Introduction on Primary Immunodeficiency Diseases

, Francisco A. Bonilla⁴, Mikko Seppänen⁵, Esther de Vries^{6, 7}, Ahmed Aziz Bousfiha^{8, 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 diseasesInfectionsAutoimmunityMalignancies

1.1 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].

Table 1.1

Modified IUIS classification of combined T- and B-cell immunodeficiencies [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 salvage pathway defects	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)
CHARGE syndrome	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)
Immuno-osseous dysplasias	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)
CD8 deficiency	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)
CRAC channelopathy	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)
IL21/IL21R deficiency	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)

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AR autosomal recessive, AD autosomal dominant, XL X-linked

Table 1.2

Modified IUIS classification of predominantly antibody deficiencies [235]

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

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AR autosomal recessive, AD autosomal dominant, XL X-linked

Table 1.3

Modified IUIS classification of phagocytes defects [235]

Diseases		Inheritance	Genetic defects
Chronic granulomatous disease	gp91 ^phoxdeficiency	XL	Cytochrome b(−245), beta subunit (CYBB)
	p22 ^phoxdeficiency	AR	Cytochrome b(−245), alpha subunit (CYBA)
	p47 ^phoxdeficiency	AR	Neutrphil cytosolic factor 1 (NCF1)
	p67 ^phoxdeficiency	AR	Neutrophil cytosolic factor 2 (NCF2)
	p40 ^phoxdeficiency	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)
3-Methylglutaconic Aciduria	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)

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AR autosomal recessive, AD autosomal dominant, XL X-linked

Table 1.4

Modified IUIS classification of genetic disorders of immune regulation [235]

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
Other immunodeficiencies associated with hypopigmentation	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)
Autosomal recessive lymphoproliferative syndromes	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)

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AR autosomal recessive, AD autosomal dominant, XL X-linked

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)
Anhidrotic ectodermal dysplasia with immunodeficiency	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)
HOIL1 and HOIP deficiencies	HOIP deficiency	AR	HOIL1-interacting protein (HOIP)
IRAK-4 and MyD88 deficiencies	IRAK–4 deficiency	AR	Interleukin 1 receptor-associated kinase 4 (IRAK4)
IRAK-4 and MyD88 deficiencies	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)
Epidermodysplasia verruciformis	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)
Monocyte/dendritic cell deficiencies	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)
Pulmonary alveolar proteinosis		AR	Colony-stimulating factor 2 receptor, beta (CSF2RB)
Isolated congenital asplenia		AD	NK2 homeobox 5 (NKX2–5)
Isolated congenital asplenia		AD	Ribosomal protein SA (RPS)

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AR autosomal recessive, AD autosomal dominant, XL X-linked

Table 1.6

Modified IUIS classification of autoinflammatory disorders [235]

Diseases		Inheritance	Genetic defects
Familial mediterranean fever		AR	Mediterranean fever (MEFV)
Mevalonate kinase deficiency	Hyper–IgD and periodic fever syndrome	AR	Mevalonate kinase (MVK)
Mevalonate kinase deficiency	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)

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AR autosomal recessive, AD autosomal dominant

Table 1.7

Modified IUIS classification of complement deficiencies [235]

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)
Deficiencies of lectin pathway components	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)
Deficiencies of alternative pathway components	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)

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AR autosomal recessive, AD autosomal dominant, XL X-linked

Table 1.8

Modified IUIS classification of other well-defined immunodeficiencies [235]

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)
POLE deficiency	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)

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AR autosomal recessive, AD autosomal dominant, XL X-linked

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 patients^a	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, 246]
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	[309, 324, 325]
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]

JMF Jeffrey Modell Foundation Diagnostic and Referral Centers, ESID European Society of Immunodeficiency, LASID Latin American Society for Primary Immunodeficiency Diseases, USIDnet US Immunodeficiency network

^aThere may be some overlapping between registries; i.e. JMF Referral Centers, ESID, LASID and other databases

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 (gamma_c, 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. Gamma_c 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.

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Jun 12, 2017 | Posted by admin in PEDIATRICS | Comments Off

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