Immunology - Immune Response/Physiology Flashcards
What are the stages of a normal innate response?
- Phagocytes are produced in the bone marrow and released into the blood
- Endothelial cells express adhesion molecules
- Phagocytes stick to the blood vessel wall and migrate into the tissue
- Phaogcytes engulf the micro-organisms
- Phaogcytes kill the micro-organisms through oxidate and non-oxidative killing
- Neutrophils die after phagocytosis and form pus
- Macrophages are activated and use cytokines for cell-cell communication (predominantly with T cells)
What are three consistutive, non-specific barriers to infection?
- Skin
- Mucosal surfaces
- Commensal bacteria
How does skin act as a barrier to infection
- Tightly packed keratinised cells physically limits colonisatioin by micro-organisms
- Physical factors (e.g. low pH, low oxygen tension)
- Hostile wall with sebaceous glands (hydophobic oils repel water + micro-organisms, lysozyme destroys bacterial cell wall, ammonia and defensins = antibacterial)
How do the mucosal surfaces act as a barrier to infection?
- Secrete mucous = traps invading pathogens (secretory IgA prevents bacteria/virus attachment to cell membrane, lysozyme kills invading pathogens, lactoferrin starves bcteria of iron)
- Cilia directly trap and remove mucous, assited by physical manoeuvres (sneezing/coughing)
How do commensal bacteria act as a barrier to infection?
- Compete with pathogenic micro-organisms for scarce resources
- Produce fatty acids that inhibit growth of many pathogens
What aspects are part of the innate immune system?
Cells:
- polymorphonuclear cells = neutrophils, eosinophils, basophils
- monocytes + macrophages
- natural killer cells
- dendritic cells
- granulocytes
Soluble components:
- complement
- acute phase proteins
- cytokines + chemokines
How do cells generally work as part of the innate immune system?
- Express receptors for cytokines/chemokines (detect inflammation)
- Express pattern recognition receptors (detect pathogens)
- Phagocytosis / oxidative + non-oxidative killing
- Secrete cytokines + chemokines (regulate inflammation)
What is the role of polymorphonuclear cells / granulocytes in the innate immune system?
- Produced in bone marrow
- Rapid migration to site of injury
- Express Fc receptors for Ig (detect immune complexes)
- Release enzymes, histamine, lipid mediators of inflammation from granules
What is the role of monocytes/macrophages in the innate immune system?
- Monocytes produced in bone marrow, circulate in blood + migrate to tissues where they differentiate into macrophages
- Present processed antigens to T cells
- Name dependent on tissure (e.g. Kupffer cell = liver, osteoclast = bone, langerhans cells = skin)
What is the process of oxidative killing?
- NADPH oxidase complex converts oxygen to reactive oxygen speces (e.g. hydrogen peroxide)
- Myeloperoxidase catalyses production of hydrochlorous acid (from hydrogen peroxide and chloride)
- Hydrochlorous acid = effective oxidant and anti-microbial
What is the process of non-oxidative killing?
- Release of bactericidal enzymes (lysozymes + lactoferrin) into phagolysosome
- Enzymes present in granules (each has unique antimicrobial spectrum = broad coverage against bacteria + fungi)
What is the role of the neutrophil in the innate immune system
Death of the phagocyte
- Phagocytosis depletes neutrophil glycogen reserves (energy expensive) which leads to cell death
- As cell dies, residual enzymes released causing liquefaction of close tissue
- Assumulation of dead/dying neutrophils forms pus
- Extensive localised formation of pus causes abscess formation
What is the role of the natural killer cell (cytotoxic lymphocyte) in the innate immune system?
- Present within blood + migrates to inflamed tissue
- Expresses inhibitory receptors for self-HLA molecules (prevents inappropriate activation by normal self)
- Expresses range of activating receptors (e.g. natural cytotoxicity receptors) that recognise heparan sulphate proteoglycans
- Cytotoxic
- Secrete cytokines to regulate inflammation
What is the definition of cytotoxic?
Kills “altered self”, malignant or cirus infected cells which lack inhibitory signals
What is endocytosis facilitated by and what does it do?
Opsonisation = Opsonins act as bridge between pathogen and phagocyte receptors
- Abs bind to Fc receptors
- Complement components bind to complement receptors
- Acute phase proteins
What is the role of dendritic cells in the innate immune system?
Mediate transition from innate immunity to adaptive immunity
- Reside in peripheral tissues
- Express Fc receptors for Ig to detect immune complexes
- Mature after phagocytosis (upregulate expression of HLA molecule, express costimulatory molecules, migrate via lymphatics to lymph nodes - mediated by CCR7)
- Present processed antifent to T cells in lymph nodes
- Express cytokins to regulate immune response
What are the components of the adaptiv immune system?
- Humoral immunity = B lymphocytes + antibody
- Cellular immunity = T lymphocytes (CD4 + CD8)
- Soluble components = cytokines + chemokines
What are the primary lymphoid organs and what do they produce?
Organs involved in lymphocyte development
- Bone marrow: T + B lymphocytes derived from haematopoeitic stem cells + site of B cell maturation
- Thymus: site of T cell maturation
What are the secondary lymphoid organs?
