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Primary Immune Deficiency


Failure to kill organism results in localized infection and abscess (CGD) ... Recurrent neutropenia associated with oral ulcers and perirectal abscesses ... – PowerPoint PPT presentation

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Title: Primary Immune Deficiency

Primary Immune Deficiency
  • Chiraag S. Patel

  • Raise awareness about primary immune deficiency
  • Definition of PID
  • Discuss prevalence
  • Review basic Immunology
  • Overview of common PID
  • Special attention to adult onset disorders
  • Touch upon rare PID (because they are
    fascinating, to me at least)

Primary Immune Deficiency
  • Classified by an intrinsic defect in either the
    innate or adaptive immune system often marked by
    an increased susceptibility to infections
  • More than 120 recognized
  • International Union of Immunological Societies,
    Budapest 2005

PID prevalence
  • textbooks report 1 in 10,000
  • 1999 U.S. Immune Deficiency Foundations survey
    found 1 in 5,000
  • 2007 telephone survey of 27,000 household members
    found 1 in 1,200
  • antibody deficiencies account for approximately
    65 of PID cases

Telephone survey 2007
PID Prevalence
  • IgA- 1400-1,000
  • Most asymptomatic
  • Board correlate IgG2 and IgA deficiency
  • CVID- 125,000-50,000
  • XLA SCID- 1100,000
  • CGD- 1200,000
  • WAS- 11,000,000

PID prevalence cont
  • Many undiagnosed cases
  • 17 of 59 subjects (29)
  • Journal Allergy and Clinical Immunology 2004
  • Mimics other more common chronic conditions
  • asthma or sarcoidosis
  • Annals of Internal Medicine 1997

PID contd
  • Delay of several years from the onset of symptoms
    to the diagnosis of PID
  • 5-6 years for Common Variable Immunodeficiency
  • Clinical Immunology 1999
  • In the interim, patients suffer from recurrent
    infections, especially of the sinopulmonary tract

Immunology Basics
  • Innate
  • Phagocytes
  • Macrophages, neutrophils, dendritic cells
  • Complement
  • Adaptive
  • B-cells (humoral or antibody-mediated)
  • Extracellular pathogens
  • T-cells (cell-mediated)
  • Intracellular pathogens

  • Defects in phagocytes generally associated with
    recurrent or severe/unusual pyogenic infections
  • S. aureus, Serratia, Burkholderia, Nocardia,
    Chromobacterium, fungi (esp. Aspergillus)
  • Tend to occur at interfaces between host and
    environment skin, respiratory, GI or GU tracts
  • Failure to kill organism results in localized
    infection and abscess (CGD)
  • Failure to mobilize WBCs to tissues (LAD,
    Chediak-Higashi) may result in rapid spread of
    infection systemically

  • Neutropenia
  • Primary treat with G-CSF, antibiotics as needed
  • Secondary chemotherapy, other immune
    suppressing agents, infection, autoimmune, drugs
  • Suspect in people with unusual, recurrent or
    multiple abscesses

  • Chronic Granulomatous Disease (CGD)
  • 1 200,000
  • Due to genetic deficiencies in NADPH oxidase for
    neutrophil oxidative burst required for
    intracellular killing
  • X-linked most common (65-70), also AR
  • Mean age of presentation 0-8 yrs
  • Older possible, e.g. 31 y/o male case report
    (Mudry, Chest 2005)
  • Infections with catalase positive organsims
  • S.aureus, B. cepacia, S. marcescens, Aspergillus
    spp., Nocardia spp.
  • Granulomatous inflammation lymphadenitis,
    osteomyelitis, visceral abscess, pneumonia
  • Prophylaxis with TMP-SMX, INF-?, itraconazole

Diagnosis - Nitroblue Tetrazolium
  • Normal activated neutrophils reduce NBT and
    produce dark blue crystals
  • Stimulated neutrophils from a CGD patient fail to
    reduce NBT
  • Lab will report positive cells in unstimulated
    and stimulated samples for your patient and a
    healthy control

Neutrophil Oxidative Burst Assay
  • White blood cells are incubated with
    dihydrorhodamine 123 (DHR) and catalase
  • Stimulated with Phorbol 12-Myristate 13-Acetate
  • Dihydrorhodamine oxidation to rhodamine by the
    respiratory burst of the cell is measured by flow

