Immunology Flashcards
What is a antigen ?
Antigen
* All cells have surface markers called antigens; protein, lipid, sugar, nucleic acids
* can be recognised as self or non self (foreign)
* a foreign antigen can bind specifically to an antibody (AB) or generate peptide fragments which may be recognised by a T cell
* What makes a good antigen - size, complexity, “foreigness”, route of administration and dose
* molecules which stimulate an immune response are called immunogens
What is an antibodie (AB), and what are their functions ?
Antibodie
* are funtional proteins also known as immunoglobulin (Ig)
* made by specialised B lymphocytes (B cells)
* exposure to an antigen induces the production of antibodies IgM, IgG, IgA, IgE and IgD
* AB can assist in the identification of many diseases
Function
* enhance phagocytosis
* enhance complement mediated killing
* neutralise toxins
* prevent pathogen attachment
What is an epitope ?
Describe the differences between immediate-innate immunity and adaptive immunity ?
Innate
* natural present before infection
* non-specific - same response
Provide the five defining characteristics of the adaptive immune system ?
What is humoral immunity ?
Humoral Immunity - body fluids
mediated by by antibody molecules that are secreted by plasma cells
- an antigen is administered to elicit an immune response
- after a lag period there is an antibody response which will decline with time
- following a second dose of antigen, there is a shorter lag period and the antibody persist for a longer period
- antibody responses are specific to a certain antigen
What are granulocytes ?
Granulocytes
All possess cytoplasmic granules and a lobed nucleus
The granulocytes are named according to the ability of the granules to react with acidic or basic dyes
* Neutrophils - neutral granules most numerous important in antibacterial immunity
* Eosinophils - granules stain red with acid dyes important in antiparasite immunity
* Basophils - stain with basic dyes contain vasoactive amines, important for allerhic reactions
Where do lymphocytes develop ?
Discuss neutrophils ?
Neutrophils
* Phagocytosis and activation of bactericidal mechanisms
* spend approximately 12 hours in the blood stream
* total life span only a few days
* function - capture and destruction of foreign material (phagocytosis)
* respiratory burst is an important antibacterial defense
Disscuss Eosinophil ?
Eosinophil
* granules stain red acid dye
* killing of antibody coated parasites
* spend approximately 12 days in tissues / half life in circulation is 30 mins
* phagocytic function similar to neutrophils
* more suited to extracellular destruction of large parasites
* important defense against parasitic and fungal infections
Discuss Basophils ?
Basophils
* basic dye
* promotion of allergic response and augmentation of anti parasitic immunity
* less common than other granulocytes
* the basophilic granules contain vasoactive amines such as histamine and serototonin
* function is less well known - but involved in hypersensitivity and allergic reactions
Describe the function and morphology of a macrophage ?
Macrophage
* large phagocytic cell
* live longer than neutraphils
* antigen presentation (APC)
* cytokine secretion
* tissue reorganisation and wound healing
* tumor cell destruction
* monocytes migrate from blood into tissue where they mature into macrophages.
What is the function of interleukin 1
Cytokine Interleukin 1 IL-1
* co-stimulator of TH2 cells, eg acute phase response
* activates vascular endothelium
* activates lymphocytes, local tissue distruction and increases the access of effector cells
* increases the production of IL-6 resulting in fever
What is the function of tumor necrosis factor TNF-alpha
Cytokine TNF-alpha
* stimulates T cell growth (cytotoxic) + acute phase response
* trigger inflammation
* activates the vascular endothelium and increases permeability (leading to increased entry of IgG)
* increased fluid drainage to the lymph nodes
* causes fever, mobilization of metabolites and potential shock
What is the function of IL-6
Cytokine IL-6
* induces fever
* induces B cell differentiation + acute phase response
* increases phase protein production which helps recognise and destroy pathogens (C reactve protein)
Describe the function of Dendritic cells ?
Dendritic cells
* Antigen uptake in peripheral tissues and antigen presentation
* derived from myeloid progenitors
* specialised antigen presenting cells (APC)
* they take up antigen, process it and display the antigens for recognition by T cells
* immature Dendritic cells migrate from blood into tissues where they reside
* mature - secondary lymphoid tissue
* both phagocytic and micropinocytic
Describe the function of a MAST cell is ?
Mast cell
* tissue cells
* release granules containing histamine and active agents
* interface between innate and adaptive immunity
* role in infection and diseases eg allergy
What is the role of natural killer cells ?
