Immune System Flashcards
What is the immune system?
A complex network of cells and soluble molecules which interact with one another to remove foreign material from the body. Includes bacteria, viruses, parasites and other infection-causing pathogens, as well as some cancer cells.
Extremely effect in performing its function but error can occur in this highly complex system, which results in allergic reaction, immunopathology or autoimmunity.
Name 4 importances of the immune system.
- Immune system plays an important role in inflammation and immunity.
- Immune system failure can cause severe disease, such as primary immune deficiencies and immunodeficiency viruses.
- Many diseases or symptoms are caused by the immune system: allergy, autoimmunity and immunopathology.
- Understanding how to harness the power of the immune system can be extremely beneficial to vaccination and immunotherapy for example.
Use feline influenza virus as an example of when the immune system fails to control disease.
- FIV is characterised by a decline of CD4 T-cells
- T-cell immunodeficiency results in symptoms
- CD8 T-cells control viral load during chronic phase
- This control does not last forever
- CD8 T-cells get exhausted
- Virus escapes from the CD8 T-cell response
- Highlights the importance of T-cell immunity
Define immunopathology.
Tissue damage caused by an excessive immune response.
Define autoimmunity.
The failure to distinguish self from non-self.
Define allergy.
Inappropriate response to an environmental antigen.
What is the aim of vaccination?
Vaccination aims to establish immunological memory.
- Primary immune response
- On exposure to the pathogen, secondary immune response because the immune system has immunological memory to get a rapid and robust response.
Where do all cells in the immune system arise from?
Pluripotent haematopoietic stem cell from bone marrow.
Name the cells that these stem cells give rise to.
- Common lymphoid progenitor cells
- Common myeloid progenitor cells
What do common lymphoid progenitor cells give rise to?
- B cells – when activated, they differentiate into plasma B cells, which produce antibodies.
- T cells – activate to become activated T cells
- NK cells – natural killer cells, important for viral infection control
What do common myeloid progenitor cells give rise to?
Granulocyte/macrophage progenitor cells and megakaryocyte/erythrocyte progenitor cells
What do megakaryocyte/erythrocyte progenitor cells give rise to?
Platelets and red blood cells
What do granulocyte/macrophage progenitor cells give rise to?
- Neutrophils
- Eosinophils
- Basophils
- Unknown precursor of mast cell and monocytes, which differentiate to form macrophages
What do dendritic cells do?
Forms a link between the innate and adaptive immune system
What are the cellular components of innate immunity?
Phagocytes
Macrophages/monocytes
Neutrophils
Eosinophils
Basophils
Mast cells
Natural killer cells
What are the characteristics of innate immunity?
- Recognition of the nature of the challenge, for example, recognition is non-specific
- No memory of the challenge, as the second encounter triggers the same response
- Barriers to infection
- Soluble factors involved in immune response
What is the function of innate immunity at best and worst?
At best: can eradicate infection
At worst: slows down/delays infection until adaptive immune response is generated
Name and describe 5 barriers.
- Skin – physical barrier, chemical barrier (sweat) and microbial barrier (commensals)
- Respiratory tract – patrolled by alveolar macrophages and mucociliary escalator
- Alimentary tract – physical barrier (peristalsis) and chemical barrier (stomach acid)
- Urinary tract – low pH of urine and flushing
- Corea/conjunctiva – blinking and antibodies in tears
Name and give the function of the cells of the innate immune system.
- Macrophages – kill intracellular pathogens
- Sentinel cells – raise alarm following infection
- Neutrophils – kill rapidly dividing bacteria
- Eosinophils – kill parasites
- NK cells – kill virus infected cells
- Mast cells – trigger inflammatory response
- Dendritic cells – activate adaptive immune response
What are the 3 functions of the soluble factors of the innate immune system?
- Complement – coats/opsonises pathogens with layer of molecules that cells of the innate immune system have receptors for/complement receptors.
