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Congenital or Primary Immunodeficiency

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Chapter 21 Congenital or Primary Immunodeficiency (PID) – PowerPoint PPT presentation

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Title: Congenital or Primary Immunodeficiency


1
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)

4
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

7
  • Defects in Innate Immunity

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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 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

17
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 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 Receptor Pathways
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
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

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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.

28
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 Omenns
    syndrome

29
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

30
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

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DiGeorge's Syndrome
32
  • Antibody Deficiencies Defects in B Cell
    Development and Activation

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X-Linked Agammaglobulinemia An X-linked
Pre-BCR Signaling 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 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 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 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)

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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

47
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

51
  • 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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