Principles Immunology

• Tc cells and NK cells can recognise virally infected cells
• Antibodies attach to and neutralise viruses on entry, and reduce risk of viral infection
• Cytokines e.g. interferons, prevent the synthesis of new viral particles and alert neighbouring cells that they need to adapt to protect themselves

Viruses can fight back by removing and hiding the viral proteins present on the infected cell surface

However, sometimes regular surface proteins e.g. MHCs can be removed

NK cells detected where there are missing MHCs, and know to attack the affected cell

• Antibodies bind to antigenic material on the worm and become activated; alerting immune cells that a parasite is present
• Eosinophils, Mast cells, and Basophils with phagocytic properties can attack
• T cells and B cells are a waste of time as the parasitic worm is too large to attack

Small proteins and peptides which modulate the behaviour of cells

• Interferons - anti-viral activity
• TNFa - a pro-inflammatory cytokine
• Chemokines - control and direct cell migration
• Interleukins - various functions

Natural Killer (NK) Cells

• Large granular lymphocytes
• Can kill tumour cells or virally infected cells which do not display normal MHC antigens
• Can also kill antibody-bound cells and pathogens

T cells

• Helper T cells = regulatory
• Cytotoxic T cells = recognise and kill virally infected body cells which display viral proteins
• Mature cells circulate through the blood, lymph and secondary lymphoid tissues

B cells

• Responsible for antibody production and secretion
• Differentiate into activated plasma cells

These cells are involved in allergic reactions and acute inflammation

They are highly granular cells which release chemical such as histamine and allow defence against larger pathogens such as parasites

Mast Cells

• Live in tissues and protect mucosal surfaces
• Found near small blood vessels, near cells exposed to the external environment

Basophils and Eosinophils

• Found in small numbers
• Circulate in the blood
• Recruited by inflammatory signals
• Proliferate in response to parasitic infection

30 different proteins which are produced in the liver, and circulate constantly as inactive precursor proteins which act in a biological cascade

• Complement proteins enzymatically cleave and therefore activate other downstream complement proteins
• Final products can attack pathogens, attract inflammatory cells or promote inflammation 
• Pathogen opsonisation = protein fragments coat pathogens to make them more attractive to phagocytes

The Alternative Pathway

• Spontaneous breakdown of C3 into C3a and C3b
• Triggered directly by C3b binding to a bacterial cell surface component

The Classic Pathway

• Antibody molecules bind to antigen
• The associated conformational change exposes binding sites on antibodies for the first protein in the cascade (C1)

Complement-mediated killing

• Complement is important in the defense against encapsulated bacteria
• C5b binds to the surface of pathogens
• C6-C9 assemble with C5b forming the 'Membrane attack complex' 
• MAC inserts into target cell walls, creating a pore
• This results in osmotic cell lysis of the pathogen

Opsonisation

• The coating of pathogens by opsonins (humoral factors) to facilitate phagocytosis
• Phagocytes express receptors for specific opsonins on their surface
• C3b and C-reactive protein are opsonins

Leukocyte Recruitment & Inflammation

• C3a and C5a  are known as anaphylatoxins which promote inflammation
• They stimulate mast cells to produce more chemokines and recruit macrophages etc.
• They also increase the permeability of blood vessels

The phagocytic 'eating' cells - these cells ingest and kill bacteria and fungi via. phagocytosis

They also ingest and clear debris e.g. apoptotic cells, antigen-antibody complexes

Monocytes

• Circulate in the blood
• Migrate into peripheral tissues and differentiate into macrophages

Macrophages

• Long-lived tissue resident phagocytes
• Secrete inflammatory cytokines
• Can be an antigen-presenting cell

Neutrophils

• Polymorphonuclear cells - often have a bi/tri nucleus
• Rapidly recruited into inflamed, damaged and infected tissues

Antigen-presenting cells

These cells look like neurons - with branching dendrites

They have different names in different tissues

• Present in peripheral tissues in an 'immature' state
• They phagocytose antigens
• Mature and migrate into secondary lymphoid tissues where they act as APCs to T cells

The Innate Immune System

• Acute inflammatory response which slows down infection, but cannot fully eliminate infection
• Rapid response as long as pathogen is present
• Same general biological response no matter what the pathogen is (non-specific)
• Involves macrophages, mast cells, NK cells, neutrophils, complement

Dendritic cells act as a bridge between the two branches of the immune system - APCs to T cells

The Adaptive Immune System

• Totally eliminates pathogen from the body
• A specific response, which can take days to occur
• Responsible for the generation of immunological memory
  
• Involves B cells, antibodies, T cells

Receptor : Ligand Interactions

Immune cells express particular receptors for particular ligands on pathogens/other immune cells

If they interact correctly, a signal will be sent into the immune cell, activating it and altering its physiology

E.g. MHC : TCR (T cell receptor)

Cytokines

Injured tissue and activated immune cells can secrete cytokines

Interferons are produced by virally infected host cells - induce an antiviral environment in local area, preventing replication if neighbouring cells are infected.