- Acute phase – similar to complement proteins. Also activates complement system.
- Interferons – activate cells to produce anti-viral proteins
Which cells are capable of phagocytosis?
Mononucleated leukocytes are capable of phagocytosis: monocytes and macrophages
Polymorphonucleated leukocytes are also capable of phagocytosis: neutrophils, basophils and eosinophils
Give a brief overview of phagocytosis.
- Chemotaxis
- Adherence
- Membrane activation
- Initiation of phagocytosis
- Phagosome formation
- Fusion
- Killing and digestion
- Release of degradation products
Define antigen.
A substance which binds to a lymphocyte receptor and in so doing may initiate an immune response.
Name the 4 types of antigen.
Heteroantigens
Autoantigens
Alloantigens
Xenoantigens
What are heteroantigens?
Foreign to the body: infectious agents, environmental substances and chemicals like drugs
What are autoantigens?
Also called self-antigens, recognition triggers autoimmunity
What are alloantigens?
Cells from same species but genetically different
What are xenoantigens?
Cells from a different species. Particular interest for transplantation field.
Describe the concept of epitopes and immunodominance.
Antigenic epitope (determinant) – one antigen may have multiple epitopes, some of which may be immunodominant – majority of immune response is targeted at a certain set of epitopes.
What is a hapten?
A small chemical group, which when chemically conjugated to a large molecules (carrier protein) will alter its specificity creating a new epitope. A hapten cannot by itself stimulate antibody production, but can combine with antibody once linked to a carrier protein.
What is the clinical relevance of haptens?
Cutaneous drug eruption: drug (ketoconazole) binds to a dermal protein which stimulates an Immune response.
What is an adjuvant?
A substance which, when combined with antigen, non-specifically enhances the immune response. May also have a depot effect allowing slow release of antigen.
Describe the structure of an immunoglobulin.
2 heavy and 2 light chains, bound by disulphide bridges.
At the end of each, there are domains labelled V, meaning variable. Variability is all located at ends, as this determines which antigen the molecule will bind to. Letter C means constant, domains which are the same across molecules.
How are immunoglobulins classed?
By the heavy chain:
- Gamma = IgG
- Mu = IgM
- Alpha = IgA
- Delta = IgD
- Epsilon = IgE
Each with a kappa or lambda light chain.
Define valence.
Number of antigens an antibody can bind to
What is the structure of IgG?
Single Y shaped unit, gamma heavy chain, valance 2, subclasses exist
Where is IgG found?
Main serum Ig, for example, found in the blood. Diffuses easily to extravascular tissue.
What are the functions of IgG?
- Fixes complement
- Opsonin
- Neutralise toxins, such as bacterial toxins
- Main Ig in secondary immune response
What is opsonin?
Enhancing phagocytosis.
What is the structure of IgM?
- 5 Y shaped units
- Valence 10
- Mu heavy chain
- Extra heavy chain domain (CH4)
- J chain
Where can IgM be found?
Intravascular, stays in the blood due to large size
What are the functions of IgM?
- Agglutinates particulate antigen
- Fixes complement
- Main Ig in early immune response
- Important in bacteraemia
What is the structure of IgA?
- Valence 4
- Monomer or dimer in serum (species dependent)
- Dimer in mucosal secretions (all species)
- Alpha heavy chain
- Dimer linked by J chain
- Subclasses exist
What are the functions of IgA?
- Dimer at mucosal surfaces has secretory piece – provides protection from enzymatic degradation
- Mucosal immune defence
- Inhibits microbial attachment
- Neutralises toxin
- Weak opsonin
What is the structure and location of IgD?
- 1 Y shaped unit
- Valance 2
- Delta heavy chain
- Found only on surface of immature B lymphocytes
What is the structure of IgE?
- 1 unit, valence 2
- Epsilon heavy chain
- Extra domain CH4
Where is IgE found?
