Current Immunology Reviews (Discontinued) - Volume 7, Issue 3, 2011

Mucosal surfaces such as those in the ocular surface, oral cavity, and gut are protected by a network of organized structures known as the Common Mucosal Immune System. These mucosal associated lymphoid tissues (MALT) include different glands, the Waldeyer's ring, Peyers patches and isolated lymphoid follicles. Several excellent articles have recently reviewed various aspects of these specialized tissues therefore, I have selected for this hot topic, contributions that highlight recent advances in closely related yet distinct fields of research. In the first article Li et al. focus on the superficial ocular environment describing the roles of defensins in combating ocular infection and in the modulation of inflammation. They also examine the biological activities and regulated expression of defensins in corneal and conjunctival epithelial cells. Echegaray et al. review the participation of corneal epithelium in the regulation of the ocular immune responses and describe how the corneal epithelial cells have the ability to respond to innate immune responses throughout the whole corneal tissue and regulate the recruitment of immunological cells in a way that corneal clarity is maintained. Then Valentich et al. highlight advances in the recent knowledge about the anatomy/histology of the oral cavity and the associated immunological structures trying to envisage what may happen when antigens enter in the mouth. Oral mucosa has received attention in the last decade because it offers excellent accessibility and avoids degradation of proteins and peptides. Although the moist lining tissue of the oral cavity, the oral mucosa, is continuous with the remaining gastrointestinal tract, structurally the oral mucosa has more in common with skin than with the gastrointestinal mucosa. The review of Correa et al. deals with the cross talk between intestinal epithelial cells (IECs) and leukocytes. The network of dendritic cells (DCs) in the vicinity of IECs is crucial in this process as DC maturation across the epithelial barrier seems to be dependent on the presence of specific surface factors. IECs are broadly unresponsive to gram-positive bacterial components, notably TLR-2 ligands, in contrast to gram-negative bacterial components. The TLR signalling is tightly regulated in IECs to avoid uncontrolled inflammation by several negative regulators. The nature and the species of micro flora acquired in the first few months of life depends on many factors including, external environmental micro flora, use of antibiotics, immunomodulatory agents, and breast or artificial feeding. Mucosal epithelial cells and Paneth cells produce a variety of effectors molecules that protect mucosal surfaces against invading microbes. The colonizing microbes participate in the host development and homeostasis as well. Finally Lira et al. discuss expression and function of chemokines in the intestine trying to clarify the picture of the role of chemokines in trafficking of leukocytes in the different areas of this organ.

Although several excellent articles have reviewed different aspects of mucosal associated lymphoid tissues (MALT), there is not enough information about the oral cavity immune response. In this manuscript we highlight advances in the recent knowledge about this topic focusing on the anatomy/histology of the oral cavity, the associated immunological structures and the role of dendritic cells and Toll signalling, trying to envisage what happen when microorganisms or soluble antigens enter in the mouth. Oral mucosa has received attention in the last decade because it offers excellent accessibility and avoids degradation of proteins and peptides. Although the oral mucosa is continuous with the remaining gastrointestinal tract, structurally the oral mucosa has more in common with skin than with the gastrointestinal tract.

The mucosal immune system is ruled by a distinctive set of mechanisms derived of the local microenvironment demands. Intestinal epithelial cells (IECs) represent a unique population of cells that exist in direct contact with a burden of bacteria and provide a primary physical barrier between the antigenic overload of the lumen and leukocytes settled in the lamina propria. The cross talk between these compartments maintains the intestinal homeostasis. The network of dendritic cells (DCs) in the vicinity of IECs is crucial in this process as DC maturation across the epithelial barrier seems to be dependent on the presence of specific surface factors. IECs are broadly unresponsive to gram-positive bacterial components, notably TLR-2 ligands, in contrast to gram-negative bacterial components. The TLR signaling is tightly regulated in IECs to avoid uncontrolled inflammation by several negative regulators that include IAP, A20, NOD2, and IRAK-M.

The intestinal mucosa, the innermost layer of the bowel wall, is involved in various immunological and inflammatory processes orchestrated by a large number of mucosal immune cells and migrated leukocytes. Migration of leukocytes into the intestinal mucosa appears to be regulated by chemokines, a large group of chemotactic cytokines produced by multiple cell types including epithelial cells, endothelial cells and leukocytes. They mediate their activities by binding to an array of shared and specific chemokine receptors on leukocytes. Here we review the evidence supporting a role for chemokines and their receptors in gut homeostasis and disease, and discuss their potential use in therapy of inflammatory bowel diseases.

