Primary Immunodeficiencies Dr. Katia Sitnitskaya.
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Transcript of Primary Immunodeficiencies Dr. Katia Sitnitskaya.
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Primary Immunodeficiencies
Dr. Katia Sitnitskaya
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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
Host defenseHost defense
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US: how many we are talking about ?
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Most common ?
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Complement cascade you
DON’T HAVE TO
remember
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Complement: - opsonization: C3b, C5b- opsonization: C3b, C5b - chemotaxis: C3a, C5a - chemotaxis: C3a, C5a
- membrane attack: C5-9 - membrane attack: C5-9
ChemotaxisChemotaxisOpsonizationOpsonization
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Complement deficiencies: very rare
(-) opsonins(-) opsonins
++
chemotaxischemotaxis
Pyogenic Pyogenic
infectionsinfections
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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 C2 = most common opsonins Pyogenic in 1/5
(SLE)
< 10%
Properdin (Xp11)Properdin (Xp11) opsonins Pyogenic NormalNormal(AH50 low)(AH50 low)
C5 - 8C5 - 8 chemotaxis
membrane attack
Recurrent N.men < 10%
C9C9 membrane attack Recurrent N.men 50%
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Phagocytic Phagocytic disordersdisorders
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Phagocytic disordersPhagocytic disorders
LADLAD
““Indigestion” = CGD, Chediak-HigashiIndigestion” = CGD, Chediak-Higashi
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LAD: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
Phagocytic Disorders: 1. “commuting”Phagocytic Disorders: 1. “commuting”
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Leukocyte adhesion deficiencyLeukocyte adhesion deficiency (LAD)(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 periodontitis & recurrent GI, GU, and respiratoryrecurrent GI, GU, and respiratory infections infections
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Congenital agranulocytosis Congenital agranulocytosis
Kostmann DiseaseKostmann Disease
• AR, 1: 1 000 000
• An abnormal G-CSF–induced intracellular signal transduction ?
• ANC < 500/mmANC < 500/mm33 + normal WBC count because of the monocytosis.
• Abnormal CD64+ (FCgRI receptor) on neutrophils
• Mild anemia may be present from chronic inflammation.
• + Hyper--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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1. NADPH oxidase catalyzesreduction of O2 to
superoxide anion (O–•2 )superoxide anion (O–•2 ) 2. Superoxide dismutase convert it to H2O2
3. Neutrophil-derived myeloperoxidase (MPO) converts H2O2 into a
HOCl–bleach Cl2
Phagocytic Phagocytic disordersdisorders
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Clinical Features of CGDClinical Features of CGD
A. Inflammation of the nares.
B. Large granuloma in the neck
C. Severe gingivitis
D. An esophageal stricture caused by a granuloma. Resolution after treatment with CSs
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Chediak-Higashi syndromeChediak-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 disodersPhagocytic disoders
A. Normal peripheral blood smear
B. Peripheral blood smear from a patient with the Chédiak–Higashi syndromeChédiak–Higashi syndrome: large perinuclear granules.large perinuclear granules.
C. Peripheral-blood smear from a patient with agranulocytosisagranulocytosis: the cytoplasm is pale, no granules are present, and nuclei are notched and hyposegmented.
D. Nitroblue tetrazolium test (NBT) in normal neutrophilsNitroblue tetrazolium test (NBT) in normal neutrophils: phagocytosis results in dark-blue staining of the cytoplasm
E. NBT in neutrophils from a patient with CGDNBT in neutrophils from a patient with CGD: there is no phagocytosisno phagocytosis = no dark-blue cytoplasmic staining.
F. A hair hair from a patient with the Chédiak–Higashi Chédiak–Higashi syndrome in which giant granulesgiant granules are present, ( normal hair on thr right).
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Phgocytic disorders summaryPhgocytic disorders summary
Common infections with GN and catalase (+),
like Staph. aureus, Pseudomonas a. + Aspergillus.
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LYMPHOCYTE DIFFERENTIATION
THY
Ag
T ,T ,T ...H C S/R
Hematopoeiticstem cell
CommonLymphocyte
Precursor
Pre-B
Pre-T
B
T
IgM...
RBC
GranulocytesMonocytes
Platelets
CR
Ab-forming cells
T-effectorT - cells
CR
H,C,S
CR = complement receptor; , = membrane IgM and IgD
“Central” immunodeficiencies: bone marrow / thymic events
3. Severe Combined ImmunoDeficiency (SCID): multi-modal 3. Severe Combined ImmunoDeficiency (SCID): multi-modal
2. DiGeorge Syndrome = Thy. aplasia: microdelition, chrom. 22q2. DiGeorge Syndrome = Thy. aplasia: microdelition, chrom. 22q
1. Bruton’s 1. Bruton’s -globulinemia: XR, chrom. Xq22-globulinemia: XR, chrom. Xq22
3311
22
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T cell disordersT cell disorders
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Severe combined ImmunoDeficiency (SCID)Severe combined ImmunoDeficiency (SCID)
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SCIDSCID
Loss of the MHC molecule =
“Bare lymphocyte syndrome”:
no recognition of other cells
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SCIDSCIDThe only host defenses are:The only host defenses are:
- Complement
- Phagocytosis
Maintenance:Maintenance:
- Bactrim Px, Azithro Px
- IVIG
Salvage:Salvage:
- Recombinant ADA injections
- BMTBMT
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DiGeorge Syndrome: DiGeorge Syndrome: “CATCH-“CATCH-22”22”
• Sporadic microdeletion of 2222q
• Hypertelorism, down-slanted eyes, + cleft palate (“midline defects”)
Developmental defect of the 3-d & 4-th pharyngeal pouchesDevelopmental 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 transplantTreatment: thymus transplant
CCardiac malf.
