Immuno 1S: Immune Response to Infection / Primary Immune deficiencies Flashcards
What are the constitutive barriers to infection?
- skin barrier
- Mucosal Surface Barrier
- Commensal Bacteria Barrier
What defence mechanisms does the skin barrier have?
- Tightly packed keratinised cells
-
Physiological factors
- Low pH
- Low O2 tension
-
Sebaceous glands
- Hydrophobic oils repel water/microorganisms
- Lysozyme destroys cell walls
- Ammonia/defensins have anti-bacterial properties
What defence mechanisms does the mucosal surface barrier have?
-
Secreted mucous
- Physical barrier
- Secretory IgA (prevent entry/attachment into epithelia)
- Lysozyme
- Lactoferrin starves bacteria of iron
- Cilia – trap and remove pathogens
What are the components of the innate immune system?
-
Cells
- Polymorphonuclear cells (neutrophils, eosinophils, basophils)
- Monocytes and macrophages
- Natural killer cells
- Dendritic cells
-
Soluble components
- Complement
- Acute phase proteins
- Cytokines and chemokines
Features of the cells of the innate immune system?
- Identical in all individuals
- Cells express receptors that allow them to detect and home to sites of infection
- Cells express genetically encoded receptors (pattern recognition receptors) that allow them to detect pathogens at site of infection
- Cells have phagocytic capacity that allows them to engulf the pathogens
- Cells secrete cytokines and chemokines to regulate immune response
Name the Polymorphonuclear cells
neutrophils, eosinophils, basophils/mast cells
How do Polymorphonuclear cells carry out their function?
- Produced in bone marrow
- Migrate rapidly to site of injury
- Express receptors for cytokines/chemokines (to detect inflammation)
- Express pattern recognition receptors – to detect pathogens
- Express Fc receptors for Ig (to detect immune complexes)
- Capable of phagocytosis / oxidative & non-oxidative killing – particularly neutrophils
- Release enzymes, histamine, lipid mediators of inflammation from granules
- Secrete cytokines and chemokines to regulate inflammation
Name the Mononuclear cells
monocytes, macrophages, lymphocytes
Where are the Mononuclear cells produced and where do they differentiate?
- monocytes produced in bone marrow and circulate in blood to migrate to tissues to differentiate into macrophages
How do mononuclear cells carry out their function?
- Present within tissue
- Express receptors for cytokines and chemokines (to detect inflammation)
- Express pattern recognition receptors –to detect pathogens
- Express Fc receptors for Ig (to detect immune complexes)
- Capable of phagocytosis / oxidative and non-oxidative killing
- Secrete cytokines and chemokines to regulate inflammation
- Capable of presenting processed antigen to T cells
How do macrophages differ from neutrophils in terms of their capabilities?
Capable of presenting processed antigen to T cells
What are macrophages called in each of these organs?
Liver
Kidney
Bone
Spleen
Lung
Neural tissue
Connective tissue
Skin
Joints
Organ
Name for macrophage cells
Liver = Kupffer 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 Synoviocytes
Describe the process of phagocyte recruitment carried out by macrophages
- Cellular damage and bacterial products -> local production of cytokines and chemokines
- Cytokines -> activate vascular endothelium -> enhanced vascular permeability
- Chemokines attract phagocytes (not macrophages as they are already present, mainly neutrophils)
Describe the process of microorganism recognition by macrophages and neutrophils
- Pattern-recognition receptors (PRR) – e.g. Toll-like Receptors (TLRs), Mannose Receptors
- Recognise generic motifs (Pathogen-Associated Molecular Patterns – PAMPs)
- PAMPs = bacterial sugars, DNA, RNA
- Fc receptors bind to the Fc portion of Ig to allow for recognition
Which process facilitates macrophages in phagocytosis?
Opsonisation
What do opsonins do?
- Opsonins act as a bridge between the pathogen and the phagocyte receptors
Give 2 examples of opsonins
- Antibodies -> Fc receptors;
- complement -> complement receptors;
- Acute Phase Proteins (APP) i.e. CRP
What is the name of the structure within the macrophage into which the pathogen is taken up into?
Phagosome
What happens once the pathogen is taken up into the macrophages’ and neutrophils’ phagosomes?
Phagosome fuses with lysosome –> phagolysosome
Where in the macrophage and neutrophil does killing of the pathogen occur?
phagolysosome
What are the 2 types of killing mechanisms (of pathogens) in a macrophage and neutrophil?
Oxidative killing
Non-Oxidative killing
What is oxidative killing?
