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| REVIEW ARTICLE |
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| Year : 2019 | Volume
: 3
| Issue : 1 | Page : 3-7 |
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Complements and allergic asthma
Ching-Yuang Lin1, Yi-Giien Tsai2
1 Clinical Immunology Center, China Medical University, Children's Hospital, Taichung, Taiwan
2 Department of Pediatrics, Changhua Christian Hospital Children's Hospital, Changhua, Taiwan
| Date of Web Publication | 9-May-2019 |
Correspondence Address:
Ching-Yuang Lin
Clinical Immunology Center, China Medical University, Children's Hospital, No. 2, Yun-Der Road, Taichung 40402
Taiwan
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/prcm.prcm_5_18
Regulatory T (Treg) cells play a central role in protecting against the development of allergic asthma and interleukin-10 (IL-10) producing T regulatory type 1 (Tr1) cells contribute to the regulation of asthma. Complement regulatory protein CD46 was shown to stimulate the development of IL-10 producing Tr1 cells. Crosslinking of CD46 during CD4+ T cell priming induces production of large amount of IL-10 and granzyme B. These CD46-induced regulatory T cells (Tr1) does not require pre-existing basal expression of FoxP3. Through local IL-10 and granzyme B secretion, such Tr1 cell could control T-cell-mediated inflammation. In asthmatic patients, we found that diminished IL-10, granzyme B, and CCR 4 expression from CD3/CD46-activated Tr1 cells. CD3/CD46-activated Tr1 cells from asthma patients co-cultured with BEAS-2B cells suppressed dermatophagoides pteronyssinus 2 (Der p 2)-induced nuclear factor-κB/p65 by cell contact inhibition. Decreased interaction of CD3/CD46-activated Tr1 and BEAS-2B cells from asthmatics was associated with downregulation of phosphorylation of protein kinase B expression. Decreased interaction between CD46-mediated Tr1 and lung epithelial cells with less IL-10 and granzyme B production may contribute to airway inflammation in allergic asthma. Der p specific immunotherapy enhances the suppressive function of IL-10 in CD46-mediated Tr1 cell from asthmatic patients and suppresses airway inflammation in these patients. Based on these results, it might be possible to design therapeutic strategies to manipulate complement activated Tr1 cells to achieve allergen tolerance and suppress airway inflammation in patients with allergic asthma.
Keywords: Allergic asthma, CD46, interleukin-10, Tr1 regulatory T cell
How to cite this article:
Lin CY, Tsai YG. Complements and allergic asthma. Pediatr Respirol Crit Care Med 2019;3:3-7 |
| Introduction | |  |
The traditional concept of the complement system was an effector arm of antibody response that destroys bacteria by lysis. Complement cascade is initiated through three pathways: classical pathway, lectin pathway, and the alternative pathway. Although triggered differently, these pathways culminate in the formation of the C3 convertases (C3bBb and C4bC2a) and C5 convertase (C3bBbC3b and C4b C2aC3b) which involves cleavage of C2 and C4 in classical and lectin pathways or the serine proteases factor B and factor D in alternative pathway. Deposition of clusters of C3b or C4b on a pathogen leads either to immune adherence and subsequent ingestion by phagocytic cells (opsonization) or to lysis by engagement of the membrane attack complex.[1] The coating of the pathogen with opsonic fragments derived from C3 and C4 is a robust process and is minimally influenced by complement inhibitors.[1],[2] This powerful effector system requires tight regulation. This is achieved through plasma and membrane regulatory proteins that inhibit complement activation in the fluid phase and on self. There are three major different mechanisms of regulation which are through serine protease factor I in conjunction with CD46, complement receptor 1 (CR1, CD35) or by factor H and C4b-binding protein.[1] The complement system is an important component of humoral immune response.[2] It serves as a natural adjuvant, lower the threshold for B cell activation, promotes the development of optimal B cell memory, and maintains B-cell tolerance.[3],[4] Complement also can modulate T-cell responses during the induction and effector phases and contraction phase.[5] These effects arise through direct modulation of T cell itself or indirectly through the alteration of antigen presenting cells (APCs).[6] The possible roles of the complement system in asthma will be discussed here.
