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214 Cards in this Set
- Front
- Back
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Innate Immunity
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-"Non-specific responses"
-Present and available from birth -Allows protection without gene rearrangements needed to generate a large repertoire of antigen-recognition molecules -Rapid response (minutes to hours) -Associated with the initiation of the immune response -No memory of antigen -Can influence the development of adaptive immune responses -Signals to host to respond to antigen |
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Innate immunity Components
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-Physical barriers
--integument, skin, mucosal surfaces, tears, saliva, mucus -Preformed cpds (fatty acids, pH) -Enzymes, natural antibiotics (defensins), lysozyme C -Complement proteins -Phagocytic cells -Natural killer cells -Pattern recognition receptors |
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Defensins
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-Natural antibodies
-First found in frogs -In saliva -Possible therapeutic cpds |
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Acquired/Adaptive Immunity
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- Develops over time, does not exist at birth or in utero
-Antigen-specific -Only present invertebrates -Acquired through contact with antigen -Slow response, activated over days -10^10 different specificities (infinite specificities) -Genetically determined capability to recognize any bit of "foreign" material (antigen) -Has memory component |
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Colostrum
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-From mother, in milk
-Provides protection during early early after birth period --Adaptive immune system has not yet kicked into full gear --individual needs full support |
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Immunization
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-Elicits and immune response without leading to morbidity
-Vaccine must be low morbidity, otherwise no one will use it -Assume that immunity lasts for life --acquire immunological memory |
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Antigen
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-Any structure or substance capable of binding to cells of the immune system and inducing an immune response directed specifically against that substance or structure
-Induces an immune response against itself -Carbohydrates, proteins, lipids/glycolipids, nucleic acids can all be forms of antigens |
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Carbohydrate antigens
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-Polysaccharides
-Good B-cell antigens of coupled to proteins -Ex: blood group antigens, glycoproteins on bacteria and viruses |
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Protein Antigens
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-Most antigens are proteins, can be folded or in peptide fragments
-Very antigenic -Antibodies: recognize 3-dimensional conformation of proteins -T-cells: recognize peptides -Antigenicity is proportional to molecular size |
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Lipids/glycolipid Antigens
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-generally weak antigens
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Nucleic Acid Antigens
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-DNA/RNA
-Not typically antigenic unless coupled to proteins -Ex: SLE |
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Epitope
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-Antigenic Determinant
-Small #-d array of structure and charge recognized and bound by and antigen receptor/antibody combining site -Portion of antigen that binds to a receptor and triggers response -Can have many epitopes per pathogen/antigen |
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Immunogen
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-Agent capable of evoking an immune response
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Adjuvant
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-Amplifies a response to a vaccine
-Substance that increases the immunogenicity of an antigen within the adjuvant -May be a pathogen product that binds to PRR-like Toll-like receptors (TLR) -Increase biological half-life of an antigen (keeps antigen around longer) -Increases production of local inflammatory cytokines --increases co-stimulatory receptors -Improves antigen processing/presentation by APCs -Can activate innate response |
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Active Immunity
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-Induced by administration or natural introduction of an antigenic substance
-Vaccination/immunization |
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Immune characteristics that make vaccination possible
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1. INDUCIBILITY:
2. SPECIFICITY: infinite range of antigen specificities 3. MEMORY 4. SELF-RECOGNITION |
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Passive Immunity
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-Immunity provided by transfer of antibodies from immunized individual
-Colostrum from mother: sampling of all antibodies the mother has -Antibodies in the blood of an immune individual can be transferred to another individual |
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Adoptive Immunity
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-Immunity is provided by transfer of immune cells
-Bone marrow transplant |
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History of vaccination
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-1200's: Small pox lesion applied to cuts in skin of infants
--not highly effective -1798: Jenner observed that milk maids were resistant to small pox --exposed to cowpox -1879: Pasteur and botched fowl cholera experiment |
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Pasteur and Chickens Experiment
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-Injected normal chickens with aged bacteria, chickens did not die
-Inject normal and previously injected chickens with fresh bacteria, normal chickens died and previously injected chickens did not |
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Primary Immune Response vs. Secondary Immune Response
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-Primary immune response is not protective
-Secondary immune resonse occurs with no delay, rises rapidly to a much higher level of response, and persists for longer --protective response -Specificity does not change between primary and secondary exposures, affinity does |
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Adaptive immunity takes days to develop
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-Less than 1 in 100,000 circulating mature lymphocytes are specific for a specific antigen
-Once it does develop, can create identical progeny/clonal offspring --platoon vs. batallion to fight a war -Certain threshold for protective effector function exists, number of cells has to surpass threshold to have protective effects |
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Key properties of adaptive immunity triggered by vaccination or natural exposure
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1. Inducibility
2. Specificity: immune recognition by lymphocyte against a single antigen and not others 3. memory: secondary exposure to an antigen results in a more vigrous response due to memory 4. Self vs. non-self recognition |
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Cells that mediate adaptice/specific immunity
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1. T Lymphocytes: bone marrow-derived progenitors, mature in thymus
--produce cytokines and directly kill targets 2. B Lymphocytes: originate and mature in bone marrow (or bursa) --make antibodies |
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Antigen presenting Cells
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-Lymphocyte antigen receptors that impart specificity
-Mainly macrophages and dendritic cells -Process and present antigen -Produce immuno-regulatory cytokines |
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Plasma cells
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-Terminally differentiated B-cells
-Produce antibodies |
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T-cells
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-Produced in bone marrow, mature in thymus
-Produce cytokines -Respond to small peptide antigens --recognize and bind to small linear peptides --May be fragments of the same larger antigens that B-cells see -Destroy abnormal cells including cells containing intra-cellular pathogens that are invisible to B-cells -Activated by direct contact with APC |
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B-cells
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-Produced and mature in bone marrow
-Become plasma cells and make antibodies -Reciognize particulate antigens (whole bacteria, viruses, toxins) -Recognize and bind large soluble 3-dimensional antigens directly |
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Antigen Recognition
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-Key to all adaptive responses
-Immune system recognizes MANY distinct antigens -Each lymphocyte recognizes only one antigen |
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B Lymphocyte Antigen Receptor
BCR |
-Stimulation induces antibody production and secretion
-Has similar structure and specificity as secreted antibodies |
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T lymphocyte antigen Receptor
TCR |
-Stimulatio induces production of soluble cytokines and chemokines
-Cell-mediated immunity is induced --can lead to direct killin of target cells |
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Antigen Affinity
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-Dictates a lymphocyte's fate
-Dictates duration of receptor occupancy --initiates intracellular fate of specific signals -Specific domains of b-cell receptor or antibody binds to antigen -Antigen/antibody interactions are non-covalent and reversible -Many weak forces mediate the interaction between the antigen and the receptor --H-bonds, VDWalls, electrostatic, and hydrophobic interactions |
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Molecular Mechanism of Antigen-triggered Immunity
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1. Antigen binds ot antigen receptor (BCR/TCR)
2. Antigen receptors expressed to B and T lymphocytes --come Ba nd T cells nay recognize the same lymphocyte 3. Antigen/Antibody receptor interactions trigger cascade of intracellular signals --induces proliferation and effector functions |
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Effector functions of antigen/Antibody binding interaction
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1. Cytokine production in T-cells
2. Secretion of inflammatory mediators 3. Cell killing |
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Clonal selection hypothesis
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1. Lymphocyrtes exist before contact with the antigen
2. Antigen and receptor must interact to activate immune function --TCR= small peptides --BCR= intact, globular proteins 3. A lymphocyte is mono-specific or clonal and expresses identical antigen receptors --Proliferation increases effector cell frequency in a population 4. After activation, lymphocyte maintains specificity for same antigen --In B-cells, progeny secrete same antibodies as parent |
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Cell-Mediated Immunity
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-T-cell mediated
-production of immuno-regulatory cytokines -Direct elimination or killing of cells bearing foreign antigens |
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Humoral response
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-B-cell mediated
-Soluble molecules (Antibodies/Immunoglobulins) secreted by B-lymphocytes and plasma cells into the body |
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B and T cell co-regulation
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-B-cells and T-cells regulate each other
-Cytokines from T-cells are important for antibody production -B-cell derived cytokines can regulate type of T-cell differentiation induced by a specific antigen |
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Diversity in the Immune Response
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-Mostly due to immunoglobulin genetic development
-Also happens with TCRs -Variable regions on the heavy and light chains provide diversity |
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Variable region segment on Immunoglobulins
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-Responsible for interacting with antigens
-Allows immune system to mount responses to all types of diverse pathogens |
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How is diversity in the Immune system generated?
