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 Complement mediated injury; Asthma; Anaphylatoxins

Summary Asthma is the most common respiratory disorder, and is characterized by distal airway inflammation and hyperresponsiveness. This disease challenges human health because of its increasing prevalence, severity, morbidity, and the lack of a proper and complete cure. Asthma is characterized by TH2eskewed inflammation with elevated pulmonary levels of IL4, IL-5, and IL-13 levels. Although there are early forays into targeting TH2 immunity, lessspecific corticosteroid therapy remains the immunomodulator of choice. Innate immune injury mediated by complement components also act as potent mediators of the allergic inflammatory responses and offer a new and exciting possibility for asthma immunotherapy. The complement 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 permeability, 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 Asthma is a chronic inflammatory disease of the bronchi arising because of inappropriate immunological responses to common environmental antigens in genetically susceptible individuals [1]. It is thought to be mediated by CD4þ T lymphocytes that produce TH2 cytokines linked with elevated specific IgE, eosinophilia, and airway hyperresponsiveness (AHR) [2e4]. This perspective will explore how an important component of the innate immunity, the complement system, normally a key defense against mucosal bacteria, viruses, fungi, helminthes, and other pathogens, may also play an important role in the pathogenesis of asthma. Although complement factors have been associated with development of pathophysiology of asthma [5,6], the role of individual complement components in the pathogenesis of allergic asthma is not clear. Biologically active fragments (C3a, C5a), generated through the

Classical

classical, alternative, lectin pathways, and by the direct action of certain proteolytic enzymes on C3 or C5 [7] (Fig. 1), participate in AHR induction. Infections, and allergens of respiratory tract activate local complement activation participate in AHR [8e10] because of their ability to recruit, activate leukocytes, increase vascular permeability, stimulate contraction of smooth muscle, and trigger degranulation of mast cells [9,11e13]. In addition to allergens, other triggers of asthma have been shown to activate complement cascade in human, and in animal models [13]. It has been demonstrated that bronchoalveolar lavage (BAL) of asthma individuals contain quantitatively higher levels of C3a and C5a as compared to healthy control subjects at baseline [14]. In asthma, overproduction of activated complement fragments may promote asthma susceptibility [13]. This imbalance results in up regulation of biologically active fragments, C3a and C5a, which may act on cells of the

Lectin

Alternative

C4b2a

C3bBb C3

C3a bind to C3aR

C3b C4b2a3b

C3bBb3b C5

C5b

MAC

C5a Release of histamine CD4+

Mast cell

Release of IL-17 and IL-4, Il-13, IL-5 (neutrophil inflammation)

Airway narrowing and AHR

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 IL-2

C3a

C5a

Th1 response

C5a blockade

Th2 response

Figure 2 Model explains Th1 to Th2 shift during the development of asthma pathogenesis, and, C3a and C5a as a potential targets to rescue asthma by blocking local T cell recruitment.

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 response [8e10,15] with C3a regulating TH2 cytokine production possibly through the recruitment, and activation of TH2 cells [13]. C5a plays a dual immunoregulatory role by protecting against the TH2-polarized adaptive immune response and mediates type 2 inflammatory responses once inflammation proceeds [13] (see Fig. 2). Complement may participate in the development of susceptibility to asthma, despite a normal level of complement fragments generated during complement activation. Different models of experimental allergic asthma suggest that the C3a and C5a not only promote pro-allergic effector functions during the allergic effector phase, but also regulate the development of TH2 immunity during allergen sensitization [16]. Generation of C3a on airway surfaces induce TH2-mediated inflammatory responses to a variety of environmental triggers of asthma (i.e., allergens, pollutants, viral infections, cigarette smoke) [9,11]. C5a is dominant during allergen sensitization, and protects against the development of maladaptive TH2 immunity [13,16]. By contrast, C3a and C5a appear to act synergistically and drive allergic inflammation during the effector phase [10]. In addition to its proinflammatory effector functions, complement regulates adaptive immunity at many levels [12], and play critical role as well in causing vascular injury in allografts [17,18]. It has been observed that allergen challenged C3aRdeficient mice and guinea pigs are protected against bronchoconstriction and AHR [16]. Interestingly, there was no difference in eosinophilic airway inflammation, TH2 cytokine production, IgE production between C3a receptordeficient, and in wild type animals which demonstrate that airway inflammation, and AHR are two independent features of asthma [2,3]. Several studies have demonstrated that blocking of IL-4 reduces AHR in the lung, and that RAG/ mice, which lack Th2 cells, fail to develop AHR, mucus hyper-secretion, and eosinophilia during the course of asthma [19]. However, airway inflammation, and the immune responses at cellular and molecular levels have led to the proposition of a number of mechanisms such as mast cell degranulation [18,20,21], neurogenic dysfunction,

