Current Immunology Reviews (v.7, #3)

Mucosal surfaces such as those in the ocular surface, oral cavity, and gut are protected by a network of organized structuresknown as the Common Mucosal Immune System. These mucosal associated lymphoid tissues (MALT) include differentglands, 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 thishot 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 ocularinfection and in the modulation of inflammation. They also examine the biological activities and regulated expression ofdefensins in corneal and conjunctival epithelial cells.Echegaray et al. review the participation of corneal epithelium in the regulation of the ocular immune responses and describehow the corneal epithelial cells have the ability to respond to innate immune responses throughout the whole corneal tissue andregulate 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 theassociated immunological structures trying to envisage what may happen when antigens enter in the mouth. Oral mucosa hasreceived 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 ofdendritic cells (DCs) in the vicinity of IECs is crucial in this process as DC maturation across the epithelial barrier seems to bedependent 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 toavoid uncontrolled inflammation by several negative regulators. The nature and the species of micro flora acquired in the firstfew 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 ofeffectors molecules that protect mucosal surfaces against invading microbes. The colonizing microbes participate in the hostdevelopment 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 ofchemokines in trafficking of leukocytes in the different areas of this organ.

Oral Cavity-Associated Immune System: What is New? by Mirta Ana Valentich, Thamara Analia Cafaro, Horacio Marcelo Serra (253-263).
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 highlightadvances in the recent knowledge about this topic focusing on the anatomy/histology of the oral cavity, the associatedimmunological structures and the role of dendritic cells and Toll signalling, trying to envisage what happen whenmicroorganisms or soluble antigens enter in the mouth. Oral mucosa has received attention in the last decade because itoffers excellent accessibility and avoids degradation of proteins and peptides. Although the oral mucosa is continuouswith the remaining gastrointestinal tract, structurally the oral mucosa has more in common with skin than with thegastrointestinal tract.

Gut Epithelial Lining Makes the First Move by Maria Magdalena Canali, Carina Porporatto, Silvia G. Correa (264-270).
The mucosal immune system is ruled by a distinctive set of mechanisms derived of the local microenvironmentdemands. Intestinal epithelial cells (IECs) represent a unique population of cells that exist in direct contact with a burdenof bacteria and provide a primary physical barrier between the antigenic overload of the lumen and leukocytes settled inthe 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 theepithelial barrier seems to be dependent on the presence of specific surface factors. IECs are broadly unresponsive togram-positive bacterial components, notably TLR-2 ligands, in contrast to gram-negative bacterial components. The TLRsignaling is tightly regulated in IECs to avoid uncontrolled inflammation by several negative regulators that include IAP,A20, NOD2, and IRAK-M.

Chemokines and their Receptors in Gut Homeostasis and Disease by George Kolios, Sergio A. Lira (271-279).
The intestinal mucosa, the innermost layer of the bowel wall, is involved in various immunological andinflammatory processes orchestrated by a large number of mucosal immune cells and migrated leukocytes. Migration ofleukocytes into the intestinal mucosa appears to be regulated by chemokines, a large group of chemotactic cytokinesproduced by multiple cell types including epithelial cells, endothelial cells and leukocytes. They mediate their activitiesby binding to an array of shared and specific chemokine receptors on leukocytes. Here we review the evidence supportinga role for chemokines and their receptors in gut homeostasis and disease, and discuss their potential use in therapy ofinflammatory bowel diseases.

Regulation of Ocular Immune Responses by Corneal Epithelium by Jose J. Echegaray, Victor L. Perez (280-294).
The cornea of the eye provides a privileged transparency and unique refractive properties that enable light toenter the inner ocular environment and reach the posteriorly located retina for the achievement of vision. The preservationof corneal physiological functionality greatly depends on maintaining a delicate equilibrium between a vast array ofdefensive immunological mechanisms designed to combat pathologic insult and injury to the cornea. The cornealepithelium serves as ground zero for an amalgamation of immunoregulatory pathways that efficiently modulate the ocularsurface mucosal microenvironment in conjunction with neighboring structures such as the conjunctiva and lacrimalglands. This article reviews the most recent findings in corneal surface immunity and its regulation by the cornealepithelium. Understanding the manifestations of immunoregulation by the corneal epithelium is critical to developingmore specific and efficient treatment protocols that can prevent acute patients from developing chronic and autoimmunedisease. Moreover, the ocular surface mucosal microenvironment shares numerous common immune pathways withmucosal-associated, gut-associated, and bronchial-associated lymphoid tissue. Therefore, further basic and translationalresearch on corneal surface immunoregulation can offer promising therapeutic applications to similar mucosal tissuesthroughout the body and benefit numerous patients that suffer from disease catalyzed by failure of immunoregulation.