Complement system is activated locally and systemically to amplify inflammatory response in allergic asthma.[7],[8],[9] CD46 are widely expressed in airway epithelial cells, leukocytes, and fibroblasts. Human lamina propria contains T cells with a cytokine expression profile that is characteristic of CD 46-induced Tr1 cell.[10],[11],[12],[13] In the present review, we elucidated the role of CD46-induced Tr1 cells in airway mucosal immunity and mechanism for CD46 modulation of Tr1 cells. We addressed as: (i) induction of T cell proliferation, (ii) induction of Tr1 differentiation, and (iii) competition effect of interleukin-2 (IL-2) in the Th1/Tr1 balance. Cross-linking of CD46 during T-cell receptor (TCR) activation leads to strong CD4+ T-cell proliferation and synthesis of large amount Il-10 and granzyme B similar to what is seen in inducible Tr1 cells.
| T Cells, Interleukin-10, and Complement Regulatory Proteins | | |
Allergic asthma is a chronic airway inflammatory disease. Recent studies reported that regulatory T cells (Treg) play a central role in protecting against the development of allergic asthma.[14] Treg cells such as IL-10 producing T regulatory type 1 (Tr1) also contribute to the regulation of asthma.[15],[16] IL-10 producing Tr1 cells can be induced in vitro[17] and with Vitamin D3 and dexamethasone.[18] Human CD4+ CD25+ Tregs can induce IL-10 production via direct contact under anti-CD3/CD28 stimulation in vitro.[19],[20] This is an important pathway for the induction of IL-10 producing Tr1 cells. Interestingly, the complement regulatory protein CD46 was shown to be physiological stimulants for the development of IL-10 producing Tr1 cells. CD4+ T cells stimulated with anti-CD3/CD46 in the presence of IL-2 produced massive IL-10, confirming a Tr1 phenotype.[8] Moreover, the supernatants from CD4+ T cells activated by CD3/CD46 plus IL-2 inhibited the proliferation of bystander CD4+ T cells.[9] IL-10 has been shown to protect against airway hyperresponsiveness in asthma through its effects on the proliferation and cytokine production of Th2 cells, on the activation of mast cell and eosinophil, and on the IgG4:IgE ratio.[21],[22],[23]
Two membrane-bound complement regulators, CD46 and CD55 participate directly in modulating function of APCs.[17] CD46 is a measles receptor.[24] Measles infection can induce transient spontaneous remission of minimal change nephrotic syndrome in children.[25] The cross-linking of CD46 with measles virus leads to calcium flux and suppress IL-12 production.[26] It is one reason for the suppression of T-cell response during measles infection. Cross-linking of CD46 during CD4+ T cell priming induces synthesis of large amounts of IL-10 and granzyme B.[19],[20] However, the mechanism of CD46 modulating effect on APC and T-cell function is not fully understood.
