Immunology Flashcards
What are the 2 types of immune response in mammals?
Acquired and innate
What are the 2 types of acquired immunity?
T and B cell
What are the 3 types of innate immunity?
- Complement cascade
- Phagocytes
- Physical barriers
Name the innate immunity mammalian leukocytes
- Neutrophil
- Eosinophil
- Basophil
- NK cells
- Mast cells
Name the antigen presenting cells
- Monocyte
- Macrophage
- B lymphocytes
- Dendritic cells
What is the relationship between plasma cells and B cells?
Plasma cells are differentiated B cells
What is the relationship between monocytes and macrophages?
Macrophages differentiate from monocytes once they are in tissues. Monocytes are found in blood
What are the 3 pathways of complement activation?
- Classical
- Lectin
- Alternative
What are the outcomes of complement activation?
- Altered membranes allowing bacterial lysis and opsonisation
- Opsonisation facilitates phagocytosis of the pathogen
- Inflammation leading to, and caused by, mast cell degranulation and neutrophil chemotaxis, which also causes pathogen destruction
How does the complement activation lead to inflammation?
Stimulation of histamine release from mast cells (mast cell degranulation)
How does the complement system lead to direct bacterial lysis?
Pore formation in cell membranes by Membrane Attack Complexes (formed by complement components)
What is the activating signal for the classical complement pathway?
Antigen:Antibody complex
Outline the classical complement pathway
- Antigen and antibody converts inavtive C1 to active C1
- C1 binds to constant region of antibody
- C3 convertase produced
What is the activating signal for the lectin complement pathway?
Host mannose-binding lectin:pathogen mannose
Outline the Lectin complement pathway
- Binds surface of pathogen via soluble protein
- Activates MASP-2 enzyme, which activates C4 via cleavage. product binds to C2, product activated by MASP-2 again
- Product (C3 convertase) then activates C3
What is the activating signal for the alternative complement pathway?
C3 binding to pathogen carbohydrates or proteins (binds directly to the pathogen surface)
Outline the alternative complement pathway
- C3 binds to pathogen surface directly
- Binds to factor B in presence of an activating surface (pathogen)
- Activated by 2 step process, product is C3 convertase which then activates C3
- Positive feedback loop
Outline the significance of C3 in the complement pathway
- Breakdown products are the active products
- C3b binds to microbe surface via carbohydrates, binds to factor H on host cells taking C3b out of circulation
- C3a acts as chemoattractant or anaphylotoxin
Which complement proteins are involved in the membrane attack complex?
C5b, C6, C7, C8 and multiple copies of C9
Outline the response of the complement cascade to infection
- Causes cascade reaction
- Complement proteins circulate in the blood as inactive precursors
- Rapid amplification of activated proteins is result
Which complement proteins are anaphylatoxins?
C3a, C4a, C5a
What effects to anaphylatoxins have on the body?
- Contraction of smooth muscle
- Increased vasodilation in local blood vessels increasing movement within tissues and lymph flow
- Activates mast cells or neutrophils
- Increases fluid in tissue and speeds up lymph flow
- Increases chemotaxis
Outline the development of acute inflammation at mucosal surfaces
- Epithelium damaged due to breach by pathogen
- Leads to cytokine production and chemokine release from epithelial cells (ECs)
- Stimulates resident cells e.g. mast cells
- Recruits innate immune cells
- Histamine and other vasoactive substances increase vascular permeability from mast cells
What is the effect of neutrohphils on inflammation?
Increases inflammation, are pro-inflammatory
What are the results of acute inflammation?
- Increased vascular permeability
- Recruitment of cells and diapedesis
Where are acute phase proteins/reactants produced?
In the liver
What stimulates the production of acute phase proteins/reactants?
Cytokines secreted during inflammation IL-6 and IL-1, TNFalpha)
What acute phase proteins are secreted in response to IL-6?
C-reactive protein (CRP) and fibrinogen
What acute phase proteins are secreted in response to IL-1 and/or TNFalpha?
Serum amyloid A protein
What is the clinical significance of acute phase proteins?
- Can be markers for systemic inflammatory response
- Determine severity of disease
- Can be used to monitor the response to treatment
Name the pro-inflammatory cytokines
- TNFalpha
- IL-1
- IL-6
- CXC-8/IL-8
Name the anti-inflammatory cytokines
- IL-4
- IL-10
What are the effects of pro-inflammatory cytokines
Recruit cells to area for inflammatory response
What are the effects of anti-inflammatory cytokines?
- Promote production of antibody
- Mops up pathogen and reduces inflammatory response
- Adaptive response present, more specific and will resolve disease faster
What factors determine the immunity to pathogens?
- Intracellular vs extracellular pathogen
- Innate and adaptive immune responses
- Ig isotype location and function
- Complement, opsonisation, phagocytosis and removal of pathogen
Give the events leading to immunological memory
- Pathogen/antigen invasion
- Ag capture and processing, Ag recognition
- Selection of lymphocytes specific for that antigen
- Cell activation
- Proliferation of antigen specific lymphocytes to form a clone
- Differentiation into a function (effector) state or memory state
What is the function of antigen tolerance?
