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CHAPTER 80 environmental mycobacteria, Cryptosporidium, Giardia lamblia), persistent or

IMMUNODEFICIENCY recurrent candidiasis, narrow susceptibility to a selective type of pathogens,
autoimmunity, increased susceptibility to malignancies, and may be associ-
DISEASES ated with typical signs of specific immunodeficiency syndromes.
With the exception of immunoglobulin (Ig) A deficiency and DiGeorge syn-
drome, PIDDs are generally rare, with a prevalence of approximately 1 in 10,000
to 1 in 50,000 of the general population. However, prompt recognition of PIDD
Hans D. Ochs and Luigi D. Notarangelo is of importance, because diagnostic delay is associated with increased risk of
death and of irreversible complications. Most forms of PIDD follow mendelian
inheritance; however, some, like common variable immunodeficiency (CVID),
SUMMARY have a multifactorial origin. In most cases, PIDDs present in childhood, but late
presentations may occur or even predominate in some forms, such as CVID.
Primary immune deficiency diseases (PIDDs) are characterized by increased The diagnostic approach to PIDD is based on a detailed family and clinical
susceptibility to infections, often associated with autoimmunity and inflam- history, physical examination and appropriate laboratory tests. Lymphopenia is
mation and an increased risk of malignancies because of impaired immune characteristic of severe combined immune deficiency. Abnormalities affecting
homeostasis and surveillance. Depending on the nature of the immune defect, neutrophils can be observed in patients with disorders of neutrophil produc-
the clinical presentation of PIDD may vary and may include recurrence of upper tion (e.g., congenital neutropenia, leukocyte adhesion deficiency; Chap. 65) or
and lower respiratory tract infections, invasive bacterial infections, purulent function (e.g., chronic granulomatous disease; Chap. 66), respectively. Evalu-
lymphadenitis, skin or deep abscesses, infections sustained by poorly viru- ation of serum immunoglobulin levels and of antibody responses to immuni-
lent or opportunistic pathogens (Pneumocystis jirovecii, cytomegalovirus, zation antigens is of value for patients with a history of recurrent infections.

