Immune response to infections Flashcards
How do infections get into the body?
External Epithelia: Physical contact, wounds and abrasions, insect bites
Mucosal surfaces: Airway, GI tract, reproductive tract
What are the constitutive barriers to infection in the skin?
- Tightly packed keratinised cells
- Physiological factors (Low pH and Low oxygen tension)
- Sebaceous glands (Hydrophobic oils, Lysozyme, Ammonia and defensins)
What are the constitutive barriers to infection in mucosal surfaces?
- Secreted mucous (Physical barrier, Secretory IgA, lysozyme/ AntiMicrobial peptides, Lactoferrin)
- Cilia (trap and move)
What are the constitutive barriers to infection by commensal bacteria?
100 trillion normal bacteria
- Competition
- Produce fatty acids and bactericidins that inhibit growth
What are the cells of the innate immune system?
Polymorphonuclear cells – neutrophils, eosinophils, basophils
Monocytes and macrophages
Natural killer cells
Dendritic cells
What are the soluble components of the innate immune system?
Complement
Acute phase proteins
Cytokines and chemokines
What is the cell response in the innate immune system?
Essentially identical responses 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
What are the polymmorphonuclear cells?
Neutrophils, eosinophils, basophils and mast cells
Where are PMNCs produced?
Bone marrow
What can PMNCs do?
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
What are the Mononuclear cells?
Monocytes and macrophages
What is the difference between monocytes and macrophages?
Monocytes are produced in bone marrow, circulate in blood and migrate to tissues where they differentiate to macrophages
What type of macrophage is in the liver?
Kupffer cell
What type of macrophage is in the Kidney?
Mesangial
What type of macrophage is in the Bone?
Osteoclast
What type of macrophage is in the Spleen?
Sinusoidal lining
What type of macrophage is in the Lung?
Alveolar macrophage
What type of macrophage is in the Neural Tissue?
Microglia
What type of macrophage is in the Connective tissues?
Histiocyte
What type of macrophage is in the Skin?
Langerhans cell
What type of macrophage is in the joints?
Macrophage like synoviocytes
Where are macrophages?
Tissues
What do macrophages make?
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
What does cellular damage/ bacterial products trigger?
Local production of inflammatory cytokines (activate vascular endothelium enhancing permeability) and chemokines (attract phagocytes)
What are PRR?
Pattern recognition receptors such as Toll-like receptors and mannose receptors which recognise generic motifs known as pathogen-associated molecular patterns (PAMPs) such as bacterial sugars, DNA, RNA
Fc receptors for Fc portion of immunoglobulin to allow recognition of immune complexes
What is opsonisation?
Opsonins act as a bridge between the pathogen and the phagocyte receptors
Antibodies binding to Fc receptors
Complement components binding to complement receptors
Acute phase proteins eg C reactive protein (CRP)
This allows endocytosis!
How is the phagolysosome?
Phagosome and lysosome fuse to form phagolysosome
Protected compartment in which killing of the organism occurs
How does oxidative killing work?
NADPH oxidase complex converts oxygen into reactive oxygen species – superoxide and hydrogen peroxide
Myeloperoxidase catalyses production of hydrochlorous acid from hydrogen peroxide and chloride
Hydrochlorous acid is a highly effective oxidant and anti-microbial
How does non oxidative killing work?
Release of bacteriocidal enzymes such as lysozyme
and lactoferrin into the phagolysosome
Enzymes present in granules
Each has a unique antimicrobial spectrum
Results in broad coverage against bacteria and fungi
When do neutrophils die?
Process of phagocytosis depletes neutrophil glycogen reserves and is followed by neutrophil cell death
> As the cells die, residual enzymes are released, causing liquefaction of closely adjacent tissue.
> Accumulation of dead and dying neutrophils within infected tissue results in the formation of pus
> Extensive localised formation of pus causes abscess formation
What are natural killer cells like?
Present within blood and may migrate to inflamed tissue
Express inhibitory receptors for self-HLA molecules that prevent inappropriate activation by normal self
Express a range of activatory receptors including natural cytotoxicity receptors that recognise heparan sulphate proteoglycans
Integrate signals from inhibitory and activatory receptors
Cytotoxic - kill ‘altered self’ as in malignant or virus infected cells
Secrete cytokines to regulate inflammation – promote dendritic cell function
How do you NK cells get triggered into causing lysis?
If the inhibitory receptor is not filled by target cell
What are dendritic cells like?
Reside in peripheral tissues
Express receptors for cytokines and chemokines - to detect inflammation
Express pathogen recognition receptors – to detect pathogens
Express Fc receptors for Ig - to detect immune complexes
Capable of phagocytosis
Following phagocytosis dendritic cells mature:
Upregulate expression of HLA molecules
Express costimulatory molecules
Migrate via lymphatics to lymph nodes – mediated by CCR7
Present processed antigen to T cells in lymph nodes to prime the adaptive immune response
Express cytokines to regulate the immune response
What are lymphatics?