  • Leukocyte adhesion deficiency
  • Failure of neutrophil adhesion and migration to
    site of infection due to defect in CD18 (LAD 1)
  • Neutrophilia, recurrent life-threatening
    infections, little inflammation at site of
  • Delayed cord separation, severe periodontal
  • Myeloperoxidase deficiency
  • Failure to generate hypochlorous acid in
    neutrophil, AR
  • Most common inherited neutrophil disorder
  • Rarely develop serious infection diabetics at
    risk for fungal infections
  • Chediak-Higashi syndrome
  • AR, results in abnormal neutrophil granule
    formation abnormal chemotaxis and degranulation
    with delayed killing
  • Recurrent cutaneous and respiratory infections,
    progresses to malignancy
  • Also oculocutaneous albinism, photophobia and
    nystagmus, neuropathy

  • Hyper-IgE syndrome (Job syndrome)
  • Classified as a phagocytic disorder, but most
    likely represents an abnormality of T cell
    function (dysregulated cytokine IgE production)
  • Candida infections, occult infections due to
    Pneumocystis, Cryptococcus
  • Recurrent pyogenic infections with massively
    elevated IgE levels
  • Recurrent sinopulmonary infections,
    pneumatoceles, severe atopic dermatitis
  • S.aureus most common pathogen
  • IRAK4 deficiency
  • Important signaling molecule in Toll-like
    receptor 4 pathway in macrophages
  • Deficiency leads to recurrent, life-threatening
    Staphylococcal and pneumococcal infections

  • Defects lead to susceptibility to encapsulated
    organisms (S. pneumoniae, N. meningitidis)
    autoimmunity (SLE)
  • Classical pathway
  • activated by IgG, IgM, CRP bound to a microbe
  • MBL pathway
  • activated by Mannan Binding Lectin bound to a
  • Alternative pathway
  • fluid phase activation, amplified on microbe

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  • Early classical complement component deficiencies
  • may be associated with recurrent pyogenic
    infections and or collagen vascular disease (SLE)
  • Alternative pathway deficiencies
  • C3 collagen vascular disease and significant
    infections with encapsulated bacteria
  • Properdin deficiency X-linked, fulminant/fatal
    infections due to a N. meningitidis
  • MBL deficiency
  • Autoimmune, worse prognosis for other infections
    (AIDS), immunosuppressed patients, liver
  • Terminal component deficiencies
  • Associated with infections due to N. meningitidis
    and N. gonorrheae, chronic meningococcemia

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  • Alternate pathway
  • Discovered by Dr. Louis Pillemer in 1954 (CWRU,
    Dept of path)
  • Stabilizes C3 convertase (C3Bb)

Complement- Acquired Def.
  • Lack of synthesis
  • Severe liver dysfunction
  • Increased consumption
  • Immune complex mediated (SLE)
  • DIC, endocarditis, disseminated gonococcal
    infection, hepatitis
  • Some glomerulonephritides C3 nephritic factor
    causes C3 depletion
  • Loss
  • Nephrotic syndrome

  • Shorter mean survival time after AIDS diagnosis
    in men with low serum MBL
  • Cystic fibrosis life expectancy 8 years shorter
    due to increased bacterial colonization of the
    lung (Trevisiol, J. Cystic Fibrosis 2005)
  • Transplant patients rely on innate immunity
  • MBL variant alleles in the donor liver, but not
    in the recipient, associated with increased
    infections following transplantation in a
    gene-dose-dependent way (Bouwman,
    Gastroenterology 2003)

  • Four major classes - IgM, IgG, IgA and IgE
  • neutralize viruses
  • activate complement
  • bind to specific receptors on phagocytes for IgG,
    IgA, IgE
  • Primary Ab response - predominantly IgM
  • Secondary Ab - enhanced recall response, switch
    to IgG (IgA)
  • largely T cell dependent (Th2)

  • Ear and sinus infections more common in antibody
    deficient subjects than in the general population
  • Especially recurrent/refractory pneumonia GI
    infections with viral pathogens or Giardia
  • Rules of thumb
  • Quantitative IgG lt 1000 is abnormal
  • Quantitative IgM lt 100 is abnormal
  • Quantitative IgA lt 200 is abnormal

Antibody IgA deficiency
  • IgA lt 5 mg/dl
  • most common (1400-11000)
  • often asymptomatic, may have recurrent
    sinopulmonary infections
  • may co-exist with IgG subclass deficiency
  • allergy/autoimmunity
  • No treatment (only for infections)