Natural killer cells
* releases lytic granules that kill some virus infected cells
* non T/B cytotoxic lymphocytes
* innate immunity
What is the difference between a primary and secondary lymphoid organ ?
Primary lymphoid organ
= are those in which lymphocytes develop and mature (rearrange the receptor sites) bone marrow, thymus, bursa of fabricus (birds)
* thymus where T cells learn their roles and to not self react
* bone marrow blood producing tissue
Secondary lymph node
* those in which naive lymphocytes encounter antigen antigen and are stimulated to become effector and memory populations
* spleen, lymph nodes, MALT (mucosa associated lymphoid tissue)
Describe the structure of a lymph node and its function ?
Lymph node structure - contains most lymphocytes present in the body.
Lymph node structure faciliatates generation of adaptive immunity
* afferent lymphatic vessels drain into the lymph node
* efferent lymphatics leave the lymph node
Major site of antigen presentation
* T cells paracortex
* B cells follicles
* APCs located in the paracortex strategically placed to sample for foreign antigens
Describe the development and differentiation of B cells ?
B cell development / differentiation
In mammals the bone marrow serves as the primary lymphoid organ for B cells
* leave BM, circulate in blood and end up in secondary lymphoid organs
* Naive activated by antigen and interaction with helper T cells
* first antibody to be produced in a humoral response is IgM
* activated B cells undergo subsequent isotype or class switching and secrete Ab of different isotypes
* some B cells become antibody producing cells and others memory B cells
Describe the development of T cells ?
T cell development
- T cell progenators in the bone marrow complete their development in the thymus
- development by rearanging their antigen-receptor genes and undergo repertoire selection
- negative selection = thymic epithelial cells act as APC and if the lymphocytes respond to self antigens they are destroyed
- Positive selection* = lymphocytes capable of responding to a foreign antigen are stimulated to grow
thymic cells secrete cytokines which act upon the T cells
Describe how B and T cells recognise their antigen ?
What is MHC ?
major histocompatibility complex
What is inflammation, and what are the cardinal signs ?
Inflammation - itis
* non specific response to cell damage
* a process by which cells of the immune system and their products are concentrated at a site of damage/ infection
* the purpose is to aid eradication or repair of damaged tissue
The five cardinal signs
* heat
* swelling
* pain
* loss of function
* redness
What are the three major events of inflammation ?
Three events of inflammation
1. blood supply to site increases
2. capillary permeability increases
3. leukocytes migrate to the site of inflammation
What are PAMPS ?
PAMPS = pathogen associated molecular patterns
How is inflammation triggered ?
Initiation of inflammation
* PAMPS (pathogen associated molecular patterns) on invading microorganisms are recognised by the body
* PAMPS are recognised by Toll like receptors (TRL) found on microphages, DC, mast cells and mucosal epithelial cells (sensor cells)
* signals from TLR acitivate genes that are involved in the production of cytokines IL-1, IL-6 and TNF alpha being the major proinflammatory cytokines
* sensor cells DC, mast cells and macrophages turn on genes associated with inflammation
Identify the cell derived inflammatory mediators ?
Cell derived
* preformed sequesterd and released (mast cell histamine)
* synthesised as needed prostaglandins, cytokines
Histamine
* secreted by Mast cells, when they are stimulated or injured
* potent action on venules, arterioles and capillaries
* vasodilation, venular endothelial contraction and junctional widening
Prostaglandins and leukotrrienes
* synthesised from Arachidonic acid (eicosanoids)
* prostaglandins and thromboxine cycloxygenase pathway cause vasodilation and prolong odema (aspirin, NSAIDS)
* Leukotrienes via lipoxygenase pathway, chemotaxis, vasoconstrictors cause increased vascular permeability
* may result in the sensation of pain
Describe the plasma derived inflammatory mediators
plasma derived inflammatory mediators
Complement, kinins, and coagulation factors
* Kinins (bradykinin) - vasodilation, increased permeability and pain
* sentinel cells (macrophages) produce cytokines that have local and systemic effects
What is the role of nitric oxide in inflammation ?
Nitric oxide
* short acting soluble free-radical gas with many functions
* produced by endothelial cells and macrophages
* causes vascular smooth muscle relaxation and vasodilation
* kills microbes in activated macrophages
What is the function of IL-2 cytokines
IL-2 Cytokines
* activates NK cells
* induces the differentiation of CD4 T cells into TH1 cells
Describe the complement system and its role in inflammation ?
