History Flashcards
Edward Jenner variolated his patients
Dried smallpox scabs were introduced to an abrasion of the skin of a boy’s arm. He then contracted a mild form of the disease. Upon recovery, the individual was immune to smallpox (tested by reintroduction). Between 1% to 2% of those variolated died as compared to 30% who died when they contracted the disease naturally.
Louis Pasteur developed weakened (attenuated) strains of Pasteurella after noticing that repeated cultures reduced its pathogenicity.
Immunity
the ability of the human body to protect itself from infectious disease
Innate immunity
Innate immunity is non-specific and non-adaptive It is the immunity that is present from birth. It includes:
* Physical barriers (e.g. intact skin and mucous membranes)
* Chemical barriers (e.g. gastric acid, digestive enzymes and bacteriostatic fatty acids of the skin)
* Biological barriers (e.g. phagocytic cells and the complement system)
Acquired immunity
Acquired immunity is generally specific to a single organism or to a group of closely related organisms. Acquired immunity is developed by active or passive processes.
Active immunity
Active immunity is protection that is produced by an individual’s own immune system and is usually long-lasting. Such immunity generally involves cellular responses (cell-mediated), humoral responses (antibody-mediated) or a combination acting on the infecting organism. Active immunity can be acquired by natural disease or by vaccination. Vaccines generally provide immunity similar to that provided by the natural infection, but without the risk from the disease or its complications.
Cell-mediated immunity
Cell-mediated immunity is controlled by a subset of lymphocytes called T lymphocytes or T cells. T cells mediate three principal functions: help, suppression and cytotoxicity.
* Cytotoxic T cells (CTLs, where CD8+ is the most common) recognise and destroy infected cells by phagocytosis to destroy
pathogens.
* T-helper cells (CD4+) stimulate and modulate the immune response of other cells; they activate phagocytic macrophages by
cytokines, in particular IFN-g, to destroy and engulf bacteria.
Antibody-mediated immunity
Antibody-mediated responses are produced by B lymphocytes (B cells). When a B cell encounters an antigen that it recognises, the B cell is stimulated to proliferate and produce large numbers of lymphocytes secreting an antibody to this antigen. Replication and differentiation of B cells into plasma cells is regulated by contact with the antigen and by interactions with T cells (a type of lymphocyte), macrophages and complement. They provide immunity by:
* Neutralising antibodies (nABs), which block the binding of pathogens to cell-surface receptors, preventing the pathogen from becoming infective
* Antibody dependent cellular cytotoxicity (ADCC), which makes CD8 cells target infected cells
* Opsonising, which involves coating pathogens and targeting them for phagocytosis
* Complement cascade, where the antibody-antigen complexes activate the cascade leads to destruction of pathogen via
phagocytosis or bacterial membrane attack.
Role of antibodies:
IgM is a major antibody in the complement cascade. It is induced by vaccination.
IgG is systemic, found in blood, lymph nodes and tissues. It performs all major roles (nABs, ADCC, Opsonisation & complement cascade). It is induced by vaccination.
IgA is the principle isotope in mucosal secretions in the gastro-intestinal, respiratory & genital tracts. It is a less potent opsonin and a weak activator of complement but is a strong viral neutraliser
Passive immunity
Passive immunity is protection provided from the transfer of from immune individuals. Naturally, immunity is passed from mother to child across the placenta (IgG) during the last 10 weeks of pregnancy and from breast milk (secretory IgA). This protects against lung and GI infections; bottle-fed babies are 60x more likely to develop pneumonia in first 3 months of life compared to breast-fed babies. However, protection provided by the cross-placental transfer of antibodies from mother to child is more effective against some infections (e.g. tetanus and measles) than for others (e.g. polio and whooping cough). This protection is temporary, lasting for only a few weeks or months.
Passive immunity can be caused by transfusion of blood or blood products including immunoglobulin.
Immunological Memory
Vaccines produce their protective effect by inducing active acquired immunity and providing immunological memory; memory cells allow the immune system to recognise and respond rapidly to re-infection, which higher antibody concentrations.
For a vaccine to be effective, it must trigger the proliferation of naïve t-cells. Success depends on whether CD4+ Th1 and CD8+ responses are induced (intracellular organisms) or CD4+ Th2 responses are induced (extracelullar organisms).
Naïve T-cells proliferate
in response to an antigen, forming effector cells (which deal with the present infective agent) and memory cells (which remember the infective agent so upon re-infection, the immune system can respond very quickly and potently to destroy it)
Naïve B-cells
proliferate in response to an antigen, forming plasma cells (which deal with the present infective agent) and memory cells (which remember the infective agent so upon re-infection, the immune system can respond very quickly and potently to destroy it).
Paediatric immunity
Babies are at their most vulnerable for the first 28 days of their life. Although antibody synthesis begins in foetus at 20 weeks, infants are reliant on maternal ABs for the first 2 months. Because of this, children under 8 weeks cannot be vaccinated. After 8 weeks, they can be vaccinated. However, their adaptive immune system is immature (T-cells are all naïve but do not respond to antigens) and attenuated viruses pose the risk of virulence. As a consequence, toxoids, glycoconjugates and recombinant protein vaccines can be used, with aluminium-based adjuvants. These are weakly immunogenic and require booster immunisations.
The first paediatric vaccines are given at 2 months because maternal antibodies begin waning. The inactivated components of the Infanrix vaccine are safe to use, and there is a high risk of infection from pathogens contained in the vaccine. There is also a high risk of infection of Men B & Rotavirus. PCV conjugate vaccine is given because the immature immune system cannot process polysaccharide-only vaccines. Boosters are given at 12 & 16 weeks, to ensure immunity. Side effects of the Infanrix vaccine include dermatitis, restlessness, crying and disturbed sleep; the Rotarix vaccine may cause vomiting/ diarrhoea.
At 1-year, thymic T cells develop. These cope with attenuated vaccine, unless there is a malignancy/disease where the immune system is compromised. The MMR vaccine is given at 1-year, and the flu vaccine is given at 2-years. By age 5, the immune system is fully developed. The MMR vaccine may cause malaise (general discomfort), fever or rash.
Elderly immunity
T-cells stop living after about 40 divisions due to the short length of telomeres. B-cell clones can outgrow and become malignant. T & B cell senesce results in more infections, especially respiratory tract infections. The elderly may contract shingles due to latent chickenpox virus (varicella zoster); this is a sign of secondary immunodeficiency due to malignant B-cells.
Vaccines
Vaccines must be safe, with low toxicity. They must offer effective protection against infective agent to rapidly generate herd immunity and ideally, produce long-lived immunity to reduce the amount of booster doses required; this reduces the cost involved and complexity of vaccine regimens. They should be cheap, or cost-effective, as they will be administered widely.
They should contain only purified components (i.e. the key antigens only): for intracellular organisms, CTL and Abs are needed, for extracellular organisms, only Abs are needed. They should target specific epitopes (the part of an antigen molecule to which an antibody attaches itself), as some epitopes do not generate protective Abs/ CTLs and may cause adverse side effects. Stimulation of mucosal immunity may be required to provide defence at the point of entry. They may have to include pre- existing antibodies to form the antigen-antibody complex which is phagocytosed (e.g. diphtheria & tetanus endotoxins) or block viral-ligand cell receptor interaction (e.g. Polio & HIV).
