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asthma

Wednesday 12 November 2003

Asthma is a chronic respiratory condition that affects children and adults. Genetic predisposition and environmental factors interact to produce the disease.

Types

- acute asthma
- chronic asthma

Synopsis

- mucus plugs
- mucosal eosinophilic infiltrate
- mucosal basement membrane thickening with sunmembranous collagen deposition
- basement membrane thickening of bronchus
- submucosal infiltrates of eosinophils with chronic inflammatory cells.
- distinctive inclusions in airway mucus

  • Charcot-Leyden crystals
  • creola bodies
  • Curschmann spirals

- epithelial shedding (desquamation)
- goblet cell metaplasia (goblet cell hyperplasia)
- squamous metaplasia
- airway wall edema
- bronchial mucus gland hyperplasia
- airway smooth muscle hyperplasia

Susceptibility

- ORMDL3 at 17q21 (17611496)
- IL12B at 5q31-33 (15322986)
- 6p21
- IL13 (TH2 cytokine signaling pathway)
- ADAM33
- DPP10 (peptidase gene)
- PHF11 at 13q14
- Locus AS1 : 14q24 (12119603)
- Tim1 (mouse)
- C5

Among the genes discovered through association studies, the first group is involved in triggering the immune response and directing CD4+ T helper (TH)-cell differentiation. This group includes genes encoding pattern recognition receptors (CD14, TLR2, TLR4, TLR6, TLR10, NOD1 and NOD2), immunoregulatory cytokines (IL10 and TGFB1), the transcription factor STAT3, molecules involved in antigen presentation (HLA-DR, HLA-DQ and HLA-DP alleles) and the prostaglandin receptor PTGER2.

The second group of asthma susceptibility genes includes those that regulate TH2-cell differentiation and TH2-cell effector functions (GATA3, TBX21, IL4, IL13, IL4RA, FCER1B, IL5, IL5RA, STAT6 and IL12B). The third group of genes is expressed in epithelial cells, and includes chemokines (CCL5, CCL11, CCL24 and CCL26), antimicrobial peptides (DEFB1), CC16 and factors involved in maintaining the integrity of the epithelial-cell barrier (SPINK5 and FLG).

The group of asthma susceptibility genes discovered through positional-cloning approaches includes ADAM33, DPP10, PHF11, GPRA, HLA-G, IRAKM and COL29A1 (which encodes collagen XXIX). These genes are expressed in the epithelium and/or smooth muscle.

Physiopathology

Two main mechanisms have been identified that underlie airway obstruction in experimental asthma. The first, type I hypersensitivity, is principally an antibody-mediated reaction.

Following activation by antigen, T-helper type 2 (TH2) cells produce interleukin-4 (IL-4), which is required for B-cell maturation and IgE synthesis, IL-5, which is required for eosinophil growth and differentiation, and IL-4 and IL-9, which are required for mast-cell development. IgE is then captured on the cell surface by its receptor (FcRI), which is present on mast cells and eosinophils.

Crosslinking of this receptor during subsequent encounters with antigen stimulates the release of various toxic products, including histamine, proteases and cytokines, which together elicit three airway changes that contribute to obstruction, airway hyper-responsiveness, goblet-cell metaplasia with mucus overproduction and mucosal oedema.

The second mechanism that contributes to airway obstruction, type IV hypersensitivity, also crucially involves TH2 cells. The TH2 cytokines IL-4 and IL-13 signal through the -chain of the IL-4 receptor (IL-4R), which is present on target tissues of the lung, such as smooth muscle and the airway epithelium, to elicit airway obstruction more directly. IgE, immunoglobulin E.

Videos

- Asthma by Washington Deceit

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References

- Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, Depner M, von Berg A, Bufe A, Rietschel E, Heinzmann A, Simma B, Frischer T, Willis-Owen SA, Wong KC, Illig T, Vogelberg C, Weiland SK, von Mutius E, Abecasis GR, Farrall M, Gut IG, Lathrop GM, Cookson WO. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature. 2007 Jul 4; PMID: 17611496

Reviews

- Discovering susceptibility genes for asthma and allergy. Donata Vercelli. Nature Reviews Immunology 8, 169-182 (March 2008)

- Makinde T, Murphy RF, Agrawal DK. Immunomodulatory role of vascular endothelial growth factor and angiopoietin-1 in airway remodeling. Curr Mol Med. 2006 Dec;6(8):831-41. PMID: 17168735

- Barnes PJ. New therapies for asthma. Trends Mol Med. 2006 Nov;12(11):515-20. PMID: 17011826

- Kay AB. The role of eosinophils in the pathogenesis of asthma. Trends Mol Med. 2005 Apr;11(4):148-52. PMID: 15823751

- Wills-Karp M, Ewart SL. Time to draw breath: asthma-susceptibility genes are identified. Nat Rev Genet. 2004 May;5(5):376-87. PMID: 15143320

- Weiss ST, Raby BA. Asthma genetics 2003. Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R83-9. PMID: 14764626

- Cookson W. A new gene for asthma: would you ADAM and Eve it? Trends Genet. 2003 Apr;19(4):169-72. PMID: 12683965

- Cookson WO, Moffatt MF. Genetics of asthma and allergic disease. Hum Mol Genet. 2000 Oct;9(16):2359-64. PMID: 11005790

Portfolio

  • Asthma pathogeny
  • Candidate genes for asthma predisposition