The cornea of the eye provides a privileged transparency and unique refractive properties that enable light to enter the inner ocular environment and reach the posteriorly located retina for the achievement of vision. The preservation of corneal physiological functionality greatly depends on maintaining a delicate equilibrium between a vast array of defensive immunological mechanisms designed to combat pathologic insult and injury to the cornea. The corneal epithelium serves as ground zero for an amalgamation of immunoregulatory pathways that efficiently modulate the ocular surface mucosal microenvironment in conjunction with neighboring structures such as the conjunctiva and lacrimal glands. This article reviews the most recent findings in corneal surface immunity and its regulation by the corneal epithelium. Understanding the manifestations of immunoregulation by the corneal epithelium is critical to developing more specific and efficient treatment protocols that can prevent acute patients from developing chronic and autoimmune disease. Moreover, the ocular surface mucosal microenvironment shares numerous common immune pathways with mucosal-associated, gut-associated, and bronchial-associated lymphoid tissue. Therefore, further basic and translational research on corneal surface immunoregulation can offer promising therapeutic applications to similar mucosal tissues throughout the body and benefit numerous patients that suffer from disease catalyzed by failure of immunoregulation.

The cornea, the clear tissue at the front of the eye, is responsible for the majority of the optical power of the eye and thus for focusing light on to the retina. However, sitting at the front of the eye as a thinly epithelialized tissue, it is vulnerable to environmental trauma and pathogen invasion. Due to this vulnerability, the mechanisms of innate immunity are critical for routine protection of the cornea as well as the entire visual organ. Inflammation is a common component of many ocular surface diseases as well as the response to infection. Understanding the role of innate immunity in inflammation and particularly the path to the involvement of the systemic immunity is critical in order to minimize the effects of acute and chronic inflammation. In addition to forming a physical barrier, epithelial cells possess multiple molecular mechanisms in pathogen sensing and control of inflammation. In this article, we will review the recent progress in understanding the roles of defensins in combating ocular infection and in the modulation of inflammation. We will also examine the biological activities and regulated expression of defensins in corneal and conjunctival epithelial cells.

Ocular Immunology is a growing field in the last years. For a long time the eye was regarded as a “protuberance” of the brain, but now many special characteristics different from the brain and other regions of the body have been identified. The inner eye is “immune privileged”, which prevents spontaneous assaults from the immune system and rather induces immune tolerance than defense. The external surfaces of the eye have to deal with the environment, which includes harmless antigens as well as pathogens. Those pathogens that can cause tremendous problems to the surface (cornea) as well as in the inner eye are herpes viruses, which commit a life-long relationship with their host. Herpes keratitis and HSV uveitis are sight-threatening diseases, which are caused by the viruses themselves and, on the other side, by the host's own immune system. The characteristics of the infection by various herpes viruses as well as the immune reaction of the host is extensively reviewed by G.M.G.M Verjans and A. Heiligenhaus (Herpes Simplex Virus-induced ocular diseases - Detrimental interactions between virus and host) in this issue. Herpes keratitis can blur the corneal stroma to an extent that needs corneal transplantation. The normally clear cornea allows the light to pass through and reach the retina for photoperception, and enables us to directly observe the intraocular tissues and inflammatory events. The cornea is a part of the anterior chamber-associated immune privilege, which confers long-term acceptance of corneal grafts under non-inflamed conditions. The latter is, however, abolished after herpes infection. J.Y. Niederkorn describes in his review “Cornea: Window to ocular immunology” how and why the cornea is involved in the immune privilege and what happens when the immune privilege breaks down. In addition to the capabilities of the cornea to protect itself against infection and contribute to the immune privilege of the anterior chamber, the author also covers the immune principles of dry eye disease. The immune privilege of the eye has been a topic of intensive research in the past decades, for it protects the delicate intraocular tissues from irreversible damage by the immune system. Not only the anterior chamber, but also the retina is concerned about its integrity and is thus provided with mechanisms to downregulate potentially deteriorating immune responses, as described by J. Stein-Streilein and K. Lucas in their article “A current understanding of ocular immune privilege”. Each eye takes care of the other, that is, the generation of regulatory T cells that confer tolerance will also protect the contralateral eye from deleterious immune responses. On the other hand, this group has recently show that loss of ACAID in one eye leads to loss of protection in the contralateral eye as well, an effect that could be attributed to neuropeptide mediators. S.W. McPherson and his colleagues N.D. Heuss, U. Lehmann and D.S. Gregerson focus on the “Generation of regulatory T cells to antigen expressed in the retina”, and they describe that regulatory T cells specific for sequestered retinal antigens can be generated from mature, peripheral T cells. Their transgenic mouse model enabled the authors to dissect the generation of regulatory T cells by ectopic expression of antigen in the thymus from the generation of Tregs by antigen expressed exclusively in the retina. These cells are able to protect from experimental autoimmune disease directed against the retina. Despite of the necessity for preventing the eye from immune assault, it is sometimes essential for the immune system to be active within the eye, especially when pathogens have invaded. This will lead to a breakdown of the blood-ocular barriers and the tolerance that is usually established by ACAID. Innate as well as adaptive immune responses can result in sight-threatening conditions. In their article “Intraocular immune reactions during uveitis” J. Curnow, G. Wallace, A. Denniston and P. Murray focus on human disease. They cover the different immune reactions in autoimmunity and autoinflammation, the role of genetic factors such as HLA-associations, cytokines and chemokines that are related to different types of uveitis, and finally dwell on the mechanisms underlying the current therapies....

