Elsevier

Fish & Shellfish Immunology

Volume 35, Issue 6, December 2013, Pages 1729-1739
Fish & Shellfish Immunology

The mucosal immune system of fish: The evolution of tolerating commensals while fighting pathogens

https://doi.org/10.1016/j.fsi.2013.09.032Get rights and content

Abstract

The field of mucosal immunology research has grown fast over the past few years, and our understanding on how mucosal surfaces respond to complex antigenic cocktails is expanding tremendously. With the advent of new molecular sequencing techniques, it is easier to understand how the immune system of vertebrates is, to a great extent, orchestrated by the complex microbial communities that live in symbiosis with their hosts. The commensal microbiota is now seen as the “extended self” by many scientists. Similarly, fish immunologist are devoting important research efforts to the field of mucosal immunity and commensals. Recent breakthroughs on our understanding of mucosal immune responses in teleost fish open up the potential of teleosts as animal research models for the study of human mucosal diseases. Additionally, this new knowledge places immunologists in a better position to specifically target the fish mucosal immune system while rationally designing mucosal vaccines and other immunotherapies. In this review, an updated view on how teleost skin, gills and gut immune cells and molecules, function in response to pathogens and commensals is provided. Finally, some of the future avenues that the field of fish mucosal immunity may follow in the next years are highlighted.

Introduction

Most infections start at or affect the mucosal epithelia of animals. Mucosal surfaces face many antigens while living in harmony with commensal microorganisms, known conjunctionally as microbiota. Over the last few years, the literature has been filled with many studies on how the microbiota shapes the host and its immune system [1], [2], [3]. Commensal colonization brings many physiological, metabolic and immunological benefits to the host. Some specific examples include harvesting of nutrients from food, providing essential vitamins and producing biofilms that block pathogen entrance [4]. The mucosal immune system of vertebrates comprises a unique array of innate and adaptive immune cells and molecules that act in concert to protect the host against pathogens (Fig. 1). At the same time, the mucosal immune system has evolved to permit the colonization of mucosal surfaces with complex and diverse microbial communities [4], [5]. For example by developing lymphocytes with high specificity and memory capacities, the vertebrate mucosal immune system is capable of remembering commensals and pathogens. In a parallel way, commensals have evolved decreasing its pathogenicity in order to inhabit the advantageous and nutritious mucosal surfaces, like the gut, without being eliminated [4]. This represents an intricate example of co-evolution that scientists are slowly beginning to unravel.

Both pathogens and commensals share “microbe-associated molecular patterns” (MAMPs) recognized by the pattern recognition receptors (PRRs) of the immune system. This means that the immune system cannot distinguish, for instance, if the lipid A core binding motif of LPS that interacts with TLR4, in fact originates from a commensal or a pathogen [6]. Therefore, permitting commensal colonization requires precise homeostatic regulatory mechanisms from the host's immune system. Commensals may nevertheless become harmful if homeostasis is breached and they access the host's internal milieu [4].

Fish live in aquatic environments, which are an ideal medium for microorganism growth compared to air. These conditions may pose additional challenges to the mucosal immune system of aquatic vertebrates versus their terrestrial counterparts. As a consequence, some of the principles of mammalian mucosal immunity may not be necessarily applicable to aquatic vertebrates. In teleosts, the gut, the skin and the gills are the main mucosal surfaces and immune barriers. Lower vertebrates, like cartilaginous and teleost fish, are the oldest animals with an adaptive immune system based on antibodies, B cells and T cells [7]. Additionally, teleost fish are the most primitive vertebrates where dedicated antibodies specific to mucosal surfaces have been characterized [8]. These large and multifunctional surfaces represent the sites where the innate and adaptive immune systems first had to cooperate during the evolution of vertebrates to allow “good” while avoiding “bad” microorganisms.

As described later in this review, the gut, skin and gills of fish, despite having some functional and structural differences, all share many characteristics with type I mucosal surfaces of mammals [9] (Fig. 1). Mammalian type I mucosal surfaces are represented by the intestine, the respiratory tract and the uterus, and they exert physiological functions in a similar way to those of teleost mucosal surfaces. Type I mucosal surfaces contain mucus-secreting cells generally arranged in a simple one-layered epithelium. Teleost mucosal surfaces also contain mucus-producing cells arranged in a simple columnar epithelium in the gut [10], one to four layers of cuboidal or squamous epithelial cells in the gills [11], and a stratified squamous epithelium in the skin [12]. In mammalian mucosal surfaces the main immunoglobulin is IgA, which is mostly produced by plasma cells present in the gut lamina propria. In a similar way, the teleost IgA homologue, IgT/IgZ, has a preponderant role in gut mucosal immunity [8]. Additionally, in mammals Igs are exported across epithelial barriers into the lumen via the polymeric immunoglobulin receptor (pIgR) expressed by epithelial cells. The pIgR is also expressed in the gut [8] and skin [13] of teleosts and it is responsible for the transport of IgM and IgT across mucosal barriers. Further, many other immunological elements of the adaptive and innate immune system, like the presence of T cells, macrophages, mast cells, dendritic cells and the coordinated expression of cytokines, are common to mucosal surfaces of mammals and teleost fish as illustrated in Fig. 1. Thus, the study of fish mucosal immunity is not only exciting because of its interest to aquaculture researchers and evolutionary biologists but also because it offers a unique model to study unresolved aspects of mucosal immunity in mammals.

