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Innate and adaptive immune connections in inflammatory bowel diseases

Rakoff-Nahoum, Seth; Bousvaros, Athos

Current Opinion in Gastroenterology: November 2010 - Volume 26 - Issue 6 - p 572–577
doi: 10.1097/MOG.0b013e32833f126d
Immunology: Edited by W. Allan Walker
Free

Purpose of review To review the current knowledge of the connections between the innate and adaptive immune systems in the etiology and pathogenesis of inflammatory bowel disease (IBD).

Recent findings Immune homeostasis in the mammalian intestine balances colonization by a symbiotic microbial flora and host defense. IBD is thought to be a breakdown of this balance. Although early studies shed light on the role of the adaptive immune system and negative regulators of homeostasis in IBD pathogenesis, here we review recent findings on the role of the innate immune system and microbial symbionts in the development of IBD.

Summary Both the inflammatory and immune responses may be characterized according to modules of initiators, triggers, mediators and effectors. Use of this framework may guide our understanding of disease pathogenesis. Here we apply this model to the pathogenesis of IBD.

Inflammatory Bowel Disease Center, Children's Hospital Boston, Boston, Massachusetts, USA

Correspondence to Athos Bousvaros, MD, MPH, Associate Director, Inflammatory Bowel Disease Center, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA Tel: +1 617 355 2962; e-mail: athos.bousvaros@childrens.harvard.edu

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Introduction

Crohn's disease and ulcerative colitis are two forms of inflammatory bowel disease (IBD), conditions of recurring and relapsing idiopathic intestinal inflammation. Although the Crohn's disease and ulcerative colitis differ in a number of ways, both entities are characterized as chronic inflammatory states in which elements of the adaptive (or specific) immune system, most notably T cells, play an important role. Over the last 15 years, the prevailing theory is that IBD results from a perturbation in the balance between the host's immune system and some aspect of the intestinal microbial flora. During this period, there has been a revolution in our understanding of how the immune system works, particularly how microorganisms are recognized by the innate immune system and how this recognition leads to the coordination of defined types of adaptive immune responses. In the following article, we attempt to review the current knowledge of the connections between the innate and adaptive immune systems in the etiology and pathogenesis of IBD, with focus on recent advances and future directions within the field.

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Inflammatory, innate and adaptive theory

Diseases of the inflammatory and/or immune systems can be categorized using a number of different qualifiers. Inflammatory responses can be defined as acute or chronic based on whether there is resolution and return of tissue function or persistence and tissue dysfunction, respectively [1••]. Inflammation may be conceived of as containing four components: triggers/initiators (e.g. pathogen-associated or microbial-associated molecular patterns), sensors [e.g. toll-like receptors (TLRs)], mediators (e.g. cytokines and chemokines) and effectors (e.g. B cells and cytotoxic and helper T cells) [2]. In acute inflammatory states, the inflammatory process is downregulated and resolves. In contrast, in chronic inflammatory diseases such as IBD, derangements of homeostatic mechanisms lead to persistent inflammation. In vertebrates, the immune system has been classically broken down into the adaptive and innate immunity (Table 1 is a generalized summary of adaptive and innate immunity). The adaptive immune system refers to responses that involve cells with receptors generated from gene rearrangement such as T lymphocytes and B lymphocytes, which allows for antigen specificity and memory. By default, the innate immune system, in all its complexity, may be defined as all aspects of the host defense to infection other than the adaptive immunity. Both innate and adaptive immune responses may be considered using the inflammatory framework as outlined above. One example of this is the original demonstration of the innate control of adaptive immunity with the recognition of pathogen (or microbial)-associated molecular patterns (PAMP/MAMPs; trigger) by pattern recognition receptors (PRR, e.g. toll-like receptor; sensor) leading to the activation and differentiation of T cells (effector) via signaling pathways leading to costimulation and helper T cell instructional cytokines (mediator) [3].

