COMPLEMENT-MEDIATED
REGULATION OF THE
ALLERGIC RESPONSE
18
Key messages
Complement-mediated regulation of the allergic response
to directly activate complement at the airway surface. Genetic de- letion of C3 in animal models has been shown to protect against the development of allergen-, pollut- ant-, and RSV-induced asthmat- ic responses and Th2 cytokine production suggesting that C3a production at the airway surface serves as a common pathway for the induction of Th2-mediated inflammatory responses thereby driving and/or exacerbating the disease (Figure 1, 2, 3). The exact mechanisms by which C3 regu- lates allergic responses are un- known, but current evidence sug- gests that C3a can both enhance antigen uptake by antigen-pre- senting cells, thereby enhancing sensitization to allergens, and ini-
tiate recruitment and activation of various inflammatory cells asso- ciated with asthma pathogenesis (Figure 4).
In humans, segmental allergen provocation resulted in a signifi- cant increase in C3a levels in the bronchoaveolar lavage of asth- matics, with no change in healthy volunteers. This differential pro- duction of C3a between individu- als with asthma and those without asthma suggest that there may be alterations in the genetic control of the production of, the activation of, or the response to various com- plement components that may un- derlie susceptibility to asthma. In- deed, associations between single nucleotide polymorphisms (SNPs) in the C3 gene and atopic asthma
77
section
a
- Allergy - from genetics to mechanisms
Figure 1 Allergen-induced asthma is C3 dependent. A) The effect of C3 deficiency on airway hyperresponsiveness (AHR) in anesthetized C3−/− and C3+/+ mice. AHR was assessed 24 hrs after the last challenge and is expressed as the provocative concentration of ACh (in micrograms per gram) that increased baseline airway resistance 200% (PC200). B) IL-4- and IFN-γ-producing cells in the lungs from C3−/− (■) and C3+/+ littermates (□) were quantitated 24 h after the last Ag
challenge. (Reproduced from Drouin SM, Corry DB, Kildsgaard J, Wetsel RA. 167:4141-4145, Copyright 2001 with permission
from the American Association of Immunologists.).
Figure 2 Air pollution exposure-induced airway hyperresponsiveness is C3-dependent. Lung sections from PM-exposed mice were stained with anti-C3 mAb (A) or (B) isotype control antibodies. Specific C3 staining is observed in the airway epithelial layer. C) Airway responsiveness (APTI) to acetylcholine stimulation is significantly reduced in C3-deficient mice
after particulate matter (PM) exposure as compared to PM-exposed wildtype mice. (P < 0.05). (Reproduced from American
Journal of Respiratory Cell and Molecular Biology, the official journal of the American Thoracic Society, Walters DM, Breysse PN, Schofield B, et al., 27, 413-418, Copyright 2002 with permission from American Thoracic Society).
Figure 3 Respiratory syncytial virus-induced airway hyperresponsiveness is C3-dependent. Airway hyperresponsiveness in wildtype and C3- and B cell-deficient mice challenged with RSV 7 days after immunization with formalin-fixed RSV. (A) B6129F2 WT (C3+/+) and C3 deficient (C3−/−), and (B) C57BL/10 (B+/+) and B10 μMT (B−/−) mice. AHR to acetylcholine challenge is defined by the time-integrated rise in peak airway pressure. (Reproduced from Journal of Experimental Medicine,
Polack FP, Teng MN, Collins PL, et al., 196, 859-65, Copyright 2002 with permission from The Rockefeller University Press).
Complement-mediated regulation of the allergic response
PBS C3 +/+ C3 -/- * 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 PC 200 ( µg/g) A 3.0 2.5 2.0 1.5 1.0 0.5 0.0 IL-4 IFN-γ B ** 800 600 200 0 PBS wt PM wt PBS C3-/- PM C3-/- 400 APTI (cm H 2 O * sec) * C +/+ -/- Mature B cells ** 1000 750 500 250 0 B 1200 900 600 +/+ -/- * 300 0 cm H 2 O - sec Complement C3 A Cells/ml (x10 3)
78
section
a
- Allergy - from genetics to mechanisms
have been reported in children and adults. Interestingly, the fre- quency of these SNPs is high, sug- gesting that these polymorphisms may have conferred evolutionary advantage in the past and perhaps in protection from parasitic infec- tions.
