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Chapter 21
Congenital or Primary
Immunodeficiency
(PID)

Defects in one or more components of the immune system can lead to serious and
often fatal disorders, which are collectively called immunodeficiency diseases (ID)

ID are broadly classified into two groups. The congenital, or primary,
immunodeficiencies (PID) are genetic defects that result in an increased
susceptibility to infection that is frequently manifested early in infancy and
childhood . PID Dx are genetic defects with prevalence in US 1: 500

Acquired or secondary immunodeficiencies develop as a consequence of
malnutrition, disseminated cancer, treatment with immunosuppressive drugs, or
infection of cells of the immune system, most notably with the human
immunodeficiency virus (HIV)
General features of PID

The principal consequence is an increased susceptibility to infection, deficient
humoral or cellular immunity

Patients with immunodeficiencies are also susceptible to certain types of cancer that
most often seen in T cell deficiencies

Immunodeficiency may result from defects in lymphocyte maturation or activation
or from defects in the effector mechanisms of innate and adaptive immunity

Paradoxically, may be associated with an increased incidence of autoimmunity
CONGENITAL (PRIMARY) IMMUNODEFICIENCIES

Inherited abnormalities affecting innate immunity most commonly affect the
complement pathway or phagocytes

Abnormalities in lymphocyte development may be caused by mutations in genes
encoding a variety of molecules, including enzymes, adaptors, transport proteins,
and transcription factors

Abnormalities in B lymphocyte development and function result in deficient
antibody production and are diagnosed by reduced levels of serum Ig, defective
antibody responses to vaccination, and, in some cases, reduced numbers of B
cells in the circulation or lymphoid tissues or absent plasma cells in tissues

Abnormalities in T lymphocyte maturation and function lead to deficient cellmediated immunity and may also result in reduced antibody production. Primary
T cell immunodeficiencies are diagnosed by reduced numbers of peripheral blood T
cells, low proliferative responses of blood lymphocytes to polyclonal T cell
activators such as phytohemagglutinin, and deficient cutaneous delayed-type
hypersensitivity (DTH) reactions to ubiquitous microbial antigens, such as
Candida antigens

Defects in Innate Immunity
Defective Microbicidal Activities of
Phagocytes: Chronic Granulomatous Disease (CGD)

CGD occures 1 in 1 million individuals, and About two thirds are X -linked
recessive

The most common X-linked form of the disease is caused by a mutation in the
gene encoding the 91-kD α subunit of cytochrome b558, an integral membrane
protein also known as phox-91

Defective production of superoxide anion, that constitutes a major microbicidal
mechanism of phagocytes

Mutations in other components of the phox complex autosomal recessive variants
of CGD

CGD characterized by recurrent infections with catalase-producing intracellular
bacterial and fungi, usually from early childhood

Dx by NBT (screening test), NitroBlue-Tetrazolium (NBT) test

The disease is often fatal, even with aggressive antibiotic therapy

IFN-γ therapy is now commonly used for the treatment of X-linked CGD
CGD
Leukocyte Adhesion Deficiencies (LAD)

Leukocyte adhesion deficiency type 1 (LAD-1) is a rare AR characterized by
recurrent bacterial and fungal infections and impaired wound healing

Adhesion-dependent functions of leukocytes include adherence to endothelium,
neutrophil aggregation and chemotaxis, phagocytosis, and cytotoxicity mediated
by neutrophils, natural killer (NK) cells, and T lymphocytes are impaired

The molecular basis of LAD-1 the defect is absent or deficient expression of the β-2
integrins (heterodimers of CD18 and the CD11 family of glycoproteins) due to
various mutations in the CD18 gene

The β-2 integrins include leukocyte function-associated antigen-1 (LFA-1 or
CD11aCD18), Mac-1 (CD11bCD18), and p150,95 (CD11cCD18)
LAD-1

In contrast, LAD-2 results from an absence of sialyl Lewis X, the tetrasaccharide
carbohydrate ligand on neutrophils that is required for binding to E-selectin and Pselectin on cytokine-activated endothelium

This abnormality in fucosylation seen in LAD-2 also contributes to a Bombay
blood group phenotype caused by the absence of all ABO blood group antigens as
well as to mental retardation and other developmental defects