Defensins: Key Molecules in Ocular Surface Protection by Jing Li, Lei Zhou, Roger W. Beuerman (295-307).
The cornea, the clear tissue at the front of the eye, is responsible for the majority of the optical power of the eyeand thus for focusing light on to the retina. However, sitting at the front of the eye as a thinly epithelialized tissue, it isvulnerable to environmental trauma and pathogen invasion. Due to this vulnerability, the mechanisms of innate immunityare critical for routine protection of the cornea as well as the entire visual organ. Inflammation is a common component ofmany ocular surface diseases as well as the response to infection. Understanding the role of innate immunity ininflammation and particularly the path to the involvement of the systemic immunity is critical in order to minimize theeffects of acute and chronic inflammation. In addition to forming a physical barrier, epithelial cells possess multiplemolecular 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 andin the modulation of inflammation. We will also examine the biological activities and regulated expression of defensins incorneal 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 eyeis “immune privileged”, which prevents spontaneous assaults from the immune system and rather induces immune tolerancethan defense. The external surfaces of the eye have to deal with the environment, which includes harmless antigens as well aspathogens.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 arecaused by the viruses themselves and, on the other side, by the host’s own immune system. The characteristics of the infectionby 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 allowsthe light to pass through and reach the retina for photoperception, and enables us to directly observe the intraocular tissues andinflammatory events. The cornea is a part of the anterior chamber-associated immune privilege, which confers long-termacceptance 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 theimmune privilege and what happens when the immune privilege breaks down. In addition to the capabilities of the cornea toprotect itself against infection and contribute to the immune privilege of the anterior chamber, the author also covers theimmune 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 delicateintraocular tissues from irreversible damage by the immune system. Not only the anterior chamber, but also the retina isconcerned about its integrity and is thus provided with mechanisms to downregulate potentially deteriorating immuneresponses, 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 thecontralateral eye from deleterious immune responses. On the other hand, this group has recently show that loss of ACAID inone 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 Tcells to antigen expressed in the retina”, and they describe that regulatory T cells specific for sequestered retinal antigens can begenerated from mature, peripheral T cells. Their transgenic mouse model enabled the authors to dissect the generation ofregulatory T cells by ectopic expression of antigen in the thymus from the generation of Tregs by antigen expressed exclusivelyin 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 beactive within the eye, especially when pathogens have invaded. This will lead to a breakdown of the blood-ocular barriers andthe tolerance that is usually established by ACAID. Innate as well as adaptive immune responses can result in sight-threateningconditions. In their article “Intraocular immune reactions during uveitis” J. Curnow, G. Wallace, A. Denniston and P. Murrayfocus on human disease. They cover the different immune reactions in autoimmunity and autoinflammation, the role of geneticfactors such as HLA-associations, cytokines and chemokines that are related to different types of uveitis, and finally dwell onthe mechanisms underlying the current therapies......

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

Cornea: Window to Ocular Immunology by Jerry Y. Niederkorn (328-335).
The ocular surface is continuously exposed to environmental agents such as allergens, pollutants, andmicroorganisms, which could provoke inflammation. However, an array of anatomical, physiological, and immunologicalfeatures of the ocular surface conspire to limit corneal inflammation and endow the eye with immune privilege. Aremarkable example of ocular immune privilege is the success of corneal allografts, which unlike all other forms of organtransplantation, survive without the use of systemic immunosuppressive drugs or MHC matching. This review describesthe anatomical, physiological, and dynamic immunoregulatory processes that contribute to immune privilege.

