Allergy & Immunology for the Boards: Primary Immunodeficiency

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Allergy Immunologyfor the Boards Primary
Immunodeficiency

• Regina D. Wells, MD
• Allergy Immunology Fellow
• Baylor College of Medicine
• Department of Pediatrics

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What the Boards want you to know

• Allergy and Immunology covers 4.5 of the test
• Only ID is higher at 5.5 of the test
• Must know
• Initial presentation of those with Primary
  Immunodeficiency (PID)
• Screening tests for initial evaluation of a
  patient with recurrent infections
• Treatment of patients with PID
• Know certain PID entities
• Chronic Granulomatous Disease (CGD)
• DiGeorge Syndrome
• Severe Combined Immunodeficiency (SCID)
• Wiskott Aldrich Syndrome (WAS)

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Objectives

• List the major components of our immune system
• Identify via history and physical exam findings
  the major primary immunodeficiencies
• Initiate work-up of patients with signs/symptoms
  of immune dysfunction
• Know when to refer to an immunologist

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Normal Frequency of Infections
Adamkeiwicz and Quie, Report on Ped ID, 1992
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Differential Diagnosis of Recurrent Infections

• Anatomic Abnormalities
• Foreign Bodies
• Defects in mucus clearance
• Atopic conditions
• Secondary Immunodeficiencies
• Primary Immunodeficiency

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Clinical conditions associated with recurrent
infections

• Collagen Vascular diseases
• Cystic Fibrosis
• Diabetes
• Genetic/metabolic conditions
• Hematologic conditions
• Newborn state
• Malnutrition
• Chronic renal insufficiency
• Sarcoidosis
• Chronic viral illnesses (EBV, HIV)
• Malignancies

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Indications for Immunological Evaluation
RED FLAG FAMILY HISTORY
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General Physical Signs of PID

• DYSMORFIC FACIES, HEART MURMUR
• ORAL THRUSH
• FAILURE TO THRIVE
• ATYPICAL ATOPIC DERMATITIS/ ERYTHRODERMA
• SMALL TONSILS
• GINGIVAL DISEASE
• ABSENCE OF PALPABLE LYMPH NODES
• LYMPHADENOPATHY/ORGANOMEGALY
• TELANGIECTASIAS

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VALUE OF SCREENING TESTS

• WBC and Differential
• Absolute neutrophil count (ANC)
• Absolute lymphocyte count (ALC)
• Platelet count and morphology (Mean Platelet
  VolumeMPV)
• Serum Immunoglobulins IgG, IgA, IgM
• Functional Antibody levels Diphtheria, Tetanus,
  HIB, Pneumococcus from the Humoral Immune Panel
  (HIP) HiB titer
• Lymphocyte subpopulations
• T cells CD2, CD3, CD4 (naïve and memory
  subsets), CD8
• NK cells CD16/56,
• B cells CD19, CD20
• Total Hemolytic Complement (CH50)
• Lymphocyte proliferation to mitogens and antigens

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Primary Immunodeficiency Diseases

• Broad Group of Heterogeneous Disorders
• Over 100 different diseases with gt100 different
  genes identified
• Early diagnosis is essential
• Effective therapies
• Improved prognosis
• Prenatal diagnosis and genetic counseling

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PID General Considerations

• 58 of cases diagnosed in children less than 15
  years of age
• 83 of these are males
• X-linked recessive, autosomal recessive,
  autosomal dominant and sporadic inheritance
  patterns are observed

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Cells involved
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Categories of Immunodeficiency

• Innate Immunity
• Neutrophil defects
• Complement defects
• Interferon-gamma/IL-12 pathway defects

• Adaptive Immunity
• Humoral immune defects
• Cellular immune defects

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Innate Immunity

• Phagocytes
• Complement

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Innate Immune Defects

• Phagocytic dysfunction
• Chronic granulomatous disease (CGD)
• Leukocyte adhesion deficiency (LAD)

• Complement Deficiency
• Two categories
• Early components (C1 to C4)
• Terminal components (C5 to C9)

Interferon-gamma/IL-12 pathway
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Clinical Presentation of Phagocyte Complement
Defects

• Phagocyte Defects
• Infection with catalase-positive organisms
• Soft tissue abscesses or lymphadenitis
• Chronic gingivitis and periodontal disease
• Mucosal ulcerations
• Poor wound healing
• Delayed separation of the umbilical cord