545 involvement of T-lymphocytes, eosinophils, altered immunosuppressive macrophages, excessive nitric oxide through inducible nitric oxide synthase, overproduction of proinflammatory cytokines and immunoglobulins [22] during the asthma development. Asthmatic inflammation may be initiated or exacerbated 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 structures, and stromal cells [5,22]. These immune responses involve many pathophysiological features of asthma that include inflammatory cell infiltration, mucus secretion, increase vascular permeability, and smooth muscle contraction [23]. This review summarizes the crucial role of complement mediators in airway inflammation, and how it affects the pathogenesis of asthma disease.

Generation of c3a and c5a in asthma Asthma is associated with activation of complement cascade and allergen induced complement generates C3a and C5a [3]. It has been demonstrated that C3a plays a crucial role in asthma primarily by regulating mast cell-ASM (Airway Smooth Muscle) cell interaction [14]. C3a and C5a are released as key active factors in complement cascade that modulate innate immunity [3,4]. C5a is, however, involved in a number of inflammatory diseases [24] such as immune-complex-mediated lung injury, microvascular injury in rejecting allografts [20] and in sepsis [14]. Levels of C3a are found elevated in bronchoalveolar lavage fluid after allergen challenge in asthmatic but not among healthy controls [3]. The C3a and C5a peptides regulate inflammatory functions by interacting with their receptors C3aR and C5aR [25,26]. These receptors were mostly present only on myeloid cells such as macrophages, neutrophils, eosinophils, basophils, and mast cells, however, the immune cells that express these receptors in the lung have been investigated, and their expression been examined during phase of asthma inflammation [27e30]. These findings suggests the participation of bronchial epithelial and smooth muscle cells in the pathology of diseases such as sepsis and asthma, the data suggest a role for complement receptors during lung inflammation [27]. It has been observed that C3aR activation is associated with the development of AHR, and inflammation in different animal models of asthma [27]. However, C3aRdeficient mice are protected from AHR in response to aerosolized ovalbumin challenge following intraperitoneal sensitization with ovalbumin [31]. Single nucleotide polymorphisms in C3 and C3aR genes have been linked with increased susceptibility to asthma [31]. This speculates the crucial role of C3a and C3aR in the development of AHR and inflammation [31]. BAL fluids of C3aR deficient mice also had low levels of TH2 cytokines (IL-4, IL-5, and IL-13), IgE titers, and mucous production that further support a role of C3a receptors in the development of AHR, and generalized inflammation [15,31,32]. It is observed that deficiency of C3aR leads to decrease airway hyperresponsiveness in a

546 mouse model pulmonary allergy [32]. In addition, increased C3a levels have been reported in bronchial lavage samples from allergen-challenged asthma patients [3]. There is a significant association has been reported between AHR and C5 level [3], however, compared to C5 sufficient mice, the C5-deficient mice are more responsive to methacholine challenges after allergen exposure [33]. The presence of C5 and C5aR is necessary for a variety of immunological responses including inflammation and host defense [14]. Elevated levels of complement anaphylatoxin peptides have been observed in the lungs of asthmatic patients [27] which further supports the significance of complement factors in asthma pathogenesis. The C5 gene and the C5aR receptor genetic regions have been identified as putative asthma susceptible loci [27]. Finally, C3aR and C5aR expression has demonstrated on lung bronchial smooth muscle cells implicating these receptors as mediators of bronchoconstriction [34].

