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Antimicrobial Immunity: A General Scheme


Antimicrobial Immunity: A General Scheme
At this point the reader will appreciate that the immune system is highly efficient at recognizing foreign substances by their shape but has no infallible way of distinguishing whether they are dangerous (‘pathogenic’). By and large, this approach works well to control infection, but it does have its unfortunate side, e.g. the violent immune response against foreign but harmless structures such as pollen grains, etc. (see Fig. 35).

Antimicrobial Immunity: A General Scheme

Would-be parasitic microorganisms that penetrate the barriers of skin or mucous membranes (top) have to run the gauntlet of four main recognition systems: complement (top right), phagocytic cells (centre), antibody (right) and cell-mediated immunity (bottom), together with their often interacting effector mechanisms. Unless primed by previous contact with the appropriate antigen, antibody and cell-mediated (adaptive) responses do not come into action for several days, whereas complement and phagocytic cells (innate), being ever present, act within minutes. There are also (top centre) specialized innate elements, such as lysozyme, interferons, etc., which act more or less non-specifically, much as antibiotics do. Innate molecules that have evolved to block virus infection are sometimes called restriction factors.
Generally speaking, complement and antibody are most active against microorganisms free in the blood or tissues, while cell-mediated responses are most active against those that seek refuge in cells (left). But which mechanism, if any, is actually effective depends largely on the tactics of the microorganism itself. Successful parasites are those able to evade, resist or inhibit the relevant immune mechanisms, as illustrated in the following five figures. Evasion molecules, together with those that directly damage the host, are known as virulence factors. With increased knowledge of the host and pathogen genomes, identification of virulence factors has become a top priority.
Entry Many microorganisms enter the body through wounds or bites, but others live on the skin or mucous membranes of the intestine, respiratory tract, etc., and are thus technically outside the body.
Surface barriers Skin and mucous membranes are to some extent protected by acid pH, enzymes, mucus and other antimicrobial secretions, as well as IgA antibody (see below). The lungs, intestine, genitourinary tract and eye each have their own specialized combination of protection mechanisms.
Natural antibiotics The antibacterial enzyme lysozyme (produced largely by macrophages; see Fig. 29) and defensins, a family of polypeptides with broad antimicrobial properties, produced especially at mucosal surfaces, provide protection against many bacteria. Recent research has also discovered a whole range of molecules blocking viruses from becoming established in cells. These ‘restriction factors’ are regulated by the antiviral interferons (see Figs 24 and 27), soluble proteins released at sites of viral entry.
C3 Complement is activated directly (‘alternative pathway’) by many microorganisms, particularly bacteria, leading to their lysis or phagocytosis. The same effect can also be achieved when C3 is activated by antibody (‘classic pathway’; see Fig. 6) or by mannose-binding protein.
TH Helper T cells perform several distinct functions in the immune response to microbes. Some respond to ‘carrier’ determinants and stimulate antibody synthesis by B cells. Viruses, bacteria, protozoa and worms have all been shown to function as fairly strong carriers, although there are a few organisms to which the antibody response appears to be T-independent. Others secrete cytokines that attract and activate macrophages, eosinophils, etc. (see Figs 21 and 24), or enhance the activity of cytotoxic T cells. The central role of T helper cells in many infections is shown by the serious effects of their destruction, e.g. in AIDS (see Fig. 28).
B Antibody formation by B lymphocytes is an almost universal feature of infection, of great diagnostic as well as protective value. As a general rule, IgM antibodies come first, then IgG and the other classes; IgM is therefore often a sign of recent infection. At mucous surfaces, IgA is the most effective antibody (see Figs 14 and 17).
Blocking Where microorganisms or their toxins need to enter cells, antibody may block this by combining with their specific attachment site. Antibody able to do this effectively is termed ‘neutralizing’. Vaccines against tetanus, diphtheria and polio all work via this mechanism, as does IgA in the intestine.
Phagocytosis by polymorphonuclear leucocytes or macrophages is the ultimate fate of the majority of unsuccessful pathogens. Both C3 and antibody improve this tremendously by attaching the microbe to the phagocytic cell through C3 or Fc receptors on the latter; this is known as ‘opsonization’ (see Fig. 9).
Intracellular killing Once inside the phagocytic cell, most organisms are killed and degraded by reactive oxygen species, lysosomal enzymes, etc. (see Fig. 8). In certain cases, ‘activation’ of macro- phages by T cells may be needed to trigger the killing process (see Fig. 21).
Extracellular killing Monocytes, polymorphs and other killer (K) cells can kill antibody-coated cells in vitro, without phagocytosis; however, it is not clear how much this actually happens in vivo.
NK Natural killer cells are able to kill many virus-infected cells rapidly, but without the specificity characteristic of lymphocytes. NK cells are activated by cells that lose expression of MHC class I molecules, a frequent characteristic of virus-infected cells and tumours that attempt to evade adaptive immune recognition in this way.
 Intracellular survival Several important viruses, bacteria and protozoa can survive inside macrophages, where they resist killing. Other organisms survive within cells of muscle, liver, brain, etc. In such cases, antibody cannot attack them and cell-mediated responses are the only hope.
T C Cytotoxic T cell, specialized for killing of cells harbouring virus, also allogeneic (e.g. grafted) cells (see Figs 21 and 39), and sometimes tumours (see Fig. 42).
Sequestration Microorganisms that cannot be killed (e.g. some mycobacteria) or products that cannot be degraded (e.g. streptococcal cell walls) can be walled off by the formation of a granuloma by macrophages and fibroblasts, aided by TH-mediated immune responses (see Figs 21 and 37).
Spread Successful microorganisms must be able to leave the body and infect another one. Coughs and sneezes, faeces and insect bites are the most common modes of spread.
Persistence Some very successful parasites are able to escape all the above-mentioned immunological destruction mechanisms by sophisticated protective devices of their own. Needless to say, these constitute some of the most chronic and intractable infectious diseases. Major strategies for immune evasion include resistance to phagocytosis and/or intracellular killing, antigenic variation, immunosuppression and various forms of concealment.
Inflammation Although some microorganisms cause tissue damage directly (e.g. cytopathic viruses or the toxins of staphylococci), it is unfortunately true that much of the tissue damage resulting from infec- tion is due to the response of the host. Acute and chronic inflammation are discussed in detail elsewhere (see Figs 7 and 37), but it is worth noting here that infectious organisms frequently place the host in a real dilemma: whether to eliminate the infection at all costs or to limit tissue damage and allow some of the organisms to survive. Given enough time, natural selection should arrive at the balance that is most favourable for both parasite and host survival.
Virulence factors include toxins, adhesion factors, resistance factors for antibiotics, enzymes that destroy immunological molecules, cytokine inhibitors, antigenic variation. Successful pathogens often possess many of these.