Recognition And Receptors: The Keys To Immunity
Before any immune mechanism can go into action, there must be a recognition that something exists for it to act against. Normally this means foreign material such as a virus, bacterium or other infectious organism. This recognition is carried out by a series of recognition molecules or receptors. Some of these (upper part of figure) circulate freely in blood or body fluids, others are fixed to the membranes of various cells or reside inside the cell cytoplasm (lower part). In every case, some constituent of the foreign material must interact with the recognition molecule like a key fitting into the right lock. This initial act of recognition opens the door that leads eventually to a full immune response.
These receptors are quite different in the innate and the adaptive immune system. The innate system (left) possesses a limited number, known as pattern-recognition receptors (PRRs), which have been selected during evolution to recognize structures common to groups of disease-causing organisms (pathogen-associated molecular patterns, PAMPs); one example is the lipopolysaccharide (LPS) in some. bacterial cell walls (for more details see Fig. 5). These PRRs act as the ‘early warning’ system of immunity, triggering a rapid inflammatory response (see Fig. 2) which precedes and is essential for a subsequent adaptive response. In contrast, the adaptive system has thousands of millions of different receptors on its B and T lymphocytes (right), each one exquisitely sensitive to one individual molecular structure. The responses triggered by these receptors offer more effective protection against infection, but are usually much slower to develop (see Figs 18–21).
Linking the two systems are the families of major histocompatibility complex (MHC) molecules (centre), specialized for ‘serving up’ foreign molecules to T lymphocytes. Another set of ‘linking’ receptors are those by which molecules such as antibody and complement become bound to cells, where they can themselves act as receptors.
Complement A complex set of serum proteins, some of which can be triggered by contact with bacterial surfaces (for details see Fig. 6). Once activated, complement can damage some cells and initiate inflammation. Some cells possess receptors for complement, which can assist the process of phagocytosis (see Fig. 9).
Mannose-binding lectin (MBL) binds the surface of bacteria and fungi, and can activate complement or act directly to assist phagocytosis.
Acute phase proteins Another complex set of serum proteins. Unlike complement, these proteins are mostly present at very low levels in serum, but are rapidly produced in high amounts by the liver following infection, where they contribute to inflammation and immune recognition. Several acute phase proteins also function as PRRs.
PRR Pattern-recognition receptors have now been described for every type of pathogen, and more are being discovered all the time. They can broadly be divided in terms of cellular localization, e.g. cell membrane, endosome/phagosome and cytoplasm. Although they are represented by a bewildering variety of types of molecules, their common functional feature is they regulate the innate immune response to infection. Note that not all PRRs are found on all types of cell, the majority being restricted to macrophages and dendritic cells (MAC, DC in figure). Further details of PRR types are given in Fig. 5.
Receptors feature in a number of other biological processes, many of them outside the scope of this book. Here are a few that are relevant to immunity.
Virus receptors To enter a cell, a virus has to ‘dock’ with some cell- surface molecule; examples are CD4 for HIV (see Fig. 28) and the acetylcholine receptor for rabies.
Cytokine receptors Communication between immune cells is largely mediated by ‘messenger’ molecules known as cytokines (see Figs 23 and 24). To respond to a cytokine, a cell needs to possess a receptor for it.
Hormone receptors In the same way as cytokines, hormones (e.g. insulin, steroids) will only act on cells carrying the appropriate receptor.
Adaptive immune system
Antibody Antibody molecules (for details see Figs 13, 14, 19 and 20) can act as both soluble and cell-bound receptors.
1 On the B lymphocyte, antibody molecules synthesized in the cell are exported to the surface membrane where they recognize small components of protein, carbohydrates or other biological macromolecules (‘antigens’) and are taken into the cell to start the triggering process. Each B lymphocyte is programmed to make antibody of one single recognition type out of a possible hundreds of millions.
2 When the B lymphocyte is triggered, large amounts of its antibody are secreted to act as soluble recognition elements in the blood and tissue fluids; this is referred to as the ‘antibody response’. Antibody in serum is often referred to as immunoglobulin (Ig).
3 Some cells possess ‘Fc receptors’ (FcR in figure) that allow them to take up antibody, insert it in their membrane, and thus become able to recognize a wide range of antigens. This can greatly improve phago- cytosis, but can also be responsible for allergies (see Fig. 35).
T-cell receptor (TcR in figure) T lymphocytes carry receptors that have a similar basic structure to antibody on B lymphocytes (for further details see Figs 12 and 18) but with important differences:
1 They are specialized to recognize only small peptides (pieces of proteins) bound to MHC molecules (see below);
2 They are not exported, but act only at the T-cell surface.
MHC molecules These come in two types. MHC class I molecules are expressed on all nucleated cells while class II MHC molecules are normally found only on B lymphocytes, macrophages and dendritic cells. Their role is to ‘present’ small antigenic peptides to the T-cell receptor. The class of MHC and the type of T cell determine the characteristics of the resulting immune response (see Figs 11 and 18). Their name comes from their important role in stimulating transplant rejection (see Fig. 39).
NK cell receptors Natural killer cells share features of both lymphocytes and innate immune cells. They are specialized for killing virus-infected cells and some tumours, and they possess receptors of two opposing kinds.
1 Activating receptors are analogous to PRRs, recognizing changes associated with stress and virus infection.
2 Inhibitory receptors recognize MHC class I molecules, preventing NK cells killing normal cells. The final result thus depends on the balance between activation and inhibition (for further details see Figs 10, 15 and 42).