Table 1

Table 1

The study of inflammatory, innate and adaptive responses has led to the discovery of sensors {TLRs, nucleotide-binding oligomerization-domain receptors [nucleotide-binding domain leucine-rich repeat containing families (NLRs); including nucleotide oligomerization domains (NODs) and NALPs], C-type lectin receptors (CLRs) and retinoic acid-inducible gene (RIG-I)-like receptors (RLRs)}. These sensors recognize microbial (bacteria, viruses and fungi) and nonmicrobial (potassium ion efflux, products of cell death and tissue injury such as heat shock proteins and components of the extracellular matrix) triggers. These sensors, located on human macrophages, dendritic cells, and other cells that recognize bacteria, initiate cascades that result in effector responses such as inflammation, tissue repair and, in the case of microbial sensing pathways, adaptive immune responses [1••]. Importantly, the specific arm of the effector response [whether isotype-specific B-cell responses, CD8-mediated and CD4 T helper (Th) 1, Th2, Th17, Tr1 and inducible regulatory T cells (Tregs)] is appropriate for the inciting trigger [4,5]. Along these lines, immune disorders can also be classified with regard to the types of inducers, sensors, mediators and effectors that initiate and sustain the disorder.

Using this conceptual framework of inflammation and the innate and adaptive immune system, we attempt to classify the pathogenesis and connections involved in IBD. Figure 1 summarizes the components of the inflammatory pathway involved in microbial recognition.

Figure 1

Figure 1

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Innate control of adaptive immune responses in inflammatory bowel disease: linking initiator/sensors and adaptive effector responses

The role of indigenous microbial flora as an initiator of IBD came from the observations that genetically-modified mice deficient in interleukin (IL) 2 or 10 developed spontaneous colitis under specific pathogen-free, but not germ-free rearing [6,7]. In most animal models of intestinal inflammation, although the commensal microbiota are an initial trigger, the development of chronic enterocolitis is dependent on intestinal T cells [8]. Such a role for T cells has been substantiated by development of colitis in adaptive immune-deficient mice [severe combined immunodeficiency (SCID) or recombination activating gene 1 (Rag1) or 2−/−] upon transfer of certain subsets of T cells such as CD45Rbhi CD4+ T cells and T cells specific for commensal antigens [8].

The pathologic and protective role of T-cell responses in animal models of chronic intestinal inflammation continues to be elucidated [9]. Initial studies empirically identified infiltrating T cells in most IBD models to exhibit Th1-type polarization, distinguished by the production of interferon gamma (IFNγ), similar to that described in the lesions of Crohn's disease. More recently, the Th17 T-cell subset, characterized by the production of IL-17A, in addition to IL-17F, IL-21 and IL-22 and important in bacterial and fungal host defense at mucosal sites, has also been shown to be increased in Crohn's disease and a number of IBD animal models [9,10]. Using neutralizing antibodies to – or T cells deficient in – IFNγ or IL-17 members, a pathogenic role of Th1 and/or Th17 responses has been demonstrated in many, but not all models of IBD [11•,12•]. Indeed, Th17-associated cytokines have also been shown to be antienterocolitigenic [13•]. In addition, although most animal models of IBD have revealed Th1/17 T-cell-mediated pathogenesis, notable exceptions to this are the Th2 [T-cell receptor alpha (TCRα−/−) and oxalazone-treated mice] or mixed Th1/Th2 (Samp1/Yit)-mediated enterocolitides, which may better reflect Th2 cell phenotype in ulcerative colitis [8]. Regulatory T cells [both naturally occurring and induced, Treg and inducible regulatory T cells (iTregs), respectively], in addition to Tr1 (IL-10 producing T cells) and in some cases Th17 cells (as mentioned above) are an important arm of the adaptive immune response, as negative regulator of effector enterocolitogenic T cells, thus, maintaining intestinal immune homeostasis [9,14].

