BCSC 8 - Ch. 6 Ocular Immunology

What are significantly upregulated in a variety of corneal inflammatory disorders, such as corneal graft rejection and dry eye disease?

Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α) Similarly, increased expression of growth factors, prostaglandins, neuropeptides, and proteases (Table 6-1) has been observed in a wide array of immune disorders of the cornea and ocular surface.

What are chemokines?

Effective immune responses to foreign antigens require cells to "traffic" through tissues. Chemokines (chemotactic cytokines) are critical mediators that provide the trafficking signals to immune cells. These are low-molecular-weight proteins those that promote neutrophil recruitment (eg, IL-8); T helper-1 (Th1) lymphocyte recruitment and activation (macrophage inflammatory protein-1β [MIP-1β]); monocyte-macrophage recruitment (monocyte chemotactic protein-1 [MCP-1]); and eosinophil recruitment (eotaxin).

Humoral immunity in the conjunctiva largely involves ?

IgA produced by the lacrimal gland, and cellular immunity is dominated by CD4+ T cells. Serosal mast cells, which contain neutral proteases, are normally present in the conjunctiva, and the number of mucosal mast cells with granules containing only tryptase is increased in the conjunctiva of atopic patients. Mast-cell degranulation produces conjunctival redness, chemosis, mucus discharge, and itching. - The conjunctiva is part of the mucosa-associated lymphoid tissue (MALT), which involves a variety of mucosal tissues in the body, including the lacrimal gland.

What is the Wessely immune ring?

The cornea can act as an immunologic blotter, soaking up antigens from the ocular surface. This phenomenon was first described by Wessely in 1911, when foreign antigen was injected into the cornea of a previously sensitized animal and a ring-shaped infiltrate formed in the corneal stroma concentric to the injection site, much like an antigen-antibody complex in an immunodiffusion test. Still called a Wessely immune ring, this infiltrate contains complement factors and/or neutrophils. Circulating antibodies are not required if sufficient local antibody production is stimulated by antigens deposited in the cornea. The antigen may be a drug, as in the peripheral corneal infiltrates associated with a neomycin reaction; a foreign body; or an unknown substance, as in the corneal infiltrates that can occur in contact lens wearers. Wessely rings may persist for some time in corneas traumatized by a foreign body, even after the foreign body is removed.

Can the cornea have an allergic rxn?

The normal cornea can have neither an acute allergic reaction (as it contains no mast cells) nor a typical Arthus reaction (as there are no blood vessels). However, the cornea does participate in immune reactions by way of humoral and cellular immune elements that enter the periphery from the limbal blood vessels. - These anatomical features may explain why so many immune-mediated disorders of the cornea occur primarily in the corneal periphery and limbus. - Alternatively, ingress of leukocytes through the ciliary body and iris root and ingress of plasma proteins through breakdown of the blood-ocular barrier (as occurs in uveitis syndromes) are other means by which immune effectors gain access to the cornea.

The normal cornea's immune privilege is due to a multitude of factors, including the following:

absence of blood vessels, which impedes delivery of immune effector cells absence of lymphatics, which minimizes flow of antigens and APCs to the draining lymph nodes expression of immunosuppressive factors, including transforming growth factor β (TGF-β), and neuropeptides, such as α-melanocyte-stimulating hormone (α-MSH) expression of Fas ligand (CD95) by corneal cells, which is believed to play a critical role in inducing Fas-mediated apoptosis (programmed cell death) of activated lymphocytes exposure to the anterior chamber, which contains immunosuppressive factors, including corticosteroid - The downregulatory immune response to antigens in the cornea and anterior chamber may lead to immune unresponsiveness or even immunologic tolerance.

In addition to containing immune cells, the conjunctiva has a plentiful supply of ?

blood vessels and lymphatic vessels, which facilitate the trafficking of immune cells and antigens to the draining lymph nodes, where the adaptive immune response is generated. This occurs through the recruitment of Treg cells, which return to the ocular surface to modulate and suppress the local immune response (Fig 6-1).

The normal, uninflamed cornea, like the conjunctiva, is endowed with ?

dendritic cells - also called langerhans cells - located primarily in the corneal periphery and limbus. - These APCs are in an activated, mature state (expressing class II major histocompatibility complex [MHC] antigens and costimulatory molecules) and hence are capable of efficiently stimulating T cells. In addition to these dendritic cells (Fig 6-2), small numbers of lymphocytes are present in the peripheral epithelium and anterior stroma of the cornea.

Vascularization of the cornea increases the risk of what in K transplants?

immune rejection after corneal transplantation, leading to a rate of graft rejection greater than 50%. This may occur even when a strict regimen of topical and systemic immunosuppressive agents is used. Lymphatic neovessels may grow in parallel with the blood vessels; this facilitates access of donor and host APCs and antigenic material to regional lymph nodes, accelerating sensitization to graft antigens.

The normal, uninflamed conjunctiva contains ?

polymorphonuclear leukocytes (neutrophils); lymphocytes (including regulatory T cells [Treg cells], which dampen the immune response); macrophages; plasma cells; and mast cells. In addition, the conjunctival stroma has an endowment of dendritic antigen-presenting cells (APCs). The epithelium contains a special subpopulation of dendritic APCs known as Langerhans cells, which are capable of both antigen uptake and priming (sensitizing) of naive (antigen-inexperienced) T lymphocytes. - Hence, these dendritic cells serve as the sentinel cells of the immune system of the ocular surface.

rheumatoid arthritis has a strong predilection for what ocular structures?

scleral and corneal involvement

Though not normally present in the cornea, blood and lymphatic vessels may extend into the cornea—as ?

sprouts of the vascular endothelium from the limbal tissue—after inflammatory, infectious, traumatic, chemical, or toxic insults. The cellular and molecular mechanisms of corneal angiogenesis and lymphangiogenesis are not completely understood. Inflammatory cells infiltrate tissue at local sites of vascular remodeling, where they secrete proangiogenic factors and metalloproteinases. Vascular endothelial growth factor (VEGF) is upregulated in inflamed and vascularized corneas in humans and in animal models. Lymphangiogenesis is thought to be secondary to angiogenesis, suggesting common molecular and cellular origins for the 2 processes.

Unlike the conjunctiva, the normal cornea is considered an immunologically privileged site, so called because ?

the generation of immune response to foreign (including transplant) antigens is relatively suppressed.