1. Primary Immunodeficiencies
Dr. Katia Sitnitskaya

2. Host defense Innate immunity AG-specific immunity Complement:
alternative pathway
Phagocytes: - neutrophils
- macrophages
Natural killers
AG-specific immunity
Complement:
classical pathway AG + AB
T cell response
B cell: AB production

3. US: how many we are talking about ?

4. Most common ?

6. Complement cascade you DON’T HAVE TO remember

7. Complement: - opsonization: C3b, C5b - chemotaxis: C3a, C5a - membrane attack: C5-9

8. Complement deficiencies: very rare
(-) opsonins +
chemotaxis
Pyogenic
infections

9. 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)
Pyogenic
Normal
(AH50 low)
C5 - 8
chemotaxis
membrane attack
Recurrent N.men C9
50%

10. Phagocytic disorders

11. Phagocytic disorders
LAD
“Indigestion” = CGD, Chediak-Higashi

12. 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

13. 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

14. Congenital agranulocytosis Kostmann Disease
AR, 1:
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.

15. 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

16. Clinical Features of CGD
A. Inflammation of the nares.
Large granuloma in the neck
Severe gingivitis
An esophageal stricture caused
by a granuloma.
Resolution after treatment with CSs

17. 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.

18. 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

19. Phagocytic disoders A. Normal peripheral blood smear
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
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).

20. Phgocytic disorders summary
Common infections with GN and catalase (+),
like Staph. aureus, Pseudomonas a. + Aspergillus.

21. “Central” immunodeficiencies: bone marrow / thymic events
1. Bruton’s A-g-globulinemia: XR, chrom. Xq22
3. Severe Combined ImmunoDeficiency (SCID): multi-modal 1 3
2. DiGeorge Syndrome = Thy. aplasia: microdelition, chrom. 22q 2

22. T cell disorders

23. Severe combined ImmunoDeficiency (SCID)

24. SCID “Bare lymphocyte syndrome”: no recognition of other cells
Loss of the MHC molecule =
“Bare lymphocyte syndrome”:
no recognition of other cells

25. SCID The only host defenses are: Complement Phagocytosis Maintenance:
Bactrim Px, Azithro Px
IVIG
Salvage:
Recombinant ADA injections
BMT

26. 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

27. 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)

28. 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

29. 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

30. T cell deficiencies: summary

31. B cell disorders

32. 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

33. 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

34. 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

35. Hyper-M X-linked disorder
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

36. 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

37. 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

38. Transient hypo-g infantorum
Delayed onset of IgG synthesis, but always > 200
Physiological nadir of IgG level 430 – 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

39. B cell disorders summary

41. 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
Pseudomonas
Neisseria,pyogenic bacteria
Viruses
CMV, EBV,
varicella,
chronic respiratory
& GI infections
Enteroviral
encephalitis
Fungi &
Parasites
Candida,
PCP
Giardiasis
Nocardia,
Aspergillus
Special
Features
OIs
failure to clear
infections
Recurrent
sinopulmonary
infections,
sepsis,
chronic meningitis

42. 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

43. 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

44. Initial Advanced Table 4. Tests of immunologic functions
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 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:
Classical = CH50
Alternative = AH50
Quantitation of individual complement
components and regulatory molecules
Serum opsonic and chemotactic assays

45. Workup for suspected P.I.D.

46. IVIG is indicated for: - Bruton’s a-g-globulinemia
- Hyper-M & Hyper-E
- CVID & Ig subcl. = if NO SPECIFIC Abs !
- SCID & Wiscott-Aldrich

47. Indications for BMT: Hyper-E syndrome SCID Wiscott-Aldrich
Chediak-Higashi
Kostmann Disease

48. Causes Examples Selected causes of secondary immunodeficiency diseases
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