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What are pattern-recognition receptors? What do they do?
- PRRs of macrophages, neutrophils, and dendritic cells recognize PAMPs (pathogen-associated molecular patterns)
- PAMPs are present on many microorganisms but NOT microorganisms
- Cells of innate immunity rely on a limited number of invariant receptors (PRRs)
Give examples of PAMPs
- mannose-rich oligosaccharides in the bacterial cell wall
- peptidoglycans and lipopolysaccharides (LPS) in the bacterial cell wall
- unmethylated CpG DNA (rare in vertebrate genomes)
What are the two ways that immature dendritic cells can be stimulated?
- PRR-dependent phagocytosis: recognize PAMPs with their PRRs which stimulate the cell to engulf/degrade the pathogen
- PRR-independent macropinocytosis: take up extracellular pathogens that their cell-surface receptors do not detect and degrade them
What happens after immature dendritic cells are stimulated at a site of infection?
- Migrate through the lymphatics to regional lymph nodes
- Arrive as fully mature non-phagocytic dendritic cells that present the antigen and express the co-stimulatory molecules necessary to activate a naïve T-cell
What are the four postulates of the clonal selection hypothesis?
- Proposed by Macfarlane Burnet
- 1. Each lymphoid progenitor gives rise to a large number of lymphocytes, each bearing a single type of antigen receptor with unique specificity
- 2. Lymphocytes bearing receptors specific for ubiquitous self antigens are deleted at an early stage in lymphoid cell development (clonal deletion)
- 3. Interaction between a foreign body and a lymphocyte receptor capable of binding that molecule with high affinity activates the lymphocyte
- 4. The differentiated effector cells derived from an activated lymphocyte will bear receptors of identical specificity to those of the parental cell from which that lymphocyte was derived
antibody vs TCR
- Antibodies are the secreted form of BCR
- TCR are the cell-surface receptor on T-lymphocytes
- Both are composed of two regions - constant and variable
- antibody: 2 identical heavy chains, 2 identical light chains
- TWO identical antigen-binding sites
- TCR: one α and one β chain, which span the T-cell membrane
- Single site for antigen-binding sites
- Both recognize antigen
- Antibody: directly binds whole antigen
- TCR: recognizes antigen fragment on APC
- No secreted form
What are the typical structures recognized by BCR/antibody?
Proteins, glycoproteins, and polysaccharides
What is an epitope?
The small part of the molecular structure of an antigenic molecule which is bound by an antibody
What is the difference beween BCR and TCR antigen recognition?
- BCR directly recognize the native antigen secreted by or on surface of pathogen
- B cells differentiate into effector plasma cells which secrete antibodies in response to this antigen
- TCR recognize antigens displayed by APCs
- Epitopes recognized by TCRs are often buried within antigens, but are presented by MHCs (major histocompatibility complexes) after degredation by the APC
Describe the ways in which lymphocyte elimination occurs during the clonal selection process
- Too much stimulation: lymphocytes that react strongly to self antigens are removed by clonal deletion through apoptosis
- Too little stimulation: If receptor is not used within entering the periphery apoptosis occurs
- blood cell production must be balanced by loss
Describe the process of antigens/lymphocytes encountering eachother
- Whole process takes 4-6 days from the time the antigen is recognized
- During an infection free antigens and APCs travel from the site of infection to lymph nodes
- Naïve lymphocytes recirculate constantly through the peripheral lymphoid tissue
- antigen-specific lymphocytes are activated
- Acitvated lymphocytes proliferate/differentiate and then leave cells via the efferent lymphatic vessel which returns them to the bloodstream and eventually the tissues
Describe lymph node structure and function
- Afferent lymphatic vessels: drain fluid from tissues, carrying APCs and free antigens to lymph nodes
- Dendritic cells actively migrate, attracted by chemokines
- High-endothelial venules (HEV): allow entry by lymphocytes, attracted by chemokines
- T lymphocytes are distributed in T cell zones (more toward cortex) and B cells along the periphery of the lymph node
- This centralization aids the activation of B cells at the border
- Germinal centers are variable areas where B cell proliferation occurs
Describe the spleen in detail
- No direct connection with the lymphatic system
- Collects antigen from the blood and lymphocytes enter/leave the spleen via blood vessels
- Collects/disposes of old RBCs
- Red pulp: site of RBC disposal
- White pulp: the site of immune response to blood-borne pathogens
Describe the white pulp in the spleen in detail
- The periarteriolar lymphoid sheath (PALS - sheath of lymphocytes around an arteriole) contains mainly T cells
- Lymphoid follicles, occurring at intervals along PALS, contain mainly B cells
- Marginal zone has few T cells, many macrophages and immature dendritic cells, and some resident non-circulating B cells (marginal zone B cells)
- Blood-borne microbes, soluble antigens, and antigen:antibody complexes are filtered from the blood by macrophages and immature dendritic cells within the marginal zone
- Dendritic cells in the marginal zones migrate to the T-cell areas after taking up antigen and present to T-cells
How do most pathogens enter the body?