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1. Immunoglobulin locus structure
2. Somatic rearrangement 3. Junctional diversity 4. Nucleotide insertions by TdT 5. Heavy and light chain assortment 6. Somatic Hypermutation 7. Class switch recombination |
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Ig Heavy Chain Locus
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-Variable region has 200 variable segments
-Diversity segments has 12 variable segments -Joining segments have a few variable segments -Constant regions -Regions can be 3 million base pairs apart |
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Ig-Kappa light chain locus
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-Looks a lot like the heavy chain locus
-Variable region has 200 variable segments -Has Joining segments and Constant region also -NO diversity segment -Regions can be 3 million base pairs apart |
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Constant Regions in Heavy chain Loci
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-Have numerous types of constant regions
-Make all of the different isotypes of antibodies --IgM, Ig1, IgG3, etc. -Have transcriptional enhancers on either side of the constant regions --important for gene expression and rearrangement |
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TCR Loci
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-Look similar to Ig heavy and light chain loci
-Same process of transcription as in BCRs |
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Somatic Rearrangement
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-1 variable region gene will combine with 1 diversity region and 1 joining region segment
--makes VDJ rearrangement, functional heavy chain antibody gene -Complex process of recombination -Timing of rearrangement is very important -Allelic exclusion -Chromosomal dynamics -Signal sequences and biochemical mechanism |
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Somatic Rearrangement
Timing of rearrangement |
-Very precise regulation of timing
1. In early pro-B cells, heavy DJ chain rearranges 2. Late pro-B cells, heavy VD rearrangement occurs --end up with VDJ rearrangement -Al heavy chain rearrangement happens before the light chains are rearranged -Something regulates accessibility of enzymes 3. Light chain KAPPA V-J rearrangement --if Kappa makes functional gene, will have functional Ig --If kappa does not make functional gene, will go on to Lambda rearrangement 4. Light chain LAMBDA V-J rearrangement |
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Allelic Exclusion
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-Nearly always get 1 heavy chain rearrangement that is functional and 1 light chain rearrangement that is functional in any B-cell
-Both alleles do not give functional rearrangement -Only 1 functional allele is expressed -Partly controlled by large-scale chromosomal dynamics, large-scale restructuring of the DNA to make mechanisms happen |
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B-cell development and rearrangement
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-Can have many rearrangements, but will only have 1 functional Ig
-Good rearrangements will stick around, poor rearrangements will die -Once a good rearrangement happens, heavy chain locus is shut off -Light chains are rearranged after heavy chains |
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Global Recombination Issues
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-Specificity of Ig and TCR loci, only get T-cells making TCRs and B-cells making Ig
-Timing of rearrangement is very specific --heavy chain rearranges first -Locus repositioning in the nucleus --starts in periphery, then moves to center of the nucleus --loci becomes more accessible via histone rearrangements |
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Ig locus localization and Contraction
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-Locus moves to the center of the nucleus
-Locus contraction is needed for distal V-gene rearrangement -Decontraction and allelic exclusion to stop further rearrangements -If specific transcription factors are knocked out, loci do not contract --V-genes that are far away do not rearrange well -Acetylation can assist rearrangements --Moves from proximal side to distal side, activates to locus for rearrangements |
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Genetic rosette rearrangements
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-DNA is held in rosette structure
--helps contract the DNA somewhat -When rearrangement starts happening, rosettes cluster around D and J segments, puts D close to J for rearrangement -Extended before rearrangement, contracted after rearrangement |
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Recombination Signal Sequences
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-Control rearrangement process of BCR and TCR
-Downstream of V gene is conserved DNA sequence --7 nucleotide sequence, 9 nucleotide sequence, identical sequences on either side --Spacers inbetween are 12 or 23 nucleotides -Nucleotide sequences are the target, bring in RAG enzyme |
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RAG enzyme
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-breaks DNA at specific conserved sequence sites
--7 and 9 nucleotide sequences, separated by spacers of 12 or 23 nucleotides -Fuses V and J segments together and deletes intervening DNA -Cut between signal sequence and either V or J segments |
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12/23 Rule
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-12 and 23 nucleotide sequences match with each other
-never get 12 matching with 12 -Only rearrange to sequences with other number sequences -Ensures that V segment attaches to J segment, and not V to V -Recombination signals target RAG enzymes to cut at each site --other enzymes fuse segments together |
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Recombination
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-RAG1 and RAG2 bind to signal sequences, make double-strand cuts
-Ku70 and Ku80 bind to broken ends of DNA -DNA-PKcs and Artemis cut hairpin loops put in by RAG1 and RAG2 -Terminal Deoxytransferase (TdT) adds nucleotides to broken ends -XRCC4 and DNA ligase 4 close broken ends |
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Missing Somatic Rearrangement Proteins
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-Results in immune deficiency in patients
-Cannot make Ig -No proteins, no Ig, no TCR -No functional B-cells or T-cells |
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Reading Frame shifts
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-Shifts at V-D and D-J segments increases diversity
-Gives thousands of different Ig specificities -Frame shifts increase diversity at junction |
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Nucleotide additions by TdT
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-Dramatically increases diversity at join sites
-Random sequences make random amino acids --increases number of antibodies that are made |
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Surrogate Light Chains
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-Heavy chains are made first
-Surrogate chains are added, bind to heavy chains -Allow heavy chain protein to be on the cell surface while it waits for the light-chain gene to rearrange --Light-chain rearrangement occurs while protein is on cell surface --Undergoes same process or rearrangement |
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Light chain gene rearrangement
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-Occurs after heavy-chain gene rearrangement
-Arranges at pre-B cell stage -Heavy chain is already on the cell surface -Undergoes same mechanism of rearrangement as heavy chain, but does not have D region -NO D region |
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Autoreactive rearrangements
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-Genetic rearrangements give rise to an antibody that recognizes self
-Receptor editing deletes regions that cause autoreactive sites -Have editing of immune system to remove autoreactive clones |
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Antigen presence and Ig rearrangement
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-Antigen is not required for rearrangement to occur
-everything except receptor editing can occur without an antigen present -Makes B-cell system more sensitive |
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Somatic Hypermutation
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-Occurs in germinal centers
-Activated B-cells form germinal center -Antibody genes undergo further maturation -Occurs ONLY over V-gene segments --point mutations in the DNA of heavy chains and light chains -Can make the antibody better or worse --if better, cells are selected to grow --If worse, cell dies -Can be really dangerous if over-expressed |