- Low level in serum
- More in animals than man
- Most bound to tissue mast cells or blood basophils
What are the functions of IgE?
- Involved in parasite rejection
- Involved in allergy
How do antigens and antibodies interact?
The antigenic epitope slots into a groove formed between the hypervariable regions of the heavy and light chains. Specific attachment – lock and key.
Firm attachment – electrostatic forces, hydrogen bonds, hydrophobic forces and van der waal’s forces. Affinity – binding strength of antibody for its epitope.
Distinguish primary and secondary lymphoid tissue.
Primary – where the immune system develops.
Secondary – site of immune responses.
Name the 4 primary lymphoid tissues.
Bone marrow
Ileal peyers patch
Thymus
Bursa of fabricius in birds
Describe the role of bone marrow in the immune system.
- Stem call – pluripotent
- Origin of T and B lymphocytes
- Site of maturation of B lymphocytes before export to secondary lymphoid tissues in humans, rabbits and rodents
- Site of some B cell differentiation to plasma cells for antibody production in the humoral response
Describe the role of ileal peyers patch in the immune system.
- Site of B cell maturation in most animal species
- Found in the small intestine, domes without villi
- Secondary follicle with germinal centres are where T cells are
Describe the role of bursa of fabricius in the immune system.
- Site of B cell maturation in birds
- Lymphoepithelial organ near cloaca
Bursectomised chicks cannot make humoral immune response/cannot make antibodies
Describe the role of the thymus in the immune response.
Anterior mediastinum in front of the heart. Involutes with age. Thymectomised or congenitally athymic (‘nude’) animals cannot mount cell-mediated immune responses.
- Site of extramedullary T cell development – takes place outside bone marrow.
- Cells generate cell mediated immunity.
- Humans, rabbits and rodents have B cell maturation before circulation.
- T cells arise in bone marrow and in all species migrate to thymus to complete maturation and then are circulated.
What are the 2 types of secondary lymphoid tissue?
Encapsulated – spleen and lymph nodes
Unencapsulated – mucosal lymphoid aggregates
Describe the structure of a lymph node.
- Encapsulated so has a capsule and then a subcapsular sinus below.
- Afferent lymphatics is where immune cells arrive at lymph nodes.
- Lymph nodes contain immune cells that perforate through the cell and exit via the efferent lymphatics.
- B and T cells sit in cortex.
- Primary follicles contain B cells that are inactive that are activated on immune response.
- Paracortex is where T cells are between follicles.
Describe the structure of the spleen.
Encapsulated: trabecula skeleton creates framework and there are areas of red pulp in between containing red blood cells, and areas of whit pulp where lymphocytes/B cells are. PALS, per-arteriolar lymphoid sheath is where T cells are found.
Describe secondary unencapsulated lymphoid tissue (MALT) and where they are located.
Secondary unencapsulated lymphoid tissue MALT – at the mucosal surfaces which are in contact with the environment.
- Gastrointestinal (GALT)
- Bronchial (BALT)
- Nasal (NALT)
- Conjunctival (CALT)
Describe the morphology of small lymphocytes (T and B cells).
- Virgin or memory (inactive)
- Little cytoplasm (large nucleus)
- Few organelles
- Condensed chromatin
Describe lymphoblast (T and B cells) morphology.
- Stimulated by antigen
- More cytoplasm
- More organelles
- Less condensed chromatin
Describe plasma cell/late stage B cell morphology.
- More endoplasmic reticulum
- Clock face chromatin
- Antibody production and secretion
How can B and T cells be distinguished?
- Anatomical location
- Function
- Expression of surface molecules unique to each population
What is the process of immunofluorescence?
Expression of these molecules by individual cells in suspension or tissue can be determined using antibodies specific for the molecule of interest which are conjugated to a fluorochrome.
Describe the process of immunofluorescence.
- Antibody to SmIg conjugated to fluorochrome.
- Added to unknown lymphocytes.