Complement mediators-immune cell interaction in asthma pathogenesis Cells of the innate immune system in asthmatics are abnormally responsive to the regulatory effects of complement followed by the development of susceptibility to asthma [10,35]. Recent research efforts have also demonstrated that CD4þ T cells, which produce a TH2 pattern of cytokines, play a pivotal role in the pathogenesis of this disease [52] and cytokines such as IL-4, IL-13, and IL-5 to contribute in bronchial hyper-reactivity, and mucus hypersecretion as well as orchestrate the recruitment, activation of mast cells, and eosinophils [19,53,54]. The complement cascade is a central player of innate immunity that coordinates a number of inflammatory responses [35]. C3a activates mast cells, basophils, eosinophils, and contraction of airway smooth muscle cell [18,24]. Both C3a and C5a can induce ASM cell contraction, increase the microvascular permeability, and regulate vasodilation [5]. C5a has been widely used as standard stimulant to eosinophil/or basophil responsivity, and active C5 fragments alone can induce airway hyperresponsiveness when administered [24]. In addition, C3a and C5a can: 1) stimulate respiratory burst in macrophages, neutrophils, and eosinophils; 2) stimulate the release of histamine from basophils and mast cells; and 3) regulate the synthesis of eosinophil cationic proteins and adhesion to endothelial cells by eosinophils [14,20]. C3a can also stimulate serotonin release from platelets, and modulate synthesis of IL-6 and TNF-a by B-lymphocytes and monocytes [36,37]. C5a is a potent chemotactic molecule for macrophages, neutrophils, T lymphocytes, and basophils [27]. Both C3a and C5a can induce chemotaxis of eosinophils and mast cells [27]. Generation of C3a at the airway surface triggers induction of AHR [13], while C5/ C5a, plays a dual immunoregulatory role by protecting against the initiation of Th2-mediated immune responses during initial allergen exposure by its ability to affect dendritic cell-T cell interactions, and a more traditional pro-inflammatory role once immune responses are established [13,16]. The interactions between C5a and the IL-12 are important for generating AHR-associated inflammation [38].

M.A. Khan et al. Direct administration of IL-12 has shown to reduce AHR, and macrophages from the C5-deficient mice were here shown to produce lower levels than the control mice [39e42]. C3b on the other hand, has been shown as capable of blocking IL-12 production by its interaction with the aMb2 integrin, an action perfectly in keeping with a positive role for C3 cleavage in AHR e either via C3a and its receptor or through C3b and reduced levels of IL-12 [43]. C5 has been associated with dendritic cells mediated induction of Tregs (CD4þCD25þ T cells) and Tregs blockade in allergen exposed C5 sufficient mice eliminated their protection from the development of AHR associated with a drop in the numbers of pulmonary dendritic cells [13]. In addition, depletion of dendritic cells and Tregs in mice results in an increased capacity to stimulate T cell proliferation and Th2 cytokine production. The balance between C3a and C5a during early life exposures to allergens may be a crucial determinant factor in the development of tolerance to inhaled antigens [9,13]. In lungs, C3 would most probably create Th2 shift, which is consistent with data suggesting that the lungs have Th2 type cell at birth in newborn [44]. Clinical studies has shown the relatively higher levels of C3a and C5a in BAL fluid of allergen induced asthmatic airways as compared with control subjects [5,10,16]. C5a contribute to the development of the proallergic environment in allergic asthma [10], and targeting C5 in allergen-induced asthma model have demonstrated that C5 may serve as a suitable target in treatment of asthma [10,45]. C5a can bind to both C5aR and C5L2 receptors [5], and, more specifically C5L2 acts at the dendritic cell and T cells interface, and control the development of TH1 and TH17 cells in response to airway antigen exposure, and drives TH2 immune responses independent of specific dendritic cells [46]. As reported earlier, C5a, and perhaps C3a may cause immediate airflow obstruction, and subsequent airway hyperactivity [27]. It has been demonstrated in murine model of AHR that C5a may act directly or indirectly to stimulate C5aR on local mast cells and/or platelets, resulting in the release of broncho constrictive mediators, and results in sensitization of the airways without cellular inflammation [47]. In a number of other asthma models, the role of IL-17 has been highlighted in inducing asthmatic response, and AHR [48]. There has been increasing evidence suggest the involvement of C3a in the asthma pathogenesis, and the relationship between C3a driven IL-17 and IgE-mediated asthmatic responses that have shown the contribution of IL-17 to an IgE-mediated late-phase asthmatic response, and AHR [48]. They reported that during repeated antigen exposure, C3a mediated antibody production (IgE) results in production of IL-17þCD4þ cells in the lungs [18,24,49] (Fig. 1).