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Germinal Center activity
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1. Somatic Hypermutation
-changes B-region sequences by inserting mutations 2. Class switch recombination -Puts different constant regions on the heavy chains -Results in plasma cells that can pump out antibodies with extremely high specificity for the antigen --Much higher affinity than original antibody -Without processes, immune system will be very weak |
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Process of Somatic hypermutation
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1. Activation Induce Deaminase enzyme changes GC to GU base pair
2. Mismatch Repair and Base-excision repair pathways will go through and "fix" mutation 3. Error prone DNA polymerases will intentionally put wrong base back in, will cause mutation 4. Hypermutations allow increased diversity --want to select for antibodies that are extremely specific to antigen presented |
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Activation induce Deaminase
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-AID
-Cytosine deaminase, turns cytosine into uracil -Enzyme required for somatic hypermutation -Causes GC to become GU base pair -Allows for different specificities -Can be very dangerous if over-expressed, will lead to lymphoma -Degraded very rapidly |
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Immunoglobulin Classes
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-IgG: Gamma heavy chains
-IgM: Mu heavy chains -IgA: Alpha heavy chains -IgD: Delta heavy chains -IgE: Epsilon heavy chains |
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Class Switch Recombination
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-Takes IgM and makes it something else
-Transforms heavy chains -Requires AID to make breaks and recombine -Involves giant loops across base pairs --brings constant regions into close proximity to make recombinations |
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Hyper IgM Syndrome
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-Lack of Class Switch recombination proteins
-Results in impaired immune function --Weak immune system -Can make low-affinity IgM, but not much else -Will suffer from infections |
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RAG mutations
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-will not get any B-cells or T-cells
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Leukocyte trafficking
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-Getting from location to location between anatomic sites
-White blood cell movement through the blood, tissues, and lymph -Distribution of effector cells and immunological memory throughout the entire body -Brings leukocytes into specific tissue compartments --not just tissue overall, but where specific infection is localized --Organ and specialized compartments |
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Effector cell activity in infected tissue
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1. Eliminate pathogens
2. Eliminate neoplastic cells (cancer) 3. Wall off pathogens that cannot be cleared 4. Phagocytose tissue debris 5. Help reorganize damaged tissue |
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inflammation can be a result of leukocyte trafficking
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-Infiltrate tissue
-Leukocyte infiltration can be very specific --specific leukocytes will be recruited to specific tissues -Inflammation can be good or bad depending on the situation --Inflammation by leukocytes infiltrating the tissue can be more damaging than the pathogen itself -Leukocytes that down-regulate inflammatory responses need to be recruited also |
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Leukocyte activity in inflamed tissue
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1. release an array of inflammatory mediators
--helpful in clearing infections 2. Local production of antibodies 3. Inflammation by leukocytes infiltrating the tissue can be more damaging than the pathogen itself 4. Maintains and induces inflammatory reaction in autoimmunity or allergy Leukocytes that down-regulate inflammatory responses need to be recruited also |
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Leukocyte trafficking Pros
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-Immunosurveillance
-Eliminate and control pathogens -Destroy neoplastic cells -Protection against re-infection |
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Leukocyte trafficking Cons
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-Tissue destruction and inflammation
-Maintain inflammatory and autoimmune diseases |
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Innate immune cells
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-One-time migration
-Have pre-programmed homing properties -Recruited from blood into tissues to fulfill function -Do not live very long -Neutrophils -Eosinophils -Monocytes -Natural Killer Cells -Mast Cells |
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Adaptive Immune Cells
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-Recirculate
-Are reprogrammed during antigen response -B-cells -T-cells -Migration pattern changes upon activation --Differentiate into effector of memory lymphocytes upon interaction with antigen --Profoundly changes migratory path |
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Lymphocyte Recirculation
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-Lymphocytes have high-endothelial venules
-Effector cells enter lymph nodes, look for antigen, and leave --leave via efferent lymph node, go into thoracic duct and back into blood stream -Occurs over and over again, circulate until they encounter an antigen -Once circulating, can migrate to secondary lymphoid tissue |
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Advantages to Recirculation
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-"Security guards" patrol areas, can cover more ground
-May want to have specific areas with higher security, but in general want full coverage -1/10,000 to 1/100,000 lymphocytes are able to recognize a specific antigen --relatively low -If not recirculating, would need all specificities in each lymph node --Would need many more lymphocytes |
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Naive lymphocytes vs. Antigen-experienced lymphocytes
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-Naive lymphocytes mostly scan secondary lymphoid tissues
--peyer's patches, lymph nodes, organized lymphoid tissues --Naive cells can't do much, have to be activated by an antigen-presenting cell first -Experienced lymphocytes can travel into many more tissue types --non-lymphatic organs --Can expel cytokines and actually do something |
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Main recirculation route of naive Lymphocytes
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Blood→ lymph node via HEV → efferent lymph→ thoracic duct and caudal vena cava
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Main recirculation route of Memory Lymphocytes
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1. Blood→ lymph node via HEV → efferent lymph→ thoracic duct and caudal vena cava
2. Blood → extralymphoid tissues and sites of inflammation → afferent lymph→ lymph node→ efferent lymph→ thoracic duct and caudal vena cava |
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Multi-step Adhesion cascade for leukocyte migration
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1. Rolling
-Initiation of contact through microvillus receptors on leukocyte -Leukocyte interacts with endothelium via microvilli -Low-affinity connection, slows leukocyte down as it moves through blood vessel 2. Activation via G-protein coupled receptors on leukocyte -Ligands on endothelium interact with G-protein coupled receptors on leukocyte -integrins are activated and cause conformational change --display high-affinity binding sites 3. Integrin Mediated Adhesion -Cell actually sticks to endothelium and migrates through via diapedesis |
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Selectins
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-Bind to carbohydrate ligands with low affinity
-L-selectin is concentrated on the tips of the microvilli of leukocytes --most protruding part of the leukocyte that touches the endothelium first |
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Selectins and their ligands
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1. E-selectin (CD62E) → E-selectin Ligand (CLA)
