AR | Tap-binding protein (TAPBP) | |
β2–microglobulin deficiency | Beta-2 microglobulin (B2M) | ||
CD8 deficiency | ZAP–70 deficiency | AR | Zeta-chain-associated protein of 70 kd signaling kinase (ZAP70) |
CD8α chain defect | AR | CD8 antigen, alpha polypeptide (CD8A) | |
Lck deficiency | AR | Lymphocyte-specific protein-tyrosine kinase (LCK) | |
Idiopathic CD4 lymphocytopenia | Variable | Unknown | |
TCRα deficiency | AR | T-cell receptor alpha chain constant region (TRAC) | |
CRAC channelopathy | ORAI–I deficiency | AR | ORAI1 or Calcium release-activated calcium modulator 1 (CRACM1) or Transmembrane protein 142A (TMEM142A) |
STIM–1 deficiency | AR | Stromal interaction molecule 1 (STIM1) | |
STK4 deficiency | MST1 deficiency | AR | Macrophage stimulating 1 (MST1) |
CARD11/BCL10/MALT1 (CBM) complex deficiencies | AR | Caspase recruitment domain-containing protein 11 (CARD11), B-cell CLL/lymphoma 10 (BCL10), Mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) | |
RHOH deficiency | AR | Ras homolog gene family, member H (RHOH) | |
OX40 deficiency | AR | Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4 or OX40) | |
IL21/IL21R deficiency | IL21 deficiency | AR | Interleukin 21 (IL21) |
IL21R deficiency | AR | Interleukin 21 receptor (IL21R) | |
IKAROS deficiency | AD de novo | Family zinc finger (IKZF) | |
IKK2 deficiency | IKBKB deficiency | AR | Inhibitor of kappa light chain gene enhancer in B cells, kinase of, beta (IKBKB) |
NIK deficiency | AR | Mitogen-activated protein 3 kinase 14 (MAP3K14) | |
CTPS1 deficiency | AR | Cytidine 5-prime triphosphate synthetase 1 (CTPS1) | |
Other combined immunodeficiencies | DOCK8 deficiency | AR | Dedicator of cytokinesis 8 (DOCK8) |
ITK deficiency | AR | IL2-inducible T-cell kinase (ITK) | |
MAGT1 deficiency | XL | Magnesium transporter 1 (MAGT1) | |
CD25 deficiency | AR | Interleukin 2 receptor, alpha (IL2RA) or CD25 | |
STAT5b deficiency | AR | Signal transducer and activator of transcription 5B (STAT5B) | |
MTHFD1 deficiency | AR | Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) | |
ICOS deficiency | AR | Inducible costimulator (ICOS) | |
LRBA deficiency | AR | Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) |
Diseases | Inheritance | Genetic defects | |
|---|---|---|---|
X-linked agammaglobulinemia | Btk deficiency | XL | Bruton tyrosine kinase (BTK) |
Autosomal recessive agammaglobulinemia | μ heavy chain deficiency | AR | Ig heavy mu chain (IGHM) |
λ5 deficiency | AR | Immunoglobulin lambda-like polypeptide 1 (IGLL1) | |
Igα deficiency | AR | CD79A antigen (CD79A) | |
Igβ deficiency | AR | CD79B antigen (CD79B) | |
BLNK deficiency | AR | B cell liker protein (BLNK) or SH2 domain containing leukocyte protein, 65-KD (SLP65) | |
Other forms of agammaglobulinemia with absent B-cells | TCF3 deficiency | AD | Transcription factor 3 (TCF3) |
LRRC8 deficiency | AD | Leucine-rich repeat-containing protein 8 (LRRC8) | |
Other forms of agammaglobulinemia | Variable | Unknown | |
PI3K syndrome | AR, AD gain-of- function | Phosphatidylinositol 3-kinase, catalytic, delta (PIK3CD), Phosphatidylinositol 3-kinase, regulatory subunit 1 (PIK3R1) | |
Common variable immunodeficiency | Variable | Unknown | |
LRBA deficiency | AR | Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) | |
CD19 complex deficiencies | CD19 deficiency | AR | CD19 antigen (CD19) |
CD21 deficiency | AR | Complement component receptor 2 (CR2 or CD21) | |
CD81 deficiency | AR | CD81 antigen (CD81) | |
CD20 deficiency | AR | Membrane-spanning 4 domains, subfamily A, member 1 (MS4A1 or CD20) | |
Other monogenic defects associated with hypogammaglobulinemia | ICOS deficiency | AR | Inducible costimulator (ICOS) |
TACI deficiency | AD or AR | Tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) | |
BAFF receptor deficiency | AR | Tumor necrosis factor receptor superfamily, member 13C (TNFRSF13C or BAFFR) | |
TWEAK deficiency | AD | Tumor necrosis factor ligand superfamily, member 12 (TNFSF12 or TWEAK) | |
NFKB2 deficiency | AD | Nuclear factor kappa-b, subunit 2 (NFKB2) | |
MOGS deficiency | AR | Mannosyl-oligosaccharide glycosidase (MOGS) | |
TRNT1 deficiency | AR | tRNA nucleotidyltransferase CCA-adding, 1 (TRNT1) | |
TTC37 deficiency | AR | Tetratricopeptide repeat domain-containing protein 37 (TTC37) | |
Immunoglobulin class switch recombination deficiencies affecting B-cells | AICDA deficiency | AR | Activation-induced cytidine deaminase (AICDA) |
UNG deficiency | AR | Uracil-DNA glycosylase (UNG) | |
MMR deficiency | AR | MutS E. coli homolog of 6 (MSH6) | |
INO80 deficiency | AR | INO80 complex subunit (INO80) | |
Selective IgA deficiency | Variable | Unknown | |
Other immunoglobulin isotypes or light chain deficiencies | Isolated IgG subclass deficiency | Variable | Unknown |
IgA with IgG subclass deficiency | Variable | Unknown | |
Ig heavy chain mutations/deletions | AR | Chromosomal deletion at 14q32 | |
k light chain deficiency | AR | Ig kappa constant region (IGKC) | |
Specific antibody deficiency with normal immunoglobulin concentrations | Variable | Unknown | |
Transient hypogammaglobulinemia of infancy | Variable | Unknown |
Diseases | Inheritance | Genetic defects | |
|---|---|---|---|
Chronic granulomatous disease | gp91 phox deficiency | XL | Cytochrome b(−245), beta subunit (CYBB) |
p22 phox deficiency | AR | Cytochrome b(−245), alpha subunit (CYBA) | |
p47 phox deficiency | AR | Neutrphil cytosolic factor 1 (NCF1) | |
p67 phox deficiency | AR | Neutrophil cytosolic factor 2 (NCF2) | |
p40 phox deficiency | AR | Neutrophil cytosolic factor 2 (NCF4) | |
Leukocyte adhesion deficiency | ITGB2 or CD18 deficiency | AR | Integrin, beta-2 (ITGB2) |
SCL35C1 or CDG–IIc deficiency | AR | Solute carrier family 35, member C1 (SLC35C1) or GDP-fucose transporter 1 (FUCT1) | |
FERMT3 or Kindlin3 deficiency | AR | Fermitin family (Drosophila) homolog 3 (FERMT3) | |
RAC-2 deficiency | AD | Ras-related C3 botulinum toxin substrate 2 (RAC2) | |
β-Actin deficiency | AD | Actin, beta (ACTB) | |
Localized juvenile periodontitis | AR | Formyl peptide receptor 1 (FRP1) | |
Papillon-Lefèvre syndrome | AR | Cathepsin c (CTSC) | |