This review emphasizes the importance of investigating the mucosal immune system of teleosts and highlights the most recent advances (both basic and applied) in the field. Furthermore, the parallelisms and differences with the mammalian mucosal immune system and predictions on future discoveries in this research area are described. Finally, mucosal immunotherapy approaches, like probiotics and vaccines, which may help improving not only the mucosal, but also the overall immune response of fish, are discussed.

Section snippets

Innate immunity at teleost mucosal surfaces

The innate components of the immune system are the first barrier that the microorganisms have to confront in their contact with the host. Thereby these components are abundant at mucosal surfaces and their interaction with commensals is highly regulated to avoid hyper reaction. In this section, the humoral and cellular innate components present at mucosal surfaces of teleosts are reviewed and compared to their mammalian homologues.

Adaptive immunity at teleost mucosal surfaces

Adaptive immunity first emerged when the earlier vertebrates (agnathans) appeared approximately 500 million years ago. One of the current evolutionary hypotheses is that adaptive immunity may have been driven mainly by the microbial colonization of mucosal surfaces [4], [80]. In this section the presence and roles of immunoglobulins (Igs), and B and T lymphocytes in mucosal surfaces of teleost fish are discussed in the context of commensals and pathogens.

Exploiting mucosal immunity for immunotherapy

The control and eradication of mucosal pathogens requires targeted immunotherapies that specifically protect local mucosal sites. Several new mucosal delivery approaches are being developed and optimized for use in mammals. The aquaculture industry will benefit from these technological advances by exploiting the strengths of the fish mucosal immune system.

Concluding remarks

The mucosal immune system of vertebrates is one of the most sophisticated examples of evolution found in nature. During vertebrate evolution, increasingly complex body structures implied higher metabolic rates and created an evolutionary pressure for new metabolic abilities. Vertebrates thus may have allowed commensals to colonize their mucosa for the benefits of new genetic material rather than coding for those new metabolic abilities themselves [133]. The metabolome is therefore defined as

Acknowledgments

This work was supported by the National Science Foundation (NSF-MCB-0719599 to J.O.S.), National Institutes of Health (R01GM085207-01 to J.O.S.) and CETI COBRE grant (P20GM103452 to I.S.).

References (157)

  • S. Lange et al.

    An immunohistochemical study on complement component C3 in juvenile Atlantic halibut (Hippoglossus hippoglossus L.)

    Dev Comp Immunol

    (2004)
  • S.R. Lange et al.

    The ontogeny of complement component C3 in Atlantic cod (Gadus morhua L.) – an immunohistochemical study

    Fish Shellfish Immunol

    (2004)
  • P.W. Kania et al.

    Evolutionary conservation of mannan-binding lectin (MBL) in bony fish: identification, characterization and expression analysis of three bona fide collectin homologues of MBL in the rainbow trout (Onchorhynchus mykiss)

    Fish Shellfish Immunol

    (2010)
  • S.F. Gonzalez et al.

    Complement expression in common carp (Cyprinus carpio L.) during infection with Ichthyophthirius multifiliis

    Dev Comp Immunol

    (2007)
  • M.M. Olsen et al.

    Cellular and humoral factors involved in the response of rainbow trout gills to Ichthyophthirius multifiliis infections: molecular and immunohistochemical studies

    Fish Shellfish Immunol

    (2011)
  • A.J. Lu et al.

    Gene expression profiling in the skin of zebrafish infected with Citrobacter freundii

    Fish Shellfish Immunol

    (2012)
  • Y.B. Shen et al.

    Molecular cloning, characterization and expression analysis of the complement component C6 gene in grass carp

    Vet Immunol Immunopathol

    (2011)
  • V. Rajanbabu et al.

    Applications of antimicrobial peptides from fish and perspectives for the future

    Peptides

    (2011)
  • R.L. Gallo et al.

    Microbial symbiosis with the innate immune defense system of the skin

    J Invest Dermatol

    (2011)
  • J.M. Bates et al.

    Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota

    Cell Host Microbe

    (2007)
  • J.H. Rombout et al.

    Teleost intestinal immunology

    Fish Shellfish Immunol

    (2011)
  • C.A. Bailey et al.

