Primary Immune Deficiency

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Primary Immune Deficiency

• Chiraag S. Patel

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Objectives

• Raise awareness about primary immune deficiency
  (PID)
• 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)

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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

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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

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Telephone survey 2007
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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

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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

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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

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Immunology Basics

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

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Phagocytes

• 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

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Phagocytes

• 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

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Phagocytes

• 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

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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

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Neutrophil Oxidative Burst Assay

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

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Phagocytes

• 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
  infection
• Delayed cord separation, severe periodontal
  disease
• 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

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Phagocytes

• 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

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Complement

• 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
  microbe
• Alternative pathway
• fluid phase activation, amplified on microbe

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Complement

• 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
  transplants
• Terminal component deficiencies
• Associated with infections due to N. meningitidis
  and N. gonorrheae, chronic meningococcemia

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Properdin

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

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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

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MBL-deficiency

• 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)

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Antibody

• 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)

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Antibody

• 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

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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)

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Antibody

• 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
  immunization
• 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

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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,
  meningococcus)
• 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,
  meningoencephalitis)

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Antibody HyperIgM Syndrome

• X-linked, defect in CD40 ligand expression
  (CD154)
• 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
  mycobacteria
• Chronic diarrhea due to Giardia or to
  Cryptosporidium, Salmonella, or Entamoeba
  histolytica
• Markedly reduced IgG IgA high or normal IgM
• Normal numbers of B and T cells

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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

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CVID contd

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

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CVID contd

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

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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

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Secondary causes of hypogammaglobulinemia

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

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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,
  Listeria
• Protozoans- Pneumocystis, Toxoplasma,
  Cryptosporidium, Giardia
• Fungi - Cryptococcus, Histoplasma, Coccidiodes
• Mucocutaneous Candidiasis
• Antibody production to newly encountered microbes
  also compromised

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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

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SCID

• 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

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SCID

• X-linked
• T-, NK-, B phenotype
• 60 of SCID, gene identified in 1992
• Defective gene encodes the cytokine common gamma
  chain
• 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

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SCID

• 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)

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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
  manifestations
• 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

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Other Forms of T Cell/Combined Immunodeficiency

• DiGeorge Syndrome
• Developmental field defect of 3rd and 4th
  branchial arches due to chromosomal deletion
  (22q)
• Cardiac/great vessel gt parathyroid gt thymic
  defect
• Severe hypocalcemia
• Characteristic facies mandibular hypoplasia,
  hypertelorism
• Great variability in the severity of T cell
  abnormality (lt1 have thymic aplasia with absence
  of T cells)

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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)

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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

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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

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Conclusion

• 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