Specific granule deficiency | AR | CCAAT/enhancer-binding protein, epsilon (CEBPE) | |
Shwachman-Diamond syndrome | AR | Shwachman-Bodian-Diamond syndrome (SBDS) | |
Severe congenital neutropenias | ELANE deficiency | AD | Elastase, neutrophil-expressed (ELANE) |
GFI1 deficiency | AD | Growth factor-independent 1 (GFI1) | |
HAX1 deficiency | AR | HCLS1-associated protein X1 (HAX1) | |
G6PC3 deficiency | AR | Glucose-6-phosphatase, catalytic, 3 (G6PC3) | |
VPS45 deficiency | AR | Vacuolar protein sorting 45, yeast, homolog of, A (VPS45A) | |
X–linked neutropenia | XL | Wiskott-Aldrich syndrome protein (WASP) | |
p14 deficiency | AR | Late endosomal/lysosomal adaptor, MAPK and MTOR activator 2 (LAMTOR2) | |
JAGN1 deficiency | AR | Jagunal, drosophila, homolog of, 1 (JAGN1) | |
G–CSF receptor deficiency | AR | Colony-stimulating factor 3 receptor, granulocyte (CSF3R) | |
Cyclic neutropenia | AD | Elastase, neutrophil-expressed (ELANE) | |
Glycogen storage disease type 1b | AR | Glucose-6-phosphatase transporter 1 (G6PT1 or SLC37A4) | |
3-Methylglutaconic Aciduria | Type II (Barth syndrome) | XL | Tafazzin (TAZ) |
Type VII | AR | Caseinolytic peptidase B (CLPB) | |
Cohen syndrome | AR | Vacuolar protein sorting 13, yeast, homolog of, B (VPS13B or COH1) | |
Poikiloderma with neutropenia | AR | Chromosome 16 open reading frame 57 (C16ORF57) | |
Myeloperoxidase deficiency | AR | Myeloperoxidase (MPO) |
Diseases | Inheritance | Genetic defects | |
|---|---|---|---|
Familial hemophagocytic lymphohistiocytosis | Perforin deficiency | AR | Perforin 1 (PRF1) |
UNC13D deficiency | AR | MUNC13–4 or UNC13D | |
Syntaxin 11 deficiency | AR | Syntaxin 11 (STX11) | |
STXBP2 deficiency | AR | Syntaxin-bnding protein 2 (STXBP2) | |
Autoimmune lymphoproliferative syndrome | FAS defect | AD, AR | Tumor necrosis factor receptor superfamily, member 6 (TNFRSF6) or CD95 or FAS |
FASLG defect | AR | Tumor necrosis factor ligand superfamily, member 6 (TNFSF6) or CD95L or FASL | |
CASP10 deficiency | AD | Caspase 10, apoptosis-related cysteine protease (CASP10) | |
CASP8 deficiency state | AR | Caspase 8, apoptosis-related cysteine protease (CASP8) | |
RAS–associated autoimmune leukoproliferative disease | AD | Unknown, Neuroblastome RAS viral oncogene homolog (NRAS) | |
FADD deficiency | AR | FAS-associated via death domain (FADD) | |
CTLA4 deficiency | AD | Cytotoxic T lymphocyte-associated 4 (CTLA4) | |
Chediak-Higashi syndrome | AR | Lysosomal trafficking regulator (LYST) | |
Griscelli syndrome, type 2 | AR | Ras-associated protein rab27a (RAB27A) | |
Hermansky-Pudlak syndrome | HPS type 2 | AR | Adaptor-related protein complex 3, beta-1 subunit (AP3B1) |
HPS type 9 | AR | Biogenesis of lysosome-related organelles complex 1, subunit 6 (BLOC1S6) | |
HPS10 | AR | Adaptor-related protein complex 3, delta-1 subunit (AP3D1) | |
Other immunodeficiencies associated with hypopigmentation | p14 deficiency | AR | MAPBP-interacting protein (MAPBPIP) or P14 |
Vici syndrome | AR | Ectopic P-granules autophagy protein 5, C. elegans, homolog of (EPG5) | |
X-linked lymphoproliferative syndromes | SAP deficiency | XL | src homology 2-domain protein (SH2D1A) |
XIAP deficiency | XL | Inhibitor-of-apotosis, X-linked (XIAP) or Baculoviral IAP repeat-containing protein 4 (BIRC4) | |
MAGT1 deficiency | XL | Magnesium transporter 1 (MAGT1) | |
Autosomal recessive lymphoproliferative syndromes | ITK deficiency | AR | IL2-inducible T-cell kinase (ITK) |
CD27 deficiency | AR | Tumor necrosis factor receptor superfamily, member 7 (TNFRSF7 or CD27) | |
Immunodysregulation, polyendocrinopathy, enteropathy, X-linked | IPEX | XL | Forkhead box P3 (FOXP3) |
CD25 deficiency | AR | Interleukin 2 receptor, alpha (IL2RA) or CD25 | |
STAT5B deficiency | AR | Signal transducer and activator of transcription 5B (STAT5B) | |
ITCH deficiency | AR | Itchy E3 ubiquitin protein ligase, mouse, homolog of (ITCH) | |
TPP2 deficiency | AR | Tripeptidyl peptidase II (TPP2) | |
COPA deficiency | AD | Coatamer Protein Complex, Subunit Alpha (COPA) |
Table 1.5
Modified IUIS classification of defects in intrinsic and innate immunity: receptors and signaling components [235]
Diseases | Inheritance | Genetic defects | |
|---|---|---|---|
Anhidrotic ectodermal dysplasia with immunodeficiency | NEMO deficiency | XL | Inhibitor of kappa light polypeptide gene enhancer in B cells, kinase of, gamma (IKBKG) or NF-kappa-B essential modulator (NEMO) |
IkBA gain–of–function mutations | AD | Inhibitor of kappa light polypeptide gene enhancer in B cells, kinase of, alpha (IKBA) | |
HOIL1 and HOIP deficiencies | HOIL1 deficiency | AR | Heme-oxidized IRP2 ubiquitin ligase 1 (HOIL1) |
HOIP deficiency | AR | HOIL1-interacting protein (HOIP) | |
IRAK-4 and MyD88 deficiencies | IRAK–4 deficiency | AR | Interleukin 1 receptor-associated kinase 4 (IRAK4) |
MyD88 deficiency | AR | Myeloid differentiation primary response gene 88 (MYD88) | |
Herpes simplex encephalitis | TLR3 deficiency | AD | Toll-like receptor 3 (TLR3) |
UNC93B deficiency | AR | UNC–93B | |
TRAF3 deficiency | AD | TNF receptor-associated factor 3 (TRAF3) | |
TRIF deficiency | AR, AD | Testis-specific ring finger protein (TRIF) | |
TBK1 deficiency | AD | Tank-binding kinase 1 (TBK1) | |
IRF3 deficiency | AD | Interferon regulatory factor 3 (IRF3) | |
Mendelian susceptibility to mycobacterial diseases | IFN–γ receptor 1 deficiency | AR, AD | Interferon, gamma, receptor 1 (IFNGR1) |
IFN–γ receptor 2 deficiency | AR, AD | Interferon, gamma, receptor 2 (IFNGR2) | |
IL–12/IL–23 receptor β1 chain deficiency | AR | Interleukin 12 receptor, beta-1 (IL12RB1) | |
IL–12p40 deficiency | AR | Interleukin 12B (IL12B) | |
DP–STAT1 deficiency | AR, AD | Signal transducer and activator of transcription 1 (STAT1) | |
LZ–NEMO deficiency | XL | NF-kappa-B essential modulator (NEMO) | |
Macrophage–specific CYBB deficiency | XL | Cytochrome b(−245), beta subunit (CYBB) | |
AD–IRF8 deficiency | AD | Interferon regulatory factor 8 (IRF8) | |
ISG15 deficiency | AR | Ubiquitin-like modifier ISG15 (ISG15) | |
Genetic defects of interferon type I and III responses other than TLR3 pathway | AR STAT1 deficiency | AR | Signal transducer and activator of transcription 1 (STAT1) |
