Posted by: Indonesian Children | August 13, 2009

Cytokines and chemokines

The function of the immune system is to protect the body from invasion. Immune cells recognise and remove foreign antigens (mainly proteins and carbohydrates) derived from other organisms, while tolerating very similar substances specified by the host genome. The distinction is normally precise: the body can often detect a single amino acid substitution, but the system is not perfect and mistakes can give rise to serious disease.

In addition to self-tolerance, the immune system commonly ignores harmless antigens present in the environment, such as foods and gut comensals, although it may react strongly if these substances are administered by a different route.

The immune response normally includes both cell-mediated immunity and humoral immunity. Cell-mediated immunity involves the direct killing and / or swallowing of infected host cells and pathogens by immune cells, whereas humoral immunity involves the production of soluble antibody proteins which circulate in the blood, and are secreted into other body fluids.

Some compounds (such as the repeating polysaccharide units in bacterial cell walls) are immediately recognised as foreign and attacked without delay. This innate immunity is particularly important after traumatic injuries. Cytokines & chemokines [see below] secreted by the first arrivals attract other immune cells to the site of the infection.

Cytokines & chemokines produced during an immune response give rise to inflammation, fever and cachexia. Inflammation involves vascular changes which allow immune cells better access to the infected tissue. This produces local pain, redness and swelling and a rise in overall body temperature which helps to combat infection. In addition, cytokines modify eating behaviour and metabolism, producing ‘cachexia’ which is the loss of appetite and tissue wasting often associated with trauma, cancer and other serious diseases.

The adaptive immune response takes several days to develop, and may depend on the route whereby antigen enters the body. The immune system can remember strong antigens for many years, and this is the basis for immunisation. Repeated exposure to the same antigen subsequently gives rise to a much more rapid and extensive response.

The peptides displayed by both types of MHC proteins are inspected by T cells, which have antigen receptors on their plasmalemma. T cell antigen receptors recognise the combined peptide + MHC complex and are therefore specific for either Class I or Class II MHC proteins. These T lymphocytes can be subdivided into “helper” Th cells and “cytotoxic” Tc cells.

Helper T lymphocytes normally bear a CD4 surface protein. They recognise peptides bound to Class II MHC molecules, usually on myeloid APCs, but they also recognise peptides displayed by B cells as explained below. Human immunodeficiency virus exploits the CD4 protein to infect and destroy these cells during the development of AIDS.

Cytotoxic T lymphocytes usually bear a CD8 surface protein. They kill any cells that display foreign peptides bound to Class I MHC molecules. This cell-mediated immunity eliminates some tumours and many virus-infected cells, before the virus can infect other cells. Herpes viruses evade detection by down-regulating MHC gene expression, making themselves invisible. Natural killer cells normally ignore cells bearing MHC proteins, so they recognise this unusual situation, and kill the virus-infected cells.

At least three separate killing methods are used by cytotoxic cells: (1) degranulation, (2) Fas ligand, (3) tumour necrosis factor [TNFa] and lymphotoxin [TNFb]. Degranulation involves the release of serine proteases called “granzymes” and perforin subunits from cytoplasmic granules in the cytotoxic cell. The target cells take up the proteases into temporary storage vesicles by receptor-mediated endocytosis. Perforin is a protein that is related to component C9 in the complement system. Like complement, perforin self-assembles when exposed to extracellular calcium concentrations and punches holes in the membranes of target cells. It is necessary for the release of vesicular granzymes into the target cell cytoplasm. Fas ligand is a protein exposed on the surface of activated CD4+ and CD8+ cells that binds to Fas receptors in the target cell plasmalemma. This triggers apoptosis of the target cell [see below]. TNFa is a soluble cytokine that kills some tumour cells and also plays a major role in some inflammatory complaints, such as Crohn’s disease and rheumatoid arthritis.

The HLA / MHC loci are highly polymorphic and hundreds of protein isoforms coexist within a breeding population. These differ in the type of peptide they most efficiently display. We inherit 3 major Class I HLA genes and 16 Class II genes from each parent. The parental copies probably differ and all are expressed. Diversity ensures that a species as a whole can resist the widest range of pathogens, although individuals might be susceptible to particular parasites which display badly on their APCs. Mice can apparently recognise individuals expressing particular MHC variants by smell, and prefer sexual partners that will maximise the immune diversity of their offspring. There is dispute as to whether humans have a similar ability.

Individual T cells recognise only a narrow range of antigen fragments displayed by APCs and most T cells have different [unique] receptors for the antigen / HLA complex. This variability is generated by error-prone somatic recombination involving the DNA within each T cell nucleus as these cells differentiate. The mechanism generating receptor diversity in T cells is a simpler version of the system used to generate antibody diversity in B cells [see below]. The recognition of an APC peptide – MHC complex by a T cell antigen receptor initiates an extremely complex transmembrane signalling system. This normally leads to the proliferation of those T cell clones which efficiently detect particular foreign antigens bound to MHC and the suppression of any T cell clones which recognise “self”.

Cytokines & chemokines

Cytokines are proteins made by cells that affect the behaviour of other cells. This definition is very broad (and should in theory include all the peptide hormones) so it is no surprise that there are already dozens of them, with more discovered every year. Chemokines are low molecular weight cytokines that are particularly involved in lymphocyte chemotaxis towards a focus of infection. The opportunities for confusion are enormous: each cytokine affects several different types of cell, most types of cell produce multiple cytokines, and several different kinds of cell may produce the same cytokine. It is neither practicable nor desirable for students to learn them all by rote, so we have tabulated a few of the most clinically important ones that we think you should know:

cytokine produced by target cells actions
interleukin 1 (IL-1) macrophages hypothalamus, pituitary
and other tissues
fever, activates CRH & ACTH production, activates T cells and other macrophages
interleukin 6 (IL-6) T cells, macrophages, endothelial cells liver etc fever, acute phase response, T & B cell growth and differentiation
TNF-a NK cells, T cells, macrophages   fever, local inflammation
interferon g T cells, NK cells macrophage activation, increased MHC synthesis improved resistance to infection and stress.
Fas ligand (FasL) T cells   apoptosis

Note: Interleukin-1 comes in two flavours IL-1a and IL-1b which are apparently the products of different genes, but with very similar actions. There is also a natural inhibitor IL-1 RA which binds to IL-1 receptors but does not activate them.

IL-1 released by macrophages acts on the hypothalamus to raise the setting of the body thermostat, producing the fever associated with infectious disease. It also promotes the synthesis of corticotropin releasing hormone (CRH) and hence indirectly ACTH and corticosteroids. This forms part of a negative feedback loop autoregulating immune system activity, because corticosteroids ultimately have an immunosuppressant effect.

IL-6 acts on the liver and initiates the acute phase response. This is an early stereotyped reaction to major trauma and infection which puts the body on a “war footing” before the nature of the threat has been properly identified. The liver synthesises increased amounts of acute phase proteins (C-reactive protein, mannan binding lectin and others) which are reasonably effective against a broad range of microorganisms although they lack individual specificity.

There is considerable overlap between the actions of the individual cytokines, so that many of the above effects are shared between TNFa, IL-1 and IL-6. In addition these pro-inflammatory cytokines activate the immune system, mobilising neutrophils from bone marrow, causing dendritic cells to migrate to lymph nodes, and also initiating changes in adipocyte and muscle metabolism to facilitate the febrile response.

Chemokines are low molecular weight cytokines that are particularly involved in attracting lymphocytes and phagocytic cells towards a focus of infection. They are important mediators of the inflammatory response.


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