Prevents damage to self and regulates immune response to environmental antigens and fetus during pregnancy
What are the types of antigen tolerance?
- Central
- Peripheral
Where and when does central antigen tolerance develop?
- Education of T lymphocytes in thymus
- B lymphocytes in bone marrow
- Occurs during maturation
Where and when does peripheral antigen tolerance develop?
- T and B cells in secondary lymphoid tissue
- Occurs after birth
What is hypersensitivity?
Sensitisation as a result of repeated exposure of genetically susceptible individuals to the same antigen
What are the types of hypersensitivity?
- Type I: antibody mediated, immediate
- Type II: antibody mediated, cytotoxic activity, days
- Type III: immune complex mediated, 24h
- Type IV: cell mediated, delayed type (DTH), 24-72h
Give examples Type I hypersensitivities
- Localised: atopic dermatitis, flea allergy dermatitis, sweet itch, allergic rhinitis, asthma, food
- Systemic: bee stings, penicillin
Give examples of Type II hypersensitivityes
- Incompatible blood transfusion e.g. in cats
- Autoimmune disease: haemolytic anaemia, thrombocytopaenia, neutropaenia, myasthenia gravis
Give examples of Type III hypersentivities
- Allergy to fungal spores in cattle
- Recurrent airway obstruction in horses
- Blue eye in dogs
- Leishmaniosis in dogs
Outline Type III hypersensitivity
- Ab excess or Ag excess
- Immune complexes (Ag - Ab) form
- Deposit in wall of small capillaries (e.g. renal glomerulus, uveal tract, synovoium, cutaneous epidermal basement membrane)
- Can lead to vasculitis and ischaemia necrosis
Give examples of causes of Type IV hypersensitivities
- Environmental allergy e.g. pemphigus foliaceus (Mycobacterium spp. response)
- Above forms the TB test for cattle
Outline the development of a Type IV hypersensitivity response
- Th cells reactivated on re-exposure to an Ag they have been sensitised to
- Release IFNy and chemokines
- HEVs form
- Upregulation of vascular adressins
- Recruitment of mononuclear cells
- Become walled off
Outline the development of a granuloma in chronic inflammation
- Granulomas are aggregates of chronically stimulates inflammatory cells
- Collection of macrophages modified to form epithelioid cells with surrounding zone of T lymphocytes
- Macrophages fuse to form Langhans giant cells
- Centre becomes caseous and necrotic, eventually undergoes fibrosis and calcification
What methods can be used to test for antibodies?
- Latex agglutination
- Serology (to detect infection, seroconversion)
- ELISA
- Coomb’s test
- Radial immunodiffusion
- ANA
- Paired serology testing for respiratory disease diagnosis
What are the 2 types of immunodeficiency?
- Primary (young animals)
- Secondary (adults)
What is an important clinical consequence of immunodeficiency regarding?
May reduce or prevent entirely, vaccination effectiveness
Outline the importance of T and B lymphocytes in veterinary medicine
- Diagnostics and herd health monitoring
- Rational design of vaccines
- Immune mediated disease
- Immunodeficiencies
- Tolerance e.g. to food antigens
- Immunosuppression
- Pharmacological control of inflammation
- Cancer e.g. leukaemia or lymphoma diagnosis and prognosis
What is primary lymphoid tissue?
The tissue in which lymphocytes are generated/matured
Name the primary lymphoid tissues
- Bone marrow
- Thymus gland
- Bursa of Fabricius (birds)
- Ileal patches (sheep, cattle, pigs, dogs, horses)
- Appendix caecal patch (rabbits)
What is secondary lymphoid tissue?
Where lymphocytes interact with APCs and immune responses are generated. Is where antigens are presented to naive lymphocytes
Name the secondary lymphoid tissues
- Lymph nodes
- MALT
- BALT
- Spleen
Outline lymphocyte recirculation
- Naive lymphocytes recirculate through blood and lymph continuously until meet specific Ag in LN
- Stimulates cell activation, division, lymph node enlarges, activated lymphocytes leave LN in lymph
- Enter blood via thoracic duct then into tissues at site of infection
- Formation of memory cells, leave blood when encounter specific Ag again
What are the subsets of T lymphocytes?
- CD4+ Th
- CD8+ Tc
- Treg
Briefly describe cytotoxic T lymphocytes
- CD8+
- MHC class I restricted
- Kill cells infected with intracellular pathogens
Briefly describe helper T lymphocytes
- CD4+
- MHC II restricted
- Th1, Th2 and Th17 subsets
Briefly describe the role of Th1 lymphocytes
- Proinflammatory
- Activate cytotoxic T lymphocytes to kill intracellular pathogens
Briefly describe the role of Th2 lymphocytes
- Anti-inflammatory
- Stimulate B cells’ antibody production and class switchin
What are the Th1 cytokines?
- Proinflammatory
- IFNy and TNFa mainly
What is the role of the Th1 cytokines?
Activate macrophages and mediate delayed type hypersensitivity
What are the Th2 cytokines?
- IL4
- IL5
What is the role of the Th2 cytokines?