STAT2 deficiency | AR | Signal transducer and activator of transcription 2 (STAT2) | |
TYK2 deficiency | AR | Protein-tyrosin kinase 2 (TYK2) | |
IRF7 deficiency | AR | Interferon regulatory factor 7 (IRF7) | |
Warts, hypogammaglobulinemia infections, myelokathexis (WHIM) syndrome | AD | Chemokine, CXC motif, receptor 4 (CXCR4) | |
Epidermodysplasia verruciformis | EVER1 deficiency | AR | Epidermodysplasia verruciformis gene 1 (EVER1) |
EVER2 deficiency | AR | Epidermodysplasia verruciformis gene 2 (EVER2) | |
Chronic mucocutaneous candidiasis | IL17RA deficiency | AR | Interleukin 17 receptor A (IL17RA) |
IL17F deficiency | AD | Interleukin 17 F (IL17F) | |
IL17RC deficiency | AR | Interleukin 17 receptor C (IL17RC) | |
STAT1 gain–of–function mutation | AD | Signal transducer and activator of transcription 1 (STAT1) | |
ACT1 deficiency | AR | Nuclear factor kappa-B activator 1 (ACT1) | |
CARD9 deficiency | AR | Caspase recruitment domain-containing protein 9 (CARD9) | |
Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy | AR | Autoimmune regulator (AIRE) | |
RORC deficiency | AR | RAR-related orphan receptor C (RORC) | |
Monocyte/dendritic cell deficiencies | AD GATA2 deficiency | AD | GATA-binding protein 2 (GATA2) |
AR IRF8 deficiency | AR | Interferon regulatory factor 8 (IRF8) | |
NK cell deficiencies | MCM4 deficiency | AR | Minichromosome maintenance complex component 4 (MCM4) |
Pulmonary alveolar proteinosis | AR | Colony-stimulating factor 2 receptor, alpha (CSF2RA) | |
AR | Colony-stimulating factor 2 receptor, beta (CSF2RB) | ||
Isolated congenital asplenia | AD | NK2 homeobox 5 (NKX2–5) | |
AD | Ribosomal protein SA (RPS) |
Diseases | Inheritance | Genetic defects | |
|---|---|---|---|
Familial mediterranean fever | AR | Mediterranean fever (MEFV) | |
Mevalonate kinase deficiency | Hyper–IgD and periodic fever syndrome | AR | Mevalonate kinase (MVK) |
Mevalonic aciduria | AR | Mevalonate kinase (MVK) | |
TNF receptor-associated periodic syndrome | AD | Tumor necrosis factor receptor superfamily, member 1a (TNFRSF1A) | |
Cryopyrin-associated periodic syndrome | Chronic infantile neurological cutaneous articular syndrome | AD | NLR family, pyrin domain containing 3 (NLRP3) or Cias1 gene (CIAS1) or Nacht domain-, leucine-rich repeat-, and pyd-containing protein 3 (NALP3) or Pyrin domain- containing APAF1-like protein 1 (PYPAF1) |
Muckle–Wells syndrome | AD | ||
Familial cold autoinflammatory syndrome | AD | ||
Blau syndrome | Pediatric granulomatous arthritis | AD | Caspase recruitment domain-containing protein 15 (CARD15) or Nucleotide-binding oligomerization domain protein 2 (NOD2) |
Pyogenic arthritis, pyoderma gangrenosum and acne syndrome | AD | Proline/Serine/Threonine phosphatase-interacting protein 1 (PSTPIP1) or CD2 antigen-binding protein 1 (CD2BP1) | |
NLRP12 associated periodic fever syndrome | AD | Nacht domain-, leucine-rich repeat-, and pyd-containing protein 12 (NLRP12) | |
Deficiency of ADA2 | AR | Cat eye syndrome chromosome region, candidate 1 (CECR1) | |
STING-associated vasculopathy with onset in infancy | AD | Transmembrane protein 173 (TMEM173) | |
Deficiency of the IL-1 receptor antagonist | AR | Interleukin 1 receptor antagonist (IL1RN) | |
Majeed syndrome | AR | Lipin 2 (LPIN2) | |
Deficiency of IL-36 receptor antagonist | AR | Interleukin 36 receptor antagonist (IL36RN) | |
Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature | AR | Proteasome subunit beta type 8 (PSMB8) | |
Early onset inflammatory bowel diseases | IL–10 deficiency | AR | Interleukin 10 (IL10) |
IL–10Rα deficiency | AR | Interleukin 10 receptor alpha (IL10RA) | |
IL–10Rβ deficiency | AR | Interleukin 10 receptor beta (IL10RB) | |
NFAT5 haploinsufficiency | AD | Nuclear factor of activated T cells 5 (NFAT5) | |
ADAM17 deficiency | AR | A disintegrin and metalloproteinase domain 17 (ADAM17) | |
Autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation | AD | Phospholipase Cγ2 (PLCG2) | |
Sideroblastic anemia, immunodeficiency, fevers, and developmental delay | AR | tRNA nucleotidyl transferase, CCA-adding, 1 (TRNT1) | |
Aicardi-Goutieres syndromes (AGS) | AGS1 | AR, AD | Three prime repair exonuclease 1 (TREX1) |
AGS2 | AR | Ribonuclease H2 subunit A (RNASEH2A) | |
AGS3 | AR | Ribonuclease H2 subunit B (RNASEH2B) | |
AGS4 | AR | Ribonuclease H2 subunit C (RNASEH2C) | |
AGS5 | AR | SAM domain and HD domain 1 (SAMHD1) | |
AGS6 | AR | Adenosine deaminase, RNA-specific (ADAR) | |
AGS7 | AD | Interferon induced with helicase C domain 1 (IFIH1) | |
CARD14 mediated psoriasis | AD | Caspase recruitment domain family member 14 (CARD14) | |
Haploinsufficiency of A20 (HA20) | AR | TNF alpha induced protein 3 (TNFAIP3) | |
Episodic fevers, enteropathy, and MAS due to NLRC4 hyperactivity | AD | NLR family, CARD domain containing 4 (NLRC4). | |
TNFRSF11A-associated disease | AD | Tumor necrosis factor receptor superfamily member 11a (TNFRSF11A) | |
Histiocytosis-lymphadenopathy plus syndrome | AD | Soluble carrier family 29, member 3 (SLC29A3) | |
Cherubism | AD | SH3 domain-binding protein 2 (SH3BP2) | |
Spondyloenchondro-dysplasia with immune dysregulation | AD | Phosphatase, acid, type 5, tartrate-resistant (ACP5) |
Diseases | Inheritance | Genetic defects | |
|---|---|---|---|
Deficiencies of classical pathway components | C1q deficiency | AR | Complement component 1, q subcomponent, alpha, beta and gamma polypeptides (C1QA, C1QB, C1QG) |
C1r deficiency | AR | Complement component C1R | |
C1s deficiency | AR | Complement component 1, s subcomponent (C1S) | |
C4 deficiency | AR | Complement component 4A and 4B (C4A, C4B) | |
C2 deficiency | AR | Complement component 2 | |
Deficiencies of lectin pathway components | MBL deficiency | AR | Lectin, mannose-binding, soluble, 2 (MBL2) or Mannose-binding protein, Serum (MBP1) |
MASP–2 deficiency | AR | Mannan-binding lectin serine protease 2 (MASP2) | |
MASP–3 deficiency | AR | Mannan-binding lectin serine protease 1 (MASP1) | |
Ficolin 3 deficiency | AR | Ficolin 3 (FCN3) | |
Collectin 11 deficiency | AR | Collectin 11 (COLEC11) | |
Deficiencies of alternative pathway components | Factor D deficiency | AR | Complement factor D (CFD) |