Summary Asthma, a complex airway inflammatory disease, is characterized by bronchoconstriction, AHR and airway remodelling [50]. Current consensus suggests that TH2 cytokine producing T cells, mast cells, and ASM cells play central roles in the pathogenesis of asthma [51]. This classification of asthma has led to the concept that the immediate

Complement components for asthma treatment response after allergen challenge is mediated by mast cells, whereas eosinophils are the predominant effector cells in the late asthmatic reaction [27]. C3 and C5 play unique roles in airway inflammation associated with asthma and the release of C3a at the airway surface mediates the induction of AHR in different asthma models, while C5/C5a plays a dual immunoregulatory role by protecting against Th2-mediated immune responses during initiation of responses, and a proinflammatory role once immune responses are established [50]. Serine proteases generated in response to classical and alternative pathways has potential to generate C3a and C5a from C3 and C5 respectively [55,56]. It is observed that different components of the complement cascade have implicated in mediating allergic inflammation [57]. As reported in other asthma models, C3a and C5a participate in shifting Th2 and Th1 balance respectively but blocking or antagonizing C5a shift response to Th2 [13] and Th2 shift results in elevated Th2 adaptive response followed by airway inflammation [42]. These anaphylatoxins can induce ASM contraction [20,58,59], mucus secretion [60,61], increased microvascular permeability [62,63] [17,24], vasodilation [64,65], leukocyte migration and activation, and degranulation of mast cells [66], which are the hallmarks features of asthma. Further, the most important, neutralization of anaphylatoxin activity through the use of blocking antibodies, genetic targeting or by using specific antagonist of various complement factors or their receptors has been shown to attenuate allergic inflammation, and AHR in mice, and guinea pigs [67,68]. It is becoming increasingly clear that immunoregulatory events occurring at the interface of innate and adaptive immunity play an important role in asthma pathogenesis [13]. The data reviewed here suggest that the complement pathway serves as a central regulator of adaptive immune responses to a variety of inhaled substances. The complement cascade consists of number of serum and cellular proteins, and the activation of complement includes a series of initiation, amplification, and release of active mediators that mediate cell lysis [35]. The whole complement cascade is regulated at various points by different complement regulatory proteins. These proteins counter check the over expression of released active fragments, make balance between self and foreign tissue, and, therefore, allows for control over the potent tissuedamaging capabilities of complement activation. Soluble, and membrane-bound complement regulators have been produced, and shown to be effective in blocking complement activation in vitro as well as in animal models of complement-mediated pathologies in different diseases [69]. Compared with conventional therapeutic options available to asthma patients, recombinant proteins for therapy remain attractive to date, for reasons having to do with both the biological properties of proteins, and the economics of drug development [18,24]. A number of complement inhibitors has been introduced as therapeutic agents for inflammatory, ischemic [70], and autoimmune diseases [42]. It has been reported that Crry-Ig treatment inhibit airway inflammation, and AHR in OVA sensitized mice [9,11]. The objective here is to present a brief and selective summary of the findings using synthetic molecules for the therapeutic inhibition of complement in asthma pathogenesis. In last couple of years, it has been

547 recognized that some of the endogenous complement regulatory proteins has been proven to serve as potential therapeutic agents in blocking inappropriate activation of complement in human diseases specially asthma [34,45,71,72]. In this review, our aim is to focus on more translational approach in the field of asthma cure with the possible use of novel complement inhibition approach to control complement mediated airway injury, hyperresponsiveness and ultimately to rescue asthma.

