This document discusses primary and secondary immunodeficiency diseases. Primary immunodeficiencies are caused by inherited genetic defects affecting the innate or adaptive immune system. They can involve defects in phagocytic cells, complement pathways, pattern recognition receptors, or lymphocyte development/activation. Examples discussed include leukocyte adhesion deficiency, chronic granulomatous disease, Chediak-Higashi syndrome, complement deficiencies, and defects causing SCID, XLA, DiGeorge syndrome, and others. Secondary immunodeficiencies are acquired and include those caused by infections, malnutrition, drugs, or radiation/chemotherapy. The document provides details on approaches to diagnosis and management of immunodeficiency patients.

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