Properdin deficiency | XL | Properdin P factor, complement (PFC) | |
Deficiency of complement component C3 | AR | Complement component 3 (C3) | |
Deficiencies of terminal pathway components | C5 deficiency | AR | Complement component 5 |
C6 deficiency | AR | Complement component 6 | |
C7 deficiency | AR | Complement component 7 | |
C8a deficiency | AR | Complement component 8, alpha subunit (C8A) | |
C8b deficiency | AR | Complement component 8, beta subunit (C8B) | |
C9 deficiency | AR | Complement component 9 | |
Deficiencies of soluble regulatory proteins | C1 inhibitor deficiency | AD | Complement component 1 inhibitor (C1NH) |
Factor I deficiency | AR | Complement factor I (CFI) | |
Factor H deficiency | AR | Complement factor H (CFH) | |
Deficiencies of the regulatory proteins and complement receptors | MCP deficiency | AD | Membrane cofactor protein (MCP) or CD46 |
DAF deficiency | AR | Decay-accelerating factor for complement (DAF) or CD55 antigen | |
CD59 deficiency | AR | CD59 antigen p18-20 (CD59) | |
PIGA deficiency | XL | Phosphatidylinositol glycan, class A (PIGA) | |
CR3 deficiency | AR | Integrin, beta-2 (ITGB2) |
Diseases | Inheritance | Genetic defects | |
|---|---|---|---|
Ataxia-telangiectasia | AR | Ataxia-telangiectasia mutated gene (ATM) | |
Ataxia telangiectasia-like disorder | AR | Meiotic recombination 11, S. cerevisiae, homolog of, A (MRE11A) | |
Nijmegen breakage syndrome | AR | Nijmegen breakage syndrome gene (NBS1) | |
RAD50 deficiency | AR | RAD50, cerevisiae, homolog of (RAD50) | |
Radiosensitivity, immunodeficiency, dysmorphic features and learning difficulties (RIDDLE) syndrome | AR | Ring finger protein 168 (RNF168) | |
Bloom syndrome | AR | Bloom syndrome (BLM) | |
Dyskeratosis congenita | Dyskerin deficiency | XL | Dyskerin (DKC1) |
NHP2 deficiency | AR | Nucleolar protein family A, member 2 (NOLA2) or (NHP2) | |
NHP3 deficiency | AR | Nucleolar protein family A, member 3 (NOLA3) or (NOP10, PCFT) | |
RTEL1 deficiency | AD, AR | Regulator of telomere elongation helicase 1 (RTEL1) | |
TERC deficiency | AD | Telomerase RNA component (TERC) | |
TERT deficiency | AD, AR | Telomerase reverse transcriptase (TERT) | |
TINF2 deficiency | AD | TRF1-interacting nuclear factor 2 (TINF2) | |
TPP1 deficiency | AD, AR | ACD, mouse homolog of (ACD) | |
DCLRE1B deficiency | AR | DNA cross-link repair protein 1B (DCLRE1B) or (SNM1/APOLLO) | |
PARN deficiency | AR | Polyadenylate-specific ribonuclease (PARN) | |
Rothmund-Thomson syndrome | AD | RECQ protein-like 4 (RECQL4) | |
Other well defined immunodeficiencies with DNA repair defects | DNA ligase IV deficiency | AR | DNA ligase IV (LIG4) |
Cernunnos–XLF deficiency | AR | Nonhomologous end-joining 1 (NHEJ1) or CERNUNNOS | |
XRCC4 deficiency | AR | X-ray repair, complementing defective, in Chinese hamster, 4 (XRCC4) | |
DNA PKcs deficiency | AR | Protein kinase, DNA-activated catalytic subunit (PRKDC) | |
DNA ligase I deficiency | AR | DNA LIGASE I (LIG1) | |
Fanconi anemia | AR, XL | FANCEF gene (FANCF) | |
PMS2 deficiency | AR | Postmeiotic segregation increased S. cerevisiae, 2 (PMS2) | |
MCM4 deficiency | AR | Minichromosome maintenance complex component 4 (MCM4) | |
Immunodeficiency, centromere instability and facial abnormalities syndrome | ICF1 | AR | DNA methyltransferase 3b (DNMT3B) |
ICF2 | AR | Zinc finger and BTB domain-containing protein 24 (ZBTB24) | |
ICF3 | AR | Cell division cycle-associated protein 7 (CDCA7) | |
ICF4 | AR | Helicase, lymphoid-specific (HELLS) | |
Hyper-IgE syndrome | STAT3 deficiency | AD | Signal transducer and activator of transcription 3 (STAT3) |
DOCK8 deficiency | AR | Dedicator of cytokinesis 8 (DOCK8) | |
PGM3 deficiency | AR | Phosphoglucomutase 3 (PGM3) | |
Comel Netherton syndrome | AR, XL | Serine protease inhibitor, Kazal-type, 5 (SPINK5) | |
Other forms of hyper-IgE syndrome | Tyk2 deficiency | AR | Protein-tyrosin kinase 2 (TYK2) |
Wiskott-Aldrich syndrome | XL | Wiskott-Aldrich syndrome gene (WAS) | |
WIP deficiency | AR | WASP-interacting protein (WIP) | |
Hepatic veno-occlusive disease with immunodeficiency | AR | Nuclear body protein SP110 (SP110) | |
POLE deficiency | POLE1 deficiency | AR | Polymerase, DNA, epsilon-1 (POLE1) |
POLE2 deficiency | AR | Polymerase, DNA, epsilon-2 (POLE2) | |
Defects of vitamin B12 and folate metabolism | Transcobalamin 2 deficiency | AR | Transcobalamin 2 (TCN2) |
SLC46A1/PCFT deficiency | AR | Soluble carrier family 46 member 1 (SLC46A1) | |
MTHFD1 deficiency | AR | Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) |
1.1.3 Epidemiology
Several PID registries have been established in different countries during the last three decades [2, 4, 9, 13, 18, 20, 35, 37, 49, 60, 106, 107, 110, 111, 119, 128, 130, 143, 145, 152, 160, 161, 164, 166, 174, 180, 181, 190, 196, 207, 243, 246, 248, 309, 322, 325]. They provide valuable epidemiological information and demonstrate wide geographical and racial variations in the prevalence of PIDs in general and of its different types (Table 1.9). Considering the reports from major databases, including ESID (European Society for Immunodeficiencies) [110], LASID (Latin American Society for Primary Immunodeficiency Diseases) [164], USIDnet (US Immunodeficiency Network) [296], as well as selected reported registries from Asia [9, 13, 18, 20, 37, 107, 130, 143, 160, 166, 174, 246, 248, 309, 322, 325], Africa [35, 49, 161, 207, 243], and Australia [153], on about 35,000 PID patients, predominantly antibody deficiencies are the most common PID, which comprise more than half of all patients (Fig. 1.1). Other well-defined immunodeficiencies, combined T- and B- cell immunodeficiencies, and phagocytes defects are also relatively common. Among them, common variable immunodeficiency (CVID) seems to be the most common symptomatic PID. Meanwhile, it seems that the distribution of diseases varies by geographical regions/ethnicities. For example, it seems that the people living in the countries located in northern earth’s equator region (0 to 30° latitude to the northern equator) are more susceptible to combined immunodeficiencies rather than other parts of the world with dominance of predominantly antibody deficiencies (Fig. 1.2).
