defects in innate immunity

1. DEFECTS IN
INNATE
IMMUNITY

2. Innate immunity
 First line defense against micro organisms
COMPONENTS OF INNATE IMMUNITY
 Epithelium
 Phagocytic cells (neutrophils and macrophages)
 Dendritic cells
 Nature killer cells
 Proteins of complement system

3. 1. Defects in leukocyte function
2. Defects affecting the complement
system

4. 1. DEFECTS in leukocyte function
1. Inherited defects in leukocyte adhesion
2. Inherited defects in phagolysosome function
3. Inherited defects in microbicidal activiy
4. Defects in TLR signaling

5. 1. Inherited defects in leukocyte
adhesion
Leukocyte adhesion deficiency type 1
 Defect in the biosynthesis of β2 chain shared by LFA-1
& MAC-1 integrins.
Leukocyte adhesion deficiency type 2
 Absence of sialyl – lewis X, the fucose containing
ligand for E - and P- selectins, as a result of a defect in
fucosyl transferase, enzyme that attaches fucose
moieties to protein backbones.
Clinical problem – Recurrent bacterial infections due to
inadequate granulocyte function.

6. 2. Inherited defects in
phagolysosome function
Chédiak-Higashi syndrome
 Autosomal recessive
 Defective fusion of phagosome and lysosomes
 Defective phagocytic functions
 Susceptibility to infections

7. 3. Inherited defects in
microbicidal activity
Chronic granulomatous disease
 Defects in bacterial killing
 Results from inherited defects in the genes encoding
components of phagocyte oxidase, phagolysosomal
enzyme that generates super oxides
 Common variants are
 X linked defect in one of the membrane bound
components (gp91phox)
 Autosomal recessive defect in the gene encoding two
of the cytoplasmic components (p47phox & p67phox).

8.  Name of this disease comes from
macrophage rich chronic inflammatory
reaction that tries to control the infection and
the initial neutrophil defect is inadequate
 This leads to collection of activated
macrophages, forming granulomas.

9. 4. Defects in TLR signaling
Defects in TLR 3
 A receptor for viral RNA.
 Resulting in recurrent herpes simplex
encephalitis
Defects in MyD88
 The adapted protein downstream of multiple
TLR’s.
 Associated with destructive bacterial
pneumonias

10. 2. Deficiencies affecting the
complement system
 Deficiency of C2, most common complement
protein deficiency
 Deficiency of C2 or C4 (Component of classical
pathway associated with increased bacterial or
viral infections)
 Many patients have no clinical manifestations,
because alternate pathway is adequate for the
control of the most infections
 Deficiency of C1q – SLE like autoimmune
diseases.

11.  Deficiency of components of alternative
pathway (properdin & factor D) is rare
 Associated with recurrent pyogenic infections

12.  Deficiency of C3 complement
 Results in susceptibility to serious and recurrent
pyogenic infections
 There is also increased incidence of immune
complex mediated glomerulonephritis

13.  Deficiency of complement C5, 6, 7, 8 & 9.
 Required for the assembly of membrane
attack complex
 Involved in lysis of organisms
 Deficiency leads to recurrent neisserial
(Gonococcal & meningococcal) infections.
 Neisseria bacteria have thin cell walls and are
susceptible to the lytic actions of the
complements

14. Deficiency of C1 inhibitor (C1 INH)
Hereditary angioedema
Autosomal dominant
Most common than complement deficiency
states
C1 INH’s targets are proteases specifically
- C1r & C1s of the complement cascade
- Factor XII of the coagulation pathway
- Kallikreine system

15.  There is unregulated activation of kallikrein
may lead to increased production of
vasoactive peptides such as bradykinin
 Although exact nature of the bioactive
compound produced is uncertain, the
patients have episodes of edema affecting
skin and the mucosal surface such as larynx
and GIT
 This may result in life threatening asphyxia,
nausea, vomiting and diarrhea after minor
trauma or emotional states
 Acute attacks can be treated with C1 inhibitor
concentrates prepared from human plasma

16.  Deficiencies of other complement regulated
proteins
 Results in paroxysmal nocturnal hemoglobinuria and
some cases of hemolytic uremic syndrome