The complement system
* group of proteins
* circulate in the blood or can be induced
* help to recruit phagocytes to the site of inflammation and activate them
* bind to receptors on phagocytes helping to remove the agent of infection from them
* form pores in the invaders or infected cells membrane
* activate mast cells to release histamine and other factors
* complement proteins include C3, C5, C4 upto 30 + proteins
Describe phagocyte migration into tissues during inflammation ?
Phagocyte migration into tissue
* neutrophils exit blood first followed by monocytes which develop into macrophages in tissues
* complement factors, prostaglandins are all chemotactic (attract) neutrophils
* PUS = dead and dying neutrophils, tissue debris and remaining pathogens
Leucocyte movement into tissue
* interaction between activated endothelium and molecules on the leukocyte
* tight binding triggered by cytokines/chemokines - enhance ability of leucocyte to adhere to their receptor on endothelium
* crossing of endothelial cell wall
* direction of migration follows gradient of cytokines/chemokines
What is systemic inflammation ?
What is fever and its effects
Fever
High levels of cytokines (!L-1, IL-6 and TNF) reset the hypothalamic set point - leading to an overall increase in body temperature
Positive effects
* indicates infection
* accompanies inflammation
* stimulates phagocytosis
* slows bacterial growth
* decreases iron in blood levels
Negative effects
* in extreme cases may lead to protein or enzyme degradation
* interuption of normal biochemical reactions
What is acute inflammation and how does this become chronic ?
Acute inflammation
* within minutes of tissue insult
* neutrophils (PMNs) than monocytes
* redness, swelling, pain, loss of function and heat
If the pathogen is not eliminated continued recruitment of inflammatory cells increase concentration of phagocyte derived molecules cytokines in plasma. - leading to chronic inflammation
- granuloma (may be present, infection can not be eliminated so the body walls it off to prevent spread).
- tissue destruction by inflammatory cells
- attempts at repair with fibrosis and angiogenesis (new vessel formation).
Occurs when the acute phase can not be resolved
- acute phase is not resolved (ulcer)
- prolonged toxic agent exposure (silica)
- autoimmune disease (thyroiditis)
Describe the cell type development of the adaptive immune system and provide the four key antigen receptors ?
Adaptive immunity components
* T and B cells
* as lymphocytes develop in (bone marrow B cells) and (Thymus T cells each cell acquires an antigen receptor that is randomly generated, individual and unique
* this is how the large pool of lymphocytes in the body can collectively recognise any Ag the individual is likely to encounter in their life time.
The four key antigen receptors
* TCR = T cell receptor
* BCR = B cell receptor
* MHC class 1 = every nucleated cell
* MHC class 2 = APCs
* each is constructed using immunoglobulin domains as building blocks - and each binds antigen through the use of variable domains
Provide the two branches of adaptive immunity ?
The two branches of adaptive immunity
Humoral immunity
* antibody mediated
* Produced by B lymphocytes and plasma cells
Cell mediated immunity
* T lymphocytes
* T helper cells help B cells make antibody
* T helper cells also help T cells with a molecule CD4 on their surface
* killer or cytotoxic T cells - kill infected cells or tumor cells with CD8 molecule on their surface
How do lymphocytes recognise their antigen
T and B cells recognise their antigen differently
* B cells recognise free intact or native antigen
* B cells acquire Ag via its BCR, process Ag than present Ag to helper T cells via MHC
- T cells recognise antigen only when they processed peptides complexed to MHC molecules displayed on the surface of an APC
- MHC-1 cytotoxic T cell; MHC-2 Helper T cell
Describe the immune cell interactions that occur within the lymph node ?
Immune cell interactions of the lymph node
* APCs prrsent antigen to T lymphocytes
* Helper T cells help B cells to produce antigen
* Helper T cells interact with Killer T cells
Note T cells are located in the paracortex and B cells are located in the cortex.
The location of the pathogen within the body affects the presentation of antigen to T cells ?
Antigen presentation to T cells is affected by location
Exogenous antigen
Ag coming from outside the APC
are predominantly loaded onto MHC class 2
recognised by CD4 T helper cells
Endogenous peptides
* Ag peptides within the cell are predominantly loaded onto MHC class 1
* recognised by CD8 class 2 T cells
T cells
* successful stimulation of T cells requires multiple signals and is highly regulated
* depending on the antigen, the T cell may be activated by signals from multiple TCRs or by appropriate costimulation
The types of T cells, what are the four types of CD4 helper T cells ?
