ImmunologyTest1Ch1.2

• 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)

• mannose-rich oligosaccharides in the bacterial cell wall
• peptidoglycans and lipopolysaccharides (LPS) in the bacterial cell wall
• unmethylated CpG DNA (rare in vertebrate genomes)

• 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

• 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

• 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

• Antibodies are the secreted form of BCR
• TCR are the cell-surface receptor on T-lymphocytes
• STRUCTURE
• 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
• FUNCTION
• Both recognize antigen
• Antibody: directly binds whole antigen
• TCR: recognizes antigen fragment on APC
• No secreted form

Proteins, glycoproteins, and polysaccharides

The small part of the molecular structure of an antigenic molecule which is bound by an antibody

• 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

• 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

• 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

• 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

• 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

• 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

• Through mucosal surface which are exposed to air, food, and natural flora
• ~50% of immune cells are under the mucosa for this reason

• Gut-associated lymphoid tissues (GALT)
• Nasal-associated lymphoid tissues (NALT)
• Bronchus-associated lymphoid tissues (BALT)
• Urogenital-associated lymphoid tissues (UALT)

• 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

• 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

• 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)

• 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

• 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

• Fluid component of blood (plasma) and extracellular fluid
• This lends to the name humoral (fluid) immunity

IgM, IgD, IgG, IgA, and IgE

• 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