2. P-selectin (CD62P) → P-selectin Ligand 3. Peripheral Node Addressin (PNAd) → L-selectin (CD62L) Sometimes selectin is expressed by leukocyte, sometimes expressed by endothelium -depends on which selectin it is All have fairly basic protein backbone and complex carbohydrate chains attached to backbone -Sugars make the whole thing fucntional |
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E-selectin
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-Expressed on endothelium
-Expressed within 4 hours of inflammatory stimulation on surface of endothelial cells --brings cells to site of inflammation -Results in constitutive expression by dermal endothelium |
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P-selectin
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-intracellular storage by endothelium
-Expressed within minutes of inflammatory stimulation --Displayed on lumenal side of mast cell within minutes -Very rapid and important |
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Peripheral Node Addressin
PNAd |
-Always expressed by HEV, steady-state expression (Constitutively expressed)
-In lymph nodes and peyer's patches |
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Integrins
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-Mediate lymphocyte trafficking
-Heterodimeric proteins that bind to a variety of cellular adhesion molecules (CAMs) and extracellular matrix components -Cytoplasmic domains interact with cytoskeleton --integrate extracellular ligand binding with motility and changes in cell shape -Can cluster -Have alpha and beta chains --bind in families, not all alpha chains bind to all beta chains |
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Chemokines
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-mediate leukocyte trafficking
-Chemotactic Cytokines -Class of chemoattractants (not all chemoattractants are cytokines) -Large family of proteins -8-17 kDa in size -Can for immobilized chemotactic gradient -Bind to chemokine receptors --7-transmembrane spanning G-protein coupled receptors |
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Chemokine Functions
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1. Trigger up-regulation of integrin affinity by inducing rapid and reversible conformational changes and integrin clustering
-Important for multi-step adhesion cascade for leukocyte diapedesis 2. Control chemotaxis -Important for cell migration within tissues |
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Chemotaxis
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-Directed migration of cells towards a chemoattractant
-Induced by chemokines -release of chemokines and concentration gradient will attract and direct cells --cell polarizes |
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Cytokines vs. chemoattractants
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Chemokines are a class of chemoattractants
-not all chemoattractants are chemokines 1. Cytokines: -Interleukins -Tumor necrosis factor -Growth factors -Colony-stimulating factors -interferons 2. Chemoattractants (Very diverse) -Formyl Peptides -C5a fragment of complement protein -Platelet activating factor (PAF) Chemokines are Cytokines and chemoattractants |
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Chemoattractants
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-Anything that can induce chemotaxis with directed migration of a cell towards higher concentration
-Can be chemokines, can also be other molecules |
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Structure of Chemokine Classes
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1. C-Chemokines: one disulfide bridge
2. CC-Chemokines: 2 disulfide bridges, middle cysteine residues are next to each other 3. CXC-Chemokines: 2 disulfide bridges, middle cysteine residues are separated by another AA 4. CX3C-Chemokines: 2 Disulfide bridges, middle cysteine residues are separated by 3 different AA residues CC-chemokines and CXC-chemokines are most common |
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Leukocyte Adhesion Deficiencies
LADs |
-In cattle, humans, dogs
-Signs: sensitive to opportunistic infections, severe ulcers on oral mucous membranes, severe peritonitis, loss of teeth, chronic pneumonia, recurrent or chronic diarrhea -Animal will die at an early age due to complications of infection -Mucous membranes are especially sensitive -Usually a point mutation in the beta-2 integrin encoding gene --leads to impaired expression and function of beta-2 integrins |
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Cellular Adhesion Molecules
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-B-2 ligands important for leukocyte trafficking
1. AlphaL-B2=LFA-1: expressed by most leukocytes (innate and adaptive) 2. AlphaM-B2=Mac-1: expressed by monocytes, macrophages, and neutrophils 3. AlphaX-B2= CD11c: expressed by dendritic cells 4. AlphaD-B2= CD11d: expressed by most leukocytes, elevated expression on activated phagocytes |
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Blood flow and leukocyte migration
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-If an organ receives less blood, there will be decreased chance for interaction and migration
-More blood, more chance to interact with endothelium -Different organs receive different amounts of blood --inflamed organs will receive more blood flow, more chance for leukocytes to interact with activated endothelium |
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Lymphocytes can migrate to multiple sites, but not at the same time
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-Lymphocyte cannot be in 2 places at once
-Can go into different types of tissues, but not at the same time -Most lymphocytes have multiple homing properties, express multiple "zip codes" |
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Lymphocyte migration within tissues
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-Regulated by integrins and chemokines
-Expression of B and Tcell attracting chemokines is confined to specialized areas within secondary lymphatic tisue |
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Lymphocyte migration through lymph nodes and spleen
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-Lymph nodes and spleen have B-cell follicles
--Specialized areas within secondary lymphoid tissues -Different areas have expression of different chemokines -B-cell follicles will express CXCL13 --Binds chemokine receptor CXCL5 (expressed by all B-cells) -T-cell areas will express CCL19 and CCL21 --Binds chemokine receptor CCR7 |
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CXCR5 Receptor
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-Receptor expressed on B-cells
-Localizes B-cells to follicle -No CXCR5 receptors, B-cells cannot find B-cell follicle and will accumulate in T-cell areas --Architecture of organ will be messed up/muddled -B-cells enter peyer's patches and lymph nodes through T-cell areas, have to be attracted to B-cell areas to accumulate there -B-cells also have small amount of CCR7 receptor, localizes to T-cell areas, especially of CXCR5 receptor is missing |
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Drugs interfering with Leukocyte recruitment in treatment of inflammatory diseases
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1. Natalizumab (Tysabri): blocks Alpha4-Integrin
-Used to treat MS and Chron's disease -Blocks migration into tissues 2. Fingolimod (Gilenya): blocks Sphingosine-1 phosphate receptors (lipid chemoattractant) -Receptor allows lymphocytes to migrate out of lymphoid tissue -Used to treat MS -Drug blocks migration out of lymphoid tissues Results in lymphopenia, decreased lymphoid accumulation --decreased reaction and response to infections |
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Treatment of inflammation
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-LOTS of drugs are used to treat inflammation
--Mostly interfere with lymphocyte migration -Side effects: --decreased reaction and response to infections |
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Afferent Lymph
Efferent Lymph |
Afferent Lymph: drains tissues
-Connects extra-lymphoid tissue with lymph node Efferent Lymph: drains lymph node -Lymphocytes from lymph nodes -More of a mix of stuff |
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Non-random homing patterns of Lymphocytes
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-Specific lymph cells will return to specific tissue
-Preferentially return to original area -Cells "know" where they came from/where the infection is, and home back to that tissue --Will scan the specific tissue before going to other areas of infection |
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Importance of Organ-specific Homing
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1. More efficient secondary response to an infection