Thoracic duct returns lymph to blood
Naive lymphocytes enter lymph nodes from blood
Antigens from sites of infection reach lymph nodes via lymphatics
What are the parts of the adaptive immune system?
Humoral immunity
Cellular immunity
Soluble components
What cells are in humoral immunity?
B lymphocytes
Antibody
What are the parts of cellular immunity?
T cells - CD4 and CD8
What are the soluble components of adaptive immunity?
Cytokines and chemokines
What are the characteristics of the adaptive immune system which are different to the innate immune system?
- Wide repertoire of antigen receptors
- Exquisite specificity
- Clonal expansion
- Immunological memory
What is a secondary lymphoid organ?
Anatomical sites of interaction between naïve lymphocytes and microorganisms
What are the secondary lymphoid organs?
Spleen
Lymph nodes
Mucosal associated lymphoid tissue
How do T lymphocytes mature?
Arise from haematopoetic stem cells
Exported as immature cells to the thymus where undergo selection
Mature T lymphocytes enter the circulation and reside in secondary lymphoid organs
What is the difference between CD4 and CD8 T cells?
CD8+ T cells recognise peptide presented by HLA class I molecules CD4+ T cells recognise peptide presented by HLA class II molecules
How does selection and central tolerance work in T cells?
> Low affinity for HLA -> not selected to avoid inadequate reactivity
> Intermediate affinity for HLA -> Positive selection (about 10% original cells)
> High affinity for HLA -> negative selection to avoid autoreactivity
How does selection occur in T cells for CD4/8?
Intermediate affinity for HLA class I -> CD8+ T cells
Intermediate affinity for HLA class II -> CD4+ T cells
What are the T cell Subsets?
Th1 Th17 Treg TFh Th2
What do CD4+ cells do?
Recognise
peptides derived 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 development of full B cell response
Provide help for development of some CD8+ T cell responses
What do CD8+ cells do?
Specialised cytotoxic cells
Recognise peptides derived from intracellular proteins in association with HLA class I HLA-A, HLA-B, HLA-C
Kill cells directly
Perforin (pore forming) and granzymes
Expression of Fas ligand
Secrete cytokines eg IFNg TNFa
Particularly important in defence against viral infections and tumours
What is T cell memory?
Response to successive exposures to antigen is qualitatively and quantitatively different from that of first exposure
Pool of ‘memory’ T cells ready to respond to antigen
More easily activated than naïve cells
What are Th1 cells?
Subset of cells that express CD4 and secrete IFN gamma and IL-2
Help CD8 cells and macrophages
What do CD8 T cells express?
Express receptors that recognise peptides usually derived from intracellular proteins and expressed on HLA class I molecules
What do Tfh cells do?
Play an important role in promoting germinal centre reactions and differentiation of B cells into IgG and IgA secreting plasma cells
They are follicular helper cells
What are Tregs?
Subset of lymphocytes that express Foxp3 and CD25
IL10/TGFb expression, CD25+/ FOXp3+
How do B lymphocytes mature?
Stem cells -> lymphoid progenitors -> Pro B cells -> Pre B cells -> IgM B cells -> Differentiated B cells (IgE, IgG, IgM)
How does central tolerance in B cells work?
No recognition of self in bone marrow -> survive
Recognition of self -> Negative selection to avoid autoreactivity
How does a Bcell antigen encounter work?
Early IgM response -> IgM secreting plasma cell
Germinal centre reaction in LN (CD4+ dependent) -> dendritic cell primes CD4Tcell -> CD4 cell helps B cell differentiation using CD40L:CD40 -> B cell proliferation, somatic hypermutation and isotype switching
High affinity IgG, IgA, IgE secreting plasma and memory cells made
How are B lymphocytes activated?
B cell receptor (surface expressed Ig) binds to antigen
Some B cells mature to plasma cells secreting IgM
If provided with appropriate signals from CD4+ T cells in secondary lymphoid tissue, stimulated B cells rapidly proliferate
Undergo highly complex genetic rearrangements
Isotype switching to IgG, IgA or IgE
Somatic hypermutation to generate high affinity receptors
Further differentiation
plasma cells which produce IgG, IgA or IgE antibody
long-lived memory cells
What are immunoglobulins?
Soluble proteins made up of two heavy and two light chains
What are the important parts in the heavy chain?
Heavy chain determines the antibody class IgM, IgG, IgA, IgE, IgD, subclasses of IgG and IgA also occur.
Antigen is recognised by the antigen binding regions (Fab) of both heavy and light chains
Effector function is determined by the constant region of the heavy chain (Fc)
What is the function of the antibody?
