Primary Immunodeficiencies

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Primary Immunodeficiencies

• Dr. Katia Sitnitskaya

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Host defense

• Innate immunity
• Complement
• alternative pathway
• Phagocytes - neutrophils
• - macrophages
• Natural killers

• AG-specific immunity
• Complement
• classical pathway AG AB
• T cell response
• B cell AB production

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US how many we are talking about ?
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Most common ?


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Complement cascade you DONT HAVE TO remember
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Complement - opsonization C3b, C5b
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chemotaxis C3a, C5a
- membrane attack C5-9
Opsonization
Chemotaxis
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Complement deficiencies very rare
(-) opsonins
chemotaxis Pyogenic infections
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Complement deficiency

• C5-9 terminal pathway deficiency 40 relapse
  of Meningoccal infection
• 3 5 of cases of Meningococcal infection
  complement deficiency
• AB-sensitized sheep RBC measurement of total
  hemolytic c. by classical pathway (CH50)
• Unsensitized rabbit RBC measurement of total
  hemolytic c. by alternative pathway (AH50)

Deficiency Mechanism Infections CH50
C2 most common opsonins Pyogenic in 1/5 (SLE) lt 10
Properdin (Xp11) opsonins Pyogenic Normal (AH50 low)
C5 - 8 chemotaxis membrane attack Recurrent N.men lt 10
C9 membrane attack Recurrent N.men 50
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Phagocytic disorders
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Phagocytic disorders
LAD
Indigestion CGD, Chediak-Higashi
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Phagocytic Disorders 1. commuting

• LAD
• - the defect is a lack of a neutrophil adhesion
  molecule no emigration into tissues.
• presents with delayed separation of the
  umbilical cord, recurrent SBIs, leukemoid
• reactions

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Leukocyte adhesion deficiency
(LAD) A. Normal neutrophils aggregate
B. Neutrophils from a patient with LAD
type 1 fail to aggregate in vitro C.
Patients with LAD type 1 have periodontitis
recurrent GI,
GU, and respiratory infections
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Congenital agranulocytosis Kostmann Disease

• AR, 1 1 000 000
• An abnormal G-CSFinduced intracellular signal
  transduction ?
• ANC lt 500/mm3 normal WBC count because of the
  monocytosis.
• Abnormal CD64 (FCgRI receptor) on neutrophils
• Mild anemia may be present from chronic
  inflammation.
• Hyper-g-globulinemia.
• Mortality rate without Tx 70 within the 1-st
  year of life
• Tx failure of G-CSF BMT, or stem cell
  transplantation.

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Phagocytic disorders
1. NADPH oxidase catalyzesreduction of
O2 to superoxide anion (O2 ) 2.
Superoxide dismutase convert it to
H2O2 3. Neutrophil-derived
myeloperoxidase (MPO) converts H2O2 into
a HOClbleach Cl2
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• Clinical Features of CGD
• A. Inflammation of the nares.
• Large granuloma in the neck
• Severe gingivitis
• An esophageal stricture caused
• by a granuloma.

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Chediak-Higashi syndrome

• AR, the long arm of chromosome 1
• The lysosomes fail to fuse with the phagosome.
• Neutropenia diminished chemotaxis giant
  lysosomes
• Dx chemotaxis assay
• Decreased NK functions.
• The platelets are abnormal (easy bruising).
• Oculocutaneous albinism, photophobia,
  enterocolitis and peripheral neuropathy.
• BMT has been used with excellent results in
  several cases.
• 85 of children with CHS, develop lymphoma-like
  condition which generally conduces to death.
• Prenatal Dx giant neutrophil granules in the
  fetal blood.

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Myeloperoxidase deficiency

• Common 1 2000, AR
• Dercreased intracellular killing (no bleach)
• Absence of myeloperoxidase enzyme in neutrophil
  and monocyte granules.
• MPO deficiency diabetes mellitus Candidal
  sepsis osteo
• Most patients are asymptomatic
• Dx chemoluminescence test
• Vacuolized neutrophils

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Phagocytic disoders A. Normal peripheral
blood smear

• Peripheral blood smear from a patient with the
  ChédiakHigashi syndrome
• large perinuclear granules.
• C. Peripheral-blood smear from a patient with
  agranulocytosis the cytoplasm is pale, no
  granules are present, and nuclei are notched and
  hyposegmented.
• D. Nitroblue tetrazolium test (NBT) in normal
  neutrophils phagocytosis results in dark-blue
  staining of the cytoplasm
• NBT in neutrophils from a patient with CGD
  there is no phagocytosis no dark-blue
• cytoplasmic staining.
• F. A hair from a patient with the
  ChédiakHigashi syndrome in which giant granules
  are present, ( normal hair on thr right).