- Antiserum labels SmIg in binding.
- Expose to UV light to excite the fluorochrome.
- Examine microscopically or count with a flow cytometer.
What are flow cytometers used for?
Used both clinically in labs and by immunologists in research labs:
- Can take a single sample, stain antibodies, and begin looking at different immune cells and analyse their phenotypes.
- Enables simultaneous measurement of up to 50 different characteristics of a single cell.
- Identification and analysis of distinctive phenotypes in heterogenous populations.
Why do lymphocytes recirculate?
Lymphocytes recirculate to maximise the chance of contact between an antigen and the appropriate responding populations of lymphocytes.
Give the path of lymphocyte recirculation.
- Tissue
- Afferent lymphatics
- Lymph nodes
- Efferent lymphatics
- Thoracic duct
- Bloodstream
- Can exit into required areas and tissues via HEVs (high endothelial venules)
What is lymphocyte homing?
Interaction between vascular addressins and homing receptors in the HEVs triggers diapedesis and turbulence, which increases the chance of interactions. Located in areas where lymphocytes exit tissues.
Give an example of specialised recirculation.
The common mucosal system: cells activated in response to an event at 1 mucosal surface can home to other mucosal surfaces.
What is the importance of the common mucosal system?
Generation of colostral antibody
Define complement.
A series of plasma proteins (around 30) which when activated, interact sequentially forming a self-assembling enzymatic cascade generating biologically active molecules mediating a range of end processes.
What are the distinct phases of the complement system which result in the elimination of microbes?
- Pattern recognition
- Protease (enzymatic) cascade amplification and C3 and C5 convertase production
- Inflammation
- Enhanced phagocytosis/opsonisation
- Membrane attack – lysis of microbial membranes
What happens once a complement pathway is triggered?
Once triggered, pathways get enzymatic cascades, each with different components of the cascade and all 3 result in the production of C3 convertase and C5 convertase.
What does the classical complement pathway involve?
Triggered by complexes between antigens and antibodies. For classical pathway, must have already had an immune response to produce antibodies. Antigen antibody complexes on the surfaces of pathogens.
Outline the process of the classical complement pathway.
- Triggered by antigen-antibody complexes on a pathogen surface. Antibodies specific to antigen from previous immune response.
- Binding of the first component, C1, which binds to part of the antibody at the CH2 region for complement fixation.
- C1 is made up of several units and there is sequential activation of each component.
- Active C1s component acts on the 2nd component, C4, causing C4 to split into 2 parts, a and b.
- C4b becomes attached to bacterial surface and C4a stays in the serum.
- C1s also acts on 3rd component, C2, which splits C2 into 2 parts, a and b.
- C4b and C2a attach to each other on the pathogen surface and together they form the C3 convertase.
- C3 convertase acts on C3, casing C3 to split into 2 components, a and b.
- C3a stays in the serum and C3b goes to the pathogen surface.
- C4b, C2a and C3b attach together on the pathogen surface and together form the C5 convertase.
What does the MB-lectin complement pathway involve?
- Mannose-binding lectin binds mannose on pathogen surface
- MBL, MASP-1, MASP-2, C4, C2
- C3 convertase
What does the alternative complement pathway involve?
- Triggered by pathway surfaces
- C3, B, D
- C3 convertase
What are the functions of C3a and C5a?
Peptide mediators of inflammation and phagocyte recruitment.
What are the functions of C3b?
Binds to complement receptors on phagocyte for opsonisation of pathogens and removal of immune complexes.
Name the terminal complement components and their function.
C5b
C6
C7
C8
C9
Membrane attack complex and lysis of certain pathogens and cells.
What is the terminal pathway?
Where C5 convertase breaks down C5 and results in the membrane attack complex, which causes lysis of pathogens (occasionally cells).
What are the consequences of complement activation?
Inflammation – due to the generation of bioactive substances, such as anaphylatoxins and chemoattractants.
