The immune system has evolved to recognise and eliminate foreign molecules through an integrated network of cellular and molecular interactions and thus provides the defence mechanism against pathogens. Defining the molecular basis and functional consequences of these molecular interactions may offer an opportunity both to diagnose and regulate qualitative and quantitative aspects of immune responses and, therefore, contribute to the prevention and treatment of immunologically based disorders.
INNATE AND ADAPTIVE IMMUNITYAs discussed above, the cellular and mediator events of the acute inflammatory response play a key role in the 'firstline' or innate immunity against infection. If, however, innate immunity fails to provide effective protection then induction of the adaptive immune system occurs. This response develops after a period of days and is mediated by lymphocytes which express antigen-specific receptors. When recirculating naive T cells recognise antigen processed by antigen presenting cells (APCs) in lymphoid organs, the population expands and differentiates into effector or regulatory cells. The latter contribute to the development of humoral responses by stimulating B cells that have bound specific antigen to secrete antibodies. The adantive immune
| CHARACTERISTIC FEATURES OF ADAPTIVE IMMUNITY |
|---|
| Specificity |
| Distinct antigens generate specific responses |
| Diversity |
| Antigens are recognised by different lymphocytes |
| Memory |
| Re-exposure to antigen induces more rapid and effective response |
| Self-regulation |
| Normal immune responses decrease with time |
| Self-/non-self-discrimination |
| During development lymphocytes learn to distinguish between self and foreign antigens |
response invariably eliminates the pathogen, as a result of which T cell activity and serum antibody levels decline. However, immunological memory remains, such that reexposure to the same antigen induces a more rapid response of greater magnitude .
ORGANISATION OF THE IMMUNE SYSTEMThe immune system must provide protection against an extensive array of pathogens and achieve this within a relatively short period of time. In order to meet these requirements, B and T lymphocytes have evolved selective biological properties, which are reflected in their unique characteristics of specificity, diversity, memory, selfregulation and self-/non-self-discrimination. At the organisational level the immune system needs to provide different environments to allow the development of clonally diverse lymphocytes and then to bring together antigen and specific mature lymphocytes as required to facilitate clonal expansion and differentiation. Mechanisms must also exist which allow effector/memory lymphocytes to traffic to sites of disease.
MIGRATION OF LYMPHOCYTESThe primary lymphoid organs (thymus and bone marrow), where stem cells where stem cells develop into T and B cells, are linked by lymphatic vessels to the secondary lymphoid organs. It is in the latter, which include lymph nodes, spleen, and mucosaassociated lymphoid tissue, that lymphocytes encounter antigen and become sensitised, converting from naive to memory/effector cells. Antigen carried by APCs or retained from afferent lymph by specialised cells is presented to recirculating lymphocytes. Naive T and B cells migrate through the high endothelial venules (HEVs) in the cortex, with T and B cells locating to the paracortical area and follicles, respectively . This process of migration through the HEVs is regulated by differential expression of cell surface adhesion molecules and is initiated by the binding of lymphocytes to the endothelium. Adhesion molecules also contribute to the activation and effector function of lymphocytes. Once activated, plasma cells leave via the efferent lymphatics and migrate to the bone marrow, while memory B cells either recirculate or remain in residual follicles. The retention of antigen in selected sites such as lymphoid follicles may be important in the maintenance of immunological memory. Memory/ effector T cells recirculate through the lymphatic system or migrate to 'tertiary' lymphoid organs. These may be anywhere in the body but are principally in the skin and mucosa of the pulmonary, genitourinary and gastrointestinal tracts.
LYMPHOCYTE POPULATIONSThe expression of clonally distributed receptors for the recognition of antigen is characteristic of both Band T lymphocytes and underlies their vast range of specificities. They also display extensive heterogeneity in function. While the properties of B cells are, in general, restricted to immunoglobulin (Ig) synthesis and antigen presentation, functional differences are reflected in the various antibody isotypes. From their expression of either the CD4 or CD8 coreceptors, T cells can be segregated broadly into regulatory (CD4+) and effector/cytotoxic (CD8+) T cells. T cells can also be categorised by their receptor complement (αβ and γδ), αβ cells play a key role in the adaptive immune response whereas γδ cells have an additional response in epithelial defence.
