Atopy is highly prevalent and remains the biggest risk factor for asthma. Atopy has a heritable component but is not due to genetic factors alone. Lipopolysaccharide (LPS) and its bioactive moiety endotoxin are common to all gram-negative bacteria, and have been used as a surrogate of microbial load. Endotoxin is found in dust collected from homes. The structure of a lipopolysaccharide(LPS) is shown on the right (image source: Wikipedia, public domain).
Our innate immune system recognizes LPS via the LPS signal transduction pathway, which has the trimolecular complex of CD14/TLR4/MD2 at the core. CD14 was the first described pattern recognition receptor (PAMP receptor).
TLR4 (for LPS)
CD14
Generally, there is an inverse dose-response relationship between exposure to endotoxin and the risk of atopy.
High exposure to endotoxin in the domestic environment is protective against the development of atopy, but only among carriers of certain alleles.
Pathogen Recognition Receptors, TLRs. This video is from: Janeway's Immunobiology, 7th Edition Murphy, Travers, & Walport. Source: Garland Science.
Pathogen Recognition Receptors, TLRs. This video is from: Janeway's Immunobiology, 7th Edition Murphy, Travers, & Walport. Source: Garland Science.
SNPs associated with atopic diseases
Filaggrin gene
Filaggrin is essential for epidermal barrier function. SNP associated with eczema and asthma.
17q12-21 gene
ORMDL3 protein defects associated with asthma.
5q22-32 gene
CD14 is a lipopolysaccharide (LPS) receptor. SNPs associated with asthma and atopy.
3p21-22 gene
CCR5 is a chemokine receptor. SNP can be protective against asthma.
Xp22 gene
TLR7 and TLR8 are recognition receptors for viral ssRNA. SNPs assciated with asthma, rhinitis, atopic dermatitis.
5q31 gene
IL-13 is a cytokine that induces IgE secretion, mucus production, and collagen synthesis (fibrosis). SNPs associated with asthma.
ADRB2 gene
ADRB2 gene encodes β2-adrenergic receptor. Argenteum (Arg) or Arg/Arg phenotype associated with decreased albuterol response compared to Gly/Gly phenotype at residue 16.
ADAM33 gene
Type 1 transmembrane protein involved in cell-to-cell interactions. SNPs associated with asthma.
References:
The role of lipopolysaccharide in the development of atopy in humans. Simpson A, Martinez FD. Clin Exp Allergy. 2009 Nov 25. [Epub ahead of print]
Asthma in African Americans: What can we do about the higher rates of disease? CCJM, 2012.
Toll-like receptors (TLRs)
Asthma in African Americans: What can we do about the higher rates of disease? CCJM, 2012.
Toll-like receptors (TLRs)
No comments:
Post a Comment