Table 1.9
Frequency of different types of PID, reported in several registries
Region/report | Year of report | Number of patientsa | Combined T- and B-cell immunodeficiencies (%) | Predominantly antibody deficiencies (%) | Congenital defects of phagocytes (%) | Genetic disorders of immune regulation (%) | Defects in innate immunity (%) | Autoinflammatory disorders (%) | Complement deficiencies (%) | Other immuno-deficiencies (%) | Unclassified (%) | Reference | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | JMF Referral Centers | 2016 | 89,634 | 5.3 | 53.0 | 5.2 | 2.9 | 1.1 | 7.1 | 5.5 | 12.9 | 6.8 | [202] |
2 | ESID | 2015 | 19,355 | 7.5 | 56.7 | 8.7 | 3.9 | 1.0 | 2.1 | 4.9 | 13.9 | 1.4 | [110] |
3 | LASID | 2015 | 5695 | 9.4 | 62.9 | 7.6 | 2.4 | 1.8 | – | 3.4 | 9.5 | 3.0 | [164] |
4 | France | 2010 | 3083 | 17.4 | 42.8 | 18.4 | 6.6 | 0.2 | – | 0.5 | 14.1 | – | [128] |
5 | USIDnet | 2015 | 2858 | 20.2 | 55.1 | 15.2 | 0.2 | 0.7 | 0.1 | 0.4 | 8.1 | 0.0 | [296] |
6 | UK | 2014 | 2229 | 9.9 | 59.6 | 4.8 | 1.3 | 0.0 | 1.0 | 9.2 | 13.8 | 0.3 | [106] |
7 | Spain | 2001 | 2030 | 8.3 | 69.1 | 4.6 | 0.5 | 1.4 | – | 10.2 | 5.0 | 0.8 | [196] |
8 | Iran | 2006, 2014 | 1661 | 16.0 | 35.7 | 22.6 | 2.4 | 2.9 | 2.3 | 1.9 | 16.2 | – | |
9 | Turkey | 2013 | 1441 | 3.0 | 73.6 | 2.9 | 1.4 | 1.7 | 13.3 | 0.4 | 3.7 | – | [152] |
10 | Germany | 2013 | 1368 | 8.4 | 62.7 | 7.7 | 3.4 | 1.3 | 3.1 | 5.4 | 3.9 | 4.0 | [119] |
11 | Argentina | 2007 | 1246 | 10.4 | 68.4 | 3.9 | 2.9 | 1.4 | – | 1.0 | 12.0 | – | [171] |
12 | Japan | 2011 | 1217 | 10.8 | 41.2 | 18.5 | 4.0 | 3.0 | 8.9 | 2.6 | 11.0 | – | [143] |
13 | Australia and New Zealand | 2007 | 1209 | 8.9 | 77.4 | 3.2 | – | 1.6 | – | 5.9 | 2.9 | 0.2 | [153] |
14 | Brazil | 2013 | 1008 | 9.9 | 60.8 | 7.3 | 4.3 | 8.3 | 1.3 | 2.9 | 5.2 | – | [60] |
15 | Italy | 1983 | 797 | 14.2 | 66.6 | 4.9 | 2.4 | – | – | 1.6 | 9.5 | 0.8 | [181] |
16 | Netherlands | 2015 | 743 | 8.5 | 60.6 | 8.6 | 4.3 | 3.1 | – | 1.5 | 9.3 | 4.2 | [145] |
17 | Tunis | 2015 | 710 | 28.6 | 17.7 | 25.4 | 4.8 | 0.4 | – | 0.4 | 22.7 | – | [193] |
18 | Czech | 2000 | 518 | 8.1 | 78.0 | 1.2 | – | – | – | 11.5 | 1.2 | – | [2] |
19 | China | 2006, 2011, 2013 | 485 | 21.4 | 38.8 | 10.9 | 2.3 | 0.8 | – | 0.2 | 25.4 | 0.2 | |
20 | Morocco | 2014 | 423 | 24.1 | 22.7 | 15.1 | 2.1 | 5.2 | 2.8 | 3.1 | 23.9 | 0.9 | [49] |
21 | Saudi Arabia | 2013 | 357 | 53.8 | 15.4 | 10.6 | 6.4 | – | – | 4.5 | 9.2 | – | [18] |
22 | Switzerland | 2015 | 348 | 11.5 | 61.5 | 8.9 | 2.3 | 2.0 | 3.4 | 4.6 | 4.3 | 1.4 | [190] |
23 | Mexico | 2007 | 399 | 15.0 | 36.3 | 14.0 | 3.5 | 2.5 | – | 1.5 | 27.1 | – | [171] |
24 | Norway | 2000 | 372 | 3.5 | 50.8 | 6.7 | – | – | – | 21.0 | 18.0 | [280] | |
25 | Poland | 2000 | 322 | 24.8 | 55.0 | 14.3 | – | – | – | 0.3 | 5.6 | [2] | |
26 | Chile | 2007 | 279 | 23.7 | 43.0 | 6.8 | 6.1 | 3.2 | – | 1.8 | 15.4 | – | [171] |
27 | India | 2012 | 275 | 12.0 | 28.4 | 14.5 | 17.1 | 4.7 | 0.7 | 1.8 | 18.2 | 2.5 | [130] |
28 | Taiwan | 2011 | 215 | 15.8 | 25.1 | 11.6 | 2.3 | – | 0.5 | 7.0 | 37.7 | – | [166] |
29 | Portugal | 2000 | 208 | 6.3 | 76.9 | 3.8 | – | – | – | 6.7 | 6.3 | – | [2] |
30 | Korea | 2012 | 152 | 10.5 | 53.3 | 28.9 | – | – | – | – | 7.2 | – | [248] |
31 | Costa Rica | 2007 | 193 | 18.1 | 24.9 | 4.1 | 4.7 | 1.0 | – | 0.5 | 46.6 | – | [171] |
32 | Sweden | 1982 | 174 | 13.8 | 43.7 | 21.8 | 1.1 | 8.0 | – | 0.6 | 10.9 | – | [111] |
33 | South Africa | 2011 | 168 | 25.0 | 50.6 | 5.4 | – | 0.6 | – | 4.2 | 14.3 | – | [207] |
34 | Russia | 2000 | 161 | 29.8 | 59.6 | 6.2 | 0.0 | 4.4 | [2] | ||||
35 | Greece | 2014 | 147 | 38.8 | 20.4 | 17.0 | 2.0 | 4.1 | 0.7 | 1.4 | 15.6 | – | [194] |
36 | Colombia | 2007 | 145 | 21.4 | 46.2 | 8.3 | 3.4 | 4.1 | – | 2.8 | 13.8 | – | [171] |
37 | Qatar | 2013 | 131 | 22.9 | 23.7 | 12.2 | 12.2 | 9.9 | – | – | 19.1 | – | [107] |
38 | Hong Kong | 2005 | 117 | 16.2 | 42.7 | 16.2 | 1.7 | 1.7 | – | 3.4 | 7.7 | 10.3 | [160] |
39 | Republic Ireland | 2005 | 115 | 12.2 | 46.1 | 9.6 | – | 2.6 | – | 27.8 | 1.7 | – | [4] |
40 | Uruguay | 2007 | 95 | 8.4 | 58.9 | 3.2 | – | 3.2 | – | 9.5 | 16.8 | – | [171] |
41 | Oman | 2012 | 90 | 14.4 | 17.8 | 38.9 | 3.3 | 3.3 | – | 5.6 | 10.0 | 6.7 | [20] |
42 | Hungary | 2000 | 90 | 0.0 | 22.2 | 14.5 | – | – | – | 63.3 | 0.0 | – | [2] |
43 | Kuwait | 2008 | 76 | 31.6 | 30.3 | 7.9 | 6.6 | – | – | 3.9 | 19.7 | – | [13] |
44 | Austria | 2000 | 71 | 26.8 | 67.6 | 2.8 | – | – | – | 1.4 | 1.4 | – | [2] |