Removal of particulate antigens and immune complexes – enhanced phagocytosis.
Cytolysis
How do C3a and C5a cause inflammation?
- Smooth muscle contraction
- Mast cell degradation
- Vasodilation, local oedema, local influx of antibody and complement, cell extravasation
- Neutrophil activation
- Attracted to chemotactic gradient
What 3 ways is phagocytosis enhanced?
- Phagocytosis by non-specific adherence - IgM increases agglutinates particulate antigens and so there is a greater chance of interaction.
- Opsonisation - specific binding between phagocyte receptors and pathogen antigens, as they are complementary. Complement involves as well further opsonisation.
- Removal of immune complexes - antigen coated in C3b attached to red blood cell as they have receptors and circulate around in the blood attached. When supplying liver or spleen, antigens are removed.
What is cytolysis?
- C5 split into C5a and C5b
- C5b starts to sequentially assemble itself with final components of complement pathway, C6, 7, 8 and 9. Forms circular structure.
- Circular structures are inserted into pathogen membranes and causes influxes of water and osmotic lysis.
How is the complement cascade controlled?
Normal cells have membrane proteins which breakdown C3 convertase. This protects normal cells. For example. DAF, decay-accelerating factor.
CD59 expressed widely on membranes and prevents formation of the MAC on normal cells.
What are the consequences of a C3 deficiency?
Causes susceptibility to bacterial infections and get symptoms from prolonged immune response. High temperatures and recurrent infections could be signs.
What is the concept of a complotype?
An individual might have multiple polymorphisms that causes susceptibility to certain infectious diseases.
Why are T cells important?
- Control/eliminate infection
- Immunity and response to vaccination
- Kill cancerous cells
- Disease pathogenesis – transplant rejection, autoimmune disease, leukaemia/lymphoma
- Therapeutic applications – cellular therapy against cancer
What are the different functional classes of T cells
CD8+ T cells – killer T cells
CD4+ T cells / TH / T helper cells
- TH1
- TH2
- TH17
- TFH (follicular helper)
CD4+ T regulatory cells – rather than stimulate an immune response, they dampen immune responses. In theory, could be used to treat autoimmune diseases.
What do T cells recognise?
T cells cannot recognise complex or whole antigens. T cells recognise small peptide fragments bound to Major Histocompatibility Complex molecules which are expressed at the cell surface
What is the role of Major Histocompatibility Complexes?
T cells express T cell receptors which are responsible for recognising cell surface peptide MHC. Therefore to trigger a T cell response, complex antigens must first be converted into a user friendly form.
Define antigen processing and presentation.
Refers to the generation of small peptide fragments which are bound to major histocompatibility complexes and transported to the cell surface.
- Antigen uptake
- Antigen processing
- Antigen presenting at the cell surface
Describe the class I MHC processing pathway.
CD8+ T cells see T cell epitopes presented by class I MHC, found on most nucleated cells:
- Antigens found in the cytoplasm, viral, self or tumour, are referred to as endogenous or cytosolic antigens.
- Endogenous (cytosolic) antigens are processed and presented with MHC class I molecules
- Presented peptide fragments are usually 8-14 amino acids in length.
What is the role of MHC class I in viral protein synthesis?
- Peptide fragments of viral proteins are transported into the endoplasmic reticulum
- Peptide fragments are bound by MHC class I and delivered to the cell surface
What are the important components of MHC class I processing pathway?
- The proteasome generates peptide fragments from cytosolic protein. During an immune response induced by interferon, modifications to the proteasome mean that it produces peptides that bind well to MHC class I.
- TAP, Transporter associated with antigen processing, delivers peptides to the endoplasmic reticulum.
Where are MHC class II found?
CD4+ helper T cells see T cell epitopes presented by class II MHC.
MHC class II is found on antigen presenting cells: dendritic cells, macrophages, B cells.
Describe the MHC class II processing pathway.