HOCl acts as an oxidant and anti-microbial
Describe the process of oxidative killing
- (1) NADPH oxidase converts O2 –> O·
- (2) Superoxide dismutase converts O· –> H2O2
- (3) Myeloperoxidase converts H2O2 (+ Cl-) –> hydrochlorus acid (HOCl)
- Requires H2O2 and chlorine
Describe the process of non-oxidative killing
- Release of lysozyme and lactoferrin into phagolysosome
- Enzymes present in distinct specific granules which can provide coverage against many bacteria and fungi
How is pus formed in a site of infection?
- The phagocytosis depletes neutrophil’s glycogen reserves and is followed by neutrophil death
- As the cell dies, residual enzymes release and liquify local tissues
- Accumulation of dead/dying neutrophils in tissues à pus formation
- Extensive pus formation causes abscess formation
Summarise the process of killing pathogens in tissue
- Expression of endothelial activation markers
- mobilisation of phagocytes and (granulocyte) precursors from bone marrow or within tissues i.e. neutrophils
- increased neutrophil adhesion and migration into tissues
- phagocytosis of pathogens by macrophages and neutrophils
- oxidative and non-oxidative killing by macrophages and neutrophils
- macrophages then communicate with T cells & neutrophils die (forming pus)
What is the main difference between macrophages/neutrophils and NK cells
Natural killer (NK) cells recognize infected or defective cells in context of MHC class. Thus, NK cells engage with the autologous cells, and will not engage with the cells of a different organism (microbial pathogens or parasites). NK cells are not phagocytic cells; they kill target cells by secreting biologically active compounds (such as granzymes) or inducing a cell suicide by apoptosis.
Macrophages are phagocytic cells, that remove dead cells and cell debris; they may also attack microbial cells, if these cells carry molecules that macrophages can recognize, or if the cells are opsonized by antibodies or complement.
Neutrophils are phagocytic cells that are primarily involved in combating bacterial or yeast infections. They are very sensitive to certain bacterial compounds (such as formylated peptides) and can also recognize opsonized cells.
What does a cell do once it has been infected by a pathogen intracellularly?
Down-regulate self-HLA molecules (for recogition by NK cells)
What are the roles of NK cells?
- Present within blood and migrate to inflamed tissues (kills ‘altered self’ or virus-infected cells)
- Express inhibitory receptors for self-HLA molecules to prevent mal-activation by normal-self cells
- Express a range of activator receptors (i.e. natural cytotoxicity receptors to recognise heparan sulphate proteoglycans)
- Integrate signals from inhibitory and activator receptors
- Secrete cytokines to regulate inflammation (promote dendritic cell function)
Where do dendritic cells reside?
peripheral tissues
What is the primary function of dendritic cells?
INNATE-ADAPTIVE immune response transition
- pick up antigens (by phagocytosis) that have been left behind,
- then process antigens
- dendritic cells mature & upregulate HLA class I molecules
- process the antigen into peptides, and presents it at the surface
- Upregulate expression of HLA molecules
- Express costimulatory molecules
- Migrate via lymphatics to lymph nodes (mediated by CCR7)
Which receptors do dendritic cells express?
- Cytokine-Rs and chemokine-R –> detect inflammation
- PRRs –> detect pathogens
- Fc receptors for Ig –> detect immune complexes
Where do dendritic cells present processed antigens to T cells?
lymph nodes (to prime the adaptive immune response)
What are the components of the adaptive immune system?
- humoral immunity
- B lymphocytes and antibodies
- cellular immunity
- T lymphocytes (CD4 & CD8 cells)
- soluble components
- cytokines and chemokines
What are the characteristics of the adaptive immune response?
-
Wide repertoire of antigen receptors
- Receptor repertoire is not entirely genetically encoded
- Genes for segments of receptors are rearranged and nucleic acids deleted/added at the sites of rearrangement almost randomly (potential to create 1011 to 1012 receptors
- Autoreactive cells are likely to be generated (mechanisms delete/tolerate these)
- Very specific – detects small differences in molecular structure
- Clonal expansion – cells with appropriate specificity will proliferate during infectio
- Immunological memory – memory cells
What are the primary lymphoid organs?
organs involved in lymphocyte development (acquired immune system)
- Bone marrow – T and B cells derived, B cells mature
- Thymus – T cells mature, most active in foetal/neonatal à involutes after puberty
What are the secondary lymphoid organs?
