9 The innate defences of the body
In the preceding chapters, we have outlined some of the fundamental characteristics of the myriad types of microparasites and macroparasites that may infect the body. We now turn to consider the ways in which the body seeks to defend itself against infection by these organisms.
When an organism infects the body, the defence systems already in place may well be adequate to prevent replication and spread of the infectious agent, thereby preventing development of disease. These established mechanisms are referred to as constituting the ‘innate’ immune system. However, should innate immunity be insufficient to parry the invasion by the infectious agent, the so-called ‘adaptive’ immune system then comes into action, although it takes time to reach its maximum efficiency (Fig. 9.1). When it does take effect, it generally eliminates the infective organism, allowing recovery from disease.
Figure 9.1 Innate and adaptive immunity. An infectious agent first encounters elements of the innate immune system. These may be sufficient (1) to prevent disease but if not, disease may result (2). The adaptive immune system is then activated (3) to produce recovery (4) and a specific immunologic memory (5). Following re-infection with the same agent, no disease results (6) and the individual has acquired immunity to the infectious agent.
The main feature distinguishing the adaptive response from the innate mechanism is that specific memory of infection is imprinted on the adaptive immune system, so that should there be a subsequent infection by the same agent, a particularly effective response comes into play with remarkable speed. It is worth emphasizing, however, that there is close synergy between the two systems, with the adaptive mechanism greatly improving the efficiency of the innate response.
The contrasts between these two systems are set out in Table 9.1. On the one hand, the soluble factors such as lysozyme and complement, together with the phagocytic cells, contribute to the innate system, while on the other the lymphocyte-based mechanisms that produce antibody and T lymphocytes are the main elements of the adaptive immune system. Not only do these lymphocytes provide improved resistance by repeated contact with a given infectious agent, but the memory with which they become endowed shows very considerable specificity to that infection. For instance, infection with measles virus will induce a memory to that microorganism alone and not to another virus such as rubella.
|Innate immune system
|Adaptive immune system
|Lysozyme, complement, acute phase proteins, e.g. C-reactive protein, interferon
Natural killer cells
|Response to microbial infection
|+ + + +
|Non-specific; no memory
Resistance not improved by repeated contact
Resistance improved by repeated contact
Innate immunity is sometimes referred to as ‘natural’, and adaptive as ‘acquired’. There is considerable interaction between the two systems. ‘Humoral’ immunity due to soluble factors contrasts with immunity mediated by cells. Primary contact with antigen produces both adaptive and innate responses, but if the same antigen persists or is encountered a second time the specific adaptive response to that antigen is much enhanced.
Before an infectious agent can penetrate the body, it must overcome biochemical and physical barriers that operate at the body surfaces. One of the most important of these is the skin, which is normally impermeable to the majority of infectious agents. Many bacteria fail to survive for long on the skin because of the direct inhibitory effects of lactic acid and fatty acids present in sweat and sebaceous secretions and the lower pH to which they give rise (Fig. 9.2). However, should there be skin loss, as can occur in burns, for example, infection becomes a major problem.
Figure 9.2 Exterior defences. Most of the infectious agents encountered by an individual are prevented from entering the body by a variety of biochemical and physical barriers. The body tolerates a variety of commensal organisms, which compete effectively with many potential pathogens.
The membranes lining the inner surfaces of the body secrete mucus, which acts as a protective barrier, inhibiting the adherence of bacteria to the epithelial cells, thereby preventing them from gaining access to the body. Microbial and other foreign particles trapped within this adhesive mucus may be removed by mechanical means such as ciliary action, coughing and sneezing. The flushing actions of tears, saliva and urine are other mechanical strategies that help to protect the epithelial surfaces. In addition, many of the secreted body fluids contain microbicidal factors, e.g. the acid in gastric juice, spermine and zinc in semen, lactoperoxidase in milk, and lysozyme in tears, nasal secretions and saliva.
The phenomenon of microbial antagonism is associated with the normal bacterial flora of the body. These commensal organisms suppress the growth of many potentially pathogenic bacteria and fungi at superficial sites, first by virtue of their physical advantage of previous occupancy, especially on epithelial surfaces, second by competing for essential nutrients, or third by producing inhibitory substances such as acid or colicins. The latter are a class of bactericidins that bind to the negatively charged surface of susceptible bacteria and form a voltage-dependent channel in the membrane, which kills by destroying the cell’s energy potential.
Perhaps because of the belief that professionals do a better job than amateurs, the cells that shoulder the main burden of our phagocytic defences have been labelled ‘professional phagocytes’. These consist of two major cell families, as originally defined by Elie Metchnikoff, the Russian zoologist (Box 9.1; Fig. 9.3):
Box 9.1 Lessons in Microbiology
This perceptive Russian zoologist can legitimately be regarded as the father of the concept of cellular immunity, in which it is recognized that certain specialized cells mediate the defence against microbial infections. He was intrigued by the motile cells of transparent starfish larvae and made the critical observation that a few hours after introducing a rose thorn into the larvae, the rose thorn became surrounded by the motile cells. He extended his investigations to mammalian leukocytes, showing their ability to engulf microorganisms, a process that he termed ‘phagocytosis’ (literally, eating by cells).
Because he found this process to be even more effective in animals recovering from an infection, he came to the conclusion that phagocytosis provided the main defence against infection. He defined the existence of two types of circulating phagocytes: the polymorphonuclear leukocyte, which he termed a ‘microphage’, and the larger ‘macrophage’.