• Complement Defects
• Abrupt onset of sepsis with encapsulated
  organisms
• Angioedema of the face hands, feet or GI tract
• Autoimmune manifestations
• Pyogenic bacterial infections
• Recurrent disseminated Neisserial infections
• History suggestive of autosomal dominant
  inheritance

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Phagocytic Defects

• Chronic Granulomatous Disease

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Chronic granulomatous disease

• Neutrophil defect characterized by impaired
  intracellular killing of bacterial and fungal
  organisms. X-linked and autosomal recessive forms
  exist.
• The neutrophils cannot produce hydrogen peroxide
  and the other superoxides required to kill
  catalase-positive organisms (Staph. aureus,
  Escherichia coli, Pseudomonas sp, Klebsiella sp,
  Proteus sp, Salmonella sp, Serratia marcescens,
  Burkholderia, Aspergillus, Nocardia).
• Common presenting symptoms lymphadenopathy
  (often with drainage), granuloma formation,
  abscesses, osteomyelitis, and hepatosplenomegaly.
• Diagnosis is made on the basis of the clinical
  picture and the nitroblue tetrazolium (NBT) dye
  reduction test, dihydrorhodamine 123 assay (DHR),
  or the chemiluminescence test

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Chronic Granulomatous Disease

• Gene defect chromosome location
• gp91 phox (XL 57 of cases)
• p22 phox (AR 5 of cases)
• p47 phox (AR 33 of cases)
• p67 phox (AR 5 of cases)
• Large gene deletions in gp91 phox have been
  associated with
• McLeods hemolytic anemia (Kell null phenotype)
• Duchennes MD
• X-linked retinitis pigmentosa

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Laboratory Tests in the Diagnosis of CGD

• Neutrophil function
• Nitroblue tetrazolium assay (NBT)
• Dihydrorhodamine Assay (DHR)
• Chemiluminescence or flow cytometry
• Chemotaxis

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Nitroblue Tetrazolium Assay

• Non-specific means of measuring neutrophil
  function
• Colorless NBT dye is changed to blue with
  neutrophil formazan formation
• Cells are evaluated at rest and following
  endotoxin stimulation

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Nitroblue tetrazolium test (NBT)

• Colorless dye
• Uptake into neutrophils
• Reduced via NADPH oxidase into blue color

NBT
NBT -
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Dihydrorhodamine 1,2,3 Assay

• DHR is a fluorescent dye used with flow cytometry
• Neutrophils are stimulated with PMA and undergo
  respiratory burst producing reactive oxygen
  species
• The dye is oxidized and causes a shift of the
  florescence to the right on the cytometer.
• Typically correlates with NBT assay but may be
  more sensitive assay than NBT, especially in
  carriers

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Normal patient unimodal shift of florescence
after PMA stimulation
X-Linked CGD absent shift of florescence after
PMA stimulation
Carrier dual population of neutrophils (some
that adequately oxidase dihydrorhodamine dye and
some that do not)
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Positive DHR in X-linked CGD

• Patient Control 1
• Date Drawn 08/26/2005 08/26/2005
• Assay Date 08/27/2005 08/27/2005
• Fluorescence
  Fluorescence
• Geometric Mean
  Geometric Mean
• Unstimulated 9.9 10.2
• Stimulated 37.6 2265.1

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Treatment Options for CGD

• Prophylaxis with antibiotics and antifungals
• Sulfonamides, rifampin
• Itraconazole, amphotericin B
• Interferon gamma
• Can up-regulate expression of cytochrome b-558
  and partially correct the metabolic defect in CGD
  phagocytes
• Effective in autosomal recessive disease also
• May cause secondary amyloidosis with long term
  usage (Maury, et.al 1987)
• Stem Cell Transplant
• Gene Therapy

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You are evaluating a 4 mo old boy who has had
three prior abscesses caused by Staphy aureus.
He also has a history of UTI caused by Serratia
marcescens. He currently has an abscess on his
buttock, which is draining copius pus. You
suspect an immunodeficiency because of his
recurrent infections. What laboratory test is
most likely to confirm the diagnosis?
Nitroblue tetrazolium test and/or
Dihydrorhodamine Assay
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Chronic Granulomatous Disease

• Phagocytic cell disorder
• Defect in oxidative metabolism inhibition of
  NADPH oxidase
• Recurrent infections S. aureus, Serratia,
  Nocardia, aspergillus, and Candida
• Diagnosed by NBT/DHR assays
• Therapy prophylaxis with Bactrim and
  Itraconazole, SQ INF-gamma