Secondary lymphoid organs
- Spleen
- Lymph nodes
- Mucosal Associated Lymphoid Tissue (MALT)
Describe the process of T lymphocyte maturation
T cells recognise HLA/peptide complexes.
Which T cells recognise antigens presented by which MHC class molecules?
Which CD is found on all T cells?
CD3
Where does the positive and negative selection of T cells occur?
Thymus
What kind of affinity for HLA must T cells have in order to be selected in the thymus? (central tolerance)
What kind of T cells do the T cell precurors differentiate into if they have affinity for HLA class I?
CD8+ T cells
What kind of T cells do the T cell precurors differentiate into if they have affinity for HLA class II?
CD4+ T cells
What are the roles for CD4+ (‘helper’) T cells?
- Recognise peptides (from extracellular proteins)
- Presented on HLA Class II molecules (HLA-DR, HLA-DP, HLA-DQ)
- Immunoregulatory functions via cell-cell interactions and expression of cytokines
- Provide help for developing full B-cell response
- Provide help for developing some CD8+ T-cell responses
What the subsets of CD4 T cells?
Which cells have MHC I and which cells have MHC II?
- Every cell has MHC I (HLA A, B, C genes)
- APCs have MHC II (HLA DP, DQ, DR genes)
What are the roles of CD8+ “Cytotoxic, Killer” cells?
- Specialised cytotoxic cells that kill cells directly
- Perforin (pore-forming) and granzymes
- Expression of Fas ligand
- Recognise peptides derived from intracellular proteins in association with HLA class I
- HLA-A, HLA-B, HLA-C
- Secrete cytokines (e.g. IFN-gamma, TNF-alpha)
- Particularly important in defence against viral infections and tumours
What is T cell memory?
How does central tolerance for B cells work?
How are B lymphocytes activated?
- B cell receptor (surface expressed Ig) binds to antigen
- Some B cells mature to plasma cells secreting IgM
- proliferation (see next cards)
- further differentiation (see next cards)
What happens to B lymphocytes if they are provided with appropriate signals from CD4+ T cells in secondary lymphoid tissue?
- stimulated B cells rapidly proliferate (undergo highly complex genetic rearrangements)
- (1) Isotype switching to IgG, IgA or IgE (TFh cells) – needs CD40: CD40L (not present in Hyper-IgM)
- (2) Somatic hypermutation to generate high affinity receptors (occurs over a long time)
What do B lymphocytes further differentiate into?
- Plasma cells which produce IgG, IgA or IgE antibody
- Long-lived memory cells
What are immunoglobulins (Ig)?
- soluble proteins made up of 2 heavy and 2 light chains
Which chain determines the antibody class of Ig?
Heavy chain
What are the classes of Ig?
IgM, IgG, IgA, IgE, IgD
Subclasses of IgG and IgA also occur
What are the functions of antibodies?
- Identify pathogens/toxins (Fab-mediated) – esp. bacteria of all kinds
- Interact with other components of immune response (Fc-mediated)
- Complement
- Phagocytes
- NK cells
What is B cell memory?
feature of the secondary immune response
Describe B cell memory
- Lag time between antigen exposure to production of antibody is decreased (to 2-3 days)
- Titre of antibodies produced is greatly increased
- Response is dominated by IgG antibodies of high affinity
- Response may be independent of help from CD4+ T lymphcocytes
Describe the process of B cell memory acquisition
What is complement?
- >20 types of proteins, produced in the liver and present as inactive molecules in circulation o
- When triggered, enzymatically activate each other in a biological cascade
What are the 3 pathways of complement activation?
Which component’s activation is a major amplification step in the complement cascade?
C3 activation is the major amplification step in the complement cascade
What does C3 activation do?
- Increase vascular permeability and cell movement
- Opsonisation of immune complexes so soluble
- Opsonisation of pathogens to promote phagocytosis
- Active phagocytes
- Promote mast cell and basophil degranulation
- Form MAC (via C5-C9) to punch holes in membranes
Learn this
What are cytokines? Give some examples of them
- Small protein messengers
- Immunomodulatory function
- Autocrine or paracrine dependent action
- Examples include IL-2, IL-6, IL-10, IL-12, TNF-alpha, TGF-beta
What are chemokines?
chemoattractant cytokines
What do chemokines do? Give some eg of chemokines
- Direct recruitment / homing of leukocytes in an inflammatory response
- CCL19 and CCL21 are ligands for CCR7 and important in directing dendritic cells to lymph nodes
- Other examples of chemokines include IL-8, RANTES, MIP-1 alpha and beta