-Pathogen will most likely re-enter body through same route -Memory lymphocytes are specific to an area and infection, go back to previously infected area 2. Site-specific immunity -70% of activated lymphocytes will be specific, 30% will be general memory lymphocytes 3. Brings lymphocytes to areas where they will have the greatest impact 4. Helps with vaccine design, design vaccines for specific areas Can have pathological consequences, may result in site-specific auto-immunity |
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Mechanism of Organ-Specific Homing
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-Organ-specific expression of homing molecules on endothelial cells
-Selectins, selectin ligands, CAMs (integrin ligands), and chemokines -Expressed on specific organs -ex: integrin ligand MAdCAM-1 expression on GALT peyer's patches --lymphocytes that can bind to MAdCAM-1 will be preferentially associated with endothelium in gut that expresses it |
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Homing "zip codes"
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-Can assign numbers to specific ligands and receptors
-Categorizes rolling receptors vs. binding receptors vs. adhesion receptors -Allows tissue-specific targeting and helps with designing vaccines --adjuvant can mimic properties that are wanted -Expression of homing molecules allows you to predict where molecule will go -Allergic inflammation and parasitic infection will have specific receptor expression patterns -Combination of rolling, activation, and integrin receptors allows localization -Receptors can be cell-type specific |
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Vitamin processing by dendritic cells
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-Imprints organ-specific homing receptors on T and B cells
-Dendritic cells communicate to B-cells and T-cells to tell where they are within the body --Communicate via vitamins |
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Vitamin D3 processing by Dendritic cells
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-Dendritic cells in the gut are able to process vitamin A into active form of retanoic acid
-T-cells and B-cells activated in presence of retanoic acid induce gut-homing receptors |
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Retanoic Acid as an Adjuvant
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-Can be used in immunization
-Causes T-cells and B-cells to be activated as gut-homing cells --induces development of gut-homing receptors -Is effective -Get more gut-homing T-cells and B-cells -Will lead to better mucosal vccines |
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Skin-homing B-cells and T-cells
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-Vitamin D3 is abundant in skin
-High-concentrations of vitamin D3 are processed by dendritic cells, converted into 1,25 (OH)2 -When T-cells are activated in presence of 1,25 (OH)2, skin-homing receptor is activated --CCR4 and CCR10 -Does not work in mice, only in humans --specific vitamin D metabolism |
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Cell-Mediated Immunity
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-T-cells
-Production of immuno-regulatory cytokines -Direct elimination or killing of cells bearing foreign antigen |
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B-cells and T-cells regulating each other
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-T-cell cytokine control antibody production by B-cells
-B-cell cytokines regulate T-cell differentiation induced by antigen |
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Humoral Response
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-B-cells
-Body fluids -Soluble molecules -Secreted by B-lymphocytes and plasma cells into the body -Soluble molecules= antibodies/immunoglobulins |
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Adaptive immune response in lymphoid organs
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1. primary: bone marrow, bursa of fabricius
--where cells develop 2. Secondary: spleen, lymph nodes, peyer's patches in gut, tonsils --where immune reaction is localized --Portals of entry, branch points in circulation 3. Tertiary: ecropic lymphoid follicles in chronic inflammatory and autoimmune diseases --rheumatoid arthritis |
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Lymph and Blood Vessels
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-Afferent and efferent lymph vessels exist
-Primary routes for cells -Very diffuse system, all over the body Immune "organ" is quire decentralized |
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Function of lymphoid Organs
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1. Primary: development and maturation of lymphocytes
2. Secondary: initiation of the adaptive immune response 3. Tertiary: pathologic aggregation of lymphoid tissue in autoimmune/inflammatory diseases |
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Secondary lymphoid organ function
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-Provide infrastructure for lymphocytes to find antigen and become activated
-Initiate primary adaptive immune response -Bring together antigen-bearing dendritic cells, B-Cells, and T-cells |
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Structure of a Lymph node
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-Capsule, subcapsular sinus, cortex, medulla
-Germinal centers in cortex --regions where B-cells and T-cells interact --regulate each other to mount immune response -Interact in germinal centers -Afferent lymphatic vessel brings in lymph from tissues -Efferent lymphatic vessel carries lymph to thoracic duct and back to blood stream |
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Structure of the Spleen
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-Red Pulp: organized as a tree of branching arterioles
--large blood-filled sinuses -White Pulp: small arterial branches sheathed by lymphoid tissue --PALS: peri-arterial lymphatic sheath -Marginal Zone: interface between red and white pulp --transit area for leukocytes leaving the blood and entering the white pulp --important for innate immune response 50% of splenocytes are white blood cells |
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Function of the Spleen
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-Functions as a secondary lymphoid organ
-Filters blood -Immune surveillance -Efficient defense against blood-borne pathogens, especially encapsulated bacteria -Can live without the spleen, but are more susceptible to blood-borne bacterial and fungal pathogens --will be missing the early innate component |
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Humoral/B-cell immunity
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-Based on immunoglobulins and antibodies
-Found in serum, soluble proteins -Antibodies and BCRs are identical molecules --BCRs are membrane-anchored antibodies --Antibodies are secreted into serum and lymph -Each antibody recognizes a single antigenic epitpoe -Specificity of BCR and antibody is genetically encoded -BCR and secreted antibodies have identical specificity to progeny B-cells -Secreted antibody is produced by terminally differentiated B-cells (Plasma cells) |
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Plasma Cells
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-Terminally differentiated B-cells
-Produce antibodies |
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Origin of B-cells
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-Bone marrow
-Bursa of fabricius Can migrate to be found in 10 lymph nodes, spleen, and bone marrow |
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Gamma-Globulin
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-First identity of antibodies
-Factor in serum that imparts immunity to another animal (passive immunity) -Found in serum, secretions, saliva, milk, gut -Abundant in serum of indiviuals with multiple Myeloma |
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Immunoglobulin Structure
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-2 light chains (25,000 MW)
-2 heavy chains (50,000 MW) -Chains are associated by disulfide bonds that stick chains together --by disrupting disulfide bonds, can break chains apart -Each chain has variable regions and constant regions --variable regions are towards the ends of the chains --variable regions form a "cleft" in which antigen associates |
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Papain digestion of antibodies
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-Produces 3 fragments of roughly equal size
-2 Fab fragments -1 Fc fragment |
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Fab
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-Fragment Antigen Binding
-Has antigen-binding capability -Variable heavy and light chain domains |