RECEPTORSAntigen-specific receptors
As regards B cells, cell-surface Ig functions as the antigen receptor. On activation, mediated by the binding of native antigen together with signals derived from helper T (TH) cells, B cells differentiate into plasma cells producing antibody with the same specificity as their initial surface receptor. In contrast to B cells which bind native antigen, T cell antigen receptors (TCR), expressed on both TH and cytotoxic (TC) cells, recognise antigen as peptide fragments which ,together with costimulatory signals, results in cytokin production and clonal expansion.
ImmunoglobulinThere are five distinct classes of Ig molecule (IgM, IgD, IgG, IgA and IgE), made up of four polypeptide chains, each with two identical light (L) and heavy (H) chains. Each L chain pairs with an H chain, and the two H chains are joined together by disulphide bonds. This allows the formation of two identical antigen-binding sites, which consist of variable regions located at the amino termini . For different Igs the variable regions have different sequences, with three regions of hypervariability, which confer their unique specificity. The constant regions of the H chains, termed the Fc fragment, determine the functional properties of the different Ig isotypes. Membrane Ig forms a complex with two other chains, CD79αand CD79β, that are required for intracellular signalling through their association with protein tyrosine kinases (PTKs).
T cell antigen receptors (TCRs)Each TCR consists of two paired polypeptide chains (αand β or γ and δ) containing a variable region, which forms the antigen binding site, and a constant domain located towards the membrane region of the molecule. The αβ and γδ heterodimers are expressed on the T cell surface associated with chains of the CD3 complex (CD3 Γ ,δ, ε; and dimers of ζ ; ζ or ζ: η;). Ligation of the TCR results in phosphorylation of CD3ζ and the subsequent activation of intracellular signalling pathways.
CoreceptorsCD19, CD21 and CD81 together form the coreceptor on B cells that binds to CD23 expressed on follicular dendritic cells and acts to amplify the signal delivered by antigen-binding.
The respective coreceptors for TH, and TC cells are CD4 and CD8. CD4 is a single-chain molecule, which binds to an invariant region of the MHC class II molecule located away from the TCR binding site. The cytoplasmic domain of CD4 is associated with a PTK. CD8 has similar functions and synergises with TCR-mediated signalling, but unlike CD4 this molecule is heterodimeric and interacts with the invariant a3 domain of MHC class I molecules.
Major histocompatibility gene complex (MHC) encoded moleculesThe principal function of MHC class I and II molecules is to bind and present antigenic peptides to the immune system. MHC class I (human leucocyte antigen (HLA)-A, -B and -C) molecules present antigenic peptides to CD8+ cells. Since the peptides are derived from proteins synthesised and processed in the cytoplasm, such as viral and tumour antigens, this is termed the endogenous pathway of antigen processing. In contrast, the peptides that MHC class II (HLA-DR, -DQ and -DP) molecules present to CD4+ T cells are generated by the exogenous pathway of antigen presentation, namely from antigens internalised and degraded in acidified intracellular vesicles. The overall structure of the peptide-binding site for both macrophages class I and Class II is similar. Each comprises a cleft formed by helical walls overlaying a floor of β sheets (e.g. MHC classII;). Variability in amino acid residues located in both the the floor and the walls of the cleft influences Peptide binding and arises as a result of polymorphism in the MHC class I and II genes. Genes encoding proteins associated with the processing (proteasomes) and transport (TAP) of antigenic peptides in the cytosol also map in the MHC locus .
Diversity in the antigen-specific receptorsIn order to recognise the vast array of potentially pathogenic microbes, B and T cells both express a broad repertoire of antigen-specific receptors that are clonally distributed and, thus, unique to each lymphocyte.
Antibody diversityDiversity in the antibody repertoire is generated through the following mechanisms
With the notable exception of somatic hypermutation, similar mechanisms operate to generate diversity in the TCP repertoire. Rearrangement occurs between the V, D and I gene segments for TCR-β chains and V and J for aαchains additional J and D segments allow greater diversity in the TCR antigen binding site. Thus the overall degree of diversity of the Ig and TCR repertoires is comparable.