A critical balance of mediators such as IL-12 (Th1), IL-6, IL-21, IL-23 (Th17) and transforming growth factor beta (TGFβ) (iTreg and Th17) leads to the differentiation and expansion of distinct helper T-cell subsets in addition to playing important roles in the efficacy of regulatory T cells [15]. Experimental inhibition of these factors has elucidated critical roles in the regulation of enterocolitogenic T-cell responses. For example, IL-6 and IL-23 neutralization or genetic deletion ameliorates or prevents enterocolitis in numerous animal models of IBD [9,10].

TLR signaling seems to be necessary for the development of spontaneous, commensal-dependent enterocolitis. In the absence of the anti-inflammatory mediator IL-10, colitis and the dysregulated production of IL-12/23 p40 is completely dependent on myeloid differentiaion factor 88 (MyD88) (a TLR signaling adaptor) [16]. A similar and more specific role for TLR was shown by the significant amelioration of enterocolitis as mice with a myeloid cell-specific deletion of Stat3 (downstream of IL-10) by the absence of TLR4 [17]. The chronic intestinal inflammation that develops in the absence of intact nuclear factor (NF)-κB signaling in intestinal epithelial cells preceded by epithelial cell apoptosis, mucosal bacterial translocation and impaired antimicrobial peptide production and from impaired negative regulation of TLR2 signaling in the absence of NOD2 is abolished in the absence of MyD88 and TLR2 signaling, respectively [18,19•]. Spontaneous colitis occurring in TLR5−/− mice in the setting of increased bacterial burden and translocation is reversed with concurrent deletion of TLR4 [20]. It appears that the development of chronic enterocolitis involves the contribution of intact TLR signaling in various cell types including hematopoetic-derived cells, dendritic cells and T cells [21,22]. These studies suggest that the chronic enterocolitis that occurs due to a variety of primary insults converges on a common pathway of TLR recognition of the microflora leading to innate and adaptive mediators and effector responses such as IL-12/23 p40, IL-6, Th1 and Th17 cells for the development of IBD.

In addition to the proenterocolitogenic role of innate microbial recognition in animal models of IBD, it appears that PRR such as NOD2 and TLR may negatively regulate disease pathogenesis. In the absence of either TLR4 or TLR5 signaling, IL-10−/− mice show accelerated and augmented colitis, whereas TLR9 has been implicated in negatively regulating chemical-induced colitis [23–25]. Spontaneous colitis develops in TLR5 deficient mice, whereas deficiency of MyD88 in intestinal epithelial cells may lead to small intestinal inflammation [5,20]. Mechanisms suggested for these phenomena include TLR-mediated induction of Treg, deviation in Treg–Th17 homeostasis, production of anti-inflammatory type I IFNs, direct inhibition on T cells, ineffective antibacterial responses and cross-tolerance [23,24,26–28]. Although the role of NOD2 in IBD pathogenesis remains unclear and may be multifactorial, data from animal models of T-cell-dependent, chronic enterocolitis suggest that NOD2 may negatively regulate TLR2-mediated recognition of microbial constituents leading via interferon regulatory factor 4 (IRF4) [19•,29•]. Together, from the limited data of TLRs and NOD2, it appears that multiple PRR are involved in both positive and negative regulation of innate–adaptive connections in IBD via numerous mechanisms.

Recent studies have demonstrated that individual members of the murine intestinal microflora may have specialized functions in the regulation of the adaptive immune response. Helicobacter hepaticus, a murine ‘pathobiont’ has been shown to both induce the production of Treg with anticolitic properties and also to inhibit the generation of colonic Th17 cells through a type VI secretion system [30,31,32•]. Indigenous Bacteroides fragilis has also been shown to induce anticolitigenic Treg (through the production of polysaccharide A (PSA) in a TLR2-dependent manner), whereas enterotoxigenic B. fragilis induces colitis-associated cancer through induction of Th17 cells [26,33,34•]. Segmented filamentous bacteria (SFB) have recently been shown to have a seemingly specialized property of inducing small intestinal Th17 cells [35••]. For many of these connections, with the notable exception of B. fragilis and TLR2, the role of PRR/sensors is yet to be determined [26]. For example, Th17 induction by SFB is NOD2/Rip2-independent and TLR-independent [35••].