Leukocyte adhesion deficiency type 3 (LAD-3) involves a defect in inside-out
signaling and thus a defect in chemokine-induced integrin activation that is
required for leukocytes to bind firmly to endothelium
Defects in NK Cells and Other Leukocytes:
Chediak-Higashi Syndrome

Rare AR disorder characterized by recurrent infections by pyogenic bacteria,
partial oculocutaneous albinism, and infiltration of various organs by nonneoplastic Iymphocyte

Neutrophils, monocytes, and lymphocytes of these patients contain giant lysosomes

Caused by mutations in the gene encoding the lysosomal-trafficking regulator
protein LYST,
◦ resulting in defective phagosome-lysosome fusion in neutrophils and
macrophages (causing reduced resistance to infection),
◦ defective melanosome formation in melanocytes (causing albinism),
◦ and lysosomal abnormalities in cells of the nervous system

Leukopenia, impaired NKC and CTL function,

Beige mouse is animal model
Inherited Defects in Toll-like Receptor
Pathways and NF-κB Signaling

These patients suffer from infections with encapsulated pyogenic bacteria, as well as
with intracellular bacterial pathogens including mycobacteria, viruses, and fungi

Severe Combined Immunodeficiencies
(SCID)

SCID are characterized by deficiencies of both B and T cells or only of T cells; in
the latter cases, the defect in humoral immunity is due to the absence of T cell
help. Children with SCID usually have infections during the first year of life,
Pneumocystis jiroveci pneumonia being particularly common, and they succumb
to these infections unless they are treated

About 50% of SCIDs are autosomal recessive; the rest are X-linked. The most
common cause of AR SCID is deficiency of the enzyme adenosine deaminase
(ADA), required for purine metabolism. X-linked SCID is caused by mutations in
the gene encoding a cytokine receptor component called the common γ chain
SCIDs
X-linked SCID

Approximately, 50% of SCID cases are X-linked and due to mutations in the gene
encoding the common (γc chain shared by the receptors for the IL-2, IL-4, IL-7, IL9, and IL-15

Is characterized by impaired maturation of T cells and NK cells and greatly
reduced numbers of mature T cells and NK cells, but the number of B cells is usually
normal or increased

Humoral immunodeficiency in this disease is due to a lack of T cell help

AR mutation in cytokine signaling that lead to impaired T cell development due to
IL-7 receptor α chain or the JAK3 kinase, which associates with the γc
ADA Deficiency and Other Forms of SCID Caused by Defects
in Nucleotide Metabolism

The most common cause of autosomal recessive SCID is deficiency of an enzyme
called adenosine deaminase (ADA) due to mutations in the ADA gene

Deficiency of the enzyme leads to the accumulation of deoxyadenosine and its
precursors S-adenosylhomocysteine and deoxyadenosine triphosphate (dATP). These
by products have many toxic effects, including inhibition of DNA synthesis

ADA deficiency leads to reduced numbers of B and T cells; lymphocyte cell
numbers are usually normal at birth but fall off precipitously during the first year of
life

A rarer autosomal recessive form of SCID is due to the deficiency of purine
nucleoside phosphorylase (PNP), an enzyme that is also involved in purine
catabolism. with toxic effects on immature lymphocytes, mainly T cells.
Autoimmune hemolytic anemia and progressive neurologic deterioration are also
features of this disorder

A particularly severe form of SCID is seen in a disease called reticular dysgenesis.
This rare disorder is characterized by the absence of T and B lymphocytes and
most myeloid cells, including granulocytes, and is due to a defect in the
development of lymphoid and myeloid progenitors. This autosomal recessive
disease is due to a mutation in the adenylate kinase 2 (AK2) gene that increased
apoptosis of lymphoid and myeloid precursors.
SCID Caused by Defects in
V(D)J Recombination and Pre-TCR Checkpoint Signaling

Absence of V(D)J recombination leads to a failure to express the pre-TCR and
the pre-BCR and a block in T and B cell development. Mutations in the RAG1 or
RAG2 genes (whose protein products mediate the cleavage step during V(D)J
recombination) or the ARTEMIS gene

