Immunity

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The immune system. Powerful, subtle, dangerous.

QuotationMarkLeft.png The results of his (Jenner) experiments were published in a famous small quarto volume in 1798.[*] From this date, smallpox has been under control. Thanks to Jenner, not a single person in this audience is pockmarked! A hundred and twenty-five years ago, the faces of more than half of you would have been scarred. We now know the principle upon which protection is secured: an active acquired immunity follows upon an attack of a disease of a similar nature. Smallpox and cowpox are closely allied and the substances formed in the blood by the one are resistant to the virus of the other. I do not see how any reasonable person can oppose vaccination or decry its benefits. QuotationMarkRight.pngWilliam Osler. lectures at Yale, 1913. The Project Gutenberg Etext of The Evolution of Modern Medicine

When a person has been exposed to an infectious disease such as chickenpox or measles, there are multiple systems in place for dealing with that infection eg production of specific antibodies against the organism. These systems have evolved in response to common pathogens over time. Earlier, primitive systems tend to be non-specific. Later systems are more specific, and may also adapt to exposure so that on subsequent exposure, a heightened response occurs - a process referred to as "immune memory". But there are complex interactions between all the different systems: specific immune mechanisms may rely on non-specific mechanisms for final clearance of a pathogen, and non-specific systems can be enhanced by factors produced by a specific immune mechanism.

A key aspect of the immune system is recognizing when a cell or substance belongs to one's own body (the self), and when it is foreign (non-self). The thymus is integral to this process. Autoimmunity occurs when the immune system fails to recognize self and targets responses towards the body's own tissue.

Immunodeficiency can be primary or secondary. Genetic causes which affect multiple aspects of the immune system tend to present early in life with overwhelming, severe infection (eg SCID). More specific defects on the other hand, may present later in life with characteristic infections (eg meningococcal disease in complement deficiency), or indeed with no obvious increase in susceptibility to infection at all (eg IgA deficiency).

In medical practice we may artificially induce immunity through vaccination - which generates "active immunity"; or through the administration of immunoglobulins which contain antibodies against the infectious organism in question, and provide "passive immunity". We also regularly suppress natural immunity with drugs eg cytotoxics, steroids either intentionally, in the treatment of autoimmune disease, or incidentally. Such immunosuppression is seen increasingly as new therapies become available for cancers and autoimmune conditions.

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Humoral immunity

This refers to substances circulating in the body. Antibodies are probably the most important type, and are specific; whereas other substances eg complement are non-specific.

Antibodies are immunoglobulins that are produced to target specific non-self antigens. An antigen is simply a protein or other substance with a unique structure that an immunoglobulin can bind to. What's special about immunoglobulin is its ability to adopt a vast range of different shapes to deal with the diversity of possible antigens. Antibody is produced by B cells (particularly plasma cells). There are five main classes of immunoglobulin, which vary with respect to their ability to neutralize toxin, opsonize, activate complement, cross the placenta etc. IgA hangs around in secretions, doing preventive work. IgM is the most important antibody in the primary antibody response: its pentavalent structure means it's good at binding lots of bacteria and complement together in a big mass ready for phagocytosis. IgG is the main antibody in the secondary response.

There are many other circulating factors which act against infection besides antibody. Perhaps the most important of these is complement, a family of proteins with multiple functions which are produced in a cascade in response to infection. This cascade can be triggered by antibody but also by the alternative pathway, which is independent of antibody. Different complement proteins can:

  • Produce a membrane attack complex, to cause cell lysis
  • Opsonize invading cells ie mark them out for phagocytosis by neutrophils and other phagocytic cells.
  • Attract phagocytic cells to the site of infection
  • Stimulate production of other factors

Other non-specific circulating factors include lactoferrin, an avid iron-binding protein, which is present in human milk and reduces the growth of E. coli. Lysozyme is an enzyme with antibacterial properties, and is found in neutrophil lysosomes and in body secretions including tears and saliva. C-reactive protein (CRP) has some immune modulating effects and can act as a nonspecific opsonin for bacterial phagocytosis. Interferon (alpha and beta) are produced by virally infected cells and have the ability to render other cells immune to virus infection, and increase natural killer cell activity.

Children with X-linked agammaglobulinaemia are prone to bacterial conjunctivitis, ear infections and sinusitis. They are also particularly prone to enterovirus and giardia infection, but not other viruses or parasites, which demonstrates how preserved cellular immunity can effectively protect without antibody.

Complement deficiency is particularly associated with severe and/or recurrent capsulated organism infection viz pneumococcus, meningococcus, haemophilus influenzae.

See also:

Cell-mediated immunity

There are many different cells involved in immunity, which can act in different ways. The phagocytic cells (neutrophils, macrophages) are important in the destruction of pathogens. Chronic granulomatous disease is characterized by defective neutrophil function, where pathogens can survive inside the phagocyte. The characteristic infecting organisms here are staphylococcus aureus, klebsiella and other enterobacteriae, and aspergillus.

Some pathogens, particularly mycobacteria and salmonella, are particularly good at surviving despite phagocytosis, and their intracellular location may then offer relative protection from other immune mechanisms. Defects in the interferon gamma receptor predispose to these kinds of infection.

Cytotoxic T cells and Natural Killer cells are important in the killing of virus infected (as well as tumour) cells. This may or may not be antibody mediated.

All the cells of the immune system produce cytokines that then have regulatory effects on other cells as well as other physiological effects. Hence a defect in cellular immunity eg ADA deficiency can predispose to a wide variety of infections and problems.

There is a crucial link between the humoral and cellular immune systems. Antibody is produced by B cells (lymphocytes) but this process is controlled by T cells (lymphocytes) through a process called antigen presentation. This is done mainly by macrophages and related cells eg dendritic cells collectively called antigen presenting cells (APCs), but also by B cells. These cells take up antigens, degrade them, and then express them on the surface where they can then interact with a passing T Cell receptor. APCs often migrate to lymphoid tissue to help achieve this communication. The antigen/receptor interaction is mediated by major histocompatibility complex (MHC) molecules.

The CD4 T-helper cell is central here. After its T cell receptor has been presented with antigen it can either promote antibody production and the switching of antibody classes, or it can stimulate cell-mediated immunity ie cytotoxic T cells and natural killer cells.

Cellular immunity is particularly important in responding to infections by intracellular organisms, fungi, protozoans, and neoplastic conditions. Frustrated macrophages produce granulomas, as seen in many different kinds of disease.

See also:

Autoimmunity

Autoimmune disease occurs when the body's immune system attacks its own tissues. Examples of autoimmune disease include:

Immune system in infancy

The response of the immune system in infancy is less good to antigens which are not presented to B-Cells by a helper T-cell (Th cells...?). Some [[1]] are conjugated in order to produce immune memory by modifying their presentation.

Infants do, however, benefit from passive immunity in the form of maternal antibodies, which cross the placenta into the foetal bloodstream, and still provide some protection (although it cannot be relied upon) until 12 months of age or longer - this is why measles vaccine is considered likely to be ineffective if given before 12 months of age, and why the second dose should not be given before 18 months of age.

This article is a work in progress. Please feel free to contribute to it.

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