  • Transient hypogammaglobulinemia of infancy
  • Maturational delay with low, persistent nadir in
    Ig production normal event in preterm infants
  • Usually recurrent sinopulmonary infections
  • Usually normal B cell number and response to
  • IgG subclass deficiency
  • Commonly overdiagnosed but may be significant if
    specific antibody production also low
  • IgG2, 4 infection with encapsulated bacteria
  • IgG3 - recurrent respiratory infections
  • May occur in association with IgA deficiency and
    evolve to common variable immunodeficiency

Antibody Brutons disease
  • A.k.a. X-linked agammaglobulinemia (XLA)
  • marked reduction in all Ig classes, B cell
    numbers, production of specific antibodies
  • normal number and function of T cells
  • defect in Brutons tyrosine kinase gene, B cell
    development frozen at early precursor stage
  • beginning after 6 months of age
  • Recurrent sinopulmonary infections
  • Diarrhea due to Giardia
  • Invasive infections (sepsis, meningitis) due to
    encapsulated bacteria (pneumococcus,
  • Skin/soft tissue infections
  • Generally no increased severity of viral
    infections, but at risk for chronic multisystem
    infection due to enteroviruses (including
    dermatomyositis-like syndrome, hepatitis,

Antibody HyperIgM Syndrome
  • X-linked, defect in CD40 ligand expression
  • 1 500,000, 90 by age 4 yrs old
  • Recurrent sinopulmonary and invasive infections
    due to encapsulated bacteria
  • Recurrent neutropenia associated with oral ulcers
    and perirectal abscesses
  • opportunistic infections caused by Pneumocystic
    jiroveci, CMV, adenovirus, Cryptococcus, and
  • Chronic diarrhea due to Giardia or to
    Cryptosporidium, Salmonella, or Entamoeba
  • Markedly reduced IgG IgA high or normal IgM
  • Normal numbers of B and T cells

Antibody CVID
  • Common variable immunodeficiency
  • 1 25,000 at the minimum, many undiagnosed
  • Bimodal distribution 5-10, 25-30 years of age
  • IgG reduced by gt 50, IgA and IgM also reduced

CVID contd
  • Normal number of B cells
  • T cell numbers and function variable
  • Recurrent sinopulmonary infections, GI infections
  • encapsulated pyogenic bacteria common, e.g. S.
    pneumoniae and H. influenzae
  • Allergy, autoimmunity and high risk of malignant
    lymphoreticular disease

CVID contd
  • Minimal response to polysaccharide and protein
  • Bronchiectasis and COPD occur leading to cor
  • 60 present with diarrhea
  • 20 with granulomatous disease mimicking
  • If suspicious send Quantitative Igs

Intravenous Immunoglobin (IVIG)
  • All severe antibody deficiencies are treated with
    replacement therapy
  • Decreases mortality and morbidity
  • Healing of skin lesions and the reversal of
    neutropenia and arthritic symptoms
  • Cost 25,000 per year
  • Pooled from at least 1000 donors
  • Other FDA approved uses
  • ITP, Kawasaki disease, graft-vs-host, CLL

Secondary causes of hypogammaglobulinemia
  • Medications, especially anticonvulsants
  • protein-losing enteropathy
  • nephrotic syndrome
  • lymphoproliferative disease
  • non-Hodgkins lymphoma
  • Multiple myeloma

T cells/combined immunodeficiency
  • T cells required for orchestrating adaptive
    immunity - loss of CD4 (helper) T cells results
    in combined cellular and humoral
    immunodeficiency, even if B cells are normal
  • Deficiency results in infections with
  • Viruses - particularly herpes group
  • Intracellular bacteria - e.g., Mycobacteria,
  • Protozoans- Pneumocystis, Toxoplasma,
    Cryptosporidium, Giardia
  • Fungi - Cryptococcus, Histoplasma, Coccidiodes
  • Mucocutaneous Candidiasis
  • Antibody production to newly encountered microbes
    also compromised

Severe Combined Immunodeficiency (SCID)
  • Presentation usually lt 6-12 mo age
  • Opportunistic infections and recurrent pyogenic
    infections, chronic diarrhea, FTT, eczema
  • Male female 41 (most common form is X-linked)
  • Often fatal before 1 year of age if untreated
  • Decreased number of T cells, variable numbers of
    B cells poor proliferation to mitogens
  • Low or absent IgG and IgA