Conflict of interest The authors have no conflict of interest.

References [1] Pawankar R, Canonica GW, Holgate ST, Lockey RF. Allergic diseases and asthma: a major global health concern. Curr Opin Allergy Clin Immunol 2012;12:39e41. [2] Krug N, Erpenbeck VJ, Balke K, Petschallies J, Tschernig T, Hohlfeld JM, Fabel H. Cytokine profile of bronchoalveolar lavage-derived CD4(þ), CD8(þ), and gammadelta T cells in people with asthma after segmental allergen challenge. Am J Respir Cell Mol Biol 2001;25:125e31. [3] Krug N, Tschernig T, Erpenbeck VJ, Hohlfeld JM, Kohl J. Complement factors C3a and C5a are increased in bronchoalveolar lavage fluid after segmental allergen provocation in subjects with asthma. Am J Respir Crit Care Med 2001; 164:1841e3. [4] Khan MA. Inflammation signals airway smooth muscle cell proliferation in asthma pathogenesis. Multidiscip Respir Med 2013;8:11. [5] Zhang X, Schmudde I, Laumonnier Y, Pandey MK, Clark JR, Konig P, Gerard NP, Gerard C, Wills-Karp M, Kohl J. A critical role for C5L2 in the pathogenesis of experimental allergic asthma. J Immunol 2010;185:6741e52. [6] Takeda K, Thurman JM, Tomlinson S, Okamoto M, Shiraishi Y, Ferreira VP, Cortes C, Pangburn MK, Holers VM, Gelfand EW. The critical role of complement alternative pathway regulator factor H in allergen-induced airway hyperresponsiveness and inflammation. J Immunol 2012;188: 661e7. [7] Maruo K, Akaike T, Ono T, Okamoto T, Maeda H. Generation of anaphylatoxins through proteolytic processing of C3 and C5 by house dust mite protease. J Allergy Clin Immunol 1997; 100:253e60. [8] Kohl J. Self, non-self, and danger: a complementary view. Adv Exp Med Biol 2006;586:71e94. [9] Kohl J, Wills-Karp M. A dual role for complement in allergic asthma. Curr Opin Pharmacol 2007;7:283e9. [10] Zhang X, Kohl J. A complex role for complement in allergic asthma. Expert Rev Clin Immunol 2010;6:269e77. [11] Kohl J, Wills-Karp M. Complement regulates inhalation tolerance at the dendritic cell/T cell interface. Mol Immunol 2007;44:44e56. [12] Walters DM, Breysse PN, Schofield B, Wills-Karp M. Complement factor 3 mediates particulate matter-induced airway hyperresponsiveness. Am J Respir Cell Mol Biol 2002;27: 413e8. [13] Wills-Karp M. Complement activation pathways: a bridge between innate and adaptive immune responses in asthma. Proc Am Thorac Soc 2007;4:247e51. [14] Guo RF, Ward PA. Role of C5a in inflammatory responses. Annu Rev Immunol 2005;23:821e52.