Although we are in the initial stag- es of understanding the role of complement pathways in asthma pathogenesis, one may postulate that changes in the activation of specific complement components due to differences in exposure to different environmental trig- gers or to genetic alterations in complement family genes or the convergence of both of these fac- tors may play an important role in susceptibility to the development
of allergic diseases. Further inves- tigations into the mechanisms by which C3a modules allergic asth- ma may offer novel therapeutic approaches for the treatment of asthma.
KEY REFERENCES
1. Drouin SM, Corry DB, Kildsgaard J, Wetsel RA. Cutting edge: the absence of C3 demonstrates a role for complement in Th2 effec- tor functions in a murine model of pulmonary allergy. J Immunol 2001;
167:4141-4145.
2. Walters DM, Breysse PN, Schofield B, Wills-Karp M. Complement Fac- tor 3 mediates particulate matter– induced airway hyperresponsive- ness. Am J Respir Cell Mol Biol 2002;
27:413-418.
3. Polack FP, Teng MN, Collins PL,
Prince GA, Exner M, Regele H, et al. A role for immune complexes in en- hanced respiratory syncytial virus disease. J Exp Med 2002;196:859- 865.
4. Wills-Karp M. Complement activa- tion pathways: a bridge between innate and adaptive immune re- sponses in asthma. Proc Am Thorac
Soc 2007;4:247-251.
5. Barnes KC, Grant AV, Baltadzhieva D, Zhang S, Berg T, et al., Variants in the gene encoding C3 are associ- ated with asthma and related phe- notypes among African Caribbean families. Genes Immun 2006;7:27- 35.
6. Hasegawa K, Tamari M, Shao C, Shimizu M, Takahashi N, et al. Var- iations in the C3, C3a receptor and C5 genes affect susceptibility to bronchial asthma. Hum Genet 2004;
115:295-301.
Figure 4 Complement activation pathways regulate Th2-mediated immune responses. Following airway exposure to a variety of environmental triggers of asthma in genetically susceptible individuals, C3 is produced and secreted by airway epithelial cells lining the airways. C3 is cleaved into its active form, C3a, presumably by proteases either contained in the allergens or produced by the epithelium. C3a then binds to its receptor, C3aR1 on antigen presenting cells, enhancing
uptake of antigen by these cells. Antigen-loaded APCs then drive the differentiation of naïve T cells to Th2 cells. Th2 cytokines in turn recruit and active the effector cells of the allergic response, eosinophils and mast cells. During the
effector phase of the response, C3a can bind its receptor on these effector cells enhancing their recruitment and activation. Growth factors and bronchoactive substances from these cells lead to increased airway smooth muscle growth
and contractile capacity.
Complement-mediated regulation of the allergic response
C3 C3a
Epithelial
Cell
Complement Production and Activation Genetic C3 SNPs Environment al Triggers Allergens Viruses Ozone PM ETSASM
Airway Contraction C3aRMast
Cell
Eos
C3aR
C3aR
DC
Ag
Th279
section
a
- Allergy - from genetics to mechanisms
• Lipid mediators regulate both the physiological status and inflammation in the airways
• Cysteinyl leukotrienes and prostaglandin D2 are the best studied inflammatory mediators of hypersensitivity and allergic disorders • Other lipid mediators, like pro-inflammatory eoxins and anti-
inflammatory lipoxins also participate in allergic reaction
• A class of phospholipid and ceramide mediators interact with immune response in allergy
Since the discovery that bron- choconstriction and edema can be mediated by cysteinyl leukot- rienes, lipid mediators attracted much attention in allergology. The biological effect of a lipid media- tor is determined by its receptor affinity and intracellular signal transduction, and receptors dif- fer in their specificity and cellular distribution. Lipid mediators of inflammation are difficult to study due to their complex metabolism, chemical similarities and rapid in- activation. Their levels in airways can be measured in bronchial or nasal lavage, induced sputum or exhaled breath condensate, while systemic production can be as- sessed in urine.
Regulation of the airways tonus, secretion or inflammation involves numerous mediators (Figures 1 and 2). Respiratory epithelium produces prostaglandin E2 (PGE2), secreted to the apical surface. It has been recently demonstrated that excessive PGE2 can impair phagocytic clearance of solid par- ticles by alveolar macrophages. A decreased number of carbon par- ticles in alveolar macrophages and increased systemic production of PGE2 metabolites were report- ed in children with asthma. Res-