Immunology 1 - The immune response to infection Flashcards
Incomplete - excludes basics and material that is mentioned in subsequent lectures
What are the constitutive barriers to infection?
Skin
Mucosal surfaces
Commensal bacteria (compete for scarce resources and produce fatty acids + bactericidins to inhibit pathogen growth)
What are the features of skin that provide a barrier to infection?
Tightly packed keratinised cells
Low pH and low O2 tension
Sebaceous glands which produce:
- Hydrophobic oils that repel microorganisms and water
- Lysozyme which destroys the structural integrity of the cell wall
- Ammonia and defensins which have antibacterial properties
What features of the mucosal surfaces provide a barrier to infection?
Cilia that trap and remove pathogens
Secreted mucous which acts as a physical barrier and produces:
- Secretory IgA (prevent attachment/entry into epithelia)
- Lysozyme
- Lactoferrins which starve microorganisms of iron
What are the cells of the innate immune system?
What are the soluble components of the innate immune system?
Cells
Polymorphonuclear cells:
- Neutrophils, eosinophils, basophils
Monocytes and macrophages
NK cells
Dendritic cells
Soluble components
Complement, acute phase proteins, cytokines, chemokines
What is the main difference in function between neutrophils and macrophages?
Macrophages can present antigen on their surface following phagocytosis, but neutrophils cannot
What are macrophages called in the:
Liver
Kidney
Bone
Spleen
Lung
Neural tissue
Connective tissue
Skin
Joints
Liver = Kuppfer cell
Kidney = Mesangial cell
Bone = Osteoclast
Spleen = Sinusoidal lining cell
Lung = Alveolar macrophage
Neural tissue = Microglia
Connective tissue = Histiocyte
Skin = Langerhans cell
Joints = Macrophage-like synoviocyte
Give two examples of pattern recognition receptor
Toll like receptor
Mannose receptor
How is pus formed?
Following phagocytosis, neutrophils die
When they die, they release residual enzymes which causes the liquefication of closely adjacent material
This forms pus
What is opsonisation?
Modification of a pathogen to attract it to a NK or phagocytic cell
May be mediated by antibodies, complement components or acute phase proteins
Enables phagocytosis
What is the difference between oxidative and non-oxidative killing?
Oxidative: uses NADPH oxidase and myeloperoxidase to form hydrochlorous acid - this acts as an oxidant and anti-microbial
Non-oxidative: release of lysosymes and lactoferrin into the phagolysosome
What role do NK cells play in regulating immunity?
Express inhibitory receptors for self-HLA molecules
If the cell’s self-HLA molecule is down regulated (e.g. because it is infected), it becomes a target cell -> lysis
Describe the changes that occurs in dendritic cells following phagocytosis
Dendritic cells mature after phagocytosis -> represents the innate-adaptive transition
- Upregulate expression of HLA-1
- Express costimulatory molecules
- Migrate via lymphatics to lymph nodes (mediated by CCR7)
- Process non-self antigen and present it to T cells in lymph nodes to prime the adaptive immune response
- Express cytokines to regulate the immune response
What are the primary lymphoid organs and their function?
Bone marrow: B + T cell production, B cell maturation
Thymus: T cell maturation
What is a secondary lymphoid organ?
Anatomical sites of interaction between naive lymphocytes and antigens e.g. spleen, lymph nodes and MALT (mucosa associated lymphoid tissue)
Describe the process of T cell maturation
Haematopoietic stem cells begin to mature in the bone marrow
Undergo TcR rearrangement in which alpha and beta chain segments are rearranged in a semi-random manner
Migrate to thymus as pre-T cells where they undergo selection for CD4 and CD8
Low affinity for HLA - not selected
Medium affinity - positive selection of ~10% of original cells
- Affinity for HLA class 1 = CD8+ differentiation
- Affinity for HLA class 2 = CD4+ differentiation
High affinity - negative selection to avoid autoreactivity (central tolerance)
Recall 2 functions of CD4+ T lymphocytes
Recognise peptides presented on HLA class II molecules
Immunoregulatory functions via cell-cell interactions and cytokine expression -> provides help for development of:
- Full B cell response
- Some CD8+ T cell responses
Which cells express HLA Class I and which cells express HLA Class 2?
Every cell has MHC I (HLA-A, HLA-B, HLA-C)
Antigen presenting cells have MHC II (HLA-DP, HLA-DQ, HLA-DR)
Which cytokines induce development of CD4 T cells into Th1 cells?
IL2 and IFN gamma
What is the function of Th1 cells?
‘Help’ CD8 T cell and macropage responses
Which cytokines induce development of CD4 T cells into Th17 cells?
IL6 and TGF beta
What is the function of Th17 cells?
‘Help’ neutrophil recruitment
Which cytokine induces development of CD4 T cells into Treg cells?
TGF beta
Which cytokine induces development of CD4 T cells into follicular T helper cells?
IL6
Which type of T cell produces CD25 and FOXP3?