CD46 with either of its two regularly expressed cytoplasmic tails, Cyt1 or Cyt2.[9],[27] Cyt1 and Cyt2 differ in size and amino-acid sequence, and both contain motifs necessary for signaling. Mice CD4+ T cells that express CD46 with the Cyt1 cytoplasmic tail proliferated strongly produced IL-10 and inhibited the contact-hypersensitivity reaction after concurrent TCR and CD46 activation. By contrast, activation of Cyt2 cytoplasmic tail on CD46 showed weak proliferation and low IL-10 production but a heightened contact-hypersensitivity reaction.[9]
Two main mechanisms for the termination of T cell response by complement are the modulation of apoptosis and induction of regulatory T cells (Treg).[13],[27] CD46 has an unanticipated function in recognizing apoptotic T cells.[11],[13],[27] CD46 was to cluster in the apoptotic blebs and then shed in microparticles and allows engulfment by phagocytes. Treg cells are divided into natural CD4+ CD25+ Treg cells, originate from thymus and inducible Treg (Tr1) and TH3 cells, originate from the periphery against both self and foreign antigen.[28],[29] The suppressive effect in Tr1 cell is primarily by secretion of IL-10, whereas the suppressive effect of TH3 cell is primarily by secretion of TGFβ1. Crosslinking CD46 during toll-like receptor (TLR) activation leads to the development of Tr1 cell. These CD46-induced Tr1 cells proliferate strongly and suppress the activation of bystander T cells through the secretion of IL-10. CD46-induced Tr1 also synthesize granzyme B and perforin, and develop contact-dependent cytotoxicity toward autologous immunocompetent T cells.[30]
Tolerance to environmental allergens encountered on airway mucosa could be mediated by the development of Treg cells to suppress airway inflammation.[31],[32],[33] In children with allergic asthma, the CD4+ CD25+ Treg cells were decreased in bronchoalveolar lavage fluid and did not inhibit pulmonary Th2 response.[33] Defective recruitment of Treg function to the airway is important in the pathogenesis of allergic asthma.[10]
| Defects of Treg in Interleukin-10 Production in Asthma Patients | | |
Human CD4+ CD25− T cells stimulated with anti-CD3/CD46 or anti-CD3/CD28 in the presence of IL-2 can induce IL-10 production in vitro. IL-10 production in undivided CD4+ T cells and co-cultured CD4+ CD25+/CD4+ CD25-and CD4+ T cells under anti-CD3/CD46 stimulation in asthma patients was significantly lower than that in healthy controls; although, the levels of IL-10 under anti-CD3/CD28 stimulation were not different between asthma patients and healthy controls.[27]
Confocal microscopic analysis of human bronchial mucosa biopsy specimens revealed lower CD4+ CD46+ T cells in mite-sensitive asthmatics than nonatopic subjects. Peripheral blood mononuclear cells (PBMCs) were stimulated with Derp 2 then analyzed by flow cytometry for CD46 surface expression on CD4+ T cells. Quantitative analysis of CD4+ CD46+ cell in PBMCs revealed that number of CD4+ CD46+ cells decreased in asthmatics compared with nonatopic controls (P < 0.05). The CD3/CD46-activated CD4+ T cells from asthmatic patients had significantly lower IL-10 and interferon gamma (IFNr) expression compared with nonatopic controls (P < 0.05). When IL-10 and IFNr was quantified from cultured soup by ELISA, a striking defect with CD46-mediated Il-10 and IFN-r production was observed in asthmatics when compared with nonatopic controls. Double immunofluorescence staining was used for CD46 and granzyme B expression in CD3/CD46-activated CD4+ T cells. Significantly decreased granzyme B in CD46-activated CD4+ T cells was noted in asthmatics then nonatopic control.[10]
Both cytoplasmic isoforms of CD46, Cyt1, and Cyt2 in asthmatic children were examined. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis of Cyt1 and Cyt2 mRNA in CD3/CD46-induced Tregs from asthmatics revealed decreased CD46-Cyt1 isoform mRNA and increased CD46-Cyt2 isoform mRNA expression compared with controls, Cyt1 inhibited the inflammatory reaction with increased IL-10 production.[33]
Migration of CD3/CD46-activated Tregs migrates across the bronchial epithelial cell (human bronchial epithelial cell line BEAS-2B was used) under aeroallergen (Derp 2 was used) stimulation, as the time course of migration capacity, was examined. Using the trans-epithelial system in vitro, percentage of CD3/CD46-activated CD4+ T cells migrating across BEAS-2B monolayer decreased in asthmatic patients. Furthermore, imaging assay was taken at intervals of 10 min for 2 h revealed higher mobility of CD3/CD46-induced T cells from healthy controls than in asthmatics.[10],[33]