45 | Thailand | 2009 | 67 | 32.8 | 52.2 | 9.0 | – | 3.0 | – | – | 3.0 | – | [37] |
46 | Iceland | 2015 | 66 | 4.5 | 39.4 | 12.1 | – | 1.5 | 3.0 | 28.8 | 10.6 | – | [180] |
47 | Egypt | 2009 | 64 | 31.3 | 35.9 | 12.5 | 3.1 | – | – | – | 17.2 | – | [243] |
48 | Belgium | 2000 | 64 | 10.9 | 64.1 | 17.2 | – | – | – | 4.7 | 3.1 | [2] | |
49 | Panama | 2007 | 59 | 15.3 | 55.9 | 8.5 | – | 1.7 | – | 3.4 | 15.3 | – | [171] |
50 | Finland | 2000 | 48 | 8.3 | 71.1 | 10.4 | – | – | – | 4.2 | 0.0 | – | [2] |
51 | Singapore | 2003 | 39 | 15.4 | 40.0 | 15.4 | – | 2.6 | – | 25.6 | 0.0 | – | [174] |
52 | Paraguay | 2007 | 39 | 10.3 | 38.5 | 33.3 | – | 2.6 | – | – | 15.4 | – | [171] |
53 | Honduras | 2007 | 37 | 16.2 | 32.4 | 10.8 | 2.7 | 16.2 | – | – | 21.6 | – | [171] |
54 | Croatia | 2000 | 30 | 6.7 | 63.3 | 0.0 | – | – | – | 30.0 | 0.0 | – | [2] |
55 | Venezuela | 2007 | 22 | 9.1 | 40.9 | 4.5 | 13.6 | – | – | 9.1 | 22.7 | – | [171] |
56 | Peru | 2007 | 17 | 17.6 | 17.6 | 5.9 | – | 5.9 | – | 11.8 | 41.2 | – | [171] |
Fig. 1.1
Relative frequencies of primary immunodeficiency diseases (Extracted from data of the reports from major databases, including ESID (European Society for Immunodeficiencies), LASID (Latin American Society for Primary Immunodeficiency Diseases), USIDnet (US Immunodeficiency network), as well as selected reported registries from Asia, Africa, and Australia)
Fig. 1.2
Distribution of different types of primary immunodeficiency diseases in the world. Dark red: dominancy of predominantly antibody deficiencies (>50 %); Light red: dominancy of predominantly antibody deficiencies (<50 %); Dark blue: dominancy of Combined T- and B-cell immunodeficiencies and other well-defined immunodeficiencies; Green: dominancy of congenital defects of phagocytes; Purple: dominancy of complement deficiencies
The exact prevalence of PIDs in the general population is unknown. Although the overall prevalence of PIDs had been estimated to be 1 per 10,000 individuals, excluding asymptomatic IgA deficiency, recent reports indicated a higher prevalence of PIDs worldwide [48, 50, 278]; this prevalence may differ among different ethnic groups and countries [278], while the discovery of new PIDs, infectious and otherwise, may necessitate a revision of previous estimates of the frequency of PIDs in the general population.
Meanwhile, conservatively defined PIDs are commonly thought to be individually and collectively rare. Rare diseases are defined as having an incidence of less than 1/2000 live births in the EU [164] or a prevalence of less than 200,000 patients in the US. However, it remains unclear whether the prevalence and incidence of PIDs have been estimated accurately. Many studies, based on different methodologies, have attempted to estimate the prevalence of PIDs in various countries and have generated inconsistent results. For example, the most recent estimates obtained were 5.93/100,000 inhabitants in France in August 2013 [152], 5.6/100,000 in Australia in 2007 [107], and 3.71/100,000 in the UK in 2013 [20]. These estimates of prevalence were based on data from registries and seem to be much lower than recently reported estimates based on specific population surveys in the US, such as prevalence of 86.3/100,000 inhabitants by a telephone survey [17] or incidence of 10.3/100,000 person-years at the Mayo Clinic epidemiologic study [207].
In the Europe, prevalence data can be easily obtained from the ESID registry. Indeed, this international registry is documented by 126 centers all around Europe by mid-2015, and its statistics are regularly updated on the ESID website [110]. However, when we go through the data, there is a relatively high heterogeneity in PID prevalence from a country to another, ranging from 0.06/100,000 inhabitants in Romania to 5.93/100,000 in France. This can be explained by the different approaches in the use of this registry. Actually, only 8 of the 29 participating countries have developed a national registry, included in the ESID registry, namely France, Spain, Italy, the Netherlands, Poland, Czech Republic, Austria and Belgium. Moreover, even national registries can miss out diagnosed patients in non-documenting centers. The prevalence produced by their data collection should be interpreted with caution, and that the observed differences are mostly due to under-reporting [165].