Promote differentiation of B cells into antibody secreting plasma cells
Briefly describe the role of Th17 lymphocytes
- Secrete IL-17
- Neutrophil recruitment, fungal infection and autoimmunity
Briefly describe regulatory T lymphocytes
- CD25+, FoxP3 +
- Release Il-10 and TGFb
What is the role of Tregs?
- Regulate immune response
- Crucial in tolerance development
What is the clinical relevance of the different subsets of lymphocytes?
- Pathogens vary in how they are present to immune system (extra vs intracellular)
- Type of immune response generated differs
- for some pathogens, Th1 bias cellular immunity, for others Th2
What is the main difference between T cell receptors and B cell receptors?
- T cell receptors will only recognise antigen if present to them on MHC class I or II molecules on other cells
- B cell receptors can bind to antigens directly (can be bound to cell or free in plasma)
What allows T cell receptors to recognise a diversity of antigens?
- T cell receptors highly diverse and unique to cell type
- Due to genetic changes that lead to alterations in structure
What is CD3?
T cell receptor
What part of the antigen to TCRs recognise?
Small peptide fragment
Describe the genetic changes that take place to allow the diversity in T cell receptors
- Somatic DNA recombination of different gene segments of V (variable) region
- V domain encoded by 3 gene segments
- V encodes first 95 amino acids, D encodes 5 amino acids, J encodes last 10-15 amino acids
What cells carry MHC class II?
Selected cells, mainly APCs
What cells carry MHC class I?
Nearly all nucleated cells in the body
Why is MHC class I present on most cells?
So virtually any cell can present peptide antigens to CTLs
What type of antigen processing is carried out by MHC class I?
Endogenous
What type of antigen processing is carried out by MHC class II?
Exogenous
Outline what happens following recognition of an antigen on an MHC I/II molecule by a CTL/Th cell
- Engagement between CTL’s TCR and CD8 molecules OR Th’s TCR and CD4 molecules
- In both cases, additional molecular binding (second signals) secure interaction and ensure activation of lymphocyte
What is processed by exogenous processing for antigen presentation?
- Infectious agents present in extracellular spaces
- Environmental agents e.g. pollen, dust mites, food
- Opsonised agents, B cell receptor bound
Outline the process of exogenous antigen processing and presentation
- Antigen enters host cell via phagocytosis and pinocytosis, in endosomes
- Large proteins of antigen broken into smaller proteins suitable for presenting to T cells
- Peptides bind with MHC class II before being taken to cell surface where endosome fuses with cell membrane
How are exogenous antigens processed by APCs?
- Pattern Recognition Receptors (PRRs) recognise PAMPs on microorganisms, bind to B cell receptors on B cells
- Phagocytosis and processing follows
What MHC class carries out exogenous antigen processing and presentation?
MHC class II
What MHC class carries out endogenous antigen processing and presentation?
MHC class I
What is processed by endogenous antigen processing?
- Antigens of self
- Tumour antigens
- Intracellular virus antigens
- Parasitic antigens
- i.e. anything intracellular
Outline the process of endogenous antigen processing and presentation
- Antigen enter cytoplasm
- Tagged with ubiquitin
- Enters proteasome
- Proteins degraded into peptides
- Transproted to endoplasmic reticulum where associate with MHC class I
- Complex moves through Golgi to be expressed on cell surface
What is the importance of cross presentation of antigens?
- Need mixed response to an antigen, not just CTL or antibody response
- However some allergens/pathogens may have a bias towards one or the other
What determines the bias of an allergen/pathogen immune response?
The route of antigen uptake i.e. more endogenous uptake leads to more CTL response
What is the clinical importance of the route of antigen processing and presentation?
Affects the method by which a vaccine or adjuvant needs to work. E.g. if an antigen is predominantly processed exogenously, a vaccine where the primary route of processing is endogenous will offer some protection but will not allow full protection against that pathogen when protected naturally
What is the function of plasma cells?
Secretion of antibodies
What do B cells differentiate into?
Lymphoblasts and plasma cells
What are the roles of B cells?
- Differentiation into lymphoblasts and plasma cells
- Proliferation of B cells
- APCs to MHC class II restricted Th cells
What stimulates the proliferation of B cells?
Binding of antigens to B cell receptors bound to the surface of the cell, allowing binding of Th cells which then release cytokines that promote division and activation of B cells
Outline the process of clonal expansion of lymphocytes
- Once antigen is presented, co-stimulation occurs
- Costimulation depends on cell type
- Lymphocyte activated then divides
- Multiple clones of identical antigen specific lymphocyte are produced
What occurs if an antigen is presented but the co-stimulation signal cascade is absent/incomplete?
Tolerance to the antigen. This may be beneficial or deleterious
What is immunodeficiency?
Immune system is damaged and unresponsive. May be genetic and is non-specific
What is the difference between immunodeficiency and antigen tolerance?
Immunodeficiency is non-specific whereas tolerance is antigen specific
Describe the changes that occur within cells during clonal expansion following antigen binding and co-stimulation
- Cell enlarges (lymphoblast)
- Lymphoblasts divide
- IL-2 secreted by T cells, promoting proliferation
- Effector and memory cells produced