- Antigens taken up from outside the APC, extracellular pathogens and toxins, are referred to as exogenous antigen.
- Exogenous antigens are processed and presented by MHC class II at the cell surface.
- MHC class II molecules are found on specialised antigen presenting cells – dendritic cells, macrophages, B lymphocytes.
- Presented peptide fragments are usually 15-24 amino acids in length.
What are the professional antigen presenting cells that express MHC class II?
Dendritic cells – several different types
Macrophages
B-cells
What are non-professional antigen presenting cells?
A range of cells hat can be induced to express MHC class II and present antigen when exposed to IFN-gamma.
What are the functions of dendritic cells?
- Activate naïve T cells, highly potent APCs
- Large surface area to increase efficiency of antigen uptake
- Widespread distribution – most epithelia and solid organs, such as the heart and kidneys
- Phagocytosis – actively ingest antigens using complement receptors and Fc receptors
- Micropinocytosis – engulf large amounts of surrounding fluid non-specifically.
- Use pattern recognition receptors to recognise pathogen.
How do dendritic cells activate naive T cells?
- Dendritic cells take up microbial antigens and become activated in peripheral tissues.
- Activated dendritic cells travel to the lymph nodes.
- At the lymph nodes, the dendritic cells become mature and activate T cells.
- CD maturation involves increased expression of MHC molecules, express co-stimulatory molecules and secrete cytokines. All 3 endow dendritic cells with a potent ability to activate naïve T cells.
What are pattern recognition receptors?
- Recognise highly conserved microbial components referred to as pathogen associated molecular patterns or associated molecules patterns.
- Sugars, proteins, lipids, nucleic acid motifs
- Not easily altered by microbes to avoid detection
What are cytokines?
Soluble factors released by one cell that bind to specific receptors on the same cell or another cell leading to altered function. Important roles in all aspects of the immune response.
What are the properties of cytokines?
- Produced by many cell, and 1 cell can make many cytokines
- Low MW proteins
- Produced locally and transiently
- Potent at picomolar concentrations
- Have specific receptors
- Binding alters target cell function
- May have multiple actions
What are the 4 different roles cytokines can have in the immune system?
- Haemopoietic, for example GM-CSF
- Regulatory, for example IL-10
- Cytotoxic, for example IFN
- Autocrine, for example IL-2
Define a chemokine.
Chemotactic recruitment of cells from blood into tissue.
Describe feline mammary carcinoma as an example of an antigen processing defect.
- Defects in antigen processing are common in human tumours
- Feline mammary carcinomas – reduced expression of MHC class I HC and proteosome components (LMP2 and LMP7) compared to normal mammary tissue.
- May cause defective processing of some tumour antigens
Describe viruses that produce UL49.5 proteins as an example of an antigen processing defect.
- Bovine herpesvirus 1 (BoHV-1), pseudorabies virus and equid herpesviruses 1 and 4 encode a UL49.5 protein that inhibits TAP mediated peptide transport.
- This impairs peptide loading of MHC class I molecules and represents an immune evasion mechanism.
What is MHC restriction?
Only activate at the right combination.
What features of the MHC make life hard for pathogens?
- Polygenic: contains several different copies MHCI and MHCII genes and all these genes are expressed at the same time.
- Polymorphic: multiple variants (alleles) of each gene in the population
- Every individual expresses a number of different MHC antigens. The specific set of MHC expressed by an individual is referred to as “tissue type”. Each set of MHC will be capable of presenting a different range of peptides
What are the clinical implications of MHC?
- Viral infection that affects a group of animals with different tissue types
- Impact on being able to find transplant donors
Describe the inheritance of MHC.
- Every individual has two sets of MHC alleles called an “MHC Haplotype”
- MHC gene expression is co-dominant
- Greater diversity is possible with MHCII genes as different α and β chains may pair together to give distinct MHCII products
- Fundamentally Mendelian - 1/4 chance of a sibling being a matched donor
Distinguish the human and chicken MHC.