Anatomical sites of interaction between naiive lymphocytes and micro-organisms
- Spleen
- Lymph nodes
- Mucosal associated lymphoid tissue
What is the process of T cell maturation?
- Arise from haematopoeitic stem cells
- Exported as immature cells to thymus where undergo positive and negative selection
- Mature T lymphocytes enter circulation and reside in secondary lymphoid organs
What are the different types of T cells and how are they different?
ALL express CD3+
- CD8+ = recognise peptide presented by HLA class I molecules
- CD4+ = recognise peptide presented by HLA class II molecules
How does positive and negative selection take place in the thymus for T cell maturation?
- Low affinity for HLA = not selected (avoids inadequate reactivitiy)
- Intermediate affinity for HLA = positive selection (~10% original cells)
- High affinity for HLA = not selected (avoids autoreactivity)
What are CD4+ T cells and what do they do?
Helper lymphocytes
- recognise peptides derived from extracellular proteins presented on HLA Class II molecules (HLA-DR, HLA-DP, HLA-DQ)
- Cell interactions + expression of cytokines
- Provides help for development of full B cell response and some CD8+ T cell responses
What are CD8+ T cells and what do they do?
Specialised cytotoxic cells (T killer cells)
- Recognise peptides derived from intracellular proteins in association with HLA Class I (HLA-A, HLA-B, HLA-C)
- Kills cells directly (perforin and granzymes + expression of Fas ligand)
- Secretes cytokines (indirect cytotoxicity)
What is the process of B cell maturation?
- Stem cells in bone marrow become lymphoid progenitors which go on to become pro B cells and then pre B cells
- Peripherally become IgM expressing B cells
- Can develop into plasma cells that secrete IgM, with antigen engagement
- OR undergo germinal centre reaction (somatic hypermutation and class switching) + become PLASMA cells expressing IgG, IgE, IgA
What is the central tolerance of B cells?
- No recognition of self-antigens means they survive
- Recognition of self-antigens in bone marrow results in negative selection (avoids autoreactivity)
What is the process of B lymphocyte activation?
- B cell receptor binds to antigen
- Some B ccells mature to IgM secreting plasma cells (pentamer)
- If received appropriate signal from CD4+ T cell in secondary lymphoid tissue, germinal centre reaction occurs resulting in rapid B cell proliferation (dendritic cells prime CD4+ T cells which then help B cell differentiation)
B cells also undergo complex genetic rearrangements (isotype switching to IgG, IgA, IgE + somatic hypermutation to generate high affinity receptors)
What are immunoglobulins?
Soluble proteins that are made up of 2 heavy and 2 light chains
- Heavy chain determines antibody class (IgM, IgG, IgA, IgE, IgD)
- Antigen recognised by antigen binding regions (Fab) or heavy + light chains
- Effector function determines by constant region of heavy chain (Fc)
What is the function of antibodies?
- Identification of pathogens + toxins (Fab-mediated)
- Interaction with other components of immune response to remove pathogens (Fc-mediated - e.g. complement, phagocytes, NK cells)
What is complement?
- 20 tightly regulated, linked proteins produced by liver + present in circulation of inactive molecules
- When triggered, enzymatically activate other proteins in a biological cascade (results in rapid, highly amplified response)
What happens when complement pathways are activated?
- Complement fragments released
- Fragments increase vascular permeability, cell trafficking, opsonise pathogens + activate immune cells
What is the classical pathway of complement activation?
The formation of Ab-Ag immune complexes
- Results in change in antibody shape (exposes binding site for C1)
- Binding of C1 to binding site on Ab results in activation of cascade
- Dependent upon activation of acquired immune response
What is the Mannose Binding pathway of complement activation?
- Activated by direct binding of MBL to microbial cell surface carbohydrates
- Directly stimulates classical pathway involving C4 + C2 but not C1
- Not dependent on acquired immune response
What is the alternative pathway of complement activation?
- Directly triggered by binding of C3 to bacterial cell wall components
- Not dependent on acquired immune response
- Involves factors B, I, P
How is C3 convertase activated?
Major activation step in complement cascade
- All pathways activate C3
- Triggers formation of membrane attack complex via C5-C9 and punches holes in bacterial membranes
What is the endpoint of the complement cascade?
The Membrane Attack Complex
What is the formation of the membrane attack complex?
Classical Pathway (C1, C2, C4)
Mannose Binding Pathway (C4, C2)
Alternative Pathway
Activates C3
Final pathway of C5-C9 activated the Membrane Attack Complex
What are cytokines and their role?
- Small protein messengers
- Immunomodulatory function
- Autocrine/paracrine dependent action
e.g. IL-2, -6, -10, -12, TNF-α, TNF-β
What are chemokines and their role?
- Chemotactic cytokines (e.g. chemoattractants)
- Direct recruitment/homing of leukocytes in inflammatory response
- CCL19 + CCL21 are ligands for CCR7 (important in directing dendritic cell trafficking to lymph nodes)
e.g. IL-8