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Fc
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-Fragment Crystallizable
-Constant fragment -Constant heavy chain domain -Specifies the biological activity of each antibody molecule -Binds to receptors on immune cells and initiates a variety of immunological responses |
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Pepsin digestion of antibodies
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-Cleaves antibody closer to C-terminus
-leaves a bivalent antigen binding fragment -2 Fab segments, still joined -Several Fc segments, separated |
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Variable Chains
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-Encode antigen specificity
-CDR1, CDR2, CDR3 -Variation and mutation is responsible for antigen association -Critical points where antigen interacts with receptor -HIGHLY variable |
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Isotype
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-Class of antibody
-IgM, IgG, IgE, IgD, IgA -Fc portion of the antibody -Alternatively spliced constant regions of the DNA sequence |
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Allotype
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-Allelic differences in antibody genes based on individuals
-Usually a few amino acid residues in a heavy chain -Differences in Fc domains by the individual |
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Idiotype
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-Antigenic region of the antibody molecule
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Antibody Specificity
|
-Dictated by variable chains
-Antigen binds to Fab regions of the heavy and light chain globular structures -CDR1, 2, and 3 form a 3-dimensional binding domain within the variable heavy and light chains |
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Complementarity Determining Regions
CDR |
-First 110 amino acids of heavy and light chains (440 amino acids total)
-Have hypervariable domains -CDR1, CDR2, CDR3 -CDRs form a 3-dimensional binding domain within the variable heavy and light chains -Antibodies and BCRs bind to same epitope |
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Antibody Functions
|
-Dictated by Fc domain (Isotype)
- |
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Antibody Structure Zones
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1. Antigen binding region: Fab domain
-composed of heavy and light chain variable regions 2. Cell-binding region: Isotype, Fc domain -Macrophages, B-cells, NK cells, granulocytes express isotype-specific Fc receptors -Antibody coated cells (pathogens) are targeted to specific immune cells 3. Complement activating region -Constant 2 region of the heavy chain -Fc domain binds to complement proteins |
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Complement System
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-Group of proteins activated by cell-bound antibody
-Activated complement destroys antibody-coated target cells --lyses antibody-bound cells -Binds to and kills pathogens -Activated by interactions with the heavy chain constant regions |
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Mechanisms of Antibody Effector Function
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Antibody Binding....
1. renders agent innocuous 2. Activates other destructive cells 3. Initiates activities of other serum proteins |
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Neutralization
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-Inhibits toxins, bacteria, viruses
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Toxins
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-Bind to cellular receptors in body
-Inhibit or block function -Cause aberrant activation -Tetanus and botulinum themselves are not lethal, toxins are -Antibodies can bind toxins and block detrimental interactions |
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Viruses
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-Obligate intracellular pathogens
-Bind to cell, enter cell, and release genetic material into host cell -Proteins expressed on the viral capsule mediate functions of virus -Antibodies can bind to virus surface proteins and inhibit entry |
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Bacteria
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-Bind to cellular receptors
-Antibodies can block bacteria binding to cellular receptors |
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Opsonization
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-"Prepare for eating"
-Antibodies greatly increase the rate of phagocytosis -Binding of an antibody with an Fc receptor on cell surface triggers phagocytosis -Opsonization of a particle with antibodies increases binding potential of the molecule with a phagocytic cell --can initiate type II hypersensitivity reaction |
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IgG
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-lasts longest in blood, lymph, CSF
-Only Ig to pass placenta --is also in colostrum -Antibody-dependent cell-mediated cytotoxicity -Binds target and Fc receptors on Natural Killer cells --focuses NK cell to its target -Activates complement system, binds ot IgG Fc domain -Neutralizes toxins (snake venom) -Immobilizes bacteria by binding to flagella or cilia -Neutralizes viruses, blocks attachment sites |
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IgM
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-First Ig produced after immunization
-Elevated IgM indicates recent infection, new infection -Pentamer, macroglobulin with extra CH domain --joined by S-S bonds and J-chain -Monomer is expressed on B-cells (BCR) -Does not pass through the human placenta -Only Ig synthesized by fetus -Includes isohemagglutinins, naturally occuring antibodies against ABO blood groups -Activates complement -Does not neutralize toxins or viruses |
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IgA
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-Major Ig in external secretions (saliva, tears, mucus, sweat, gastric fluid, colostrum)
-Dimer, linked by J-chain -Plasma cells are found in lamina propria beneath epithelial basement cell layers -Defense against local infections -Prevents attachment and penetration by microbes -Does not fix or activate complement -Antiviral, prevents viral attachment and agglutinates virus -Actively transported across epithelial cells |
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IgE
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-Parasitic and allergic reactions
-Mast cells and eosinophils have high affinity Fc receptors for IgE CH domain -Does not fix complement -Triggers massive release of inflammatory mediators --histamine, leukotrienes, heparin --Causes changes in vascular permeability and tone -Triggers hypersensitivity reactions --mosquito bites, bronchial asthma, anaphylaxis |
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IgD
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-Unknown function
-Not secreted by plasma cells, negligible amount in the serum -Co-expressed on the surface of mature B-cells with IgM |
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Type I hypersensitivity reactions
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-Immediate hypersensitivity
-Fc receptor bound anti-body mediated release of vasoactive substances -Act on vessels and smooth muscle -Mast cells and eosinophils express Fc receptors for IgE --antibody binding triggers release of inflammatory mediators, degradative factors, and endocytosis -TONS of receptors on surface, mostly IgE -Wheel and hive response, caused by hyperemia and increased vascular permeability Ex: immediate response to insect bite |
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Type II hypersensitivity reactions
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-Antibody Dependent
-Antibody-mediated disorders -Secreted antibodies promote cellular injury -Promote phagocytosis or cell lysis and tissue injury by inducing inflammation -Induce inflammation |
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Type III hypersensitivity reactions
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-Immune complex disease
-Immune complex mediated -Direct activation of inflammation -Direct activation of complement system -Leukocytes release lysosomes, enzymes, free radicals |
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Type IV hypersensitivity reactions
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-DTH-T-cell mediated
-Sensitized T-cells cause cellular and tissue injury -Delayed type |
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IgE in type I hypersensitivity reactions
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-IgE antibodies respond to antigen from invader
