>Contents>Ocular Immune Privilege
Immunity is a complex response made by the body in an effort to avoid invasion by pathogens and to nullify their virulence strategies. Two complementary forms of immunity conspire in this effort: the innate immune system and the adaptive immune system (table 1).
In the effort to eradicate invading pathogens, inflammation is usually the final common pathway employed, and both innate and adaptive immune responses are known to trigger inflammation toward this end. Not surprisingly, immune privilege in the anterior chamber of the eye acts to thwart the triggering of inflammation by both types of immune response.
Innate immunity is activated by sets of rather stereotypic molecules that are expressed on microbial pathogens; these molecules are called pathogen-associated molecular patterns (PAMPs). Bacterial lipopolysaccharide (LPS) and (alpha-lipotechoic acid, expressed by gram-negative and gram-positive organisms, respectively, are good examples. Although PAMPs vary a lot among different pathogens, there is nonetheless considerable sharing, and therefore any given PAMP is not 'specific' to any particular organism in a molecular sense. PAMPs are recognized by cells of the innate immune system that express receptors that recognize these patterns directly (called pattern recognition receptors, PRR). Examples of PRRs include certain complement components, C-reactive protein, mannose receptors, LPS-binding protein, CD14, and KIRs. PRRs are expressed on virtually all cells of the innate immune system: macrophages, dendritic cells, neutrophils, natural killer (NK) cells, mast cells, platelets, gamma/delta T cells, and B-1 B lymphocytes. When PRRs bind PAMPs they trigger an immediate cellular or molecular response (immediate, i.e. 3 h or less), and no prior exposure to the same PAMP is required for this immediate response. Mediators (cytokines, chemokines, prostaglandins, etc.) that are released during this response modify the local microvasculature and recruit additional inflammatory cells and molecules to the site. While cellular proliferation is not an important component of the ensuing response, an intense and potentially destructive inflammation is. Once the offending pathogen is eliminated, innate immunity subsides, along with its attendant inflammation. Very often an inflammatory episode, if especially intense, may produce tissue damage and leave a scar. However, no imprint of the encounter is left upon the innate immune system, and therefore 'memory' of the offending pathogen does not exist.
Adaptive immunity uses rather different mechanisms to detect and respond to pathogens, although the principle of using specialized receptors to recognize foreign molecules remains the same. Adaptive immune cells and molecules respond to unique 'fingerprints' on molecules expressed by pathogens (often very small peptides and carbohydrates derived from complex macromolecules). These molecules are called 'antigens', there are estimated to be more than 109 such molecules in our universe. More than one antigen may be expressed by any single pathogen, and each pathogen displays antigens which are uniquely its own. In an effort to devise a receptor system sufficiently diverse to detect this enormous diversity of antigens, receptors are generated somatically in the cells of the adaptive immune system: T and B lymphocytes. The recognition structures on B lymphocytes are antibodies (immunoglobulins) that can bind directly to their specific antigen. When B cells are activated by exposure to antigen, they secrete soluble versions of their surface receptors. Secreted antibodies are the effector modalities generated by B lymphocytes. Antigens are also recognized by specialized receptors on T lymphocytes (T-cell receptor – TCR – for antigen). In this case, what is recognized are small peptides derived from complex macromolecules that have been loaded onto special recognition structures (class I and II molecules encoded within the major histocompatibility complex, MHC) that are displayed by specialized antigen-presenting cells (APC). Thus, the conditions for recognition of antigen by T cells is that the antigen be processed and presented to the T cell by an APC. Unlike the cells of the innate immune system, T and B lymphocytes are not activated simply by having their receptors engage the relevant ligand. Instead, a second signal is needed for T-cell activation, and this is also prepared by the APC. This 'second signal' arises when APC is activated by an innate immune signal. Thus, activation of the adaptive immune system is dependent upon prior or simultaneous activation of the innate immune system.
Clonal expansion and differentiation of T and B lymphocytes are important consequences of antigen-specific activation. Not only are the numbers of antigen-reactive T cells increased because of clonal proliferation, but the emergent progeny display the capacity to carry out effector functions – delayed hypersensitivity, cytotoxicity, complement fixation. Moreover, many of these progeny become long-lived, helping to account for the acquisition of antigen-specific immunologic memory. Both clonal expansion and acquisition of antigen-specific memory are unique attributes of adaptive immunity, compared to innate immunity. Adaptive immune effectors are able to traffic via the blood vasculature to sites containing the offending, antigen-bearing pathogen. Upon local recognition of the antigen, these effectors trigger an inflammatory response that eliminates the pathogen. This is the second important point when the adaptive and innate immune systems cooperate in conferring protection. CD4+ T cells can only trigger a full-scale delayed hypersensitivity response if they are assisted by innate immune cells such as macrophages. Similarly, antibodies can only trigger phagocytosis of bacteria with the assistance of complement components. By contrast, in the case of CD8+ cytotoxic T cells, elimination of pathogens may occur without significant inflammation, and non-complement-fixing antibodies that neutralize viruses may similarly terminate an infection without inflammation. Thus, only a subset of adaptive immune effectors trigger destructive immunity when attacking their pathogenic targets, and it is to these effectors that immune privilege in the eye is directed.
The Eye's Dilemma
Immune Privilege
Anterior Chamber of the Eye as an Immune- Privileged Site
Inflammation of Relation to Innate and Adaptive Immune Responses
Ocular Factors That Promote Immune Tolerance of Eye-Derived Antigens
Factors That Modify Expression of Ocular Adaptive Immunity
Innate Immune Privilege in the Eye
Factors That Modify Expression of Innate Ocular Immunity
Clinical Meaning of Ocular Immune Privilege
Selected Reading
Biography
>> next