Respiratory Medicine (2014) 108, 543e549 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/rmed REVIEW Complement components as potential therapeutic targets for asthma treatment Mohammad Afzal Khan a,*, Mark R. Nicolls b, Besiki Surguladze c, Ismail Saadoun a a Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah, United Arab Emirates b Division of Pulmonary and Critical Care Medicine, VA Palo Health Care System, Stanford University, School of Medicine, Palo Alto, CA, USA c Innovative Bio-Medical Technologies Ltd, Toronto, Canada Received 6 February 2013; accepted 7 January 2014 Available online 15 January 2014 KEYWORDS Summary Complement Asthma is the most common respiratory disorder, and is characterized by distal airway inflam- mediated injury; mation and hyperresponsiveness. This disease challenges human health because of its Asthma; increasing prevalence, severity, morbidity, and the lack of a proper and complete cure. e Anaphylatoxins Asthma is characterized by TH2 skewed inflammation with elevated pulmonary levels of IL- 4, IL-5, and IL-13 levels. Although there are early forays into targeting TH2 immunity, less- specific corticosteroid therapy remains the immunomodulator of choice. Innate immune injury mediated by complement components also act as potent mediators of the allergic inflamma- tory responses and offer a new and exciting possibility for asthma immunotherapy. The com- plement cascade consists of a number of plasma- and membrane-bound proteins, and the cleavage products of these proteins (C3 and C5) regulate the magnitude of adaptive immune responses. Complement protein are responsible for many pathophysiological features of asthma, including inflammatory cell infiltration, mucus secretion, increases in vascular perme- ability, and smooth muscle cell contraction. This review highlights the complement-mediated injury during asthma inflammation, and how blockade of active complement mediators may have therapeutic application. ª 2014 Elsevier Ltd. All rights reserved. Abbreviations: AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; ASM, airway smooth muscle; MAC, membrane attack complex; Treg, regulatory T cells. * Corresponding author. Applied Biology and Biotechnology, College of Sciences, University of Sharjah, Sharjah, United Arab Emirates. Tel.: þ971 6 505 3829; fax: þ971 6 5053814. E-mail addresses: [email protected], [email protected] (M.A. Khan). 0954-6111/$ - see front matter ª 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.rmed.2014.01.005 544 M.A. Khan et al. Contents Introduction .........................................................................544 Generation of c3a and c5a in asthma . .....................................................545 Complement mediators-immune cell interaction in asthma pathogenesis . ..........................546 Summary . ...........................................................................546 Conflict of interest ....................................................................547 References ..........................................................................547 Introduction classical, alternative, lectin pathways, and by the direct action of certain proteolytic enzymes on C3 or C5 [7] Asthma is a chronic inflammatory disease of the bronchi (Fig. 1), participate in AHR induction. Infections, and al- arising because of inappropriate immunological responses lergens of respiratory tract activate local complement e to common environmental antigens in genetically suscep- activation participate in AHR [8 10] because of their ability tible individuals [1]. It is thought to be mediated by CD4þ T to recruit, activate leukocytes, increase vascular perme- lymphocytes that produce T 2 cytokines linked with ability, stimulate contraction of smooth muscle, and trigger H e elevated specific IgE, eosinophilia, and airway hyper- degranulation of mast cells [9,11 13]. In addition to al- responsiveness (AHR) [2e4]. This perspective will explore lergens, other triggers of asthma have been shown to how an important component of the innate immunity, the activate complement cascade in human, and in animal complement system, normally a key defense against models [13]. It has been demonstrated that bronchoalveo- mucosal bacteria, viruses, fungi, helminthes, and other lar lavage (BAL) of asthma individuals contain quantita- pathogens, may also play an important role in the patho- tively higher levels of C3a and C5a as compared to healthy genesis of asthma. Although complement factors have been control subjects at baseline [14]. associated with development of pathophysiology of asthma In asthma, overproduction of activated complement [5,6], the role of individual complement components in the fragments may promote