1. Speaker - Dr Rajesh kumar

2. IMMUNODEFICIENCY DISEASES
PRIMARY: SECONDARY :
• Usually hereditary
• 6 months to 2 years of
life
• Less common
• Arise as complications
of cancer, infection,
malnutrition,
immunosupression,
irradiation, or
chemotherapy
• More common
• Diseases caused by the absence or failure of
normal function of one or more elements of
immune system.

3. PRIMARY IMMUNODEFICIENCY
DISEASES
 These are the diseases caused by inherited
mutations in genes involved in lymphocyte
maturation or function, or in innate immunity.
 DEFECTS IN INNATE IMMUNITY:
-phagocytic cell defect
-complement system defect
-defect in pattern recognition receptor
 DEFECTS IN ADAPTIVE IMMUNITY:
- lymphocyte maturation defect
- lymphocyte activation defect
- associated with systemic diseases

4. COMPONENTS OF
INNATE & ADAPTIVE IMMUNITY

5. PHAGOCYTIC CELL DEFECTS

6. LEUKOCYTE ADHESION
DEFICIENCY
• Type 1 : Mutation
in beta chain of
CD11/CD18
integrin
• Type 2 : Mutation
in fucosyl
transferase
• Type 3 : Defect in
integrin activation
molecule kindling-
3

7. CHRONIC GRANULOMATOUS
DISEASE
• Defect in genes encoding
components of phagocyte
oxidase
• 2 variants:
1) X linked: Defect in
membrane bound
component i.e. gp91phox
2) Autosomal recessive :
Defect in cytoplasmic
component i.e. P47phox,
p67phox

9. CHEDIAK-HIGASHI SYNDROME
• Autosomal recessive,
involving LYST gene.
• Defective fusion of
phagosome and
lysosome.
• Leucocyte abnormalities
→ neutropenia and
giant granules
• Melanocyte
abnormalities →
albinism
• Also affects nervous
system and platelets.

10. DEFICIENCIES OF
COMPLEMENT PATHWAYS

11. NORMAL COMPLEMENT CASCADE

13. DEFICIENCIES OF PATTERN
RECOGNITION RECEPTOR
SIGNALING
• MyD88 adaptor protein deficiency →
infection with Pneumococci and Salmonella.
• IL1R-associated kinase-4 deficiency →
Gram- positive bacterial infection including
Streptococcus pneumoniae and Staph aureus.
• TLR3 deficiency → recurrent Herpes simplex
virus encephalitis

14. DEFECTS IN ADAPTIVE IMMUNITY

15. SEVERE COMBINED
IMMUNODEFICIENCY

16. X-linked SCID:- Autosomal Recessive SCID:-
Most common form (50-60%
cases)
Mutation in common gamma-
chain subunit of cytokine
receptors
Defect in IL-7 receptor
signaling, required for T cell
proliferation
Ineffective IL-15 receptor
signaling→ deficiency of NK
cells
Most common enzyme
deficiency → adenosine
deaminase
Accumulation of
deoxyadenosine & deoxy-
ATP, which are toxic to
immature lymphocytes.
Other associated
mutations:-
1.Recombinase activating
genes(RAG) gene
2.JAK3 (intracellular kinase)

17. Common Cytokine Receptor Gamma-Chain Signaling Pathways

18. X-LINKED ( BRUTON )
AGAMMAGLOBULINEMIA
• Failure of B-cell precursors (Pro-B cells & Pre-B cells) to
develop into mature B cells.
• Caused by mutation in Bruton tyrosine kinase (BTK) gene
at Xq21.22
• Serum levels of all classes of immunoglobulins are
decreased.
• HP-No germinal centre in lymph node and spleen.
• Plasma cells are absent from the tissues.
• Does not manifest upto 6 month due to presence of
maternal immunoglobulin.
• Commonly affected by H.influenzae, S.pneumoniae,
S.aureus.

19. Overview of B-cell development and defects causing antibody deficiency.

20. DiGeorge Syndrome
(thymic hypoplasia)
• Failure of development
of 3rd & 4th pharyngeal
pouch.
• Deletion of Chr 22q11.
• TBX1 gene depleted.
• Features-
1. thymic hypoplasia
→ Tcell deficiency
→ fungal & viral
infections

21. 2. Parathyroid
hypoplasia →
hypocalcemic tetany
3. Congenital defect
of heart & blood
vessels
4. Dysmorphic facies

22. Bare lymphocyte syndrome
• Mutation in transcription factors required
for class II MHC expression.
• No development of CD4+ T cell → defect
in cellular immunity.
• Humoral immunity also affected.

23. HYPER-IgM SYNDROME
• Production of IgM without IgA, IgG, or IgE
antibodies.
• 2 patterns:-
a) X-linked recessive (70% cases) :
mutation in CD40L gene
(located on Xq26)
b) Autosomal recessive :
mutation in CD40 or activation
induced deaminase (AID)

25. Clinical features:-
• Recurrent bacterial infections due to lack of
opsonizing IgG antibodies.
• Increased susceptibility to Pneumocystis
jiroveci.
• IgM antibodies act against blood cells→
autoimmune hemolytic anaemia, neutropenia
or thrombocytopenia.

