Defence Inflammation And Immunity - pediagenosis
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Friday, February 3, 2023

Defence Inflammation And Immunity

Defence: Inflammation And Immunity.

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.

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