T reg cells
By what mechanism do CD8 cells effect their cytotoxicity?
Injection of perforin, which enables granzyme entry OR Fas ligand expression
Which cytokines are secreted by CD8 T cells?
IFN gamma and TNF alpha
Process of B cell development
Arise from haematopoietic stem cells
Created through semi-random gene rearrangement to produce a diverse receptor repertoire
Cells only survive if there is no recognition of self in the bone marrow (central tolerance)
What is the first class of immunoglobulin to be made when a B cell encounters an antigen?
IgM
What is a germinal centre reaction?
Process where B cells differentiate into IgG, IgA and IgE secreting plasma cells - requires appropriate signals from CD4+ T cells in the secondary lymphoid tissue
Without CD4 cell function, the B cell response will be restricted to IgM
How do CD4 cells activate B cells?
Express CD40 ligand, which interacts with CD40 on immature B cell surface, causing the B cell to differentiate
Recall the 2 processes that B cells undergo during a germinal centre reaction
- Class/Isotype switching
- Somatic hypermutation (to become very high affinity)
Which part of an immunoglobulin determines its class?
Heavy chain
Which portion of an immunoglobulin mediates pathogen identification?
Fab portion
Which portion of an immunoglobulin mediates activation of complement/ NK cells?
Fc portion
Where is complement produced?
>20 types of protein produced in the liver
What is the classical pathway?
Antibody + C1 -> C2, C4 -> C3 -> final common pathway C5-C9
Antibody-antigen immune complexes bind to C1, leads to a change in the antibody shape and this exposes the C1 binding site -> activates the cascade
CLASSICAL PATHWAY DEPENDS ON ACTIVATION OF ACQUIRED IMMUNE RESPONSE so it’s a late response
What is the mannose binding lectin pathway?
MBL -> C2, C4 -> C3 - final common pathway C5-C9
Mannose binding lectin binds to oligosaccharides/microbial cell
surface carbohydrates on certain virions/infected cells.
This then directly stimulates C4 & C2 but not C1.
NOT DEPENDENT ON THE ACQUIRED IMMUNE RESPONSE.
What is the alternative pathway?
PAMP -> C3 -> final common pathway C5-C9
Spontaneous breakdown of C3 in serum due to it binding to components in the bacterial cell wall (e.g. lipopolysaccharide of gram –ve, teichoic acid of gram +ve).
This forms alternative C3 convertase
Involves factors B, I & P.
NOT DEPENDENT ON THE ACQUIRED IMMUNE RESPONSE
What are the functions of fully activated complement?
Formation of membrane attack complex via C5-C9 -> punches holes in membranes
Cleaved components of the complement cascade generate other effects:
- Increases vascular permeability and cell trafficking
- Opsonisation of immune complexes so they remain soluble
- Promote basophil and mast cell degranulation
- Opsonisation of pathogens: esp. capsulated bacteria
- Activate phagocytes
What are cytokines and chemokines?
Cytokines = small protein messengers which exert autocrine or paracrine effects and have an immunomodulatory action e.g. IL-2, IL-10, TNF-alpha
Chemokines = chemoattractant cytokines which directly recruit and home leukocytes in an inflammatory response e.g. CCL19, CCL21, IL-8
What is the role of the CCL19 and CCL21 chemokines?
They are ligands for CCR7 and important for directing dendritic cells to lymph nodes
Summarise the immune defence against a pathogen
Pathogen has to get through the constitutive barriers (skin, musoca, commensal bacteria)
Pathogens that get through may become intracellular (viruses, some bacteria) or extracellular (bacteria like staph and strep)
Innate Immune Response
Neutrophils are mobilised very quickly to go to the infection site, and they have pathogen recognition receptors which allows them to phagocytose pathogens -> and then the neutrophils die to form pus
Tissue-resident macrophages are already there but they still have receptors allowing them to go to the precise point of infection and they phagocytose -> but they don’t die and instead stick around to interact with T cells
NK cells can deal with intracellular pathogens providing the infected cell’s expression of self-HLA has changed -> NK cells kill the infected cells
Innate-Adaptive Transition
Dendritic cells with PRRs also phagocytose but then processes the pathogen, matures and upregulates HLA expression so it can present the antigen on its cell surface -> then it migrates to the lymph nodes
Dendritic cells present the peptides to CD4 cells in the lymph nodes -> CD4 cells provide help so that the dendritic cells can prime the CD8 cells
Adaptive Immune Response
CD8 cells go off and kill infected cells (CD8 cells express TCRs that recognise peptides presented by HLA Class 1 -> these peptides tend to come from intracellular pathogens)
B cells can bind to the pathogen’s antigen with their BCR and produce IgM early
Where the dendritic cells have primed CD4 cells, the CD4 cells can help the B cells -> isotype switching + somatic hypermutation and proliferation (germinal centre reaction) -> mature into plasma cells secreting IgG, IgA, IgE
Immunoglobulins will bind to the extracellular pathogen -> immune complexes will activate complement, bind to NK cells and bind to macrophages