- Through mucosal surface which are exposed to air, food, and natural flora
- ~50% of immune cells are under the mucosa for this reason
What are the types of mucosa-associated tissues?
- Gut-associated lymphoid tissues (GALT)
- Nasal-associated lymphoid tissues (NALT)
- Bronchus-associated lymphoid tissues (BALT)
- Urogenital-associated lymphoid tissues (UALT)
Describe the GALT in detail
- Includes tonsils, adenoids, appendix, and Peyer's patches in the small intestine
- Peyer's patches: function to collect antigen from the epithelial surfaces of the GI tract
- the antigen enters directly from the guy across specialized epithelial cells called M cells (microfold cells)
- Lymphocytes enter from the blood and leave through efferent lymphatics
- The sub-epithelial dome is rich in dendritic cells, T cells, and B cells
- B cells are housed within follicles with germination centers
- Activated dendritic cells present the antigen to T cells, and effectory lymphocytes travel through the lymphatic system, into the blood stream, and then into mucosal tissue
Describe co-stimulatory molecules
- Antigen alone is not sufficient to initiate an adaptive immune response
- Lymphocytes require additional signals delivered by cell-surface molecules (co-stimulatory molecules)
- Activated dendritic cells usually deliver this signal to naïve T cells
- Activated helper T cells deliver this signal to naïve B cells
- Contact with antigen WITHOUT costimulatory molecules inavtivates naïve lymphocytes rather than activating them
Describe the three types of APCs
- Dendritic cells: most important
- initiate adaptive immune response
- Macrophages and B cells: act as APCs at later stages after T cells have acquired particular effector activities
- All present using MHC II (MHC I is on all nucleated cells)
Describe lymphocyte proliferation in detail
- There are typically a few lymphocytes that can bind to a given foreign antigen, but not enough to mount a response
- On recognizing its specific antigen a naïve lymphocyte becomes a lymphoblast (enlarged with increased rate of RNA & protein synthesis)
- Lymphoblasts duplicate to produce a clone of around 1000 identical daughter cells (3-5 days) which differentiate into effector cells
- Effector lymphocytes do not recirculate like naïve lymphocytes
- Cytotoxic t cells: detect and migrate into sites of infection from blood
- Helper t cells: some stay in lymphoid tissues to activate B cells
- Plamsa cells: some remain in the peripheral lymphoid organs, but most return to bone marrow and "pour" antibodies into the blood stream
- Effector cells from mucosal immune system typically stay there
Why is immunological memory so effective?
- Some activated B and T cells persist after infection as memory cells
- The secondary antibody response has a shorter lag time, response level, and the antibodies have an increased affinity for the antigen (affinity maturation)
- T cells DO NOT undergo affinity maturation
Where are antibodies found?
- Fluid component of blood (plasma) and extracellular fluid
- This lends to the name humoral (fluid) immunity
What are the 5 types of constant region seen for antibodies?
IgM, IgD, IgG, IgA, and IgE
What are the 3 ways antibodies participate in host defense?
- Neutralization: binding to pathogen or products block access to host cell
- block virus from entering/replicating
- block bacterial toxins
- Opsonization: coat pathogens which facilitate phagocytosis (neutrophil or macrophage)
- This is important for the bacteria that can evade innate immunity by having a coat without PAMPs
- Complement activation: protein cascade which...
- can kill the bacterial directly (via pore)
- make pathogen easier to phagocytize
- Induces inflammatory responses which fight infection
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