In the USA, the national registry, USIDnet only account for 3430 patients in mid-2015 [296]. However, only 10 diagnosis accounts for about 85 % of the patients. Besides, the ImmuneDeficiency Foundation (IDF) performed several surveys to define PID prevalence in US. In the IDF National Survey, in 2005, they estimated that at least 250,000 PID cases would be diagnosed in the US with the prevalence of about 1 in 1200 persons in the United States [325]. On another hand, an epidemiologic study providing an estimate of PID incidence in the USA based on a survey in Olmsted County, Minnesota [160], using data of all patients treated between 1976 and 2006 whose medical records contained at least one of the ICD (International Classification of Diseases) codes relating to PIDs, showed overall incidence of 4.6/100,000 person-years for a 30-years period (1976–2006), and 10.3/100,000 person-years for the most recent period (2001–2006). Immunodeficiency Canada, a national registered charity, estimated that 13,000 people (1/2500) would have a PID in Canada [77].
In the Middle East, until recently, very few data were available on the PID epidemiology. Only two countries have developed a PID registry: the Iranian Primary Immunodeficiency Registry (IPIDR), established in 1999 [7], and the National Primary Immunodeficiency Registry in Kuwait (KNPIDR), founded in 2007 [12]. The second report from the IPIDR in 2006 [246] estimated the occurrence of PID as 6 per 100,000 live births, with a cumulative incidence of about 1.2/100,000 in the last 10 years. In Kuwait, the prevalence of PID was estimated about 12/100,000 in children [13].
In Asia, no international registry is available. Likewise, diagnosis and management vary from a country to another. In Japan, a nationwide survey was performed and published in 2011 [143]. The estimated prevalence from this survey was 2.3/100,000 inhabitants, with estimated regional prevalence ranged from 1.7 to 4.0/100,000 [143]. In China, several single-centers published their series [75, 175, 322, 326]. A single-center study from 2011 observed a PID incidence of 1/2850 children [309]. When gathering these cases, we estimated a PID prevalence of 0.4/100,000 inhabitants in 2009 in China, which should be lower than the reality. In Taiwan, a recent population-based survey reported a minimal prevalence of 0.78/100,000 [167]. In Singapore, an incidence of 2.65 per 100,000 live births was reported, which was similar to PID incidence in Australia at the time of publication [174]. On total population, prevalence reached 0.89/100,000 inhabitants. In India, some single-centers published their series recently [77, 184]. However, these series are not large enough to estimate PID prevalence in India. The observed prevalence of PID in Australia and New Zealand was 4.9/100,000 [153]. The regional estimated prevalence ranged from less than 1/100,000 in Tasmania to 12.4 in South Australasian. After adjustments, PID prevalence is estimated around 13.2–14.5/100,000 inhabitants.
In Africa, very few data are available on the PID prevalence. Indeed, definite diagnosis of PIDs and appropriate care are developed only in a few countries, such as Tunisia, Egypt, Morocco, Algeria and South Africa. Likewise, only Morocco and South Africa have established a National Registry. The African Society of Immunodeficiency (ASID) registry and the North African registry initiatives have begun, but are still in their first steps.
The Jeffrey Modell Foundation (JMF) has created a worldwide network of centers specialized in PIDs: the Jeffrey Modell Centers Network (JMCN). Every other year, a survey is sent to this network to assess PID distribution and management. The last publication reported the results from the 2015 survey, where 253 centers representing 84 countries responded. A total of 89,634 patients with PIDs who were referred to a JMCN institution was reported [202]. In another report from the JMF with 60,364 PIDs [201], a worldwide prevalence of at least 1.14/100,000 inhabitants was estimated. To be more specific, if we only consider the population of the participating countries, the prevalence should be no less than 1.56/100,000. Here again, huge variations are observed between regions, with low PID prevalence in Asia (0.22/100,000 inhabitants), Africa (0.39/100,000) and Latin America (0.86/100,000), and higher prevalence in regions involved in the field since the beginning: Europe (3.76), USA (4.98), Australia (5.35) and Canada (9.97/100,000).
Estimates of PID prevalence from registry data [e.g. 5.9/100 000 in France [142], 5.6/100,000 in Australia [153]] are much lower than the estimates based on the data from a telephone survey in the USA (86.3/100,000) [50]. Considering the estimate prevalence of PID on the later survey [50], the predicted total number of PID patients reaches six million, while considering the reported incidence data [146], more than 700,000 new cases annually could be calculated. However, more data relying on population studies are needed to define the exact prevalence and incidence of PIDs to avoid both underestimation and overestimation of these diseases.
1.2 Etiology
1.2.1 Classification
There is no single system of classification of the large and heterogeneous group of primary immunodeficiencies that suffices for every educational or clinical purpose [16, 43, 217]. Most texts utilize a functional classification wherein distinct disease entities are grouped according to the immunological mechanism whose perturbation is responsible for the principal clinical and laboratory manifestations of those diseases or syndromes [45]. One may distinguish, for example, antibody or humoral immune defects, combined immunodeficiencies (affecting both specific humoral and cellular immunity), phagocytic cell defects, complement deficiencies, and other defects of innate immunity or immune dysregulation. Note that these types of descriptive functional categories may overlap to varying degrees, for example, phagocytic cells and complement may be considered elements of innate immunity, but are usually considered separately due to the convenience of their mechanistic distinction. The assignment of one entity to a particular category is occasionally arbitrary and may have a historical basis.
The foundation for the organization of this text is the most recent classification of immunological diseases reported by the World Health Organization (WHO) in conjunction with the International Union of Immunological Societies (IUIS) [14]. This classification is conveyed in Tables 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, and 1.8. This scheme includes combined T- and B-cell immunodeficiencies (Table 1.1), predominantly antibody deficiencies (Table 1.2), phagocytes defects (Table 1.3), genetic disorders of immune regulation (Table 1.4), defects in intrinsic and innate immunity: receptors and signaling components (Table 1.5), autoinflammatory disorders (Table 1.6), complement deficiencies (Table 1.7), and other well-defined immunodeficiencies (Table 1.8). Some disease entities may be listed more than once, if they have characteristics of more than one group or for historical reasons.
The usefulness of any classification scheme depends mainly on the ultimate purpose for which it was developed [43]. The WHO/IUIS system is well suited as a framework for organizing a knowledge base on the general clinical and immunologic features of disease entities arising “primarily” from dysfunction of the immune system. This classification may be cumbersome in other contexts, for example, developing a differential diagnosis based on particular clinical or immunologic features. Other systems have been proposed or formulated with these kinds of considerations in mind [5, 257]
1.2.2 Genetic Defects
More than 200 distinct genes have been associated with clinical immunodeficiency (Tables 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, and 1.8). This number is even larger when one takes into consideration the many genetically-determined syndromes in which some fraction of individuals has been found to have a degree of immune compromise or infection susceptibility. (See Chap. 10 for more details) As can be readily seen (and not surprisingly) by surveying the genes listed in Tables 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, and 1.8, immunodeficiency may arise from disruption of a wide range of biochemical functions including transcription factors, cytokines and their receptors, cell surface and cytoplasmic signaling mediators, cell cycle regulators, DNA modifying enzymes, intracellular chaperones and transport proteins, and a variety of other specialized enzymatic functions. One may broadly generalize that perhaps more than half of these molecular species are active principally or predominantly in blood cells, lymphocytes and leukocytes, in particular, although that relative restriction clearly does not apply in many instances.
Clearly, having a molecular genetic focus adds precision to a diagnosis, although there are important practical caveats to the use of such information, some of which will be introduced here. In addition, a large proportion of patients with recurrent infections, or “clinical immunodeficiency” have syndromes whose molecular genetic basis is unknown.