Hypomorphic mutations (that only partially reduce function) in the RAG genes, in
ARTEMIS, or in the IL7RA gene are the cause of a disorder characterized by
restricted generation of T and B cells, immunodeficiency, and immune
dysregulation. This disorder is known as Omenn’s syndrome
Bare Lymphocyte Syndrome

The generation of single-positive CD4+ and CD8+ T cells from double-positive
thymocytes depends on positive selection and lineage commitment events. Specific
inherited mutations in genes that regulate the process of positive selection abrogate
the development of CD4+ T cells or of CD8+ T cells

Class II MHC deficiency, also called bare lymphocyte syndrome, is a rare
heterogeneous group of autosomal recessive diseases in which patients express little
or no HLA-DP, HLA-DQ, or HLA-DR on B lymphocytes, macrophages, and
dendritic cells and fail to express class II MHC molecules in response to IFN-γ

Affected individuals are deficient in DTH responses and in antibody responses to
T cell– dependent protein antigens

Autosomal recessive class I MHC deficiencies have also been described and are
characterized by decreased CD8+ T cell numbers and function
Defective Thymic Development:
DiGeorge's Syndrome

This selective T cell deficiency is due to a congenital malformation that results in
defective of the thymus and the parathyroid glands

Is manifested by hypoplasia or agenesis of the thymus leading to deficient T cell
maturation, absent parathyroid glands causing abnormal calcium homeostasis and
muscle twitching (tetany), abnormal development of the great vessels, and facial
deformities

Deletion in chromosome 22q 11.2 and Mutations in a gene encoding a transcription
factor called T box-1 (TBX1)

Peripheral blood T lymphocytes are absent or greatly reduced in number

Can be corrected by fetal thymic transplantation or by bone marrow
transplantation
DiGeorge's Syndrome

Antibody Deficiencies: Defects in B Cell
Development and Activation
X-Linked Agammaglobulinemia: An X-linked Pre-BCR
Signaling Defect

Bruton’s agammaglobulinemia is characterized by the absence of gamma globulin
in the blood in boys

One of the most common PID due to of a failure of B cell maturation (pre- B cell
stage)

Mutations or deletions in the gene encoding an enzyme called Bruton tyrosine
kinase (Btk)

Btk is involved in transducing signals from the pre-B cell receptor (pre-BCR) that
are required for the survival and differentiation of pre-B cells

low or undetectable serum Ig, reduced or absent B cells in peripheral blood and
lymphoid tissues, no germinal centers in lymph nodes, and no plasma cells in
tissues

The maturation, numbers, and functions of T cells are generally normal

Autoimmune disorders develop in almost 20% of patients, for unknown reasons

Knockout mice lacking Btk, as well as naturally Btk mutant Xid mice

Autosomal recessive Pre-BCR checkpoint defects include genes encoding the μ
(IgM) heavy chain, the λ5 surrogate light chain, Igα (a signaling component of the
pre-BCR and BCR), and BLNK (an adaptor protein downstream of the pre-BCR and
BCR).
Selective Immunoglobulin Isotype Deficiencies

The most common is selective IgA deficiency, 1 in 700 caucasian

Many patients are entirely normal; others have occasional respiratory infections
and diarrhea; and rarely, patients have severe, recurrent infections leading to
permanent intestinal and airway damage, with associated autoimmune disorders

IgA deficiency is characterized by low serum IgA, usually less than 50 μg/mL
(normal, 2 to 4 mg/mL), with normal or elevated levels of IgM and IgG

The defect in these patients is a block in the differentiation of B cells to IgA
antibody-secreting plasma cells

In some patients, mutation in TACl (transmembrane activator and calcium
modulator and cyclophilin ligand interactor), cytokines BAFF (B cell activating
factor) and APRIL (a proliferation-inducing ligand)
Selective IgG subclass deficiencies

Deficiency of IgG3 is the most common subclass deficiency in adults, and IgG2
deficiency associated with IgA deficiency is the most common in children
Defects in B Cell Differentiation:
Common Variable Immunodeficiency (CVID)

Defined by reduced levels of serum Ig, impaired antibody responses to infection
or vaccines, and increased incidence of infections

Ig deficiency and associated pyogenic infections are major components of these
disorders typically with Haemophilus influenzae and Streptococcus pneumoniae,
autoimmune diseases, including pernicious anemia, hemolytic anemia, and
rheumatoid arthritis