- Chicken MHC is 1/20th of the size of the human MHC at only 19 genes
- Chicken MHC has only a single classical class I and class II molecule expressed at high level
- Single dominantly expressed MHCI and MHCII molecules confer resistance or susceptibility to particular pathogens (leading to strong genetic associations with infectious disease)
- Chickens may live or die according to their dominantly expressed class I molecule
Name the 3 significances of MHC to veterinary medicine.
- Graft Rejection
- Associated with disease susceptibility, such as increasing the risk of developing a disease, especially autoimmune disease.
- Association with disease resistance and production traits in livestock.
Name 4 types of graft.
- Autografts: same individual
- Isograft: genetically identical
- Xenograft: different species (pigs)
- Allograft: same species, different genetic constitution (most common)
What is alloreactivity?
- Alloreactivity is the recognition of peptides complexed with non-self MHC
- It is estimated that 1 – 10% of all T-cells have the potential to be alloreactive which is why graft rejection can be so destructive.
- Graft rejection may be acute (days to weeks) or chronic (months to years)
List canine diseases with clear MHC associations.
Canine rheumatoid arthritis
Immune-mediated haemolytic anaemia (IMHA)
Diabetes mellitus
Lymphocytic thyroiditis
Addison’s disease
Chronic hepatitis in Dobermans
Necrotizing meningoencephalitis
Anal furunculosis
Chronic superficial keratitis
Susceptibility to leishmaniosis.
Define an anti-inflammatory reaction.
Biological response to harmful stimuli aimed at removing that stimuli and promoting healing. Should be a local response.
Give 4 examples of when anti-inflammatory responses go wrong.
- Type 1 reactions/anaphylaxis, such as vaccination reactions
- Airway disorder, such as feline asthma or recurrent airway obstruction in horses
- Autoimmune haemolytic anaemia in dogs
- Sweet itch in horses
What are the main anti-inflammatory vascular responses?
Vasodilation – caused by many mediators, such as histamine and prostaglandins
Increased vascular permeability – caused by many mediators, such as histamine
Exudation – fluid filters from the circulatory system into surrounding tissue. Carries leukocytes and components to proteolytic enzyme cascade, such as complement, coagulation, fibrinolytic and kinin systems.
What are the principal mediators of inflammation and allergy?
- Histamine
- Bradykinin
- Nitric oxide
- Cytokines – interleukins, interferons, chemokines, colony stimulating factors
- Eicosanoids – prostaglandins, thromboxanes, leukotrienes
- Other plasma proteins – complement, coagulation and fibrinolytic factors
- Platelet activating factor
- Neuropeptides
Where do the principal mediators of inflammation and allergy act?
autocoids/local hormones. Released from cells upon stimulation.
- Act on adjacent/local cells – paracrine
- Act on cell that secreted hormone – autocrine
Why must histamine be deactivated and how?
Keep them acting locally, done by 2 different pathways:
- Diamine oxidase
- Histamine-N-methyl-transferase
What are the 5 roles of histamine?
- Tissue repair, inflammation
- Control of local blood supply
- Contributes to allergic and anaphylactic reactions
- Neurotransmission in the CNS
- Gastric acid secretion
Where is histamine found throughout the body?
- High concentrations in the lungs, skin, GI tract and brain
- Present in mast cells and basophils – contain granules densely packed with histamine, heparin, proteoglycans and serine proteases in a ratio of 1:3:6
- Neurones in the brain
- Enterochromaffin like cells in the stomach
Where are mast cells produced and found?
- Produced by bone marrow
- Released as immature cells and then mature in tissue
- Found beneath skin throughout the respiratory, digestive and urinary tracts.
What is mast cell degranulation?
- Priming of mast cell: exposure to allergen creates IgE antibodies, which bind to mast cell IgE receptors.