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Phgocytic disorders summary
Common infections with GN and catalase (),
like Staph. aureus, Pseudomonas a. Aspergillus.
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Central immunodeficiencies bone marrow /
thymic events
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3
2
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T cell disorders
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Severe combined ImmunoDeficiency (SCID)
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SCID

• Loss of the MHC molecule
• Bare lymphocyte syndrome
• no recognition of other cells

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SCID

• The only host defenses are
• Complement
• Phagocytosis
• Maintenance
• Bactrim Px, Azithro Px
• IVIG
• Salvage
• Recombinant ADA injections
• BMT

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DiGeorge Syndrome CATCH-22
Cardiac malf. Abnormal face Thymic hypopl. Cleft
palate Hypo-Ca-emia

• Sporadic microdeletion of 22q
• Hypertelorism, down-slanted eyes, cleft palate
• (midline defects)
• Developmental defect of the 3-d 4-th pharyngeal
  pouches
• No thymus low T cell counts
• No parathyroid glands hypo-Ca-emic seizures
• CV interrupted aortic arch truncus arteriosus
• Treatment thymus transplant

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Ataxia-Telangiectasia

• AR, chromosome 11
• 1 case in 100,000 births
• Single gene mutation results in impaired repair
  of DNA damage cancer in1/4
• ( lymphoma)
• Usually presents in the 2-d year of life as a
  lack of balance and slurred speech.
• Ocular telactasia before age of 6. Mild MR in 1/3
• Progressive cerebellar degeneration (CT atrophy)
• immunodeficiency in 2/3
  radiosensitivity (x-ray)
• AFP, may be small thymus, dys-g-globulinemia (
  Ig G2,4 A)

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Wiscott-Aldrich disease

• WASP gene on Xp11 chromosome X-linked
  recessive
• Defective cytoskeleton of T cells and platelets
• TCP Eczema recurrent sino-pulmonary
  infections, HSV / CMV, PCP
• Labs small Plt, T cells, B cells, Ig
  A E, specific ABs
• Tx IVIG BMT
• Pre-natal Dx EM of fetal lymphocyte

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Monocytes and macrophages bind IFN- g
activation 1. production of
hydrogen peroxide (H2O2) 2. synthesis
release of IL-12 tumor necrosis factor
(TNF) A. Resolving mycobacterial infection
with normal granuloma formation B. An AR
mutation of the IFN-g receptor mycobacteria
survive in macrophages C. Same patient no
granuloma
IL-12 receptor deficiency

IL-12 produced by macrophages and dendritic cells
in the presence of a pathogen,
binds to its receptors on T cells and NK cells

inducing
the release of IFN-g
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T cell deficiencies summary
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B cell disorders
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Brutons X-linked A-g-globulinemia

• Absence or deficiency of a Brutons tyrosine
  kinase maturation
• arrest of pre-B cells
• Levels of all Ig levels are less than 10 of
  normal.
• Infections start after 5 months of age
  capsulated ( H. influenzae,
• Strep. pneumoniae, Giardia lamblia, ECHO
  viruses)
• . Tiny tonsils,
• Molecular confirmation of the Dx fluocytometry
• Treatment IVIG

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Selective Ig A deficiency

• Most common immunodeficiency 1 700 in US
• Some cases are AR.
• 1 300 in atopic population
• Majority of patients are clinically normal
• Ig A lt 5 recurrent / chronic sinopulmonary, GI,
  GU infections
• Allergy, GI (celiac disease, UC), JRA, SLE
• IgG is c/indicated unless IgG deficiency also
  present

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Hyper-E syndrome

• Pruritic dermatitis (eczema)
• Recurrent staphylococcal abscesses of skin, lung,
  joints, etc.
• Eosinophilia of blood and sputum
• Ig G, M, A usually normal
• Extremely high Ig E gt 1000 , high Ig D
• Diminished response to immunization
• Poor cellular and humoral response to neoantigens
• Tx IVIG BMT

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Hyper-M X-linked disorder
T helper
Patients have abnormal CD4 ligand on T cells,
and can not properly signal B cells Thus,
this is really a T cell problem the B cells
work fine Block in switching from Ig M to
IgG, IgA, IgE
B cell
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Hyper-M X-linked disorder

• X-linked recessive Xq26
• sporadic cases
• Recurrent pyogenic, mostly
• sinopulmonary, infections
• Sclerosing cholangitis
• Increased incidence of autoimmune
• and lymphoproliferative disorders
• Low Ig G Ig
• Neutropenia, TCP, anemia
• Tx IVIG

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Common Variable Immune Deficiency (CVID)

• AD / X-linked
• Onset after 10 y., recurrent sinopulmonary
  infections other pyogenic
• Lymphadenopathy and splenomegaly may be
  present
• IL-2, IFN-g, CD40L (defective CD4 function )
• IgG lt 50 (lt 250), Ig A M
• No specific Ab production / no response to
  vaccines
• Anti - B cell autoantibodies
• Patients may have a higher occurrence of atopic
  / rheumatalogic
• diseases, lymphoid hyperplasia
• Treatment IVIG to keep IgG gt 400