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Phagocytic Defects

• Leukocyte Adhesion Deficiency

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Leukocyte Adhesion Deficiency

• Absent ?2 integrin (CD18) of 3 cell surface
  glycoproteins (CD11 family)
• Gene defect chromosome location 21q22.3 gene
  product CD18
• Neutrophils cannot migrate toward inflammatory
  stimuli or adhere to vascular endothelium
• Diagnosis suggested by
• Delayed umbilical cord separation gt 1 month from
  birth
• Leukocytosis with neutrophilia
• Recurrent soft tissue infections
• No pus formation despite high white cell counts
• Severe peridontal disease

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LAD Types

• LAD I beta 2-integrin family is deficient or
  defective
• delayed umbilical cord separation, severe
  infections
• LAD II fucosylated carbohydrate ligands for
  selectins are absent
• mental retardation, mild infections
• LAD III activation of all betaintegrins (1, 2,
  and 3) is defective
• looks like LAD I but also has bleeding diathesis
  secondary to defective Intergin 3 found on
  platelets

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Testing and Treatment for LAD

• Testing
• Flow cytometry measurement of CD11, CD18 subunits
  will show decreased expression of CD18 for LAD
  type I
• Blood Bank analysis for presence of Bombay (hh)
  blood phenotype red cells lacking A, B, and H
  antigens for LAD type II
• Type III is very rare and mainly based on
  clinical picture
• Treatment
• Aggressively treat all infections with
  antibiotics for Type I
• Fucose supplementation 5 times daily for Type II
• Frequent blood transfusions and antibiotics for
  Type III
• Bone Marrow or Stem Cell Transplantation

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Classic Presentation

• 3 month old male presents with history of fever
• WBC 70,000 with 80 segs
• History of delayed umbilical stump separation at
  9 weeks of age
• What is your diagnosis and how to confirm this?

LAD type I confirmed with CD11/CD18 expression
analysis
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Innate Immunity

• Complement Defects

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Classic Complement Pathway
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Complement Component Deficiency

• Deficiency of most complement components have
  been reported and abnormal genes have been
  isolated
• Reported in less than 2 of all
  immunodeficiencies
• Complement component 2 (C2) deficiency most
  commonly reported
• Complements C2 and C4 related to connective
  tissue disease
• Complement deficiency of components 5 through 8
  associated with recurrent Neisseria species
  infection
• Deficiency of the complement regulatory protein
  C1 esterase inhibitor associated with angiodema
  (hereditary angiodema)
• All are associated with pyogenic infections

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Alternative Complement Pathway Deficiencies and
Disease

• Factor I
• Pyogenic, meningococcal infection
• Factor H
• Uncommon meningococcal infection, SLE association
• Properdin
• Occasional pyogenic/pneumococcal infections,
  dermal vaculitis, discoid SLE

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Complement Testing Available

• Alternate Pathway
• Measure of specific components
• Factor I, Factor H, properdin, C3
• AH50
• Indirect functional assay measuring 50 lysis due
  to alternate pathway specific components
• Classic Pathway
• Measures of specific complement components
• CH50
• Measures 50 sheep RBC lysis with complement
  containing human whole blood

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CH50 Assay
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Treatment of Complement Deficiency

• Symptomatic care
• Frequent use of antibiotics
• Immunizations with bacterial polysaccharide or
  conjugate vaccines, (e.g. Pneumococcal,
  Meningococcal vaccines)
• Recombinant C1 esterase or androgen therapy for
  HAE, fresh frozen plasma (FFP) for
  bradykinin/kalikrienin pathway defects

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Adaptive Immunity

• Humoral Immunity
• Cellular Immunity

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Immune Responses

• Humoral Immunity
• Passive Immunity
• IM or IV Ig
• Transplacental IgG
• Colostrum and breast milk IgA
• Active Immunity
• Infections
• Vaccinations

• Cellular Immunity
• APC
• Dendritic cells
• Monocytes/Macs
• T helper cells
• CD4
• Cytotoxic and NK cells
• CD8
• CD16
• CD56

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Clinical Presentation of Antibody Cellular
Defects