IFN-gamma

• Enhances the production of toxic chemicals - reactive oxygen and nitrile species (ROS &RNS)
• Increases antimicrobial and anti-tumor activity of macrophages
• Determines cytokine production of macrophages

Inflammatory Mediators

• Results in vascular changes
• Recruitment and activation of neutrophils, which interact with the endothelium
• Neutrophils can then move through gap junctions

TNF-alpha

• Released by macrophages and mast cells
• Causes interaction to be lost between proteins and gap junctions of endothelial cells
• Increases permeability

In acute inflammation, inflammatory mediators such as TNF-alpha and histamine cause vasodilatation and increased vascular permeability

• At sites of inflammation, endothelial cells are activated and express endothelial adhesion receptors (selectins) and ligands (ICAM/VCAM)
• Proinflammatory cytokines induce the production of these selectins
• Receptors correspond to carbohydrate molecules on neutrophils
• Chemokines released from macrophages guide neutrophils to the adhesion site
• Neutrophils can bind weakly to selectins on the endothelium, and roll along the surface
• Via its integrins, neutrophils attach firmly to ICAM-1 and VCAM-1 and remain stationary on the endothelial cell layer
• The neutrophil then can squeeze between endothelial cells, following the chemokine gradient

Phagocytosis

• Pathogens release chemokine-like signals that attract neutrophils
• Neutrophils use PRRs to bind to and phagocytose these pathogens
• Neutrophils release anti-microbial proteins and NADPH oxidase which result in the production of toxic ROS (reactive oxygen species) into the phagolysosome

Degranulation

• Anti-bacterial proteins from granules directly enter the extracellular matrix
• Residual enzymes are released which along with killing pathogens can cause tissue damage and systemic inflammation

Neutrophil Extracellular Traps

• Enhance phagocytosis and prevent the spread of infection
• Activated neutrophils release NETs into the extracellular environment
• NETs immobilize pathogens by preventing them from spreading, and facilitate their phagocytosis

PAMPs

• There are limited numbers of PAMPs, common to many different pathogens
• Therefore, our immune system doesn't need many receptors to respond to a range of pathogens

Antigens

• There are millions of different antigens, however, and each is unique to an individual pathogenic species
• Individual T cells can only recognise one specific antigenic epitope

T-cell Antigen Receptor

• Membrane- bound protein heterodimer with and alpha and beta chain
• Antigen binds to tips of the receptor - hypervariable loops unique to each T cell

B-cell Receptor

• Membrane-bound antibody with light and heavy chains

• Two heavy Ig chains; two light Ig chains
• The chains are held together by disulphide bonds
• The light and heavy chains both have a variable region and a constant region
• Different classes of antibody have different heavy chains
• Heavy and light chains bind together to form a structure onto which antigen can attach
• Hypervariable regions form the antigen binding site

Antibody heavy and light chain proteins are encoded for by segmented genes in germline genome of haematopoietic stem cells

Random rearrangement of these genes occurs in individual B cells as they develop

This allows a huge array of different antigenic receptors to be made from a small gene

Mature dendritic cells migrate to secondary lymphoid tissues where they take phagocytosed antigens and present them to T cells

Small peptides of antigenic proteins in combination with MHC are displayed on the surface of the dendritic cell

1. Particles and antigens from pathogens are released at infected tissue sites

2. TNF-alpha stimulates dendritic cells to phagocytose the antigens, and express co-stimulatory molecule B7

3. Dendritic cells digest pathogen-derived proteins and display small peptides in complex with MHC protein

4. They then travel to local draining lymph nodes and to secondary lymphoid tissues

T cells can only recognise peptide antigen presented to their receptors by MHC molecules

Class I MHC

• Expressed on all nucleated cells (not RBCs)
• Present peptide antigens to CD8+ T cells

Class II MHC

• Expreesed only on professional antigen-presenting cells e.g. dendritic cells
• Present peptide antigens to CD4+ T cells

T cell activation requires 2 signals:

• Peptide antigen + MHC Class I
• B7 molecule on dendritic cells

If the two signals are received, this results in:

• Clonal Expansion - rapid cell division, as a single cell on its own is not enough to fight a replicating pathogen
• Differentation - into effector cells (killing cells) and into memory cells, which stay in the body in case the pathogen is encountered again