    The use of the intestinal epithelial cell culture model, Caco-2, in pharmaceutical development

    Adv Drug Deliv Rev

    (1996)
  • O.B. Reite et al.

    Inflammatory cells of teleostean fish: s review focusing on mast cells/eosinophilic granule cells and rodlet cells

    Fish Shellfish Immunol

    (2006)
  • J. Kunii et al.

    Commensal bacteria promote migration of mast cells into the intestine

    Immunobiology

    (2011)
  • B.S. Dezfuli et al.

    Mast cell responses to Ergasilus (Copepoda), a gill ectoparasite of sea bream

    Fish Shellfish Immunol

    (2011)
  • M. Rescigno et al.

    Dendritic cells shuttle microbes across gut epithelial monolayers

    Immunobiology

    (2001)
  • V. Wittamer et al.

    Characterization of the mononuclear phagocyte system in zebrafish

    Blood

    (2011)
  • M. Inami et al.

    Immunological differences in intestine and rectum of Atlantic cod (Gadus morhua L.)

    Fish Shellfish Immunol

    (2009)
  • E. Martin et al.

    Comparison between intestinal and non-mucosal immune functions of rainbow trout, Oncorhynchus mykiss

    Fish Shellfish Immunol

    (2012)
  • S.A. Renshaw et al.

    A transgenic zebrafish model of neutrophilic inflammation

    Blood

    (2006)
  • I. Salinas et al.

    Mucosal immunoglobulins and B cells of teleost fish

    Dev Comp Immunol

    (2011)
  • X. Zhao et al.

    Cutaneous antibody-secreting cells and B cells in a teleost fish

    Dev Comp Immunol

    (2008)
  • J. Lumsden et al.

    Production of gill-associated and serum antibody by rainbow trout (Oncorhynchus mykiss) following immersion immunization with acetone-killed Flavobacterium branchiophilum and the relationship to protection from experimental challenge

    Fish Shellfish Immunol

    (1995)
  • S. Tsutsui et al.

    Serum GlcNAc-binding IgM of fugu (Takifugu rubripes) suppresses the growth of fish pathogenic bacteria: a novel function of teleost antibody

    Dev Comp Immunol

    (2013)
  • E.-S. Edholm et al.

    Insights into the function of IgD

    Dev Comp Immunol

    (2011)
  • J.H.W.M. Rombout et al.

    Differences in mucus and serum immunoglobulin of carp (Cyprinus carpio L.)

    Dev Comp Immunol

    (1993)
  • J.H.W.M. Rombout et al.

    The gut-associated lymphoid tissue (GALT) of carp (Cyprinus carpio L.): an immunocytochemical analysis

    Dev Comp Immunol

    (1993)
  • V. Fournier-Betz et al.

    Immunocytochemical detection of Ig-positive cells in blood, lymphoid organs and the gut associated lymphoid tissue of the turbot (Scophthalmus maximus)

    Fish Shellfish Immunol

    (2000)
  • S. Parker et al.

    The ontogeny of New Zealand groper (Polyprion oxygeneios) lymphoid organs and IgM

    Dev Comp Immunol

    (2012)
  • F. Takizawa et al.

    The expression of CD8α discriminates distinct T cell subsets in teleost fish

    Dev Comp Immunol

    (2011)
  • N. Romano et al.

    Antigen-dependent T lymphocytes (TcRβ+) are primarily differentiated in the thymus rather than in other lymphoid tissues in sea bass (Dicentrarchus labrax, L.)

    Fish Shellfish Immunol

    (2011)
  • F. Sommer et al.

    The gut microbiota – masters of host development and physiology

    Nat Rev Microbiol

    (2013)
  • D.A. Hill et al.

    Intestinal bacteria and the regulation of immune cell homeostasis

    Annu Rev Immunol

    (2009)
  • N. Kamada et al.

    Role of the gut microbiota in the development and function of lymphoid cells

    J Immunol

    (2013)
  • C.L. Maynard et al.

    Reciprocal interactions of the intestinal microbiota and immune system

    Nature

    (2012)
  • Chow J, Lee SM, Shen Y, Khosravi A, Mazmanian SK. Chapter 8: host–bacterial symbiosis in health and disease. In:...
  • J.C. Nussbaum et al.

    Infectious (non)tolerance-frustrated commensalism gone awry?

    Cold Spring Harb Perspect Biol

    (2012)
  • M.F. Flajnik et al.

    Origin and evolution of the adaptive immune system: genetic events and selective pressures

    Nat Rev Genet

    (2010)
  • Y.A. Zhang et al.

    IgT, a primitive immunoglobulin class specialized in mucosal immunity

    Nat Immunol

    (2010)
  • A. Iwasaki

    Mucosal dendritic cells

    Annu Rev Immunol

    (2007)
  • Cited by (0)

    View full text