Congenital or Primary Immunodeficiency

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Chapter 21

• Congenital or Primary Immunodeficiency
• (PID)

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• 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)

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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

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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 cell-mediated 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

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• Defects in Innate Immunity

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Defective Microbicidal Activities ofPhagocytes
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 a 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

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• Dx by NBT (screening test), NitroBlue-Tetrazolium
  (NBT) test
• The disease is often fatal, even with aggressive
  antibiotic therapy
• IFN-? therapy is now commonly used for the
  treatment of X-linked CGD

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CGD
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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 ß-2
  integrins (heterodimers of CD18 and the CD11
  family of glycoproteins) due to various mutations
  in the CD18 gene
• The ß-2 integrins include leukocyte
  function-associated antigen-1 (LFA-1 or
  CD11aCD18), Mac-1 (CD11bCD18), and p150,95
  (CD11cCD18)

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LAD-1
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• 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 P-selectin 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

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Defects in NK Cells and Other LeukocytesChediak-
Higashi Syndrome

• Rare AR disorder characterized by recurrent
  infections by pyogenic bacteria, partial
  oculocutaneous albinism, and infiltration of
  various organs by non-neoplastic 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

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Inherited Defects in Toll-like ReceptorPathways
and NF-?B Signaling

• These patients suffer from infections with
  encapsulated pyogenic bacteria, as well as with
  intracellular bacterial pathogens including
  mycobacteria, viruses, and fungi

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• Severe Combined Immunodeficiencies
• (SCID)

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• 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 ? chain

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SCIDs
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X-linked SCID

• Approximately, 50 of SCID cases are X-linked and
  due to mutations in the gene encoding the common
  (?c chain shared by the receptors for the IL-2,
  IL-4, IL-7, IL-9, 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
  a chain or the JAK3 kinase, which associates with
  the ?c

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ADA Deficiency and Other Forms of SCID Caused by
Defectsin 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

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• 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.

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SCID Caused by Defects inV(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 Omenns
  syndrome

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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-?
• 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

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Defective Thymic DevelopmentDiGeorge'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

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DiGeorge's Syndrome
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• Antibody Deficiencies Defects in B Cell
  Development and Activation

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X-Linked Agammaglobulinemia An X-linked
Pre-BCRSignaling Defect

• Brutons 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

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• 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 ?5 surrogate light chain, Iga (a signaling
  component of the pre-BCR and BCR), and BLNK (an
  adaptor protein downstream of the pre-BCR and
  BCR).

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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)

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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

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Defects in B Cell DifferentiationCommon
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 antibody-producing 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

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Defects in T Cell-Dependent B CellActivation
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)

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• Defects in T Lymphocyte Activation and Function

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Defects in TCR Signal Transduction

• Include impaired TCR complex expression or
  function caused by mutations in the CD3 e or ?
  genes, defective TCR-mediated signaling caused by
  mutations in the ZAP-70 gene, reduced synthesis
  of cytokines such as IL-2 and IFN-? 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

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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

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WAS
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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

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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

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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)

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Ataxia Telangiectasia
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• Therapeutic Approaches for PID

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• 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

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