Immuno: Immune response to infection Flashcards
What are the two main routes of infections of pathogens?
- External epithelia (e.g. skin)
- Mucosal surfaces (e.g. GI tract)
List some features of skin that makes it an effective barrier to infection.
- Consists of tightly-packed keratinised cells
- Low pH
- Low oxygen tension
- Sebaceous glands
What do sebaceous glands produce that has antibacterial effects?
- Hydrophobic oils - repels water and microorganisms
- Lysozyme - destroys the structural integrity of the bacterial cell wall
- Ammonia and defensins - anti-bacterial properties
Describe the defensive features of mucosal surfaces.
- Traps invading pathogens
- Cilia promote the removal of mucus
- Contains secretory IgA which binds to pathogens and prevents them from attaching to and penetrating epithelial cells
- Contains lysozyme and other antimicrobial peptides
- Lactoferrin starves invading bacteria of oxygen
How do commensal bacteria act as a barrier to infection?
Competes with pathogenic bacteria and produces various antimicrobial agents
List the cells of the innate immune system.
- Polymorphonuclear cells
- Monocytes/macrophages
- NK cells
- Dendritic cells
List the soluble components of the innate immune system.
- Complement
- Acute phase proteins
- Cytokines and chemokines
List some key features of cells of the innate immune system.
- Identical responses in all individuals
- Cells express genetically-encoded receptors (PRRs) that allow them to detect pathogens at the site of infection
- Cells have phagocytic capacity
- Cells secrete mediators (e.g. cytokines/chemokines) that regulate the immune response
Name the resident macrophage in the following tissues/organs:
- Liver
- Kidney
- Bone
- Spleen
- Neural tissue
- Connective tissue
- Skin
- Liver = Kupffer cells
- Kidney = Mesangial cells
- Bone = Osteoclasts
- Spleen = Sinusoidal lining cells
- Neural tissue = Microglia
- Connective tissue = Histiocytes
- Skin = Langerhans cells
How do macrophages differ from polymorphonuclear cells?
They can process antigens and present them to T cells
Outline the process of phagocyte recruitment in response to infection.
- Cellular damage and bacterial products trigger the production of inflammatory mediators (cytokines and chemokines)
- Cytokines enhance vascular permeability
- Chemokines attract phagocytes (chem = chemistry = attract)
Describe how cells of the innate immune system recognise pathogens.
- Neutrophils mobilised very quickly from BM and migrate to site of infection
- Pattern-recognition receptors (PRRs) recognise generic motifs called PAMPs (e.g. bacterial sugars, DNA and RNA)
- Fc receptors on these cells allow binding to the Fc portion of immunoglobulins thereby allowing phagocytosis of immune complexes
What are examples of PRRs?
- Toll-Like Receptors (TLRs)
- Mannose Receptors
What is opsonisation?
The molecular mechanism that uses opsonins to make a molecule (e.g. antigen) more palatable to the phagocyte.
I.e. opsonins act as a bridge between the pathogen and the phagocyte receptors
Which other factors can bind to phagocytes to facilitate phagocytosis?
- Complement components (e.g. by binding to CR1)
- Acute phase proteins (e.g. CRP)
- Antibodies
Describe the formation of a phagolysosome
- Pathogen taken up into phagosome
- Fuses with lysosome
- Forms phagolysosome
> > Protected compartment in which killing of organism occurs
Describe the reactions involved in oxidative killing of pathogens within phagolysosomes.
- NADPH oxidase converts oxygen into reactive oxygen species (e.g. superoxide and hydrogen peroxide)
- Myeloperoxidase catalyses the production of hypochlorous acid (from hydrogen peroxide and chloride)
What is non-oxidative killing?
- Killing by the release of bactericidal enzymes (e.g. lactoferrin, lysozyme)
Why do neutrophils die after phagocytosis? What does this form?
- Phagocytosis depletes the glycogen stores of the neutrophil resulting in neutrophil death
- The accumulation of dying neutrophils forms pus
How do NK cells determine whether to lyse cells or not?
- They have inhibitory receptors which recognise self HLA and they have activating receptors that recognise heparan sulphate proteoglycans
- The balance of these signals determines the response
- I.e. if HLA downregulated, activatory signal will become dominant
- They kill ‘altered self’ cells (e.g. malignancy or virus-infected cells)
Describe the main features of dendritic cells.
- Reside in peripheral tissues
- Express receptors for cytokines/chemokines
- Express pathogen recognitiion receptors
- Express Fc receptors for immunoglobulin
- Capable of phagocytosis
- Present processed antigens to T cells in lymph nodes to prime the adaptive immune response
What does a dendritic cell do after phagocytosis?
- Upregulate expression of HLA molecules
- Express co-stimulatory molecules
- Migrate via lymphatics to lymph nodes
Which receptor is involved in the migration of dendritic cells to lymph nodes?
CCR7
What is the difference between primary and secondary lymphoid organs?
- Primary - involved in lymphocyte development (bone marrow and thymus)
- Secondary - anatomical sites of interaction between naïve lymphocytes and microorganisms (e.g. spleen, lymph nodes, MALT)
What is a germinal centre?
Area within a secondary lymphoid organ where B cells proliferate and undergo affinity maturation and isotype switching
What are the components of the adaptive immune response?
- ‘Humoral immunity’ - B lymphocytes and antibodies
- ‘Cellular immunity’ - T lymphocytes (CD4 and CD8 cells)
- Soluble components - cytokines and chemokines
What are the key features of cells of the adaptive immune response?