• Antibody Defects
• Recurrent bacterial sinopulmonary infections or
  sepsis, particularly with encapsulated organisms
• Unexplained bronchiectasis
• Chronic or recurrent gastroenteritis (often
  Giardia or enterovirus)
• Chronic enteroviral meningoencephalitis
• Arthritis

• Cellular Defects
• Recurrent, severe, or unusual viral infections
• Failure to thrive
• Infection with fungal pathogens
• Pneumocystis jirovecii
• Graft vs. host disease

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Humoral Immunity Dysfunction
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Humoral Immunity Dysfunction

• 50 of primary immune deficiencies
• Most common immune disorder group
• X-linked agammaglobulinemia (XLA)
• AR agammaglobulinemia
• Hyper IgM syndrome (when not X-linked)
• Common Variable immunodeficiency (CVID)
• IgA deficiency
• IgG subclass deficiency
• Selective antibody deficiency

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Clinical Laboratory StudiesHumoral Immunity

• Humoral Immunity
• Serum Immunoglobulins (QIGs) IgM, IgG, IgA
• Humoral Immune Panel (HIP) Diphtheria, Tetanus,
  HiB, Pneumococcus titers
• Serum specific antibody titers

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Humoral Immunity

• Pathogens
• Encapsulated organisms
• Salmonella
• N. minnigitidis
• H. influenza
• B. pertussis
• E. coli
• Yersenia pestis
• Pseudomonas

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IgA Deficiency

• Most common primary immunodeficiency
• 1400- 13000 healthy blood donors
• Extremely low or absent IgA level
• Symptomatic patients have sinusitis, OM,
  diarrhea, malabsorption, Giardia is frequent
• Family history of Immunodeficiencies (CVID, XLA)
• Genetic studies localize the defect to the HLA
  -DQ and HLA - DR locus

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X-Linked Agammaglobulinemia (Brutons)

• Patients present at 4-6 months of age when
  maternal IgG wanes
• Lack of ability to make an antibody response to
  antigen
• Reduced to absent lymphoid tissue
• ie NO TONSILS
• Enteroviral meningoencephalitis associated with
  echovirus infxn
• Labs
• Quantitative immunoglobulins (QIGs IgM, IgG,
  and IgA) are low secondary to absent B-cells
• Humoral Immune Panel no antibodies present to
  common childhood vaccines (Diphtheria, Tetanus,
  HiB, S. pneumoniae)
• Genetic eval shows defect in the Bruton Tyrosine
  Kinase (BTK) gene on Xq 21.3-22 a signaling
  molecule necessary for early B-cell development
• Tx IVIG therapy

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XLA TREATMENT

• Ig monthly dose is 400-600mg/kg for life
• Given as an intravenous infusion or as a
  subcutaneous infusion
• Dose is titrated based on trough levels and
  clinical symptoms
• Genetic counseling regarding offspring disease
  risk

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Transient Hypogammaglobulinemiaof Infancy (THI)

• Accentuated and prolonged physiological
  hypogammaglobulinemia
• B cell and T cells
• Normal number
• Normal function
• Specific antibody responses to immunizations are
  normal
• IgG and IgA low
• Not markedly low
• Increase with time
• Treatment
• Supportive with prompt treatment of infections
• Repeat QIGs every 6 months to a year until
  normalized, some may not normalize until
  pre-teens and some will go on to develop CVID

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Antibody Deficiency Syndromes
Adapted from New Orleans Pediatric Board Review,
Ricardo Sorensen
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Cellular Immunity Dysfunction
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Cellular Immunity Dysfunction

• Characterized by increased susceptibility to
  opportunistic organisms ie CMV, Pneumocystis, and
  Candida
• DiGeorge Syndrome
• Severe combined immunodeficiency (SCID)
• Wiskott-Aldrich syndrome (WAS)
• Ataxia-telangiectasia (AT)
• NEMO immunodeficiency
• X-linked Hyper IgM syndrome

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Clinical Laboratory StudiesCellular Immunity

• CBC with diff, Blood smear
• Delayed type hypersensitivity skin testing
  (DHST) response means that the
  uptake/processing of antigen by APC, interaction
  with CD4 Th cells, cytokine production by T
  cells, and recruitment and activation of
  monocytes/macs are intact
• unreliable in kids lt1 yr
• often suppressed during viral and bacterial
  infections
• suppressed by anti-inflammatory drugs and
  immunosuppressants
• requires injection of tetanus toxoid, mumps
  antigen, candida antigen (PPD also used)
• Results Induration gt 5mm is for all ages, if
  induration gt 2 mm is sometimes considered
  positive in younger children
• Full Phenotyping identifies and of T cells
  (CD2, CD3, CD4, CD8, and NK cells)
• Lymphocyte proliferative assay (LPA) Mitogen and
  Antigen studies to assess function of T and B
  cells