--are displayed on mast cell -Mast cell degranualtes, histamine and antibodies are put into blood stream -blood vessels have Increased permeability to IgG and white blood cells -Coat worm with IgG and IgE antibodies and passively bound eosinophils |
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Antigen-Mediated B-cell activation
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1. Antigen binds to BCR:
-induces proliferation and antibody production -Antibody is processed and displayed by MHC II molecules 2. Costimulation signals from TH cells: -recognize antigen and enhance antibody production -initiates affinity maturation and isotype switching -some B-cells become plasma cells 3. Microbial antigens: -Activate B-cells in absence of T-cells -Allows rapid antibody production against bacterial pathogens -Antibodies do not undergo affinity maturation or isotype switching -Express pattern recognition type receptors |
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B-cell activation without T-cells
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-No T-cells present, no isotype switching
-Genetic splicing will not occur -only get IgM provided from B-cells |
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T-cells activating B-cells
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1. B-cells recognize and bind to soluble antigen
--antigen is internalized, processed, and presented via MHC 2. T-cells specific to presented peptides interact with B-cells 3. T-cells up-regulate CD154 (CD40L) --produce immunoregulatory cytokines (IL4) 4. CD40L/CD154 and cytokines from T-cells induces isotype switch |
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B-cell activation in lymph nodes
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1. Antigen Binding B-cells are localized in T-cell zone of lymph node
2. T-cells activated by specific antigen interact with B-cells and provide antibody production needed for immediate protection 3. Some activated B and T cells migrate to for primary follicle and eventually germinal centers 4. B-cells differentiate into memory cells or plasma cells --migrate to bone marrow, produce TONS of antibody |
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Germinal center
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-Island of proliferating B-cells
-10% T-cells -Local affinity maturation and isotype switching occurs |
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B-cell proliferation
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-identical clones generated
-enhanced by CD40 engagement and T-cell cytokines |
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B-cell differentiation
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-Memory/plasma cells need antigen-presenting cells and T-helper cells (CD40)
-Differentiation occurs in germinal centers -memory cells are long-lived and non-proliferating --localize in tissues |
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Isotype switching
|
-"Class switching"
-IgM predominates after primary exposure -IgG or other isotypes dominate secondary responses -T-cell cytokines and CD40L regulate isotype switch -Without T-cells, only IgM is made -B and T cells have to be local to each other to allow isotype switching -Occurs in germinal centers Allows an antibody with a single specificity to have different effector functions |
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Affinity Maturation
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-Overall affinity of an antigen-specific repertoire increases during secondary responses
-Somatic hypermutation -Only most effective/highest affinity cells survive --50% of cells die |
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Somatic Hypermutation
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-Allows continual development of different antibodies
-Induced within B-cells in germinal centers -Cells mutate 10,000 times more than normal -Generates B-cells with higher or lower affinity for antigen --low affinity cells die |
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Antigen-induced B-cell activation via natural infection or vaccine is the key to long-term protection
|
-Occurs in germinal centers, germinal center stimulation provides protection
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Memory cell development
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-Antigen presence triggers production of plasma and memory cells
-After infection, cells surviving in germinal centers differentiate into plasma cells or memory cells -With secondary infection, plasma cells multiply |
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Plasma Cells
|
-Develop from antigen-stimulated B-cells
-Ovoid cells with round, eccentrically located nucelus -Cytoplasm contains lots of rough-ER -Large golgi, make and secrete up to 10,000 antibodies per second -Antibody is identical to the antigen binding specificity of the BCR -MCHII is not expressed --Do not present antigen to T-cells |
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Memory cell proliferation and survival
|
-Cells are long-lived
-Antigen induces memory cells to proliferate in germinal centers --genetic changes occur in germinal centers -TH cells induce B-cell maturation into memory cells -Most activated B-cells and plasma cells die -Survival genes are induced by T-helper cells -Secondary response of antigen-primed memory cells is more rapid and robust than the primary response |
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Primary response kinetics
|
-Not protective
-Long delay, slow rise in activity, and rapid decay of cells -Does not prevent morbidity -Can limit severity or dissemination |
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Secondary Response kinetics
|
-Protective
-Rapid onset, rapid rise in activity level, larger magnitude, longer duration -Generally prevents symptoms and morbidity -Basis of vaccination -Isotype switching and affinity maturation occur with T-helper cells -Plasma cells generated |
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Fetal protection from pathogens
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1. Passive immunity
--placental barrier and materanal immune system --maternal passive transfer of antibodies 2. Acquired immunity --early vaccinations --fetus makes limited number of IgM |
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Fetal limited immune capability
|
-Neonates produce relatively minimal antibodies until several months old
-Maternal antibodies are essential -Limited phagocytic capabilities, antibody production, and complement -Fetal response to intrauterine infections depends on time of infection |
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Maternal transfer of antibodies to fetus
|
-Placental transfer in primates
-Colostrum transfer of immunoglobulins -Fetus is protected by maternal antibodies --transferred from mother via colostrum |
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Colostrum
|
-Immunoglobulins secreted in mammary gland
-Contains mostly IgG and IgA -Can also contain IgM and IgE -Absorption by neonate occurs for about 24 hours -If colostrum is not transferred, fetus fails to thrive and dies -Vaccination is essential for long-term protection against pathogens |
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Antigen-Antibody interactions
|
-Interaction between 2 proteins
-H bonds, electrostatic bonds, VDWalls, hydrophobic interactions -Lots of forces lead to antibodies and antigens interacting -Specificity is most important part of interaction -Depends on nature of the antigen and valence of the antigen -Antibody type and class is also important |
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Antibody Affinity
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-Specificity is most important
-High attraction, low repulsion = good fit -Low attraction, high repulsion = poor fit |
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Affinity
|
-Antibody binding to epitope
-Degree of affinity determines how strong the reaction is -Different antibodies have different number of binding sites, increases affinity -Intrinsic affinity |
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Avidity
|
-Functional affinity
-Multiple antibody-antigen interactions -How well antibody binds to antigen and how many times it binds -Depends on type of antibody, certain antibody types bind better than others |
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Valence of the antigen
|
-Multivalency of the antigen is essential for precipitation and agglutination of complexes between antigen and antibody
-Based on how many epitopes there are for a given antigen -Multivalent antigens have many different locations for antigen --can cross-link |
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Unideterminant Antigen
Multideterminant antigen |