Herpes simplex virus type 1 (HSV-1) is a common cause of ocular diseases, affecting all parts of the visual axis. HSV-1 keratitis and uveitis represent two prevalent ocular diseases. The outcome of these potentially sightthreatening conditions depends on prompt diagnosis and treatment in order to counteract the detrimental intra-ocular virus-host interaction. This review recapitulates current insights on the diagnosis, pathogenesis, and treatment of HSV-1 keratitis and uveitis in patients and in the respective mouse models.

The ocular surface is continuously exposed to environmental agents such as allergens, pollutants, and microorganisms, which could provoke inflammation. However, an array of anatomical, physiological, and immunological features of the ocular surface conspire to limit corneal inflammation and endow the eye with immune privilege. A remarkable example of ocular immune privilege is the success of corneal allografts, which unlike all other forms of organ transplantation, survive without the use of systemic immunosuppressive drugs or MHC matching. This review describes the anatomical, physiological, and dynamic immunoregulatory processes that contribute to immune privilege.

Immune privileged mechanisms allow the eye to be protected from the pathological consequences of inflammation by expressing immune responses that do not elicit inflammation. These mechanisms are established with rigor and very few experimental events have been capable of aborting immune privilege in the ocular environment. The multiple overlapping mechanisms that contribute to the totality of ocular immune privilege are reviewed here, in the light of contemporary knowledge of immune homeostasis throughout the organisms. The review considers the regulatory mechanisms in terms of 1) physical and structural barriers that lessen the availability of immune cells to reach the eye; 2) activities that prevent the immune response from being activated in the ocular tissue; 3) events that actively induce apoptosis or anergy of the immune cells; 4) the protective system of the pigmented cells that line the border of the eye and prevent immune activation or actually modulate the function of the activated immune cells; and 5) mechanisms of anterior chamber immune deviation, ACAID, a paradigm of mechanisms that induces Treg cells in the periphery to seed the local area and is proposed to contribute to self tolerance of ocular antigens. The consequences of losing immune privilege are considered.

Regulatory T cells (Tregs) are generated to antigens (Ag) found in the retina. Some Tregs are the result of ectopic expression of the retinal Ags in the thymus, where developing T cells are committed to enter the regulatory lineage. However, the generation of retinal Ag-specific Tregs independent of the thymus was uncertain. Our studies show that Tregs can be generated from mature, peripheral T cells based on exposure to retinal Ags. These peripherally induced Tregs limited immune responses and experimental autoimmune disease induced by retinal Ags and thus constitute a crucial component of retinal immune privilege.

Uveitis describes a group of sight threatening disorders characterized by breakdown of the blood-ocular barriers, cellular infiltration and tissue damage. Uveitis can be categorized into different groups based on site of inflammation in the eye, the onset, duration and course of disease, and causative agent. Whether these different forms of uveitis have different aetiologies is of interest with regards to prognosis and therapy in individual patients. In this review, we shall discuss mechanisms of blood-ocular barrier breakdown, cellular responses and the molecules involved in different uveitis conditions.

The eye is an immune privileged site and the protection of ocular tissue from various immunological insults is vital for the maintenance of vision. Activated complement is a double-edged sword that not only helps defend the host against pathogens, but also has the potential to inflict damage to self-tissues. This review article focuses on the crucial role played by the complement system in the protection of the normal eye as well as in the development of ocular diseases. There is increasing evidence in the literature suggesting that anti-complement agents such a recombinant complement regulatory proteins could potentially be used in the treatment of various ocular diseases.

The rat model of experimental autoimmune uveitis (EAU) is well established and has served for the development of new therapies in human uveitis. Uveitis in rats can be induced with a number of different autoantigens or peptides, while EAU in mice is only inducible with interphotoreceptor retinoid-binding protein (IRBP) or a single peptide of IRBP. For a long time the rat model was regarded as acute and monophasic, thus therapeutic interventions had to precede the induction of the disease by immunization or adoptive transfer of activated, autoantigen-specific T cells. Only recently spontaneous relapsing-remitting disease, induced with a peptide derived from IRBP, was detected in rats. Some years ago we have introduced the horse as a new animal model for uveitis: horses frequently have spontaneous uveitis (Equine Recurrent Uveitis, ERU) and will also develop the disease after immunization with retinal autoantigens. This offers the opportunity to directly compare spontaneous and induced diseases in the same species, which show high identities. Comparing different species, we found similarities between horses, rats, mice and humans with respect to the antigen-specificity of T cell responses, course of disease and histology. Proteomics of healthy and diseased equine eyes offered an insight of intraocular alterations during inflammation, which might be representative for uveitis in general.

Certain forms of uveitis, or intraocular inflammation, occur in association with systemic immune-mediated diseases. The specific location of the inflammation within the eye is often helpful in diagnosing an associated systemic disease, but it also provides clues to the pathogenic mechanisms of the ocular and systemic pathology. In this review we consider the most common uveitis-systemic disease associations. We describe clinical aspects of these diseases and discuss current concepts in relation to the pathogenesis of the ocular inflammation. By clarifying the basic mechanisms operating in these conditions, it may be possible to design disease-specific therapies to manage the ocular inflammation, as well as the associated systemic disease.