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Cellular Immunity

• Pathogens
• Replicate intracellularly
• Viruses
• Mycobacteria
• Some bacteria
• ie chlamydia
• Cells with aberrant differentiation
• Neoplasms
• Allogeneic cells
• Graft rejection

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Severe Combined Immunodeficiency

• Lymphopenia ALC lt2500
• Failure to Thrive
• Persistent infections with common organisms
• Opportunistic Infections
• Usually Presents before 6 months
• NO cellular or humoral immunity even though B
  cells can be present
• Risk for GVHD

• T- B NK-
• IL2R?, JAK3
• T- B NK
• RAG1, RAG2
• T- B- NK-
• ADA
• T-BNK
• IL7R,CD3D, CD3E

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Treatment for SCID

• Stem cell/cord blood transplant
• Gene therapy for enzyme deficiencies (ie. ADA)
• Supportive care
• PEG-ADA replacement therapy
• Intravenous or subcutaneous IgG
• PCP prophylaxis
• Irradiated PRBCs/blood products to avoid GVH risk
• Avoid live viral vaccines (rotavirus, varicella,
  MMR)

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Classic Presentation

• 3 month old male admitted with respiratory
  distress with history of severe RSV bronchiolitis
  requiring hospitalization at 1 month of age,
  persistent diarrhea even after frequent formula
  changes, and FTT
• CBC showed WBC of 2,000 and ALC of 750
• What is your diagnosis and initial clinical
  intervention?

SCID assess and treat for presumptive PCP
pneumonia
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Classic Presentation
A 4 mo old boy is admitted to the ICU after
developing seizures at home. He has a history of
chronic diarrhea, failure to thrive, recurrent
candidal diaper dermatitis. PE reveals low-set
ear and a III/VI holosystolic heart murmur at the
lower sternal border. On CXR
Hypoplastic or Absent thymus
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Digeorge Syndrome

• 22q11 deletion, 10p deletion, 5-10 of DiGeorge
  patients are FISH negative
• Maldevelopment of 3-4th branchial arches
• Midline defects and dysmorphic features
• Cardiac defects, TOF most common
• Bifid uvula
• Esophageal atresia
• Hypertelorism
• Low set ears
• Micrognathia
• Varying degree of hypocalcemia
• Varying degrees of T cell dysfunction and
  therefore varying degrees of B cell dysfunction

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DiGeorge Anomaly Partial vs Complete
Partial DGA
Complete DGA

• Uncommon
• Thymic aplasia
• CD4 cells lt 400/mm3
• B-cell numbers normal
• Antibody response decreased
• Susceptible to infections
• Susceptible to GVHD

• Thymic hypoplasia
• Most frequent
• Normal corticomedullary differentiation
• Presence of Hassalls corpuscles
• Normal thymic function
• CD4 cells gt 400/mm3
• T-cell function adequate
• B-cell numbers and function normal
• Usually free of infections

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DiGeorge Treatment

• Multi-speciality involvement
• A/I for immune evaluation should avoid all live
  viral vaccines rotavirus, MMR, Varicella, and
  nasally administered Influenza
• Genetics for family planning
• Cardiology for cardiac defects
• Endocrinology for hypocalcemic seizures
• May require prophylaxis for chicken pox exposure
  with acyclovir
• Antibiotics for frequent infections
• Best Therapeutic approach for complete diGeorge
  Thymic transplant

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Ataxia-telangiectasia
Conjunctivitis
www.ksmf.org/oftalma/ atlas/atlas/Page.html
http//pathologyoutlines.com/eye.html
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AT Background/Epidemiology

• First clinical description in a case study of a
  Belgian child by Louis-Bar in 1941
• Gene mapped to chromosome 11q23 in 1988 and
  cloned in 1995
• AR inheritance
• 1 in 20,000 to 100,000 live births
• AT mutatedATM gene

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AT Clinical Findings

• Progressive cerebellar ataxia
• Oculocutaneous telangiectasias
• Immune deficiency in 70 of patients
• Recurrent sinopulmonary infections
• Premature aging and graying of hair
• Speech difficulties