- 2nd exposure to allergen caused allergen to bind to IgE on mast cell surface.
- Activates mast cell by: increasing intracellular calcium concentration or C3a and C5a complement components
- Leads to degranulation and histamine release
How is histamine release inhibited?
Increase in cAMP by beta-adrenoreceptor agonists
What is the effect of H1 receptor activation?
Systemic vasodilation
Increased vascular permeability
Itching
Bronchoconstriction
Ileum contraction
Effects on neuronal action potential firing
What is the receptor coupling for H1 receptors?
Increased IP3 and DAG, stimulating calcium ion release.
What is the effect of H2 receptor activity?
Stimulate gastric acid secretion
Relax smooth muscle
Speed up heart rate
Inhibit antibody and cytokine production
Inhibit neutrophil activation
What is the receptor coupling of H2 receptors?
Increased cAMP
What is effect of H3 receptor activation?
Inhibits neurotransmitter release from neurones
What is the receptor coupling for H3 receptors?
Decreases cAMP
What is the effect of H4 receptor activation?
Regulates neutrophil release from bone marrow and chemotaxis in mast cells.
What is the receptor coupling of H4 receptors?
Decreases cAMP
What are H1 receptor antagonists?
- Used in treatment of allergy, such as hay fever and urticaria.
- Orally active
- Hepatic metabolism
- There are no H1 antagonists licenced for vet use in the UK. Human drugs given with owner consent.
- Have limited use in treating allergic disorders in animals.
- Most useful if given before allergen challenge: feline asthma, allergic skin disorders relief of itching, motion sickness and mild sedation.
What are 1st and 2nd generation H1 receptor antagonists?
1st generation: average duration of 4-6 hours and crosses the blood brain barrier. Such as diphenhydramine, chlorphenamine, cyproheptadine and alimemazine.
2nd generation: longer duration of 12-24 hours and does not cross the blood brain barrier. Such as cetirizine, loratadine and acrivastine.
What are H2 receptor anatgonists?
Inhibit gastric acid secretion.
Treatment of gastric ulcers. For example, cimetidine, ranitidine, famotidine.
What are H3 and H4 receptor antagonists?
Used as research tools and have been human clinical trials on antagonists of H3 and H4 receptors.
Define type 1 hypersensitivity reactions.
Immediate or anaphylatc hypersensitivity – allergic reaction. Oversensitive reaction to an allergen producing an excessive inflammatory response.
What is anaphylaxis?
- Whole body reaction of a previously sensitised animal to the sensitising allergen.
- Life threatening
- Produces immediate smooth muscle contraction, vasodilation, increased vascular permeability
- Within 2 minutes, there is nausea, abdominal pain, palpitation, urticaria, difficulty in breathing, hypotension, inadequate circulation.
- Within 4 minutes there is shock.
What are 3 possible drug treatments for anaphylaxis?
Epinephrine – immediate and subcutaneously. Intravenous administration also required to maintain intravascular volume and supply additional; medication.
Chlorphenamine and promethazine – H1 receptor antagonists intravenously
Glucocorticoids – no acute effect but suppress slow onset urticaria, bronchospasm, laryngeal oedema and hypotension.
What are cytokines?
Protein or polypeptides produced and released from immune cells during inflammation. Upregulated during inflammation
What are the characteristics of cytokines?
- Very potent – sub nanomolar (< 1 x 10-9 M)
- More than 100 exist and they are split into 4 main groups: interleukins, interferons, chemokines and colony stimulating factors
- Very complex – interact with each other, stimulate receptor upregulation for others
- Act at kinase-linked receptors or GPCRs
- Coordinate inflammatory response
What are eicosanoids?
- Generated from phospholipids
- Precursors are 20 carbon fatty acids – eicosa = 20 C
- They are not stored but generated on demand
- They are prostaglandins, leukotrienes and thromboxane
- Involved in many physiological processes with major involvement in inflammation
- Target of several groups of drugs