Fab: ID pathogens and toxins
Fc: interacts with complement, phagocytes and NK cells
Useful in defence against bacteria.
How does B cell memory work?
Response to successive exposures to antigen is qualitatively and quantitatively different from that of first exposure
- Lag time reduced to 2-3 days
- Antibody titre increased
- Mainly high affinity IgG
- Can be independent of CD4+ help
What is Pre B cell?
Exist within the bone marrow and develop from haematopoietic stem cells
What is IgA?
Divalent antibody present within mucous which helps provide a constitutive barrier to infection
What is IgG secreting plasma cell?
Cell dependent on the presence of CD4 T cell help for generation.
What is IgM secreting plasma cell?
Are generated rapidly following antigen recognition and are not dependent on CD4 T cell help
What is a primary lymphoid organ?
Include both the bone marrow and thymus; sites of B and T cell development
What is the thoracic duct?
Carries lymphocytes from lymph nodes back to the blood circulation
What is the thymus?
Site of deletion of T cells with inappropriately high or low affinity for HLA molecules and of maturation of T cells into CD4+ or CD8+ cells
What is the germinal centre?
Area within secondary lymphoid tissue where B cells proliferate and undergo affinity maturation and isotope switching
What is complement?
> 20 tightly regulated, linked proteins
Present in the circulation as inactive molecules
Where are complement proteins produced?
The liver
How does complement work?
When triggered, enzymatically activate other proteins in a biological cascade
Results in rapid, highly amplified response
What are the 3 pathways of complement activations?
Classical (C1/2/4)
MBL (C4/2)
Alternative
They go into C3 and then the Membrane Attack Complex
(Common pathway - C5-9)
How does the classical pathway work?
Formation of antibody-antigen immune complexes
Results in change in antibody shape – exposes binding site for C1
Binding of C1 to the binding site on antibody results in activation of the cascade
Dependent upon activation of acquired immune response (antibody)
How does the Mannose binding lectin pathway work?
Activated by the direct binding of MBL to microbial cell surface carbohydrates
Directly stimulates the classical pathway, involving C4 and C2 but not C1
Not dependent on acquired immune response
How does the alternative pathway work?
Directly triggered by binding of C3 to bacterial cell wall components
eg lipopolysaccharide of gram negative bacteria
teichoic acid of gram positive bacteria
Not dependent on acquired immune response
Involves factors B, I and P
What happens after the activation of C3 convertase?
Activation of C3 is the major amplification step in the complement cascade
Triggers the formation of the membrane attack complex via C5-C9
What does the MAC do?
Punches hole sin bacterial membranes
What do complement fragments do?
Increases vascular permeability and cell trafficking to site of inflammation
Opsonisation of immune complexes keeps them soluble
Opsonisation of pathogens to promote phagocytosis
Activates
phagocytes
Promotes mast cell/basophil degranulation
Punches holes in bacterial membranes
What is C1?
Triggers classical pathway via antibody binding
What is C3?
Triggers C5-9 after being cleaved through classical, alternative or MBL pathways
What is C9?
Binds to microbial surface carbohydrates to activate the complement cascade in an immune complex independent manner
What is MBL?
Part of the final common pathway resulting in the generation of the membrane attack complex
What is a cytokine?
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 is a chemokine?
Chemotactic cytokines – ie chemoattractants
Direct recruitment / homing of leukocytes in an inflammatory response
CCL19 and CCL21 are ligands for CCR7 and important in directing dendritic cell trafficking to lymph nodes
Other examples of chemokines include IL-8, RANTES, MIP-1 alpha and beta.
What is oxidative killing?
Describes killing mediated by reactive oxygen species generated by action of the NADPH oxidase complex
What is pathogen recognition mediated by?
Is mediated by Toll like receptors which recognise pathogen associated molecular patterns
What is opsonisation mediated by?
May be mediated by antibodies, complement components or acute phase proteins and facilitates phagocytosis
What is non oxidative killing?
May be mediated by bacteriocidal enzymes such as lysozyme
What are neutrophils?
Polymorphonuclear cells capable of phagocytosing pathogens and killing by oxidative and non-oxidative mechanisms
What are NK cells?
Lymphocytes that express inhibitory receptors capable of recognising HLA class I molecules and have cytotoxic capacity
What are dendritic cells?
. Immature cells are adapted for pathogen recognition and uptake whilst mature cells are adapted for antigen presentation to prime T cells
What are macrophages?
Derived from monocytes and resident in peripheral tissues
How does a wide repertoire of antigen receptors occur in the adaptive immune system?
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 in order of 10^11 to 101^2 receptors
Autoreactive cells are likely to be generated
Mechanisms must exist to delete or tolerise these autoreactive cells
What do T cells present on their surface?
CD3
CD4 or CD8
TCR
What are Th2 cells?
Helper T cells
IL-4. 5, 10 and 13