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AT Prognosis Management

• Median age at death is 20 years
• Patients succumb to progressive pulmonary disease
  caused by repeated infections
• PT/OT initiated early
• Supportive treatment as necessary

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Wiskott Aldrich Syndrome (WAS)

• X-linked congenital disorder
• In 1937, Wiskott first described three boys with
  classical WAS symptoms bleeding due to
  thrombocytopenia (SMALL platelet size), eczema,
  and frequent infections (lymphopenia)
• Estimated incidence of WAS in the United States
  is four per million live male births
• Defect in the WASP gene located at Xp11.22-23,
  exact function unknown

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Wiskott Aldrich Syndrome (WAS)

• Autoimmune dz develop in up to 50 of patients
• most common
• hemolytic anemia, vasculitis, nephritis, immune
  thrombocytopenia (ITP), inflammatory bowel dz
• less frequent
• arthritis, neutropenia, dermatomyositis, and
  uveitis
• Treatment
• frequent antibiotics for infections
• eczema management
• Surveillance for development of malignancy
• BMT for now
• gene therapy currently being researched

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NEMO Deficiency

• X-linked disorder associated with
• Anhidrotic Ectodermal dysplasia
• Recurrent bacterial infections (sepsis,
  pneumonia, osteo)
• Bronchiectasis
• Lmphedema
• Associated with NEMO (NF-KB Essential Modulator)
  gene mutations
• Impacted organ sites (liver, gut epithelia, skin)
• Immune findings
• Hypogammaglobulinemia (IgG, sometimes IgA,IgE)
• Deficient NK cell killing (not present in all
  patients and when present associated with
  recurrent mycobacterial infections)

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NF-KB Essential ModulatorNEMO

• Building component of the IkB kinase complex
• NFkB activation is responsible for B cell
  survival and function
• Impacts homeostasis of many tissues (liver, gut,
  skin)
• Impaired cytokine (TNF) production
• Treatment BMT

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When to Refer to an Immunologist by AAAAI
Eight or more new infections within one year
Two or more serious sinus infections within one
year Two or more months on antibiotic with
little or no effect Two or more pneumonias
within 1 year Failure of an infant to gain
weight or grow normally Recurrent deep skin or
organ abscesses Persistent thrush in mouth or
elsewhere on skin after age 1 year Need for
intravenous antibiotics to clear infections Two
or more deep seated infections A family history
of immune deficiency
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Basic Immune Evaluation

• CBC d/p look at WBC, ALC, ANC, Plt count, Plt
  volume
• CH50 screens for complement deficiency
• Quantitative Immunoglobulins (QIGs) IgM, IgA,
  IgM assesses B cell ability to make antibodies
• Humoral Immune Panel (HIP) HiB titer assesses
  ability to make functional antibodies to
  childhood vaccines (Diphtheria, Tetanus, S.
  pneumo, and Hemophilius influenza)
• Delayed hypersensitivity skin testing (DHST)
  candida, tetanus, mumps, PPD assesses patients
  in vivo T cell function, place only if gt 1 yr of
  age
• HIV ELISA or HIV DNA PCR
• History dependent DHR assay to assess for CGD
  CXR, PTH level, and Ionized Calcium level for
  suspected DiGeorge

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References

• Primary Immune Deficiencies Windows into the
  immune system. Pediatrics in Review. Vol 27, No.
  10 363-371.
• Current Pediatrics Diagnosis and Treatment. Hay,
  William, et. al. 16th Ed, 2003 921-936.
• American Academy of Allergy, Asthma, and
  Immunology. www.aaaai.org
• Chan, Kee et. al. Development of population-based
  newborn screening for severe combined
  immunodeficiency. J Allergy Clin Immunol.
  2005391-98.

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RESOURCES

• Immune Deficiency Foundation
• www.primaryimmune.org
• The Jeffrey Modell Foundation
• www.jmfworld.org
• Severe Combined Immunodeficiency (SCID) homepage
• www.scid.net
• NIH Clinical Trials
• www.clinicaltrials.gov
• NIAID
• www.niaid.nih.gov
• AAAAI
• www.aaaai.org
• Patient Advocacy and Support Organizations
• www.gentiva.com/access/
• BTKbase www.helsinki.fi/science/signal/
• CD40Lbase www.cd40lbase.htm1
• X-CGDbase www.helsinki.fi/science/signal/

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