-Unideterminant antigen = one type of epitope
--no cross-linking, only one type of antigen -Multideterminant antigen= many epitopes --can cross-link to form a complex formation |
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Specificity and cross-reactivity
|
- Cross reactivity: some reacting and some cross-linking
--not all sites react and interact -In a poly-clonal antibody, can have some antibodies that cross-react and some that don't |
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Monoclonal Antibodies
|
-Antibody that has been made from a cell that only identifies one epitope
-One antibody, one epitope -Taking an individual cell and cloning it so it makes a particular antibody -Get an antibody that recognizes only one epitope, makes one specific antibody -Only makes one antibody due to genetic modifications -Can be useful experimentally, clinically, diagnostically |
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Polyclonal antibodies
|
-Antibodies recognize multiple epitopes
-Can be very useful experimentally -Antigen injected goes to lymph nodes, T-cells recognize antigen presented on dendritic cells --B-cells respond specifically, T-cells help B-cells make antibodies -Initially get IgM, then IgG -Lots of antibodies recognize multiple epitopes -Can get cross-reactions |
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Hemagluttination Assay
|
-Way to detect if there is antibody present
-Recognizes red blood cells and RBC antigen -If antigen is present, RBC lyses |
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Antibody Titers
|
-Assay where an antigen-coated cell responds to an antibody
-If antibody is added to cells, cells will lyse -Know where titer is where there is no cell lysis -Taking unknown serum and diluting it in an assay --want to find how many dilutions it takes until no reaction |
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Western Blot
|
-Immunoblotting
-Diagnostic assay -Looking for antigen with an antibody -Have a gel, antigen samples at top, antigens are sized by gel and separate out -Incubate unknown antibodies and see if they bind to proteins -Antibodies are labeled in a way to see if they bind -Can see if you have a particular protein against a particular antigen of a particular molecular weight |
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Enzyme-Linked immunosorbent Assay
|
-ELISA
-Most robust method of looking at antibody types, most standard -Identify if antigens or antibodies are present -Want to know how much you have -Blocked plate will only bind specific protein you are interested in -Antibodies interact to produce and enzymatic reaction |
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Radioimmunoassay
|
-Same idea as an ELISA
-Have antibody that has been labeled with a radioactive isotope -Can measure reaction directly without 2nd antibody |
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Immunoflourescence
|
-Can tell if you have a specific antibody or not
-Particularly useful in tissues -Can look to see if particular antigens are deposited in a tissue -Direct: antibody against tissue is labeled -Indirect: antibody against tissue is not labeled --2nd antibody is labeled, binds to 1st antibody bound to tissue -Indirect complement amplified: complement binds to primary antibody, anti-complement antibody binds to complement --Amplifies response |
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Flow cytometry
|
-Laser identifies number of specifically labeled cells
-Measures the granularity of the cell and the size of the cell -Labelling antibody is fluorescent, fluoresces when laser hits cell -Run cells through flow cell --Flow cell makes cells go through one at a time --Lasers will shine light on cells, can identify how many cells fluoresced with each color -Can identify different cell types -Used experimentally, not as much clinically in vet med -Analyze cell populations in the blood |
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ELISA detecting an antigen
|
-Look to see if a specific cytokine is present in serum
-coat plate with antibodies that recognize specific antigen, block plate to all other antibodies and antigens -If specific antigen is present, will bind to cell plate |
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Complement System
|
-Immune defense system
-"first line of defense" -Recognizes foreign and altered cells -Facilitates elimination of foreign and altered cells -Physiological reactions and pathological reactions -Tightly involved in many different systems -Can be complex, but not complicated |
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Complement-Mediated surveillance and triage
|
-Tolerance
-Elimination -Danger signaling -Also has a role in regulation |
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Steps of complement activation
|
1. danger sensed, something in blood is a threat
2. Cascade of proteins is activated 3. attacks and marks particle (Opsonization) 4 amplification of response, leads to effector fucntions |
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Effector functions
|
-Cell lysis
-Phagocytosis -Immune Modulation |
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Cascade organization of complement
|
-Organized in a cascade fashion
-Starts with triggering of pathway by pattern recognition receptors -Triggers C3 convertases -leads to amplification loop (inflammatory signaling, phagocytosis, adaptive signaling) |
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Complement and blood sensing
|
-Complement system senses what is going on in the blood
-Foreign substance that comes into contact with blood will trigger complement system |
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Pathogen-associated molecular patterns
|
-PAMP
-Surface antigens, lipopolysaccharides, capsid sugars, peptidoglycans, fungal mannins -Results in direct or mediated binding of complement sensors |
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Damage-associated molecular patterns
|
-DAMP
-Identifies damaged cells -Nuclear/cytosolic proteins expressed on cell surface -DNA or RNA on cell surface -Heparin sulfate -Results in direct or mediated binding of complement sensors |
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Pattern recognition Proteins
|
-Patches of antibodies are recognized on cell surface
-Bind to accumulation of antibodies on the cell surface -C1Q: initiates classical pathway -Lactin pathway: recognize sugars responsible for fungi, cabteria -Alternative pathway: properdin recognizes lipopolysaccharides All trigger a certain activation response |
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Pattern recognition enzymes
|
-Enzymes are associated with pattern recognition proteins
-Are able to digest -Cleave different proteins in complement system |
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C3 Convertases
|
-All initiation pathways lead to the formation of C3 convertases
-Transit enzyme complexes that cleave plasma protein C3 -Opsonins C4b and C3b are put onto cell surfaces -Big molecule, abundant in plasma -Does not bind to a lot of stuff unless it is activated |
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C3a protein
|
-Portion of C3 protein embedded within structure
-Exposes thioester within C3 protein, active group -Can now attach to surfaces that will activate complement system -Targets cells and particles for elimination |
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|
Amplification of Complement
|
-Most important step
-ensures specificity to foreign cells -More convertases are formed -Amplification increases opsonization --favors formation of C5 convertases |
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C3 conversion to C3b
|
-Drives the complement reaction
|
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Membrane Attack complexes
|
-Lipid complexes
-Produced when C5 comvertase is formed --C5b is formed, leads to conversion of complexes that then act together -Insert themselves into the membrane, pierce membrane --form pore -Cell lyses and is destroyed -Important step, but not the only step |
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Immune Modulation
|
-Anaphylatoxins
-Small molecules released during activation of C3 and C5 -Small proteins -Very potent in inflammatory responses |
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C5a
|
-Anaphylatoxin
-Can act on endothelial tissue -leads to vascular permeability, leaky blood vessels -Acts as a chemoattractant --guides immune cells to site of immune reaction |
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Phagocytosis
|
-Several complement receptors recognize opsonins
-mediate uptake by phagocytosis -C3b -Cells recognize opsonins on surface and bind to receptors --cause phagocytosis -once you have an activated cell, can recognize the opsonization components on the cell surface --binding induces phagocytosis response |