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Transient hypo-g infantorum

• Delayed onset of IgG synthesis, but always gt 200
• Physiological nadir of IgG level 430 660 _at_ 4
  12 mo. Of age
• Onset of symptoms coincides with decline in
  matrnal IgG level
• Normal levels of Ig A M
• Normal IgG response to immunization
• Mature B cells plasma cells are present
• Resolves by 24 36 months of age

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B cell disorders summary
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Examples of Infectious Agents in Different Types of Immune Deficiencies Examples of Infectious Agents in Different Types of Immune Deficiencies Examples of Infectious Agents in Different Types of Immune Deficiencies Examples of Infectious Agents in Different Types of Immune Deficiencies Examples of Infectious Agents in Different Types of Immune Deficiencies
Pathogen Type T-Cell Defect B-Cell Defect Granulocyte Defect Complement Defect
Bacteria Bacterial Sepsis Streptococci, Staphylococci, Haemophilus Staphylococci, Pseudomonas Neisseria,pyogenic bacteria
Viruses CMV, EBV, varicella, chronic respiratory GI infections Enteroviral encephalitis    
Fungi Parasites Candida, PCP Giardiasis Candida, Nocardia, Aspergillus  
Special Features OIs failure to clear infections Recurrent sinopulmonary infections, sepsis, chronic meningitis    
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Warning Signs of Primary Immunodeficiency
Disorders
Medical history gt 8 ear infections / year gt 2 serious sinusitis / year gt 2 pneumonias / year gt 2 deep-seated infections, or infections in unusual areas Recurrent deep skin/organ abscesses Need for IV ABx to clear infection Infections with unusual /opportunistic organisms Family Hx of primary immunodeficiency Physical signs Poor growth, FTT Absent lymph nodes or tonsils Skin lesions telangiectasias, petechiae, lupus-like rash Ataxia (ataxia-telangiectasia) Oral thrush after1 year of age Oral ulcers


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Table 1. Indications for immune evaluation Table 1. Indications for immune evaluation
Infection frequency Infection type

Single episode OsteomyelitisSeptic arthritisMeningitis

Two episodes SepsisPneumonia

Multiple episodes SinusitisBronchitisPneumonia

D. Dube et al, POSTGRAD MED, 2002
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Table 4. Tests of immunologic functions Table 4. Tests of immunologic functions Table 4. Tests of immunologic functions Table 4. Tests of immunologic functions Table 4. Tests of immunologic functions Table 4. Tests of immunologic functions Table 4. Tests of immunologic functions
Initial Initial Initial Advanced Advanced Advanced

Cellular immunity Cellular immunity CBC ANC ALC Lymphocyte subsets Candida skin test CBC ANC ALC Lymphocyte subsets Candida skin test CBC ANC ALC Lymphocyte subsets Candida skin test CBC ANC ALC Lymphocyte subsets Candida skin test LPA, CTL activity, Cytokine production ADA level

Humoral immunity Humoral immunity Serum Ig G, A, M, E Serum Ig G, A, M, E Serum Ig G, A, M, E Diphth / Tetanus and Pneumoc. titers IgG 1 - 4 subclasses B-cell quantitation In-vitro AB production Diphth / Tetanus and Pneumoc. titers IgG 1 - 4 subclasses B-cell quantitation In-vitro AB production

Phagocytic function Phagocytic function Phagocytic function CBC, NBT test FACS H202 (for CGD) Chemoluminescence assay (for M-p-o) Chemotaxis assay (for C-H) CD 11 / 18 (LAD) FACS H202 (for CGD) Chemoluminescence assay (for M-p-o) Chemotaxis assay (for C-H) CD 11 / 18 (LAD) FACS H202 (for CGD) Chemoluminescence assay (for M-p-o) Chemotaxis assay (for C-H) CD 11 / 18 (LAD)

Complement Complement Complement Total Hemolytic Complement assay Classical CH50 Alternative AH50 Total Hemolytic Complement assay Classical CH50 Alternative AH50 Total Hemolytic Complement assay Classical CH50 Alternative AH50 Quantitation of individual complement components and regulatory molecules Serum opsonic and chemotactic assays

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Workup for suspected P.I.D.
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IVIG is indicated for - Brutons
a-g-globulinemia
- Hyper-M Hyper-E
- CVID
Ig subcl. if NO SPECIFIC Abs !
- SCID
Wiscott-Aldrich
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Indications for BMT

• Hyper-E syndrome
• SCID
• Wiscott-Aldrich
• Chediak-Higashi
• Kostmann Disease

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Selected causes of secondary immunodeficiency diseases Selected causes of secondary immunodeficiency diseases
Causes Examples

Malnutrition Protein / energy malnutrition, malabsorption syndrome

Infection HIV, congenital CMV / EBV / Toxoplasma

Drugs Corticosteroids, Phenytoin, Sulfasalazine, Cytotoxins

Chronic medical conditions Sickle cell disease, cystic fibrosis

Malignancy ALL, AML, lymphomas

Protein (Ig) loss Protein-losing enteropathy, nephrotic syndrome

Chromosomal syndromes Down syndrome