A Current Understanding of Ocular Immune Privilege by Joan Stein-Streilein, Kenyatta Lucas (336-343).
Immune privileged mechanisms allow the eye to be protected from the pathological consequences ofinflammation by expressing immune responses that do not elicit inflammation. These mechanisms are established withrigor and very few experimental events have been capable of aborting immune privilege in the ocular environment. Themultiple overlapping mechanisms that contribute to the totality of ocular immune privilege are reviewed here, in the lightof contemporary knowledge of immune homeostasis throughout the organisms. The review considers the regulatorymechanisms 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 induceapoptosis or anergy of the immune cells; 4) the protective system of the pigmented cells that line the border of the eye andprevent immune activation or actually modulate the function of the activated immune cells; and 5) mechanisms of anteriorchamber immune deviation, ACAID, a paradigm of mechanisms that induces Treg cells in the periphery to seed the localarea and is proposed to contribute to self tolerance of ocular antigens. The consequences of losing immune privilege areconsidered.

Generation of Regulatory T Cells to Antigen Expressed in the Retina by Scott W. McPherson, Neal D. Heuss, Ute Lehmann, Dale S. Gregerson (344-349).
Regulatory T cells (Tregs) are generated to antigens (Ag) found in the retina. Some Tregs are the result ofectopic expression of the retinal Ags in the thymus, where developing T cells are committed to enter the regulatorylineage. However, the generation of retinal Ag-specific Tregs independent of the thymus was uncertain. Our studies showthat Tregs can be generated from mature, peripheral T cells based on exposure to retinal Ags. These peripherally inducedTregs limited immune responses and experimental autoimmune disease induced by retinal Ags and thus constitute acrucial component of retinal immune privilege.

Intraocular Immune Mechanisms in Uveitis by S. John Curnow, Alastair K.O. Denniston, Philip I. Murray, Graham R. Wallace (350-359).
Uveitis describes a group of sight threatening disorders characterized by breakdown of the blood-ocularbarriers, cellular infiltration and tissue damage. Uveitis can be categorized into different groups based on site ofinflammation in the eye, the onset, duration and course of disease, and causative agent. Whether these different forms ofuveitis 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 indifferent uveitis conditions.

Emerging Role of Complement in Ocular Diseases by Nalini S. Bora, Purushottam Jha, Valeriy V. Lyzogubov, Puran S. Bora (360-367).
The eye is an immune privileged site and the protection of ocular tissue from various immunological insults isvital for the maintenance of vision. Activated complement is a double-edged sword that not only helps defend the hostagainst pathogens, but also has the potential to inflict damage to self-tissues. This review article focuses on the crucial roleplayed 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 complementregulatory proteins could potentially be used in the treatment of various ocular diseases.

Uveitis in Horses, Rats and Man: What Do We Learn from Our Pets? by Cornelia Deeg, Gerhild Wildner, Stephan Thurau (368-377).
The rat model of experimental autoimmune uveitis (EAU) is well established and has served for thedevelopment of new therapies in human uveitis. Uveitis in rats can be induced with a number of different autoantigens orpeptides, while EAU in mice is only inducible with interphotoreceptor retinoid-binding protein (IRBP) or a single peptideof IRBP. For a long time the rat model was regarded as acute and monophasic, thus therapeutic interventions had toprecede the induction of the disease by immunization or adoptive transfer of activated, autoantigen-specific T cells. Onlyrecently spontaneous relapsing-remitting disease, induced with a peptide derived from IRBP, was detected in rats. Someyears 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. Thisoffers the opportunity to directly compare spontaneous and induced diseases in the same species, which show highidentities. Comparing different species, we found similarities between horses, rats, mice and humans with respect to theantigen-specificity of T cell responses, course of disease and histology. Proteomics of healthy and diseased equine eyesoffered an insight of intraocular alterations during inflammation, which might be representative for uveitis in general.

Intraocular Inflammation and Systemic Immune-Mediated Diseases by Justine R. Smith, James T. Rosenbaum (378-384).
Certain forms of uveitis, or intraocular inflammation, occur in association with systemic immune-mediateddiseases. The specific location of the inflammation within the eye is often helpful in diagnosing an associated systemicdisease, but it also provides clues to the pathogenic mechanisms of the ocular and systemic pathology. In this review weconsider the most common uveitis-systemic disease associations. We describe clinical aspects of these diseases anddiscuss current concepts in relation to the pathogenesis of the ocular inflammation. By clarifying the basic mechanismsoperating in these conditions, it may be possible to design disease-specific therapies to manage the ocular inflammation,as well as the associated systemic disease.