548 [15] Humbles AA, Lu B, Nilsson CA, Lilly C, Israel E, Fujiwara Y, Gerard NP, Gerard C. A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature 2000;406: 998e1001. [16] Zhang X, Lewkowich IP, Kohl G, Clark JR, Wills-Karp M, Kohl J. A protective role for C5a in the development of allergic asthma associated with altered levels of B7-H1 and B7-DC on plasmacytoid dendritic cells. J Immunol 2009;182: 5123e30. [17] Khan MA, Maasch C, Vater A, Klussmann S, Morser J, Leung LL, Atkinson C, Tomlinson S, Heeger PS, Nicolls MR. Targeting complement component 5a promotes vascular integrity and limits airway remodeling. Proc Natl Acad Sci U S A 2013;110:6061e6. [18] Khan MA, Nicolls MR. Complement-mediated microvascular injury leads to chronic rejection. Adv Exp Med Biol 2013;734: 233e46. [19] Drouin SM, Corry DB, Kildsgaard J, Wetsel RA. Cutting edge: the absence of C3 demonstrates a role for complement in Th2 effector functions in a murine model of pulmonary allergy. J Immunol 2001;167:4141e5. [20] Ali H, Panettieri Jr RA. Anaphylatoxin C3a receptors in asthma. Respir Res 2005;6:19. [21] Mizuno S, Farkas L, Al Husseini A, Farkas D, Gomez-Arroyo J, Kraskauskas D, Nicolls MR, Cool CD, Bogaard HJ, Voelkel NF. Severe pulmonary arterial hypertension induced by SU5416 and ovalbumin immunization. Am J Respir Cell Mol Biol 2012; 47:679e87. [22] Holgate ST. Innate and adaptive immune responses in asthma. Nat Med 2012;18:673e83. [23] Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM. Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 2000;161: 1720e45. [24] Khan MA, Jiang X, Dhillon G, Beilke J, Holers VM, Atkinson C, Tomlinson S, Nicolls MR. CD4þ T cells and complement independently mediate graft ischemia in the rejection of mouse orthotopic tracheal transplants. Circ Res 2011;109: 1290e301. [25] Soruri A, Kim S, Kiafard Z, Zwirner J. Characterization of C5aR expression on murine myeloid and lymphoid cells by the use of a novel monoclonal antibody. Immunol Lett 2003;88: 47e52. [26] Soruri A, Riggert J, Schlott T, Kiafard Z, Dettmer C, Zwirner J. Anaphylatoxin C5a induces monocyte recruitment and differentiation into dendritic cells by TNF-alpha and prostaglandin E2-dependent mechanisms. J Immunol 2003; 171:2631e6. [27] Drouin SM, Kildsgaard J, Haviland J, Zabner J, Jia HP, McCray Jr PB, Tack BF, Wetsel RA. Expression of the complement anaphylatoxin C3a and C5a receptors on bronchial epithelial and smooth muscle cells in models of sepsis and asthma. J Immunol 2001;166:2025e32. [28] Fayyazi A, Sandau R, Duong LQ, Gotze O, Radzun HJ, Schweyer S, Soruri A, Zwirner J. C5a receptor and interleukin-6 are expressed in tissue macrophages and stimulated keratinocytes but not in pulmonary and intestinal epithelial cells. Am J Pathol 1999;154:495e501. [29] Zwirner J, Fayyazi A, Gotze O. Expression of the anaphylatoxin C5a receptor in non-myeloid cells. Mol Immunol 1999; 36:877e84. [30] Zwirner J, Gotze O, Begemann G, Kapp A, Kirchhoff K, Werfel T. Evaluation of C3a receptor expression on human leucocytes by the use of novel monoclonal antibodies. Immunology 1999;97:166e72. [31] Hasegawa K, Tamari M, Shao C, Shimizu M, Takahashi N, Mao XQ, Yamasaki A, Kamada F, Doi S, Fujiwara H, et al. Variations in the C3, C3a receptor, and C5 genes affect

M.A. Khan et al.