  • severe deficits in cellular and humoral immunity
  • Classified by inheritance pattern and pattern of
    lymphocytes present
  • X-linked
  • IL-2R? chain - more than half of all cases
  • Same ? chain found in many interleukin receptors
  • Autosomal Recessive
  • RAG, ADA/PNP, JAK3, IL-7Ra??ZAP-70

  • X-linked
  • T-, NK-, B phenotype
  • 60 of SCID, gene identified in 1992
  • Defective gene encodes the cytokine common gamma
  • Mild lymphopenia (mean ALC 1500)
  • 40 have a positive family history
  • Adenosine Deaminase (ADA) Deficiency - AR
  • 15 of all SCID
  • Early onset
  • Profound lymphopenia
  • Clinically heterogeneous
  • ADA is a widely expressed enzyme, involved in
    purine metabolism
  • Build up of toxic metabolic products toxic to T
    cell development

  • RAG1 and RAG2 Deficiency - AR
  • T-, B-, NK
  • 10 of SCID, genes identified in 1989
  • RAG1 and RAG2 form a heterodimer that is required
    to initiate VDJ recombination
  • Moderate lymphopenia (mean ALC 1000)
  • Amino acid substitutions can cause Omenn Syndrome
    (SCID with hyper-eosinophilia)
  • JAK-3
  • T-, NK-, B phenotype
  • 7 of SCID, gene identified in 1994
  • Defective gene encodes a tyrosine kinase
    activated by the cytokine common gamma chain
  • Mild lymphopenia (mean ALC 1500)

Other Forms of T Cell/Combined Immunodeficiency
  • Purine nucleoside phosphorylase (PNP) deficiency
    - AR
  • Rare form of cellular deficiency associated with
    defective Ab production and autoimmunity
  • May present later in childhood
  • 2/3 of patients develop progressive neurological
  • Ataxia-Telangiectasia - AR
  • Mutation in protein required for DNA repair
  • Ocular telangiectasias, cerebellar ataxia
  • Recurrent sinopulmonary infections variable IgA,
    IgG2, IgG4 and T cell deficits
  • Risk of Malignancy in patients and carriers

Other Forms of T Cell/Combined Immunodeficiency
  • DiGeorge Syndrome
  • Developmental field defect of 3rd and 4th
    branchial arches due to chromosomal deletion
  • Cardiac/great vessel gt parathyroid gt thymic
  • Severe hypocalcemia
  • Characteristic facies mandibular hypoplasia,
  • Great variability in the severity of T cell
    abnormality (lt1 have thymic aplasia with absence
    of T cells)

Other Forms of T Cell/Combined Immunodeficiency
  • Wiskott-Aldrich Syndrome
  • X-linked partial combined immune deficiency
  • thrombocytopenia, eczema and recurrent infections
  • sinopulmonary, herpes group viruses and
    occasionally Pneumocystis
  • few, small platelets elevated IgE, reduced IgM
  • Defect in cytoskeletal organization by WASp
    (Wiskott Aldrich Syndrome protein)

X-linked lymphoproliferative disorder (XLP or
Duncan Disease)
  • 1 in 1,000,000
  • Avg age of onset 2.5 yrs old, older reported
  • Unique predisposition to uncontrolled infection
    with Epstein Barr virus
  • EBV induces
  • Fatal/severe infectious mononucleosis
  • Secondary agammaglobulinemia
  • Lymphoma
  • Bone marrow failure
  • Defect in SAP loss interferes with NK and CD8
    CTL function
  • Tx bone marrow transplant

Selective IFN-? receptor, IL-12, IL-12/23
receptor deficiency
  • Age varies
  • Persistent/fatal infection with MAI, BCG, other
    non-tuberculous mycobacteria and MTB
  • Increased risk of severe/recurrent disease due to
    Salmonella, Listeria
  • Defect in IFN-g mediated macrophage activation

  • Immunlogy basics
  • Immune deficiencies
  • Prevalence at least 1 in 1,200
  • Presentation in adulthood not a rarity
  • Innate
  • Phagocytes complement --gt abscesses
  • Adaptive
  • Special attention to CVID
  • Send quantitative immune globulins if suspicious
  • Combined
  • SCID, WAS, AT, XLP, DiGeorge, IFGR def