How the body fights infectious disease

Reaction to Foreign Material

Antigen

• Usually a protein (but polysaccharides, nucleic acid and lipids also act as antigens)
• Self-antigen
  • Only found on the host's own cells and does not trigger an immune response
  • As these are proteins, their structure depends on the amino acid sequence
  • The gene for this sequence is highly polymorphic, having several alleles at each loci
  • There is great genetic variability between individuals
  • Thus, antigen is different in other people → injection would cause an immune response
  • There is only 25% chance that siblings will possess an identical antigen (transplant will not be rejected)
• Non-self-antigen
  • Found on cells entering the body (e.g. bacteria, viruses, another person's cell)
  • Can also be displayed by cancer cells
  • May cause an immune response

Antibody (Immunoglobin Protein)

• Secreted by B-lymphocytes and produced in response to a specific (foreign) non-self antigen
• B-lymphocyte's receptor site matches the non-self-antigen
• Each antibody is produced by one type of B-lymphocyte for only one type of antigen
• Has a Y-shape
  • The two ends of the Y are called the Fab fragments
  • The other end is called the Fc fragment
  • Fab fragments are responsible for the antigen-binding properties
  • Fc fragment triggers the immune response
• B cells divide and form memory cells and antibody-secreting plasma cells
• Glossary
  • Agglutination makes pathogens clump together
  • Antitoxins neutralise toxins produced by bacteria
  • Lysis digests bacterial membrane, killing the bacterium (phagocytosis)
  • Opsonisation coats pathogen in protein that identifies them as foreign cells

Phagocytosis

• White cells (phagocytes) contain digestive enzymes within lysosomes
  • Neutrophils primarily engulf bacteria
  • Macrophages engulf larger particles; including old and infected red blood cells
• Found in blood, lymph systems and tissues
  • Squeeze through gaps in the walls of venules to enter tissues
  • This allows them to move faster to tissues infected with pathogens
• Mechanism
  • Phagocytes are attracted by chemotaxis
  • Opsonisation by antibodies
    • Bacteria becomes coated with antibody
    • As a result, binding between bacteria and phagocytes is improved
  • Phagocytes form pseudopodia around the particle
  • This positions the particle into a phagocytic vacuole (also called phagosome)
  • Lysosome fuses with the phagosome
  • Intracellular killing by digestive enzymes from the lysosome
  • Pus is formed at the site of infection if no extensive vasculature is present

Types of Immune Response

• Lymphocytes undergo maturating before birth, producing different types of lymphocytes
• Humoral response - B lymphocytes
  • Produce and release antibodies into blood plasma
  • Produce antibodies from B plasma cells
  • Direct recognition of foreign antigen
• Cellular response - T lymphocytes
  • Bind to antigen carrying cells and destroy them and/or activate the humoral response
  • Recognize foreign antigens displayed on the surface of normal body cells
• Primary response produces memory cells which remain in the circulation
• Secondary response new invasion by same antigen at a lower state. Immediate recognition and distraction by memory cells - faster and larger response usually prevents harm

B-Lymphocytes: Humoral Response

• Production of antibodies in response to antigens found on pathogens not entering cells (bacteria)
• Each B-lymphocyte (B cell) recognizes one specific antigen
• Primary response
  • Antigen binds to specific Fab fragment of B cell
    • This produces a short and weak response
    • T helper cells are required to trigger the true potential of B cells
  • Once activated, the B cell grow and produce many clone cells
  • Clone cells have the same Fab fragment that recognizes the same antigen
  • Most differentiate into plasma cells
    • Secrete large amounts of antibodies
    • Bind to antigens and mark them for destruction
  • Some differentiate into memory cells
• Secondary response
  • Exposure of same antigen causes activation of memory cells
  • They immediately recognize the antigen
  • Antibodies are produced more rapidly and in larger amounts

