Review of Immunological Processes

• Mechanical barriers to infection:

  • Skin - flow of fluid, perspiration, sloughing off of skin
  • Gastrointestinal tract - flow of fluid, mucus, food, and saliva
  • Respiratory tract - flow of fluid and mucus eg by cillia, airflow
  • Urogenital tract - flow of fluid, urine, mucus, sperm
  • Eyes - flow of fluid, tears
• Chemical barriers to infection:

  • Skin - sebum (fatty acids, lactic acid, lysozyme)
  • Gastointestinal tract - acidity, enzymes (proteases)
  • Respiratory tract - lysozyme in nasal secretions
  • Urogenital tract - acidity in vaginal secretions, spermine and zinc in semen
  • Eyes - lysozyme in tears
• Microbiological barriers to infection:

  • Skin - normal flora of the skin
  • Gastorintestinal tract - normal flora of the gastrointestinal tract
  • Respiratory tract - normal flora of the respiratory tract
  • Urogenital tract - normal flora of the urogenital tract
  • Eyes - normal flora of the eyes
• Barriers of infection:

  • Flow of fluid can wash away infections
  • Sloughing off of skin takes any attached bacteria with it
  • Mucous production (mucous = mucin + water) - enables us to coagulate and swallow bacteria
  • Acid is bacteriocidal
  • Enzymes like lysozyme will lyse bacterial cell walls
  • Antimicrobial peptides are specifically designed to penetrate bacterial cell walls and lyse them
• Non-specific responses of innate immunity are necessary for the initiation of adaptive immunity:

  • Innate immunity isn't just the early immediate responses to infection, it's also the main way in which adaptive immunity is signalled
  • So once a bacterial infection is established, this will activate elements of the innate immune response, which include complement and neutrophils, and then it will also signal the adaptive immune response to recognition through cells such as macrophages and dendritic cells
• Non-specific responses of innate immunity are necessary for the initiation of adaptive immunity:

  • Macrophages activate endothelial cells, which will further encourage neutrophils to spread to the site of infection
  • Neutrophils work with complement because they're the main phagocytes in the body
  • Dendritic cells, and macrophages to a certain extent, will present antigen to T cells and then the presence of a range of cyotkines will cause a differentiation of effector T cells - these T cells form a whole range of different functions

  
• Neutrophils have a multi-lobular nucleus with lots of granules present in the cytoplasm. They are designed to ingest and digest bacteria and destroy them.

  
• The complement system is a series of serum proteins, which is held in an inactive form - only to be activated in the presence of infections. It's signalled by a number of different pathways. Once the complement system is activated, it mediates a number of different functions, including recruitment of inflammatory cells like neutrophils, the opsonisation of pathogens (coating the pathogens, allowing them to be recognised by neutrophil receptors and therefore phagocytosed), and the direct perforation of pathogen cell membranes (leading to cell lysis).

  
• The lymphocytes are the main cells of the adaptive immune response - small white blood cells with a large nucleus.

  
• The cytokine milieu and T-cell effector function:

  • Lymphocytes are regulated by the T lymphocytes
  • There's a wide range of different T lymphocytes/T cells that perform a wide range of different functions
  • The way in which T cells develop is dependent on the environment of the cytokine milieu
  • Cytokines differentiate the T cells along different pathways, and these different T cells have different functions in the immune response

  
• The cytokine milieu and T-cell effector function:

  • They're mutually regulated - so if you get an expansion of TH1 cells, it will suppress the differentiation of other types of T cells
  • Phenotypic plasticity means that these effector cells could change their function depending on the type of infection you have and its dynamics

  
• The dynamic of cellular immune responses during viral infections:

  • The innate immune response is mediated by the secretion of interferons
  • The adaptive immune response is mediated by antigen-specific T cells
  • Once you get good innate immune response and you produce interferons, this will activate the antiviral response, which includes the production of natural killer cells, which will kill infected cells

  
• The dynamic of cellular immune responses during viral infections:

  • This element of the immune response suppresses the expansion of viral infection, but it doesn't clear it - clearance can only be obtained once you've developed the antigen-specific T cell response, which will specifically target infected cells to clear the infection

  
• Once a B cell has taken up and presented antigen to a T follicular helper cell, the T cell activates B cell maturation into antibody-secreting plasma cells.

