primary immunodeficiencies
DESCRIPTION
Primary Immunodeficiencies. Dr. Katia Sitnitskaya. Host defense. Innate immunity Complement: alternative pathway Phagocytes: - neutrophils - macrophages Natural killers. AG-specific immunity Complement: classical pathway AG + AB T cell response - PowerPoint PPT PresentationTRANSCRIPT
Primary Immunodeficiencies
Dr. Katia Sitnitskaya
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
US: how many we are talking about ?
Most common ?
Complement cascade you
DON’T HAVE TO
remember
Complement: - opsonization: C3b, C5b- opsonization: C3b, C5b - chemotaxis: C3a, C5a - chemotaxis: C3a, C5a
- membrane attack: C5-9 - membrane attack: C5-9
ChemotaxisChemotaxisOpsonizationOpsonization
Complement deficiencies: very rare
(-) opsonins(-) opsonins
++
chemotaxischemotaxis
Pyogenic Pyogenic
infectionsinfections
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%
Phagocytic Phagocytic disordersdisorders
Phagocytic disordersPhagocytic disorders
LADLAD
““Indigestion” = CGD, Chediak-HigashiIndigestion” = CGD, Chediak-Higashi
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”
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
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.
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
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
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.
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
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).
Phgocytic disorders summaryPhgocytic disorders summary
Common infections with GN and catalase (+),
like Staph. aureus, Pseudomonas a. + Aspergillus.
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
T cell disordersT cell disorders
Severe combined ImmunoDeficiency (SCID)Severe combined ImmunoDeficiency (SCID)
SCIDSCID
Loss of the MHC molecule =
“Bare lymphocyte syndrome”:
no recognition of other cells
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
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
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)
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
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
T cell deficiencies: summaryT cell deficiencies: summary
B cell disordersB cell disorders
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
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
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
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
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
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
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
B cell disorders summaryB cell disorders summary
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
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
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
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
Workup for suspected P.I.D.
IVIG is indicated for: - Bruton’s a--globulinemia
- Hyper-M & Hyper-E
- CVID & Ig subcl. = if NO SPECIFIC Abs !
- SCID & Wiscott-Aldrich
Indications for BMT:
• Hyper-E syndromeHyper-E syndrome
• SCIDSCID
• Wiscott-AldrichWiscott-Aldrich
• Chediak-HigashiChediak-Higashi
• Kostmann DiseaseKostmann Disease
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