T-Lymphocytes: Cell-Mediated Response

• Pathogens that quickly enter cells are more difficult to remove (viruses, tuberculosis)
• Infected cell is directly destroyed / no antibodies involved
• This is done by binding to the self and non-self antigen
  • Prevents destruction of harmless cells
  • Self antigen is a MHC (Major Histocompability Complex) protein present on almost all body cells
  • Non-self antigen (from viruses, bacterium, cancer, foreign cell, parasite) is processed and displayed on the surface of the infected cell
• Primary response
  • Macrophage
    • Engulfs the pathogen and processes its foreign antigen
    • Non-self antigen is transported to the plasma membrane surface of the macrophage
    • Now called an antigen presenting cell (APC)
  • T Helper cells (Th cells)
    • Recognize foreign antigen on APC
    • Activates cytotoxic T cells and B cells to destroy the infected cell
  • T killer cells (cytotoxic T cells)
    • Must recognize self and non-self antigen to attach to infected cell
    • Directly kill pathogen by injecting proteases into the infected cell
    • Detach to search for more foreign cells
  • T-Suppressor cells switch off the T and B cell responses when infection clears
• Secondary response
  • Some T cells differentiate into T-memory cells
  • Remain in the circulation and respond quickly when same pathogen enters body again
• HIV destroys T-helper cells
  • Other immune cells are not activated
  • Humoral response cannot be launched without Th cells / require co-stimulation of Th cells
  • No immune response in patients with AIDS

Immunity and Vaccines

• Vaccination is an artificial active immunity
• Types
  • Live attenuated: organism is alive but has been modified/weakened so that it is not harmful
    • MMR (measles, mumps, rubella) - vaccine does NOT cause autism!
    • BCG for tuberculosis
  • Inactivated: dead pathogen but antigen is still recognised and an immune response triggered
    • Pertussis (whooping cough)
    • Poliomyelitis
  • Toxoid: vaccine contains a toxin
    • Diphtheria
    • Tetanus
  • Subunit: contains purified antigen that is genetically engineered rather than whole organism
    • Haemophilus influenza b - causes epiglottitis, meningitis
    • Meningococcal C - causes serious septicaemia, meningitis
    • Pneumoccocal - causes meningitis which results in permanent disabilities in >30%!
• Vaccine may cause swelling, mild fever, and malaise
• NEVER give live vaccines to children with an impaired immune system!
• NEVER give vaccines if a child is ill (has a fever)

Monoclonal Antibodies (Magic Bullets)

• Hybridoma
  • B cells are fused with tumour cells in the lab
  • Divide rapidly to form a clone of identical cells
  • Specific monoclonal antibodies are continuously produced and useful as
    • Tumour markers (antigens not present on non-cancer cells / attach to cancer cells only)
    • Anti-cancer drugs attached to monoclonal antibodies - deliver drug directly to cancer cells, fewer side effects
•  Uses of monoclonal antibodies
  • Monoclonal antibody is an antibody that is of just one type
  • Used to target the treatment of cancer cells or to screen (AIDS) in contaminated blood
  • Antibody direct enzyme prodrug therapy techniques (ADEPT)
    • Monoclonal antibodies are tagged with an enzyme that converts the prodrug (inactive drug) to an active form that kills cells (i.e. is cytotoxic)
    • The prodrug is injected in high conc
    • Attached to a monoclonal antibody, enzyme activates the drug and kills only cancer cells
  • In immunoassays, they can be labelled (radioactively) making them easy to detect
  • In the enzyme-linked immunosorbant assay (ELISA) technique, they are immobilised on an inert base and a test solution is passed over them
    • Target antigen combines with immobilised monoclonal antibodies
    • Second antibody attaches with an enzyme and binds to the monoclonal antibodies
    • and to the target antigen as well
    • Substrate is added which is converted to a coloured product by the added enzyme
    • Conc. of colour tells us the amount of antigens present in the test solution
  • Used to detect drugs in urine of athletics or in home pregnancy tests (where an antigen in human chorionic gonadotrophin (hCG) is secreted by the placenta)
  • Transplanted organs have non-self-antigens triggering antibodies to attack the organ, leading to its rejecting
    • T-Lymphocytes are needed for B-lymphocytes to function
    • Monoclonal antibodies against T-lymphocytes can be used to prevent B-lymphocytes from functioning, thus blocking the rejection of transplanted organs
  • [EXAM] Helping to diagnose between two pathogens because
    • Antigens are on cell-surface membrane
    • Monoclonal antibody reacts with specific antigen only
    • Thus, detects presence of special bacteria because of a different antigen on another, different bacteria