- Wide repertoir of antigen receptors (NOTE: not entirely genetically encoded because of VDJ recombination)
- Highly specific
- Clonal expansion
- Immunological memory
Outline T cell maturation
- T cells arise from hematopoietic stem cells
- Exported as immature T cells to the thymus where they undergo positive and negative selection
- Cells with low and high affinity for HLA are deleted
- Cells with intermediate affinity will survive (10%)
- Mature T lymphocytes enter the circulation and reside in secondary lymphoid organs
How do T cells recognise HLA/peptide complex?
- T cells express CD3 and T cell receptor
- T cell receptor recognises peptides presented by HLA molecule on APC
Which class of HLA do CD4 and CD8 cells recognise?
CD4 - HLA-II
CD8 - HLA-I
Outline the functions of CD4+ T helper cells.
- Recognise peptides derived from extracellular proteins
- These peptides are presented on HLA-II (HLA-DP, DQ and DR)
- Provide help for the development of a full B cell response
- Provide help for the development of some CD8+ T cell responses
List the subsets of CD4+ T cell.
- Th1
- Th2
- Th17
- Follicular T cell
- Treg
For each of the following subsets of CD4+ T cell, list their polarising factors and effector factors.
- Th1
- Th2
- Th17
- Follicular T cell
- Treg
Th1
- Polarising
- IL-12
- IFN-gamma
- Effector
- IL-2
- IL-10
- IFN-gamma
- TNF-alpha
Th2
- Polarising
- IL-4
- IL-6
- Effector
- IL-4
- IL-5
- IL-10
- IL-13
Th17
- Polarising
- IL-6
- TGF-beta
- Effector
- IL-17
- IL-21
- IL-22
Follicular T cell
- Polarising
- IL-6
- IL-1b
- TNF-alpha
- Effector
- IL-2
- IL-10
- IL-21
Treg
- Polarising
- TGF-beta
- Effector
- IL-10
- Foxp3
- CD25
Describe the function of CD8+ T cells.
- Specialised cytotoxic cells
- Recognise peptides derived from intracellular proteins presented on HLA class I (A, B and C)
- Kills cell directly via perforin and granzyme or expression of Fas ligand
- Perforin destablises cell membrane and also allows granzyme to enter cell
- Granzyme is a serine protease that activate caspases to trigger apoptosis
NOTE: particularly important against viral infections and tumours
In what form are B cells found in the periphery?
IgM B cells
What is the early IgM response of B cells?
If the B cell in the periphery engages an antigen it can cause an early IgM response where the cell differentiates into an IgM secreting plasma cell.
What is a germinal centre reaction?
- Dendritic cells present an antigen, thereby priming the CD4+ T helper cells
- CD4+ T helper cells provide help for B cell differentiation via CD40L: CD40 interaction
- This causes B cell proliferation
- They undergo somatic hypermutation and isotype switching (from IgM to IgG/A/E)
- They will become plasma cells and produce antibodies
NOTE: this process is dependent on CD4+ T helper cells
Which part of an antibody detects antigen and which part is responsible for its effector function?
- Antigen is recognised by the antigen binding region (Fab) which is made up of the variable region of both heavy and light chains
- Effector function is determined by the constant region (Fc) of the heavy chain
Outline the function of antibodies.
- Identification of pathogens and toxins (Fab-mediated)
- Interact with other components (complement, phagocytes, NK cells) of immune responses to remove pathogens (Fc-mediated_
NOTE: antibodies are particularly important against bacteria
How is a secondary response to T-dependent antigens different from the primary response?
- Lag time between antigen-exposure and antibody production is decreased (to 2-3 days)
- Titres of antibody produced is increased
- Response is dominated by IgG antibodies with high affinity
- The response is independent of help from CD4+ cells
Describe B cell maturation
Stem cells in BM > lymphoid progenitors > Pro B cells > Pre B cells > IgM B cells in periphery
Describe the central tolerance of B cells
- No recognition of self-antigens = survive
- Recognition of self-antigens in BM = negative selection to avoid autoreactivity
What is complement?
- 20 tightly regulated, linked proteins
- Produced by liver
- When triggered, enzymatically activate other molecules in a biological cascade
- Results in rapid, highly amplified response
In what form are complement proteins present in the circulation?
Inactive molecules
Draw a schematic of the complement pathway.
Outline the classical pathway of complement activation.
- Activated by immune complexes
- Formation of antibody-antigen complexes results in a conformational change exposing a binding site for C1 on the antibody
- This binding results in activation of the cascade (this = formation of C3 convertase)
NOTE: this is dependent on antibodies, therefore it requires prior activation of the adaptive immune response (i.e. it does NOT occur very early in the immune response)
Outline the mannose binding lectin pathway of complement activation.
- Activated by the direct binding of MBL to microbial cell surface carbohydrates
- This directly stimulates the classical pathway involving C4 and C2 (but NOT C1)
NOTE: this is NOT dependent on the adaptive immune response
Outline the alternative pathway of complement activation.
- Directly triggered by the binding of C3 to bacterial cell wall components
- This is NOT dependent on the adaptive immune response (continuously active at low levels)
- Involves factors B, D and P
State an example of bacterial cell wall components that can activate complement in Gram-positive and Gram-negative organisms.
Gram-negative: lipopolysaccharide
Gram-positive: teichoic acid
What is the major amplification step of the complement cascade?
C3 convertase
What are the effects of complement fragments that are released during complement activation?
- MAC
- Opsonisation
- Chemotaxis
- Increase vascular permeability (anaphylatoxin)
What are the ligands for the CCR7 receptors on dendritic cells?
- CCL19
- CCL21
- This interaction is important in directing dendritic cells towards lymph nodes