T helper cell types
Naive CD4 when activated by APC/Ag may differentiate into any one of a number of different effector cells with different functions (produce different cytokines)
TH1 cells
* activate infective macrophage
* help B cells for antibody production
* target microbes which exist in macrophage vessicles
Th2 cells
* provide help to B cells in antibody production
* especially antibody switching to IgE for helminth parasites
TH17
* enhance neutrophil response and promote barrier integrity (skin, intestine)
CD4 Regulatory
* suppress T cell response
What are the three main actions of T helper cells ?
Describe the cytokines produced by CD4TH1 and CD4TH2 cells ?
What is the extrinsic and intrinsic pathway in cytotoxic T cells ?
Describe memory T lymphocytes ?
What is type one hypersensitivity meachanism ?
Type one hypersensitivity - immediate hypersensitivity
* immediate Mast cells and IgE are significant players
* eg allergy, anaphylaxis
Phase one
* individual is first senesitised to allergen
* allergen specific B cells make IgE (TH2 make IL4 to make IgE)
* IgE binds to mast cells
Phase two
* upon subsequent exposure to allergen mast cells degranulate
* rapid release of inflammatory molecules from mast cells - histamine, heparin, serotonin
* synthesis of other mediators leukotrienes, PGS
The result
* compounds release cause constriction of smooth muscle (airways)
* vasodilation (oedema)
* acute inflammation, nerve ending (puritis, itch)
* initial symptoms are rapid 15-20mins, late response 4-24hrs
* can be localised or systemic
What conditions would be considered a type one hypersensitivity ?
Conditions of type one hypersensitivity
* allergy, asthma, hay fever, allergic conjunctivitis
Clinical signs
* hay fever, conjunctivitis, hayfever
* rash
* itchy skin
* wheezing stridor
* asthma
* swollen lips toungue or face
What is atopy ?
Atopy
* geneitic predisposition to type one hypersensitivity
* type one hypersensitivity is generally encounted at mucosal surfaces
* atopic individuals have a predisposition to overactive TH2 immunity and high levels of IL-4 and IgE
* TH2, IL-4, IgE and eosinophils (effectors) are the main players in type one hypersensitivity
* AG involved in allergies is referred to as allergins
*
What is type one hypersensitivity meachanism ?
Type one hypersensitivity - immediate hypersensitivity
* immediate Mast cells and IgE are significant players
* eg allergy, anaphylaxis
Phase one
* individual is first senesitised to allergen
* allergen specific B cells make IgE (TH2 make IL4 to make IgE)
* IgE binds to mast cells
Phase two
* upon subsequent exposure to allergen mast cells degranulate
* rapid release of inflammatory molecules from mast cells - histamine, heparin, serotonin
* synthesis of other mediators leukotrienes, PGS
The result
* compounds release cause constriction of smooth muscle (airways)
* vasodilation (oedema)
* acute inflammation, nerve ending (puritis, itch)
* initial symptoms are rapid 15-20mins, late response 4-24hrs
* can be localised or systemic
What is the role of eosinophils in type one hypersensitivity ?
Eosinophils role in type one hypersensitivity
* large numbers of eosinophils are attracted to mast cells degranulation products
* large presence of eosinophils at site is regarded as a hall mark of type one hypersensitivity
* eosinophils degranulate to release their own products - contribute to inflammation
* further increase type one response
TH2 and mast cells produce IL5 eotaxins which mobilise eosinophils from the bone marrow.
How would we go about diagnosing a type one hypersensitivity ?
Diagnose
* history breed, age, diet, environment
* ELISA IgE
* intradermal skin testing
Treat - corticosteroids, prevent exposure to allergen, immuotherapy (TH2 to TH1)
What is type two hypersensitivity ?
Type two - AB mediated cytotoxic hypersensitivity
Occurs when antibody reacts with the surface of normal cells
- normal cells will then be destroyed by complement or cytotoxic cells
- complement deposition result in lysis of the cell - rapid
- lesions may develop as a result of cell destruction - delayed
The main players = IgG (or IgM) + complement, macs (phagocytosis), or NK cells
eg incompatible blood transfusions or organ transplants, autoimmune haemolytic anaemia
How dose a type two hypersensitivity occur to mismatched blood transfusion ?
How does the type two hypersensitivity - haemolytic disease of the newborn occur ?
Describe the mechanisms of type three hypersensitivity ?
