DEFECTS IN INNATE IMMUNITY

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

1. Defects in leukocyte function

2. Defects affecting the complement system

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

1. Inherited defects in leukocyte adhesionLeukocyte adhesion deficiency type 1 Defect in the biosynthesis of 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.

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

3. Inherited defects in microbicidal activityChronic 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).

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.

4. Defects in TLR signalingDefects in TLR 3 A receptor for viral RNA. Resulting in recurrent herpes simplex

encephalitisDefects in MyD88 The adapted protein downstream of

multiple TLR’s. Associated with destructive bacterial

pneumonias

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.

Deficiency of components of alternative pathway (properdin & factor D) is rare

Associated with recurrent pyogenic infections

Deficiency of C3 complement Results in susceptibility to serious and

recurrent pyogenic infections There is also increased incidence of

immune complex mediated glomerulonephritis

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

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

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

Deficiencies of other complement regulated proteins Results in paroxysmal nocturnal

hemoglobinuria and some cases of hemolytic uremic syndrome

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