| Der P2-Activated Bronchial Epithelial Cells and Treg Migration | | |
Der p2-activated bronchial epithelial cells (BEAS-2B) induce nuclear factor-κB (NF-kB)/P65 in a dose-dependent manner. Transwell inset experiments (pore size 0.4 μM) demonstrated that CD3/CD46-activated CD4+ migrated to Der p 2-activated BEAS-2B cells by cell contact. CD3/CD46-activated Tregs inhibit NF-kB activity in Der p 2-activated BEAS-2B cells. Asthmatic patients have decreased NF-kB/p65 induction on Der p 2 stimulated BEAS-2B cells and suppressed CD3/CD46-activated Treg migrating to BEAS-2B cells. To test whether CD3/CD46-activated Tregs migrating suppression to Der p 2-activated EBAS-2B cells was through IL-10, IL-10 neutralizing antibody was added to co-cultures. Enhanced NF-kB from BEAS-2B cells in co-culture with CD3/CD46-induced Treg following treatment with neutralizing anti-IL-10 mAb was noted both in asthmatics and controls. Percentage of ICAM-1 on Der p 2-stimulated BEAS-2B cells when co-cultured with CD3/CD46-activated Tr1 Tregs was greater in healthy controls that than in asthmatics.[10],[33]
Expression of CCR4, CCR5, CCR7, and CCR8 on Tregs might slow migration toward inflammatory sits leading to inhibition of responding cells. Percentage and expression of CCR4 on CD3/CD46-activated Tregs declined significantly in asthmatics compared with healthy controls.[10]
Decreased AKT phosphorylation was noted in Der p 2-stimulated BEAS-2B in touch with CD3/CD46-activated Tregs in asthma patients compared with controls.[10],[33]
| Der P Immunotherapy and Enhance CD3/CD46 Induced Treg in Suppressing Allergic Inflammation in Asthmatics | | |
Defects in CD3/CD46-induced Tr1 function in regulating immune responses have been shown in asthmatics [Figure 1]. We demonstrated that Dermatophyagoides pteronyssinus (Der p) immunotherapy activated human bronchial epithelial cells and recruit CD3/CD46-activated Tr1 cells to the airway to suppress airway inflammation. Clinically, all the asthmatic patients who received Der p specific immunotherapy (SIT) had improved asthma scores, increased pulmonary function (forced expiratory volume in one second) and decreased exhaled nitric oxide after 1 year of SIT.[6],[7],[8],[34],[35],[36] The number of CD4+ FoxP3+ T cells increase and CD4+ IL-4+ cells decreased after 1 year of SIT. Increased IL-10 and IFNr expression in CD3/CD46-induced Treg were noted after 1 year of SIT in asthmatic patients. IL-10, IFNr, GM-CSF, and soluble CD40 ligand production from CD3/CD46-induced Treg was increased in asthmatic patients after 1 year of SIT. Quantitative RT-PCR analysis of Cyt1 and Cyt2 mRNA in the CD3/CD46-induced Treg from asthmatic patients after 1 year of SIT revealed a reciprocal change in the increase in CD46-induced Cyt1 mRNA expression associated with decreased CD46-induced Cyt2 mRNA expression. Der p SIT also increased CD3/CD46-induced T-cell suppression of CD25-depleted CD4+ T-cell proliferation.[7] | Figure 1: Airway inflammation pathway and their link to CD46+ Tr1 cells. Airway epithelial cell overaction by aeroallergen has been implicated in airway inflammation. Allergic asthma patients defect in recruit CD46+ Tr1 cells to suppress airway inflammation. Derp specific immunotherapy can enhance the suppressive function in CD46+ Tr1 cells from asthmatic patients.
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Down regulation of the effector T cell response through the development of a T-cell lineage with suppressive properties might be a novel role for complement in the contraction of an immune response.[7],[8],[33] CD46 can induce the development of a distinct immune-modulatory T cell population to produce IL-10 and granzyme B. CD3/CD46-activated Tr1 cell can suppress airway inflammation in asthmatic patients [Figure 1]. Further understanding of how CD46 activates IL-10 producing Tr1 cell during Der p SIT, and the dose of mite allergen might be important.
CD3/CD46-activated Tr1 cell permit dendritic cell activation through their simultaneous secretion of GM-CSF and soluble CD40 leading to mucosal tolerance.
| Conclusion | | |
Asthmatic patients have dysfunctional CD46+ Tr1 cell that fail to suppress mite-induced airway epithelial cell inflammation. Der p SIT can rescue the suppressive function of CD46+ Tr1 cells and achieve allergen tolerance for asthmatic patients.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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