Type three hypersensativity
Immune complexes are formed as a result of antigen antibody complexes and this activates complement
* sensitization with antibody = increase in circulating antibody
* localised or systemic response
* immune complexes activate complement locally
* immune complexes may become deposited in blood vessel walls
Phagocytic cells may be recruited
* phagocytic cells release oxidants and other enzymes causing causing acute inflammation and tissue damage
Examples = serum sickness, Arthus reaction, Lupus
Describe the mechanism behind the Arthus reaction in type three hypersensitivity ?
What is type four hypersensitivity ?
Type four delayed type hypersensitivity
Is cell mediated (T cells) has delayed onset (24-72 hours)
* sensitisation phase generates TH1 cells and AG specific memory T cell
* subsequent exposure to the sensitising Ag leads to reactivation of these memory cells >TH1
* these cells home to the tissue site of Ag exposure and release IFNY and other cytokines chemokines
* this leads to recruitment of other memmory cells including MACs and granulocytes causing tissue damage
Some antigens when injected into the skin induce a slow developing inflammatory resonse, sometimes used to assess exposure of an individual to Ag
- Q fever test, contact dermatitis, contact hypersensitivity
Describe the four types of hypersensitivity ?
Describe the two types of immune deficency ?
Two types of immune deficiency
Primary immune deficiency
* inherited, congenital
* mutation in a gene encoding a molecule of the immune system
* clinical signs appraent early in life
* breed suceptability
* defects in inate or adaptive immunity
* relatively rare
* best characterised in horses and dogs
Secondary immune deficiency
* acquired (not born with the disease)
* cytotoxic drugs, viral infections, exercise, tumors, age, medical therapy or chronic disease
Provide an example of a primary innate immune deficiency ?
Define an immunodeficiency ?
Immunodeficiency = impairment in function of part or parts of the immune system, that renders the immunodeficient individual susceptible to disease
What is a primary and secondary immunodeficiency ?
Primary immunodeficiency
* Inherited
* A mutation in a gene encoding a molecule of the immune system
* inherited, congenital (present from birth)
*clinical signs appear early in life
* severe disease often depends on having two copies of the disease (homozygote)
* breed susceptibility
> relatively rare (secondary immune deficiencies more common)
Secondary immunodeficiency
* Acquired
* can affect animals of any breed, relatively common compared to immunodeficiency one
Provide an example of a primary immune deficiency ?
Primary immune deficiency
- CLAD/BLAD canine/bovine leukocyte adhesion deficiency
- Cyclical neutropenia
- Defects in the granules of neutrophils (NK and CTLS)
- defects of the adaptive immune system
What are the red flags of an underlying immune deficiency ?
Describe the primary immune deficiency of cyclic congenital neutropaenia and defects in neutrophil garnules ?
Primary immune deficiency
Cyclical congenital neutropaenia
Affects bone marrow - neutrophils, platelets and monocytes may be affected
* stem cell growth factor defects
* cyclic fluctuation in the number of white blood cells
* the number of neutrophils falls sharply 10-12 days, then returns to normal
* episodes of infection
grey collie syndrome, pups rarely live beyond three years of age
Defects in granules of neutrophils
Rare Chediak Higashi syndrome
* poor bactericidal activity, making the animal suspectable to bacterial infections
* melanin granules may also be affected
* blue smoke Persian cat, Hereford cattle, killer whales, mink and humans
*
Identify any red flags indicating an underlying immune deficiency ?
What is a primary immune deficiency ?
Primary immune deficiency
A mutation in a gene encoding a molecule of the immune system
- inherited, congenital (there from birth)
- clinical signs often appear early in life
- severe disease often depends on having 2 copies of the gene, ie homozygous
- disease less severe in heterozygotes
- breed susceptability
- relatively rare compared to secondary immune deficiency
- most common and best describe in horses and dogs
Identify four potential primary immune deficiencies ?
Primary immune deficiency
1) CLAD/BLAD canine/bovine leukocyte adhesion deficiency
2) cyclic congenital neutropenia
3) defects in granules of neutrophils
4) defects of the adaptive immune system
What is clad / blad and its effects ?
What is cyclic congenital neutropenia, and defects in granules of neutrophils, and what species would you observe these effects ?
Describe the effects of the primary immune deficiency of adaptive immunity ?
What is SCID ?
What is a secondary immune deficiency, and what could cause this ?
How do tumours avoid recognition by the immune system ?