AAbnormal face
TThymic hypopl.
CCleft palate
HHypo-Ca-emia
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Ataxia-TelangiectasiaAtaxia-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--globulinemia ( Ig G2,4 & A)
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Wiscott-Aldrich diseaseWiscott-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, PCPTCP + 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- IFN- activation:
1. production of hydrogen peroxide (H2O2)
2. synthesis & release ofsynthesis & release of IL-12IL-12
& tumor necrosis factor (TNF)
A. Resolving mycobacterial infection with normal granuloma formation
B. An AR mutation of the IFN- receptor : mycobacteria survive in macrophages
C. Same patient: no granuloma
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-
IL-12 receptor deficiencyIL-12 receptor deficiency
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T cell deficiencies: summaryT cell deficiencies: summary
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B cell disordersB cell disorders
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Bruton’s X-linked A-g-globulinemiaBruton’s X-linked A-g-globulinemia
• Absence or deficiency of a Bruton’s 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 deficiencySelective 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 < 5Ig A < 5: recurrent / chronic sinopulmonary, GI, GU infections
• Allergy, GI (celiac disease, UC), JRA, SLE
• IgG is c/indicated unless IgG deficiency also presentIgG is c/indicated unless IgG deficiency also present
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Hyper-E syndromeHyper-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 > 1000 , high Ig D
• Diminished response to immunization
• Poor cellular and humoral response to neoantigens
• Tx: IVIG BMT
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Hyper-M Hyper-M X-linked disorderX-linked disorder
T helperT helper
B cellB cell
Patients have abnormal CD4 ligand on T cells, and can not properly signal B cells
Thus, this is really a T cell Thus, this is really a T cell problem; the B cells work fineproblem; the B cells work fine
Block in switching from Ig M Block in switching from Ig M to IgG, IgA, IgE to IgG, IgA, IgE
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Hyper-M Hyper-M X-linked disorderX-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 Common Variable Immune Deficiency (CVID)(CVID)
• AD / X-linked
• Onset after 10 y., recurrent sinopulmonary infections & other pyogenic
Lymphadenopathy and splenomegaly may be present
• IL-2, IFN-IL-2, IFN-CD40L (defective CD4 function )CD40L (defective CD4 function )
• IgG < 50% (< 250), Ig A & M
• No specific Ab production / no response to vaccinesNo 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 > 400Treatment: IVIG to keep IgG > 400
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Transient hypo-Transient hypo- infantorum infantorum
• Delayed onset of IgG synthesis, but always > 200
• Physiological nadir of IgG level 430 – 660 @ 4 – 12 mo. Of agePhysiological nadir of IgG level 430 – 660 @ 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 immunizationNormal IgG response to immunization
• Mature B cells & plasma cells are present
• Resolves by 24 – 36 months of age Resolves by 24 – 36 months of age
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B cell disorders summaryB cell disorders summary
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Examples of Infectious Agents in Different Types of Immune Deficiencies
Pathogen TypePathogen Type T-Cell DefectT-Cell Defect B-Cell DefectB-Cell Defect Granulocyte Granulocyte DefectDefect
Complement Complement DefectDefect
BacteriaBacteria Bacterial Sepsis Streptococci, Staphylococci, Haemophilus
Staphylococci, Pseudomonas
Neisseria,pyogenic bacteria
VirusesViruses CMV, EBV, varicella, chronic respiratory & GI infections
Enteroviral encephalitis
Fungi & Fungi & ParasitesParasites
Candida, PCP
Giardiasis Candida,Nocardia, Aspergillus
Special Special FeaturesFeatures
OIsfailure to clearinfections
Recurrent sinopulmonary infections, sepsis, chronic meningitis
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Warning Signs of Primary Immunodeficiency Disorders
Medical history
• > 8 ear infections / year • > 2 serious sinusitis / year • > 2 pneumonias / year • > 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
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
Initial Advanced
Cellular immunity
CBC: ANC & ALC Lymphocyte subsets Candida skin test
LPA, CTL activity, Cytokine productionADA level
Humoral immunity
Serum Ig G, A, M, E Diphth / Tetanus and Pneumoc. titers IgG 1 - 4 subclasses B-cell quantitation In-vitro AB production
Phagocytic function
CBC, NBT test FACS = H202 (for CGD) Chemoluminescence assay (for M-p-o) Chemotaxis assay (for C-H) CD 11 / 18 (LAD)
Complement Total HemolyticComplement 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: - Bruton’s a--globulinemia
- Hyper-M & Hyper-E
- CVID & Ig subcl. = if NO SPECIFIC Abs !
- SCID & Wiscott-Aldrich
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Indications for BMT:
• Hyper-E syndromeHyper-E syndrome
• SCIDSCID
• Wiscott-AldrichWiscott-Aldrich
• Chediak-HigashiChediak-Higashi
• Kostmann DiseaseKostmann Disease
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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