[32]

[33]

[34] [35]

[36]

[37]

[38]

[39]

[40] [41]

[42]

[43]

[44] [45] [46]

[47]

[48]

susceptibility to bronchial asthma. Hum Genet 2004;115: 295e301. Drouin SM, Corry DB, Hollman TJ, Kildsgaard J, Wetsel RA. Absence of the complement anaphylatoxin C3a receptor suppresses Th2 effector functions in a murine model of pulmonary allergy. J Immunol 2002;169:5926e33. Drouin SM, Sinha M, Sfyroera G, Lambris JD, Wetsel RA. A protective role for the fifth complement component (c5) in allergic airway disease. Am J Respir Crit Care Med 2006;173: 852e7. Kohl J. Drug evaluation: the C5a receptor antagonist PMX-53. Curr Opin Mol Ther 2006;8:529e38. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol 2010;11:785e97. Babu AN, Murakawa T, Thurman JM, Miller EJ, Henson PM, Zamora MR, Voelkel NF, Nicolls MR. Microvascular destruction identifies murine allografts that cannot be rescued from airway fibrosis. J Clin Invest 2007;117:3774e85. Ulrich S, Nicolls MR, Taraseviciene L, Speich R, Voelkel N. Increased regulatory and decreased CD8þ cytotoxic T cells in the blood of patients with idiopathic pulmonary arterial hypertension. Respiration 2008;75:272e80. Conroy A, Serghides L, Finney C, Owino SO, Kumar S, Gowda DC, Liles WC, Moore JM, Kain KC. C5a enhances dysregulated inflammatory and angiogenic responses to malaria in vitro: potential implications for placental malaria. PLoS ONE 2009;4:e4953. Melendi GA, Hoffman SJ, Karron RA, Irusta PM, Laham FR, Humbles A, Schofield B, Pan CH, Rabold R, Thumar B, et al. C5 modulates airway hyperreactivity and pulmonary eosinophilia during enhanced respiratory syncytial virus disease by decreasing C3a receptor expression. J Virol 2007;81:991e9. Henson P. Complementing asthma. Nat Immunol 2000;1: 190e2. Park JW, Taube C, Joetham A, Takeda K, Kodama T, Dakhama A, McConville G, Allen CB, Sfyroera G, Shultz LD, et al. Complement activation is critical to airway hyperresponsiveness after acute ozone exposure. Am J Respir Crit Care Med 2004;169:726e32. Taube C, Rha YH, Takeda K, Park JW, Joetham A, Balhorn A, Dakhama A, Giclas PC, Holers VM, Gelfand EW. Inhibition of complement activation decreases airway inflammation and hyperresponsiveness. Am J Respir Crit Care Med 2003;168: 1333e41. Hogan SP, Rosenberg HF, Moqbel R, Phipps S, Foster PS, Lacy P, Kay AB, Rothenberg ME. Eosinophils: biological properties and role in health and disease. Clin Exp Allergy 2008;38:709e50. Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 2007;7:379e90. Makrides SC. Therapeutic inhibition of the complement system. Pharmacol Rev 1998;50:59e87. Kawikova I, Paliwal V, Szczepanik M, Itakura A, Fukui M, Campos RA, Geba GP, Homer RJ, Iliopoulou BP, Pober JS, et al. Airway hyper-reactivity mediated by B-1 cell immunoglobulin M antibody generating complement C5a at 1 day post-immunization in a murine hapten model of non-atopic asthma. Immunology 2004;113:234e45. Lajoie S, Lewkowich IP, Suzuki Y, Clark JR, Sproles AA, Dienger K, Budelsky AL, Wills-Karp M. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol 2010;11:928e35. Mizutani N, Goshima H, Nabe T, Yoshino S. Complement C3ainduced IL-17 plays a critical role in an IgE-mediated latephase asthmatic response and airway hyperresponsiveness

Complement components for asthma treatment

[49]

[50] [51] [52]

[53] [54] [55] [56]

[57]

[58]

[59] [60]