26. COMMON VARIABLE
IMMUNODEFICIENCY
• Hypogammaglobulinemia, generally affecting
all the antibody classes, but sometimes only
IgG.
• Relatives have high incidence of selective IgA
deficiency.
• Normal or near- normal B cells, but unable to
differentiate into plasma cells.
• Mutations:
 Receptor for a cytokine BAFF
 ICOS ( inducible costimulator)

27. Features:-
• Typically present with recurrent sino-
pulmonary pyogenic infections.
• Recurrent Herpes virus infections (20% cases)
• Persistent diarrhoea due to Giardia lamblia.
• Affects both sexes equally and onset is late
• Hyperplastic B cell zones
• Increase incidence of autoimmune disease
and lymphoid malignancy

28. ISOLATED IgA DEFICIENCY
• Extremely low level of both serum and
secretory IgA.
• Impaired differentiation of naive B
lymphocyte to IgA producing plasma cell.
• Molecular basis not known. Probably due to
defect in receptor for BAFF.
• Mucosal immunity mostly affected.
• Recurrent sino-pulmonary infections &
diarrhoea.
• Increase incidence of allergy & autoimmune
disorders.

29. X LINKED
LYMPHOPROLIFERATIVE
SYNDROME
• Mutation in gene encoding SLAM
associated protein.
• Diminished NK & T cell activation.
• Inability to eliminate EB virus leading to
fulminant Infectious mononucleosis.

30. WISKOTT ALDRICH SYNDROME
• X linked disease.
• Triad of thrombocytopenia, eczema and recurrent
infections.

31. • Mutation in gene for WASP located at Xp11.23
• WASP protein involved in cytoskeleton dependent
responses including cell migration & signal
transduction.
 Features :-
• Normal thymus but loss of T lymphocyte in
peripheral blood and lymph node.
• No antibody production to polysaccharides and
poor response to protein antigens.
• IgM ↓↓, IgG – Normal,
IgA & IgE -↑↑
• Increased incidence of B cell lymphoma.

32. ATAXIA TELANGIECTASIA
• Autosomal recessive
• Mutation of gene encoding ATM on Chr. 11
• ATM protein is a sensor of DNA damage →
activates P53 to activate cell cycle checkpoints
→ apoptosis in cells with damaged DNA.
• ATM contributes to the stability of DNA double-
strand break complexes during V(D)J
recombination.

33. • Characterized by
1) ataxia
2) vascular
malformation
3) neurological deficit
4) increase incidence
of tumor and
immunodeficiency
• Both T & B cell affected.
• Humoral immunity
predominantly affected.
• Defective production of
IgA & IgG2.

34. APPROACH TO PATIENTS WITH
SUSPECTED IMMUNODEFICIENCY
• Detailed history
• Physical examination
• Investigations

35. KEY HISTORY
• History of infections: location,
organism, frequency, response to
therapy, hospitalization
• Family history – consanguinity
• History of allergy
• Developmental delays

36. 10 warning signs of
Immunodeficiency
1
Eight or more new ear
infections within one year
Recurrent deep skin
or organ abscess
6
2
Two or more serious sinus
infections within one year
Persistent thrush in mouth or
elsewhere on skin after age
one.
7
3
Two or more months on
antibiotics with little effect
Need for I/V antibiotics to
clear infections
8
4
Two or more pneumonias
within one year
Two or more deep seated
infections
9
5
Failure of an infant to gain
weight or grow naturally
Family history of primary
immunodeficiency
10

37. PHYSICAL FINDINGS
• Failure to thrive
• Abnormal facial features
• Skin and mucosa: eczema, petechiae, abscess,
pyoderma, telangiectasia, delayed umbilical
cord separation
• Respiratory tract: bronchial breath sound, fine
crepitations

38. INVESTIGATIONS
 CBC:-Absolute lymphocyte count
-Absolute neutrophil count
-Platelet count
 Peripheral smear
 Delayed-type hypersensitivity skin
tests
 Chest x-ray

39.  serum immunoglobulins
 lymphocyte subset analysis by
flowcytometry
 antibody response to
-known exposure
-known immunizations

40.  enzyme assays: ADA,NADPH OXIDASE
 chemotaxis assays
 nitroblue tetrazolium slide test
 dihydro rhodamine flowcytometry
 Complement level:C3,C5,CH50
 biopsies: skin,lymphnode,thymus
 cytogenetic analysis: FISH for 22q11
mutation analysis: CD40L,JAK3,ZAP70

41. Nitroblue Tetrazolium Slide Test
 Neutrophils make
reactive oxygen species
which reduces colorless
NBT dye into a blue
colored formazan salt
 In CGD these reactive
oxygen species are not
formed, so dye is not
reduced to blue color

42. TREATMENT
• SUPPORTIVE THERAPY- antibiotics
• REPLACEMENT THERAPY- IV
immunoglobulins, enzymes
• DEFINITIVE THERAPY- fetal thymic grafts,
bone marrow transplantation
• GENE THERAPY