Primary Immunodeficiencies
Dr. Katia Sitnitskaya
Host defense
Innate immunity
AG-specific immunity
• Complement:
alternative pathway
• Complement:
classical pathway AG + AB
• Phagocytes: - neutrophils
- macrophages
• T cell response
• B cell: AB production
• Natural killers
US: how many we are talking about ?
Most common ?
Complement cascade you
DON’T HAVE TO
remember
Complement: - opsonization: C3b, C5b
- chemotaxis: C3a, C5a
- membrane attack: C5-9
Opsonization
Chemotaxis
Complement deficiencies: very rare
(-) opsonins
+
chemotaxis
Pyogenic
infections
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)
< 10%
Properdin (Xp11)
opsonins
Pyogenic
Normal
(AH50 low)
C5 - 8
chemotaxis
membrane attack
Recurrent N.men
< 10%
C9
membrane attack
Recurrent N.men
50%
Phagocytic
disorders
Phagocytic disorders
LAD
“Indigestion” = CGD, Chediak-Higashi
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
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
Congenital agranulocytosis
Kostmann Disease
• AR, 1: 1 000 000
• An abnormal G-CSF–induced intracellular signal transduction ?
• ANC < 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.
Phagocytic
disorders
1. NADPH oxidase
catalyzesreduction of O2 to
superoxide anion (O–•2 )
2. Superoxide dismutase
convert it to H2O2
3. Neutrophil-derived
myeloperoxidase (MPO)
converts H2O2 into a
HOCl–bleach
Cl2
Clinical 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 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 disoders
A. Normal peripheral blood
smear
B. Peripheral blood smear from a patient with the Chédiak–Higashi 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
E.
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 Chédiak–Higashi syndrome in which giant granules are
present, ( normal hair on thr right).
Phgocytic disorders summary
Common infections with GN and catalase (+),
like Staph. aureus, Pseudomonas a. + Aspergillus.
“Central” immunodeficiencies:
bone marrow / thymic events
RBC
Platelets
Granulocytes
Monocytes
Ag
CR
CR
3
Pre-B
Common
Lymphocyte
Precursor
CR = complement receptor;
,  = membrane IgM and IgD

Ab-forming cells
THY
Pre-T
IgM...
B
1
Hematopoeitic
stem cell

TH,C,S
2
TH,TC,TS/R...
T-effector
T - cells
LYMPHOCYTE DIFFERENTIATION
1. Bruton’s A-g-globulinemia: XR, chrom. Xq22
2. DiGeorge Syndrome = Thy. aplasia: microdelition, chrom. 22q
3. Severe Combined ImmunoDeficiency (SCID): multi-modal
T cell disorders
Severe combined ImmunoDeficiency (SCID)
SCID
Loss of the MHC molecule =
“Bare lymphocyte syndrome”:
no recognition of other cells
SCID
The only host defenses are:
- Complement
- Phagocytosis
Maintenance:
- Bactrim Px, Azithro Px
- IVIG
Salvage:
- Recombinant ADA injections
- BMT
DiGeorge Syndrome:
• Sporadic microdeletion of 22q
“CATCH-22”
Cardiac malf.
Abnormal face
• Hypertelorism, down-slanted eyes, + cleft palate
(“midline defects”)
Thymic hypopl.
Cleft palate
Hypo-Ca-emia
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
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)
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,
• Tx: IVIG
T cells,
B cells,
BMT
• Pre-natal Dx: EM of fetal lymphocyte
Ig A & E,
specific ABs
IL-12 receptor deficiency
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 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
T cell deficiencies: summary
B cell disorders
Bruton’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 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 < 5: recurrent / chronic sinopulmonary, GI, GU infections
• Allergy, GI (celiac disease, UC), JRA, SLE
• IgG is c/indicated unless IgG deficiency also present
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 > 1000 , high Ig D
• Diminished response to immunization
• Poor cellular and humoral response to neoantigens
• Tx: IVIG
BMT
T helper
Hyper-M
X-linked disorder
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
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
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 < 50% (< 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 > 400
Transient hypo-g infantorum
• Delayed onset of IgG synthesis, but always > 200
• Physiological 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 immunization
• Mature B cells & plasma cells are present
• Resolves by 24 – 36 months of age
B cell disorders summary
Examples of Infectious Agents in Different Types of Immune Deficiencies
Pathogen Type
Bacteria
T-Cell Defect
Bacterial Sepsis
B-Cell Defect
Streptococci,
Staphylococci,
Haemophilus
Viruses
CMV, EBV,
varicella,
chronic respiratory
& GI infections
Enteroviral
encephalitis
Fungi &
Parasites
Candida,
PCP
Giardiasis
Special
Features
OIs
failure to clear
infections
Recurrent
sinopulmonary
infections,
sepsis,
chronic meningitis
Granulocyte
Defect
Staphylococci,
Pseudomonas
Candida,
Nocardia,
Aspergillus
Complement
Defect
Neisseria,
pyogenic
bacteria
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
Physical signs
• Poor growth, FTT
• Absent lymph nodes or tonsils
• Skin lesions: telangiectasias,
petechiae, lupus-like rash
• Recurrent deep skin/organ abscesses
• Ataxia (ataxia-telangiectasia)
• Need for IV ABx to clear infection
• Infections with unusual /opportunistic
organisms
• Family Hx of primary immunodeficiency
• Oral thrush after1 year of age
• Oral ulcers
Table 1. Indications for immune evaluation
Infection frequency
Infection type
Single episode
Osteomyelitis
Septic arthritis
Meningitis
Two episodes
Sepsis
Pneumonia
Multiple episodes
Sinusitis
Bronchitis
Pneumonia
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 production
ADA 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 Hemolytic
Complement assay:
Quantitation of individual complement
components and regulatory molecules
Classical = CH50
Alternative = AH50
Serum opsonic and chemotactic assays
Workup for
suspected P.I.D.
IVIG is indicated for:
- Bruton’s a-g-globulinemia
- Hyper-M & Hyper-E
- CVID & Ig subcl. = if NO SPECIFIC Abs !
- SCID & Wiscott-Aldrich
Indications for BMT:
• Hyper-E syndrome
• SCID
• Wiscott-Aldrich
• Chediak-Higashi
• Kostmann 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