[61] [62]

via neutrophilic inflammation in mice. J Immunol 2012;188: 5694e705. Qu H, Ricklin D, Lambris JD. Recent developments in low molecular weight complement inhibitors. Mol Immunol 2009; 47:185e95. Barnes PJ, Chung KF, Page CP. Inflammatory mediators of asthma: an update. Pharmacol Rev 1998;50:515e96. Barnes PJ, Lim S. Inhibitory cytokines in asthma. Mol Med Today 1998;4:452e8. Wang YH, Voo KS, Liu B, Chen CY, Uygungil B, Spoede W, Bernstein JA, Huston DP, Liu YJ. A novel subset of CD4(þ) T(H)2 memory/effector cells that produce inflammatory IL17 cytokine and promote the exacerbation of chronic allergic asthma. J Exp Med 2010;207:2479e91. Walsh ER, August A. Eosinophils and allergic airway disease: there is more to the story. Trends Immunol 2010;31:39e44. Walsh ER, Stokes K, August A. The role of eosinophils in allergic airway inflammation. Discov Med 2010;9:357e62. Janeway Jr CA. How the immune system protects the host from infection. Microbes Infect 2001;3:1167e71. Janeway Jr CA. How the immune system works to protect the host from infection: a personal view. Proc Natl Acad Sci U S A 2001;98:7461e8. Markiewski MM, Lambris JD. The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol 2007;171:715e27. Stimler NP, Brocklehurst WE, Bloor CM, Hugli TE. Complement anaphylatoxin C5a stimulates release of SRS-A-like activity from guinea-pig lung fragments. J Pharm Pharmacol 1980;32:804. Stimler NP, Hugli TE, Bloor CM. Pulmonary injury induced by C3a and C5a anaphylatoxins. Am J Pathol 1980;100:327e48. Marom Z, Shelhamer J, Berger M, Frank M, Kaliner M. Anaphylatoxin C3a enhances mucous glycoprotein release from human airways in vitro. J Exp Med 1985;161:657e68. Marom Z, Shelhamer JH, Kaliner M. Human monocyte-derived mucus secretagogue. J Clin Invest 1985;75:191e8. Konno S, Tsurufuji S. Inability of rat anaphylatoxin to induce histamine release in rats. Jpn J Pharmacol 1985;38:185e93.

549 [63] Konno S, S Tsurufuji. Inhibitory effect of a novel anticomplementary agent, K-76COONa, on the release of histamine induced by zymosan and compound 48/80. Jpn J Pharmacol 1985;38:116e9. [64] Schumacher WA, Fantone JC, Kunkel SE, Webb RC, Lucchesi BR. The anaphylatoxins C3a and C5a are vasodilators in the canine coronary vasculature in vitro and in vivo. Agents Actions 1991;34:345e9. [65] Shushakova N, Skokowa J, Schulman J, Baumann U, Zwirner J, Schmidt RE, Gessner JE. C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex-induced lung disease. J Clin Invest 2002; 110:1823e30. [66] Thangam EB, Venkatesha RT, Zaidi AK, Jordan-Sciutto KL, Goncharov DA, Krymskaya VP, Amrani Y, Panettieri Jr RA, Ali H. Airway smooth muscle cells enhance C3a-induced mast cell degranulation following cell-cell contact. FASEB J 2005; 19:798e800. [67] Lambrecht BN. An unexpected role for the anaphylatoxin C5a receptor in allergic sensitization. J Clin Invest 2006;116:628e32. [68] Lukacs NW, Glovsky MM, Ward PA. Complement-dependent immune complex-induced bronchial inflammation and hyperreactivity. Am J Physiol Lung Cell Mol Physiol 2001;280:L512e8. [69] Glovsky MM, Ward PA, Johnson KJ. Complement determinations in human disease. Ann Allergy Asthma Immunol 2004;93:513e22. quiz 523e5, 605. [70] Kalli KR, Hsu P, Fearon DT. Therapeutic uses of recombinant complement protein inhibitors. Springer Semin Immunopathol 1994;15:417e31. [71] Fridkis-Hareli M, Storek M, Mazsaroff I, Risitano AM, Lundberg AS, Horvath CJ, Holers VM. Design and development of TT30, a novel C3d-targeted C3/C5 convertase inhibitor for treatment of human complement alternative pathway-mediated diseases. Blood 2011;118:4705e13. [72] Holgate ST, Djukanovic R, Casale T, Bousquet J. Anti-immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy. Clin Exp Allergy 2005;35:408e16.