The ability to assign genes and molecular functions to an observable characteristic leads to the concept of the genotype-phenotype correlation. Common examples include the genetic basis of traits such as eye color, or ABO blood group. This also applies in a general way to disease associations, for example, mutations of BTK lead to Bruton’s agammaglobulinemia (Chap. 3) while mutations of WAS lead to Wiskott-Aldrich syndrome (Chap. 9). However, the concept may also be applied in a more detailed way. Within a group of individuals having any specific immunodeficiency diagnosis, one may distinguish a spectrum of clinical phenotypes. This may relate to the degree of frequency or severity of infections (“severity” of the immunodeficiency), or to the expression of other associated features of the disease such as autoimmunity or malignancy. Thus, one may ask: “does the identification of a particular genetic change affecting even submolecular functions (ligand binding, association with signaling intermediates or chaperones, enzymatic activity, cellular transport, etc.) permit one to predict the severity of the immunodeficiency, the occurrence of autoimmunity or malignancy, etc.?” In some cases, “yes”, although there are many important exceptions making a generalization difficult. In some instances, identical mutations may lead to a severe phenotype in one individual, and may be mild, or may not even be expressed at all, in another. For example, some entirely well people have been found incidentally to have mutations of BTK, while siblings carrying the same mutation have classic clinical X-linked agammaglobulinemia. (See Chap. 3 for more details) Does an individual who is completely well and who has a “disease-causing” mutation of BTK have X-linked agammaglobulinemia? The answer is not a simple one because we do not know if it is possible for any such individual to be “completely healthy” with a “normal” lifespan.
It is axiomatic that many (all?) gene products, as well as the environment, interact to determine phenotype. Thus, the clinical and immunologic heterogeneity that we observe with identical genotypes is due to the influence of these interactions. Given the possibility of molecular diagnosis, and the heterogeneity of expression of genotypes, then all syndromes defined solely by clinical and immunologic criteria should be considered diagnoses of exclusion [45]. Common variable immunodeficiency (CVID, Chap. 3) is a useful illustration of this point. CVID is defined primarily by recurrent infections with hypogammaglobulinemia and impaired antibody response to natural and/or intentional immune challenge [72, 86]. Several genetic lesions have been identified in individuals “diagnosed” with CVID including BTK, SH2D1A (mutated in X-linked lymphoproliferative syndrome), ICOS (inducible T cell costimulator), CD19, CD20, CD81 and BAFFR [259]. The particular natural history associated with each of these mutations is distinct, so it is most beneficial for patients to know their molecular diagnosis whenever possible. This also creates opportunities for more informed genetic counseling. Note that the principal presenting phenotype associated with X-linked lymphoproliferative syndrome (Chap. 5) is fulminant infectious mononucleosis. This is a good example of how an environmental factor (Epstein-Barr virus infection) may interact with a gene defect (SH2D1A) to affect the clinical presentation.
Some individuals expressing mild or variant forms of immunodeficiency have a reversion of a deleterious mutation. These patients are mosaics, they have abnormal mutant cells and another population of cells with normal or near-normal function that have arisen from a precursor that has repaired the defect, either from a second “corrective” mutation, or possibly gene conversion. This has been found in rare cases of adenosine deaminase deficiency, X-linked severe combined immunodeficiency, Wiskott-Aldrich syndrome, leukocyte adhesion deficiency type I, and possibly X-linked chronic granulomatous disease [88, 157, 204, 298, 318].
Some X-linked immunodeficiencies affect females through extreme non-random X chromosome inactivation. In most females, roughly half of all somatic cells will inactivate one X chromosome, and half inactivate the other. In some individuals, 95–100 % of cells will all have inactivated the same X chromosome. If the remaining active X carries a mutation causing immunodeficiency, that disease will become manifest. This phenomenon has been observed with chronic granulomatous disease, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, and X-linked immunoglobulin class switching recombination (CSR) deficiency [25, 141, 173, 285].
1.2.3 Pathophysiology
The infection susceptibility and other clinical features of a given immunodeficiency arise from the absence or altered function of one or more gene products. All of the details of these aspects of each disorder depend on the biochemical roles of these gene products and the cells or tissues in which they are expressed. As discussed above, the products of interacting genes and their polymorphisms and environmental factors also play a role. For most immunodeficiencies, we still have very much to learn regarding all of the biochemical, cellular, organic, and systemic consequences of a particular defect. The majority of the genetically defined immunodeficiencies will be discussed in the remainder of this book. Here we give a few examples of an interesting phenomenon in immunodeficiency: syndromes having identical or very similar clinical and immunologic phenotypes may arise from the disrupted function of molecular entities that interact with one another to subserve a single biochemical function or pathway.
Bruton’s disease, or X-linked, agammaglobulinemia (XLA) was one of the first immunodeficiencies to be defined at the molecular level [39]. The Bruton’s tyrosine kinase (BTK) is critical for transducing a signal from the B cell surface immunoglobulin receptor (Fig. 1.3). In the pre B cell, this receptor consists of an immunoglobulin M heavy chain, the heterodimeric surrogate light chain containing lambda 5 and VpreB, and the signal transducers Ig alpha, and Ig beta. Within the cytoplasm, BTK interacts with other kinases, and with so-called scaffold or adaptor proteins that serve to juxtapose other signaling molecules, permitting activation to proceed downstream along the pathway. One of these is B cell linker protein (BLNK). Several of these interacting molecules have been associated with autosomal forms of agammaglobulinemia that are indistinguishable from XLA in their clinical and laboratory characteristics; these are IgM heavy chain, lambda 5, Ig alpha, Ig beta, and BTK [39]. Agammaglobulinemia is the subject of Chap. 3.
Fig. 1.3
This is a highly simplified diagram summarizing the relationships of several molecules whose absence is associated with agammaglobulinemia. All of the defects indicated here in red affect signaling through the pre-B cell receptor and block B cell development at the pre-B cell stage in the bone marrow. The pre-B cell receptor itself is made up of an IgM heavy chain, the surrogate light chain heterodimer of λ5 and VpreB, and the signal transducers Igα and Igβ which bear the immunoreceptor tyrosine based activation motifs (ITAMs). The ITAMs are phosphorylated by Lyn, a Src family tyrosine kinase, while Syk is the prototype of the tyrosine kinase family that bears the same name. Btk is a member of the Tec family of tyrosine kinases. B cell linker protein (BLNK) is a scaffold or adaptor protein, while Vav is a guanine nucleotide exchange factor for downstream GTPases. PLCγ2 is phospholipase C γ2; PKC is protein kinase C
X-linked severe combined immunodeficiency (XSCID) is the result of a defect in the cytokine receptor common gamma chain (gammac, Fig. 1.4) [212]. This molecule is a signal-transducing component of the multimeric receptors for 6 different cytokines: interleukins 2, 4, 7, 9, 15, and 21. Gammac signals through the kinase JAK3. Mutation of the JAK3 gene results in a very similar form of SCID with autosomal recessive inheritance [301]. Mutations in the genes encoding the ligand binding chains of the receptors for IL-2 and IL-7 also lead to forms of SCID [301]. Severe combined immunodeficiency is the subject of Chap. 2.