asthma susceptibility [13]. This pathogenesis of allergic asthma is not clear. Biologically imbalance results in up regulation of biologically active active fragments (C3a, C5a), generated through the fragments, C3a and C5a, which may act on cells of the Classical Lectin Alternative C4b2a C3bBb C3 C3b C4b2a3b C3bBb3b C3aR C5 C5b C3a bind to C3a bind MAC C5a Release of histamine Mast cell CD4+ Release of IL-17 and Airway narrowing and AHR IL-4, Il-13, IL-5 (neutrophil inflammation) Figure 1 Model explains the generation of C3a and C5a through classical, lectin and alternative pathway during airway inflammation. Further, C3a binds to C4aR on CD4þ T cells and promotes recruitment of IL-17þCD4þ cells, neutrophil inflammation and activation of Mast cells that leads to histamine mediated AHR. Complement components for asthma treatment 545 IL-2 involvement of T-lymphocytes, eosinophils, altered immu- nosuppressive macrophages, excessive nitric oxide through C3a C5a Th1 response inducible nitric oxide synthase, overproduction of proin- flammatory cytokines and immunoglobulins [22] during the C5a blockade asthma development. Asthmatic inflammation may be initiated or exacerbated Th2 response by amplification of the complement cascade [11e13]. Complement components, especially C5 and C3 with their associated cleavage products C5a and C3a, regulate the magnitude of adaptive immune responses via ligation of their respective receptors expressed on antigen-presenting cells, and T lymphocytes, as well as on pulmonary struc- tures, and stromal cells [5,22]. These immune responses involve many pathophysiological features of asthma that Figure 2 Model explains Th1 to Th2 shift during the devel- include inflammatory cell infiltration, mucus secretion, in- opment of asthma pathogenesis, and, C3a and C5a as a potential crease vascular permeability, and smooth muscle contrac- targets to rescue asthma by blocking local T cell recruitment. tion [23]. This review summarizes the crucial role of complement mediators in airway inflammation, and how it affects the pathogenesis of asthma disease. innate immune system to favor asthma development [9,11]. The anaphylatoxins C3a and C5a have been characterized as potent mediators of the effector phase of the allergic Generation of c3a and c5a in asthma response [8e10,15] with C3a regulating TH2 cytokine pro- duction possibly through the recruitment, and activation of Asthma is associated with activation of complement TH2 cells [13]. C5a plays a dual immunoregulatory role by cascade and allergen induced complement generates C3a protecting against the TH2-polarized adaptive immune and C5a [3]. It has been demonstrated that C3a plays a response and mediates type 2 inflammatory responses once crucial role in asthma primarily by regulating mast cell-ASM inflammation proceeds [13] (see Fig. 2). Complement may (Airway Smooth Muscle) cell interaction [14]. C3a and C5a participate in the development of susceptibility to asthma, are released as key active factors in complement cascade despite a normal level of complement fragments generated that modulate innate immunity [3,4]. C5a is, however, during complement activation. involved in a number of inflammatory diseases [24] such as Different models of experimental allergic asthma sug- immune-complex-mediated lung injury, microvascular gest that the C3a and C5a not only promote pro-allergic injury in rejecting allografts [20] and in sepsis [14]. Levels effector functions during the allergic effector phase, but of C3a are found elevated in bronchoalveolar lavage fluid also regulate the development of TH2 immunity during after allergen challenge in asthmatic but not among allergen sensitization [16]. Generation of C3a on airway healthy controls [3]. The C3a and C5a peptides regulate surfaces induce TH2-mediated inflammatory responses to a inflammatory functions by interacting with their receptors variety of environmental triggers of asthma (i.e., allergens, C3aR and C5aR [25,26]. These receptors were mostly pre- pollutants, viral infections, cigarette smoke) [9,11]. C5a is sent only on myeloid cells such as macrophages, neutro- dominant during allergen sensitization, and protects phils, eosinophils, basophils, and mast cells, however, the against the development of maladaptive TH2 immunity immune cells that express these receptors in the lung have [13,16]. By contrast, C3a and C5a appear to act synergis- been investigated, and their expression been examined tically and drive allergic inflammation during the effector during phase of asthma inflammation [27e30]. These find- phase [10]. In addition to its proinflammatory effector ings suggests the participation of bronchial epithelial and functions, complement regulates adaptive