Although Metchnikoff held the somewhat polarized view that cellular immunity based upon phagocytosis provided the main, if not the only, defence mechanism against infectious microorganisms, we now know that the efficiency of the phagocytic system is enormously enhanced through cooperation with humoral factors, in particular antibody and complement.
As a very crude generalization, it may be said that the polymorphs provide the major defence against pyogenic (pus-forming) bacteria, while the macrophages are thought to be at their best in combating organisms capable of living within the cells of the host.
Macrophages originate as bone marrow promonocytes, which develop into circulating blood monocytes (Fig. 9.4) and finally become the mature macrophages, which are widespread throughout the tissues and collectively termed the ‘mononuclear phagocyte system’ (Fig. 9.5). These macrophages are present throughout the connective tissue and are associated with the basement membrane of small blood vessels. They are particularly concentrated in the lung (alveolar macrophages), liver (Kupffer cells) and the lining of lymph node medullary sinuses and splenic sinusoids (Fig. 9.6), where they are well placed to filter off foreign material (Fig. 9.7). Other examples are the brain microglia, kidney mesangial cells, synovial A cells and osteoclasts in bone. In general, these are long-lived cells that depend upon mitochondria for their metabolic energy and show elements of rough-surfaced endoplasmic reticulum (Fig. 9.8) related to the formidable array of different secretory proteins that these cells generate.
(Courtesy of P.M. Lydyard.)
Figure 9.7 Localization of intravenously injected particles in the mononuclear phagocyte system. (Right) A mouse was injected with fine carbon particles and killed 5 min later. Carbon accumulates in organs rich in mononuclear phagocytes: lungs (L), liver (V), spleen (S) and areas of the gut wall (G). (Left) Normal organ colour shown in a control mouse.
(Courtesy of P.M. Lydyard.)
The polymorph is the dominant white cell in the bloodstream and, like the macrophage, shares a common haemopoietic stem cell precursor with the other formed elements of the blood. It has no mitochondria, but uses its abundant cytoplasmic glycogen stores for its energy requirements; therefore, glycolysis enables these cells to function under anaerobic conditions, such as those in an inflammatory focus. The polymorph is a non-dividing, short-lived cell, with a segmented nucleus; the cytoplasm is characterized by an array of granules, which are illustrated in Figure 9.9.
Figure 9.9 Neutrophil. The multi-lobed nucleus and primary azurophilic, secondary specific and tertiary lysosomal granules are well displayed. In some granules there is an overlap in the contents between azurophilic and secondary granules. Typical conventional lysosomes with acid hydrolase are also seen.
(Courtesy of D. McLaren.)
|Vitamin B12 binding protein
|BPI (bactericidal permeability increasing protein)
The first event in the uptake and digestion of a microorganism by the professional phagocyte involves the attachment of the microbe to the surface of the cell through the recognition of repeating pathogen-associated molecular patterns (PAMPs) on the microbe by pattern recognition receptors (PRRs) on the phagocyte surface (Fig. 9.10). A major subset of these PRRs belongs to the class of so-called ‘Toll-like receptors’ (TLRs) because of their similarity to the Toll receptor in the fruit fly, Drosophila, which, in the adult, triggers an intracellular cascade generating the expression of antimicrobial peptides in response to microbial infection. A series of cell surface TLRs acting as sensors for extracellular infections have been identified (Fig. 9.11) which are activated by microbial elements such as peptidoglycan, lipoproteins, mycobacterial lipoarabinomannan, yeast zymosan and flagellin. Other PRRs displayed by phagocytes include the cell bound ‘C-type (calcium-dependent) lectins’, of which the macrophage mannose receptor is an example, and ‘scavenger receptors’, which recognize a variety of anionic polymers and acetylated low density proteins. Examples of intracellular PAMPs are the unmethylated guanosine-cytosine (CpG) sequences of bacterial DNA and double-stranded RNA from RNA viruses.
Figure 9.10 Phagocytosis. (A) Phagocytes attach to microorganisms (blue icon) via their cell surface receptors which recognize pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide. (B) If the membrane now becomes activated by the attached infectious agent, the pathogen is taken into a phagosome by pseudopodia, which extend around it. (C) Once inside the cell, the various granules fuse with the phagosome to form a phagolysosome. (D) The infectious agent is then killed by a battery of microbicidal degradation mechanisms, and the microbial products are released.
Figure 9.11 Recognition of PAMPs by a subset of pattern recognition receptors (PRRs) termed Toll-like receptors (TLRs). TLRs reside within plasma membrane or endosomal membrane compartments, as shown. All TLRs have multiple N-terminal leucine-rich repeats forming a horseshoe-shaped structure which acts as the PAMP-binding domain. Upon engagement of the TLR ectodomain with an appropriate PAMP (some examples are shown), signals are propagated into the cell that activate the nuclear factor kB (NFkB) and/or interferon regulated factor (IRF) transcription factors, as shown. NFkB and IRF transcription factors then direct the expression of numerous antimicrobial gene products such as cytokines and chemokines, as well as proteins that are involved in altering the activation state of the cell.
The attached microbe may then signal through the phagocyte receptors to initiate the ingestion phase by activating an actin-myosin contractile system, which sends arms of cytoplasm around the particle until it is completely enclosed within a vacuole (phagosome; Fig. 9.12; see Fig. 9.11). Shortly afterwards, the cytoplasmic granules fuse with a phagosome and discharge their contents around the incarcerated microorganism.
(Courtesy of C.H.W. Horne.)