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Adaptive control of innate immune responses in inflammatory bowel disease

In addition to the classic pathway of innate control of adaptive immune responses active in IBD pathogenesis (as reviewed above), innate–adaptive connections in IBD also involve the adaptive control of innate immune responses. Regulatory T cells have been shown to regulate innate-mediated colitis in various animal models [36]. In addition, products of the adaptive immune system [such as secretory immunoglobulin A (IgA)] may indirectly impact on the adaptive immune system by binding microbial peptides and other antigens, thus limiting the amount of antigen that contacts cells on the intestinal surface, and regulatory T cells may control this IgA response [37]. Although it has been shown that luminal IgA specific either to commensal antigen or molecular patterns, such as lipopolysaccharide or flagellin, appears important in limiting activation of the innate immune response, the significance of this phenomenon to the pathogenesis of animal and human IBD is unknown [37,38•].

Antibodies to commensal bacteria have been identified in the serum of patients with IBD for over 20 years, and some of these serum antibodies are utilized in diagnostic testing of patients with IBD [39]. Although the use of serologies for diagnosis remains controversial, an increasing amount of data suggest that serologic testing may have predictive value for determining the risk of complications in patients with IBD [39–41]. For example, antiflagellin and antiSaccharomyces cerevisiae antibodies (ASCA) are associated with IBD, yet whether these antibodies reflect particular aspects of pathogenesis (cause or effect) is unclear, but perhaps may involve recognition of bacteria and yeast by PRR.

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Conclusion

The animal model data outlined above suggest that the development of chronic intestinal inflammation is a complex process, in which several different mechanistic derangements may give rise to a similar phenotype characterized by small and large bowel inflammation. Genetic studies of human IBD have provided additional evidence to suggest that derangements in innate and adaptive immunity result in human IBD. The first gene clearly identified to increase the risk of Crohn's disease in humans was NOD2, a gene encoding a PRR that regulates both innate and adaptive immune responses [42]. As geneticists identify novel IBD genes through multicenter genome-wide scans, researchers will characterize the role of these genes in disease pathogenesis.

As summarized above, there have been significant advances in our knowledge of the initiators, sensors, mediators and effectors in innate–adaptive connections in IBD. Future studies should decipher the role of these connections in the different stages such as initiation, perpetuation/maintenance (such as of memory T cells) and resolution/remission of chronic intestinal inflammation and IBD. Currently, the most well characterized aspects of innate–adaptive connections in IBD exist for TLR, NOD2 and Th1 and to a lesser extent Th17 pathways. Both the physiological and pathophysiological pathways involved in both Th17 and Th2 responses in the intestine are likely to receive more attention, as the innate control of adaptive immunity along this pathway becomes better appreciated.

It remains to be determined what elements of innate control of adaptive immune responses are at hand in the relationship between endoplasmic reticulum stress, autophagy and IBD [9]. Do these insults trigger the innate immune system through undiscovered mechanisms involving the homeostatic imbalances such as those involved in metabolism [1••]? Alternatively, does an individual develop IBD because of a convergence of multiple factors (e.g. autophagy gene mutation combined with commensal bacteria and superimposed viral infection) [43••]? Deeper knowledge of the semantics of innate immune recognition (microbial, pathogen-specific, cell death or an unknown feature such as those based on ecology) and of newly discovered and undiscovered PRR, such as NLR, RLR and dectins and the recognition of viruses and fungi, together with the complex biology of the host–microbial interface of the mammalian intestine, and insights into novel biological pathways from genomic studies of human IBD will further expand our knowledge of innate–adaptive connections in the intestine.

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Acknowledgements

S. R.-N. would like to thank W. Lencer and R. Medzhitov for their support.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 659).

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Keywords:

inflammatory bowel disease; innate immunity; microbial flora

© 2010 Lippincott Williams & Wilkins, Inc.