Associate with high incidence of malignant tumors particularly lymphomas

Mature B lymphocytes are present in these patients, but plasma cells are absent in
lymphoid tissues, which suggests a block in B cell differentiation to antibodyproducing cells

Multiple abnormalities, including intrinsic B cell defects, deficient T cell help, and
excessive "suppressor cell" activity may due to deletion in the ICOS (inducible T
cell costimulator) gene. ICOS is required for T follicular helper cell generation
Defects in T Cell-Dependent B Cell
Activation: Hyper-lgM Syndromes

The X-linked hyper-IgM syndrome is caused by mutations in the gene encoding the
T cell effector molecule CD40 ligand (CD154)

X-linked associated with defective switching of B cells to the IgG and IgA isotypes

Patients suffer from infections with defects in cell-mediated immunity
(Pneumocystis jiroveci)

AR form with genetic defects may be in CD40 or in the enzyme activation-induced
deaminase (AID) and uracil N glycosylase (UNG)

Defects in T Lymphocyte Activation and Function
Defects in TCR Signal Transduction

Include impaired TCR complex expression or function caused by mutations in the
CD3 ε or γ genes, defective TCR-mediated signaling caused by mutations in the
ZAP-70 gene, reduced synthesis of cytokines such as IL-2 and IFN-γ and lack of
expression of IL-2 receptors

May have deficiencies predominantly in T cell function or have mixed T cell and B
cell immunodeficiencies despite normal or even elevated numbers of blood
lymphocytes
Wiskott-Aldrich Syndrome (WAS)

Variable degrees of T and B cell immunodeficiency, an X-linked disease
characterized by eczema, thrombocytopenia (reduced blood platelets), and
susceptibility to encapsulated bacterial infection,

With increasing age, the patients show reduced numbers of lymphocytes and more
severe immunodeficiency

Mutated gene is WASP (Wiskott-Aldrich syndrome protein) leads to defective
activation and synapse formation in lymphocytes, and defective mobility of all
leukocytes
WAS
X-linked Lymphoproliferative Syndrome

Characterized by an inability to eliminate Epstein-Barr virus (EBV), eventually
leading to fulminant infectious mononucleosis and the development of B cell
tumors and associated hypogammaglobulinemia

In about 80% of cases, the disease is due to mutations in the gene encoding an
adapter molecule called SAP (SLAM-associated protein) that binds to a family of
cell surface molecules involved in the activation of NK cells and T and B
lymphocytes

Resulting enhanced apoptosis of T cell and NK-T cells leads to a marked depletion
of these cell
Defective CTL and NK Cell Activation:
The Familial Hemophagocytic Lymphohistiocytosis Syndromes

HLH syndromes are a group of life-threatening immunodeficiency disorders in
which NK cell and CTL granule secretion is defective

As a result, viral infections are not held in check, and uncontrolled macrophage
activation is a feature of these syndromes

A late but striking feature of these disorders is the ingestion of red blood cells by
activated macrophages (hemophagocytosis). Mutations in the perforin gene, as
well as mutations in genes encoding the cellular machinery

Specifically, mutations in RAB27A, a small guanosine triphosphatase involved in
vesicular fusion, and in MUNC13-4, which encodes an adaptor that participates in
granule exocytosis
Multisystem Disorders with Immunodeficiency:
Ataxia Telangiectasia

AR disorder characterized by abnormal gait (ataxia), vascular malformations
(telangiectases), neurologic deficits, increased incidence of tumors, and
immunodeficiency

The most common humoral immune defects are IgA and IgG2 deficiency

T cell defects which are usually less pronounced are associated with thymic
hypoplasia

Disorder is located on chromosome 11 and encodes a protein called ATM (ataxia
telangiectasia mutated)
Ataxia Telangiectasia
Therapeutic Approaches for PID

Passive immunization (IVIG): for agammaglobulinemic patients

Hematopoietic stem cell transplantation, Bone marrow transplantation (BMT) :
for ADA deficiency, Wiskott-Aldrich syndrome, bare lymphocyte syndrome, and
leukocyte adhesion deficiencies

Enzyme replacement therapy: for ADA and PNP deficiencies

In theory, the therapy of choice for PID is gene therapy