  
• • An important function of T follicular helper cells is to recognise antigen presented by B cells, and this is the first step along the way to activating the B cells themselves to develop into antibody-secreting plasma cells
  • This whole process relies on the recognition of antigen

  
• • Once T follicular helper cells recognise their specific antigen, they'll start to secrete cytokines, which will provide molecular help to B cells to differentiate into plasma cells
  • During this process there's a switching of the isotypes, so for instance IgN might turn into an IgG antibody or an IgA antibody, as befits the type of infection
  • Affinity maturation = it'll mutate at a genetic level in order to produce antibodies at the highest affinity for antigens

  
• • Another function of T cells is to activate macrophages
  • Many bacteria will invade cells such as macrophages and attempt to hide from the macrophage's digestive capability
  • This is illustrated here by Mycobacterium tuberculosis
  • TH1 cells will come along, recognise antigen presented on the surface of the macrophage
  • They'll provide help to activate the macrophages through the mediation of cytokines such as Interferon gamma
  • This will help the macrophage to digest the mycobacterium and will also help to recruit more macrophages

  
• • Vaccines provide prophylaxis against infectious diseases
  • They exploit the principle of immunological memory, whereby a second encounter with an infectious agent (vaccine) provides a more rapid and vigorous response, protecting against infection

  
• • Memory is provided by B and T cells
  • They're produced simultaneously with effector cells, such as plasma cells, during immune responses
• Memory B-cells:

  • Develop in lymph nodes after primary immune response
  • Long-lived (quiescent [they don't divide much]), high affinity, class switched Ig (immunoglobulin) - ready for the immediate neutralisation of infections
  • Circulate and are more easily activated than naïve B-cells
  • Secondary immune response is quicker, stronger and an IgG response predominates
  • Memory T-cells also produced
• Major issues in vaccine medicine:

  • Important diseases with no vaccine - like HIV and the common cold
  • Don't have data on long term vaccine effectiveness - because many vaccines are new
  • Collateral damage to immune system by viruses
  • Secondary immunodepression/dysfunction
  • Vaccine uptake - remains a major issue
  • Vaccine apathy
  • Practical issues (cost of manufacture, transport and storage)
  • Economic issues (overall cost provision of vaccine to a population)
  • Herd immunity (if it's not established then it will affect the effectiveness of vaccines)
• Major issues in vaccine medicine:

  • Most vaccines will maintain their effectiveness throughout life
  • But infection with viruses in non-immunised hosts affects the memory responses to other viruses - so if you don't get vaccinated and you suffer from the actual viral disease, it can affect your immune capability against other diseases
  • The elderly and obese are much more difficult to vaccinate
• What happens if the immune system is compromised?

  • This can directly cause many human diseases
  • E.g. an allergy, often called hypersensitivity, is an inappropriately excessive response to environmental antigens - just as an autoimmune disease is an inappropriate response to internal self antigens
  • Both responses can be very diverse in terms of their pathogenesis, but they can be divided into categories
  • Both can also lead to temporary or long-lasting tissue damage often associated with inflammation, which can lead to disease and disability

  
• Immunopathological mechanisms:

  • Inappropriate (excessive) response to certain environmental Ag (allergens) lead to immunopathology (type I hypersensitivity)
  • Acute and chronic inflammation (persistent bacterial infection - can lead to type IV hypersensitivity; also Crohn's disease a genetic disease causing a break down in tolerance of commensal bacteria)
  • Autoimmune disease (self immune reactions - defect in T-cell development, also coeliac disease - gluten intolerance)
  • Primary and secondary immunodeficiency diseases (B cell, T cell, complement)
• Immunopathological mechanisms:

  • Type I hypersensitivities (asthma, hay fever, food allergies, pet allergies, etc) are mediated by mast cells
  • Chronic infections (eg tuberculosis) have the characteristics of Type IV hypersensitivities - characterised by T cells - also seen in some allergies and autoimmune diseases
  • Immunodeficiencies can either be primary (caused by genetic defects), or secondary (caused by infections, radiotherapy or chemotherapy for cancer)
  • Secondary immunodeficiencies are quite common - primary immunodeficiencies are rare
• Immunotherapy:

  • Therapeutic monoclonal antibodies: 'biologics'
  • eg Rituximab (anti CD20) kills tumour cells in lymphoma
  • eg Infliximab (anti-TNF) blocks inflammation in rheumatoid arthritis
  • eg Impilimumab (anti-CTLA-4) blocks immunosuppression in melanoma
  • Drugs
  • eg corticosteroids (e.g. Prednisone), cytotoxics (e.g. Cyclophosphamide), T-cell immunosuppressants (e.g. Cyclosporine)
  • Adoptive cellular immunotherapy
  • eg chimeric antigen receptor expressing T-cells targeting CD19 (CART-19) therapy for acute lymphoblastic leukaemia (ALL)
• Immunotherapy:

  • Therapeutic antibodies are increasingly being used in a wide range of diseases, in particular autoimmune disease, such as arthritis and certain cancers (particularly haematological, like lymphoma or leukaemia)
  • Immunosuppressive drugs aren't just used in acute severe infections, but also to prevent transplant rejection
  • Sophisticated immunotherapies involve the use of cells tailored to the individual - it's likely these will become more available in the future