Acronyms and Abbreviations: AD, autosomal dominant; ADA, adenosine deam- ITK, interleukin-2–inducible T-cell kinase; IVIG, intravenous immunoglobulin; J,
inase; AD-HIES, autosomal dominant hyperimmunoglobulin E syndrome; joining; JAK3, Janus-associated tyrosine kinase 3; LCK, lymphocyte-specific pro-
aHSCs, autologous hematopoietic stem cells; AID, activation-induced cytosine tein tyrosine kinase; LGL, large granular lymphocytic leukemia; LIG4, DNA ligase
deaminase; AIRE, autoimmune regulator; ALPS, autoimmune lymphoprolif- IV; LRBA, lipopolysaccharide responsive beige-like anchor; LYST, lysosomal
erative syndrome; APECED, autoimmune polyendocrinopathy, candidiasis, and trafficking regulator; MAGT1, magnesium transporter 1; MHC, major histocom-
ectodermal dystrophy; APS, autoimmune polyglandular syndrome; AR-HIES, patibility complex; MMF, mycophenolate mofetil; MonoMAC, monocytopenia,
autosomal recessive hyperimmunoglobulin syndrome; AT, ataxia-telangiectasia; B-cell and NK-cell lymphopenia associated with mycobacterial, fungal, and viral
ATLD, ataxia-telangiectasia–like disorder; ATM, ataxia-telangiectasia mutated; infections; MSMD, mendelian susceptibility to mycobacterial disease; MyD88,
BCG, bacillus Calmette-Guérin; BLM, the causative gene of Bloom syndrome; myeloid differentiation factor 88; NBS, Nijmegen breakage syndrome; NEMO,
BS, Bloom syndrome; BTK, Bruton tyrosine kinase; C, complement; CARD, cas- nuclear factor-κB essential modulator; NF, nuclear factor; NK, natural killer; NKT,
pase recruitment domain-containing protein; CD40L, CD40 ligand; CHARGE, natural killer T cell; ORAI1, calcium release-activated calcium channel protein
coloboma of the eye, heart defects, atresia of the nasal choanae, retardation 1; PI3K, phosphatidylinositol 3-kinase; PIDD, primary immune deficiency dis-
of growth and/or development, genital and/or urinary abnormalities, and ear ease; PLDN, pallidin; PMS2, postmeiotic segregation increased 2 (Saccharomyces
abnormalities and deafness; CID, combined immune deficiency; CMC, chronic cerevisiae); PNP, purine nucleoside phosphorylase; RAG1/2, recombination acti-
mucocutaneous candidiasis; CMV, cytomegalovirus; CSR, class switch recombi- vating gene 1/2; RMRP, ribonuclease mitochondrial RNA processing complex;
nation; CTL, cytotoxic T lymphocyte; CTLA-4, cytotoxic T-lymphocyte antigen-4; SAP, signaling lymphocyte activation molecule (SLAM)-associated protein; SCID,
CTPS1, cytidine 5-triphosphate synthase 1; CVID, common variable immunode- severe combined immune deficiency; SHM, somatic hypermutation; SLAM,
ficiency; D, diversity; DC, dendritic cell; DGS, DiGeorge syndrome; DOCK8, ded- signaling lymphocyte activation molecule; SMARCAL1, switch/sucrose nonfer-
icator of cytokinesis 8; EBV, Epstein-Barr virus; FHL, familial hemophagocytic mentable (SWI/SNF)-related matrix-associated actin-dependent regulator of
lymphohistiocytosis; G-CSF, granulocyte colony-stimulating factor; GM-CSF, chromatin subfamily A–like protein 1; SNP, single nucleotide polymorphism;
granulocyte-macrophage colony-stimulating factor; GS2, Griscelli syndrome STIM1, stromal interaction molecule 1; TAP-1/2, transport-associated protein
type 2; HIES, hyperimmunoglobulin E syndrome; HLA, human leukocyte anti- 1/2; TCR, T-cell receptor; T EMRA , T memory; TLR, toll-like receptor; TNF, tumor
gen; HLH, hemophagocytic lymphohistiocytosis; HPV, human papillomavi- necrosis factor; TRAF, TRIF-related adaptor molecule; TREC, T-cell–receptor exci-
rus; HSCT, hematopoietic stem cell transplantation; HSE, herpes simplex virus sion circle; TRIF, toll-interleukin 1 receptor domain-containing adaptor-inducing
encephalitis; HSV, herpes simplex virus; IBD, inflammatory bowel disease; ICF, IFN-β; TYK2, tyrosine kinase 2; UNG, uracil N-glycosylase; V, variable; VODI,
immunodeficiency with centromere instability and facial anomalies; IFN, inter- venoocclusive disease with immunodeficiency; WAS, Wiskott-Aldrich syndrome;
feron; Ig, immunoglobulin; IGF-1, insulin-like growth factor 1; IGHM, immuno- WASp, Wiskott-Aldrich syndrome protein; WHIM, warts, hypogammaglobuline-
globulin heavy constant mu; IGLL1, immunoglobulin lambda-like polypeptide mia, infections, myelokathexis; WIP, WASp-interacting protein; WRN, Werner
1; IKK, IκB kinase; IL, interleukin; IL-7R, IL-7 receptor; iNKT, invariant natural syndrome, RecQ helicase-like; XHIGM, X-linked hyperimmunoglobulin M; XLA,
killer T cell; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked agammaglobulinemia; XLP1 and XLP2, X-linked lymphoproliferative
X-linked; IRAK, IL-1 receptor-associated kinase; IRF8, interferon-regulated factor syndrome types 1 and 2; XLT, X-linked thrombocytopenia; ZAP-70, zeta-asso-
8; ISG15, interferon-stimulated gene 15; ITCH, itchy E3 ubiquitin protein ligase; ciated protein of 70 kDa.

Kaushansky_chapter 80_p1211-1238.indd 1211 9/18/15 10:00 AM