Defence: Inflammation And Immunity.
Physical defence against infection by bacteria,
viruses, fungi, and parasites
is provided by the skin, and
epithelia lining the airways and gut. The latter secrete anti-microbial chemicals
and mucus, which traps microorganisms and is removed by cilia (Chapter
25) or peristalsis. Haemostasis quickly seals breaches (Chapter 9). Organisms
evading these defences are targeted by the immune system, where leucocytes
play a central role (Chapter 8). The innate immune response is fast
but non-specific and causes inflammation, characterised by heat,
redness, swelling and pain. The adaptive response is
slower, highly specific, and more potent.
Innate immune response
Tissue damage and invasion of
pathogens activate mast cells (similar to basophils) and resident
phagocytes, primarily macrophages and dendritic cells,
which release inflammatory mediators, signalling molecules (cytokines)
and cytotoxic agents (Fig. 10a). Inflammatory mediators cause vasodilation
(heat and redness), stimulate nocicep- tors (pain) and
increase endothelial permeability, leading to extrava- sation of
protein and fluids and thus oedema (swelling) (Chapters 2 and
23). Cytokines (e.g. interleukin 8, IL8) attract many more phago cytes,
chiefly neutrophils (chemotaxis); these leave the blood by
squeezing between endothelial cells (diapedesis). Phagocytes ingest (phagocytose)
microorganisms, and in the case of macrophages also damaged cells and debris.
Pathogens can be detected because they express pathogen-associated molecular
patterns (PAMPs) not found in mammals (e.g. bacterial mannose
residues, viral RNA and fungal glucans). PAMPs are recognised by phagocyte pattern
recognition receptors (PRRs); relatively few different PRRs are
required (<1000) because PAMPs
are common across wide groups of pathogen.
On binding a PAMP, PRRs initiate
phagocytosis and release of cytokines and cytotoxins. Injured, infected or cancerous cells express
PAMPlike molecules recognised by natural killer (NK)
lymphocytes, which kill the cells and activate macrophages to remove the
debris. In major infections cytokines such as IL1 cause fever; high
temperatures may assist the immune response.
Complement is an important non-cellular mechanism
comprised of a cascade of plasma proteins. On activation it coats and opsonizes
(facilitates phagocytosis) pathogens, kills by membrane rupture,
recruits phagocytes and induces inflammation. It is activated by some surface
molecules (e.g. bacterial mannose) and by antibodies (e.g. IgM; Fig. 10b) that have ‘tagged’ a
pathogen or material as foreign.
Antibodies (immunoglobulins)
Adaptive immunity depends on antibodies,
which are made by lymphocytes and recognise highly specific molecular
sequences (epitopes) on proteins, polysaccharides, lipids and small
chemicals. Molecules that react with antibodies are called antigens.
There are five antibody classes (Fig. 10b). All have a constant region (FC)
attached to two hyper-variable branches (Fab) which recognise the
epitope. The hyper variability is due to random mutations in antibody genes
during lymphocyte maturation, so each cell can end up with one of ∼109
different antibodies. Although individual
cells express just one variant, the large number of lymphocytes and random nature of production means that every
variant will be expressed somewhere, if only in a small group of cells. Such
groups of lymphocytes with identical antibodies are called clones. Any lymphocytes with
antibodies directed against self are (normally) destroyed during maturation. Antibodies neutralise toxins
and prevent attachment of pathogens; target, opsonize or agglutinate (clump
together) antigens for phagocytosis; target pathogens and foreign
material for complement; and, crucially, act as antigen receptors on
lymphocytes.
Adaptive immune response
The adaptive response takes ∼5 days
to become effective, and peaks after
1–2 weeks. It has two intertwined branches: humoral immunity, mediated by B lymphocytes (B cells)
which mature in bone marrow, and cell-mediated immunity, mediated
by T lymphocytes (T cells) which mature in the thymus. Naïve (not
yet activated) lymphocytes continually recirculate between lymphoid
tissues (e.g. lymph nodes, tonsils and spleen) until they encounter a
matching antigen.
Humoral immunity (Fig. 10c) is particularly effective against
extracellular pathogens, as it involves secretion of antibodies into
extracellular fluid. Only B cells can do this, or have antigen receptors that
can recognise all types of antigen (e.g. protein, polysaccharide, lipid,
etc.). When an antigen binds to its matching receptor on naïve B cells, the
latter activate and undergo clonal expansion – rapid proliferation
resulting in a large number of identical cells expressing the same antibody.
These differentiate into plasma cells, which secrete the antibody in
massive amounts. For nonprotein antigens the whole process is T cell
independent. However, if the antigen is a protein, T helper (TH, CD4+) cells substantially enhance the response. T cells
only recognise protein (or peptide)
antigens, and then only when they are
presented to them by major histocompatibility complex (MHC
II) on antigen presenting cells (APC), which include
dendritic cells, macrophages and B cells. B cells activated by protein antigen
attract and attach to TH cells, to which they present the antigen via MHC II.
If a TH cell’s receptors identify the antigen, the cell proliferates and
releases cytokines which strongly potentiate B cell proliferation and
performance; this is often essential for an effective response. TH cytokines
also induce B cell class switching, e.g. from production of IgM to IgE
(Fig. 10b).
Memory cells which persist for years are also produced
during clonal expansion. These respond much more rapidly and powerfully to
subsequent exposures to the same pathogen, and provide long term immunity.
This is the basis of immunization.
Cell-mediated immunity (Fig. 10d) is directed towards antigens within
cells, which are made visible by MHC. MHC I is found on the surface
of all cells and displays cytosolic antigens (e.g. viral proteins), but
only to cytotoxic TC (CD8+) cells, which proliferate on recognising the
antigen and destroy any similarly infected cells. In contrast,
MHC II displays antigens retained
within vesicles, i.e. that have been phagocytosed, and is found only in
APCs which activate TH cells. Dendritic cells, and to a lesser extent
macrophages, are the most important phagocytic APCs. After phagocytosing a
pathogen they migrate to lymphoid tissues and present the antigen (via MHC II)
to naïve TH cells. TH cells that recognise the antigen activate, proliferate
and stimulate B cells (and thus a humoral response) as described above.
Importantly, they also release cytokines that regulate the activity of other
immune cells, including macrophages, TH, TC, NK, plasma and mast cells. TH
cells therefore play a critical coordinating role in the immune response.
