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181 Cards in this Set
- Front
- Back
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defensins
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35-40aa peptides in skin and mucosa barriers
- amphipathic can insert themselves into membranes of bacteria, fungi and viruses to kill them |
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lysozyme
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enzyme present in respiratory tract nasal secretions and tears
- substrate = bacterial cell wall - allows antimicrobial peptides (defensins) to insert themselves in bacterial membrane - osmotic shock to bacteria |
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What are the different phagocyte receptors on macrophages?
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1. Mannose/glucan receptors
- recog carbs in conserved patterns or orientations not found in mammalian cells 2. CR3 3. scavenger receptor - polysaccharides, nuc acids - LTA (present on gram positive bacteria) 4. LPS receptor (CD14) - complement - LPS (gram - bacteria) 5. Toll-like Receptor - signal transduction for cytokine production |
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What's the major difference between macrophage and neutrophil receptors
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NO TLR on neutrophils
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What is gram-negative bacterial LPS recognized by on macrophages?
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complex of TLR4, CD14 (LPS receptor), and MD2
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what does the TLR recognize on bacteria to indicate infection?
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unmethylated CpG
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what cells is TLR found on?
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macrophages and dendritic cells
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what are the 2 different types of TLRs? (based on location)
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1. cell surface --> bind bacteria outside cell (TLR 1, 2, 4, 5, 6)
2. endosomal --> dsRNA only found after been phagocytosed or virus infected cell (3, 7, 8, 9) |
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what is the signaling pathway of TLR's leading to cytokine release/inflammation?
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1. LPS binding TLR4
2. kinase cascade 3. IKK activation (inhibitor of IkB - in hibitor of nf kappa b) 4. phosphorylation of IkB 5. release of NFkB --> translocation to nucleus --> activates transcription of genes for inflammation/cytokines |
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what molecules are responded for tight binding of leukocytes to endothelium during inflammation?
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- ICAM-1
- CXCL8 - both on endothelium - results in results in conformational change --> stable binding |
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what cytokine responsible for fever, inducing acute phase protein production by hepatocytes?
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IL6
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what are the actions of IL-1 in inflammation?
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LOCAL
1. activates vascular endothelium 2. activates lymphocytes 3. local tissue destruction 4. increases access of effector cells SYSTEMIC 1. fever 2. production of IL6 |
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what are the actions of TNFalpha in inflammation?
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LOCAL
1. activates vasculr endothelium 2. increases vascular permeability --> increased entry of complement and cells to tissues and increased fluid drainage to LNs SYSTEMIC fever, mobilization of metabolites, shock |
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what is the role of CXCL8 (aka IL8) in inflammation?
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chemotactic factor (neutrophils and basophils)
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what is the role of MASP's (mannose-activating serine proteases) in complement activation?
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lectin pathway
- recog pattern of residues on pathogen (spacing and distribution of mannose residues that mamm tissue doesn't) - cleave C4 and C2 |
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how are IgG and IgM regulated in complement classical pathway to prevent overactivation?
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IgM planar form in circulation, hides binding sites
surface-bound form = staple --> binding sites available to C1 complex IgG needs to have at least a couple adjacent to each other w/in sufficent distance so C1 can bind |
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factor D
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cleaves Factor B/C3b or Factor B/iC3 in alternative pathway, results in C3 convertease
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properdin
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binds C3bBb C3 convertase, providing it stability so can be long-lasting
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which complement receptor activates B cells as part of co-receptor stim?
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CR2
- ligands = iC2b, C3d, C3dg - expressed on B cells and cells and FCDs |
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what complement receptor clears immune complexes on opsonizes?
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CR1
- C3b, C4b - on phagocytes and RBC's - C1Q recog and binds Ag/Ab complex in circ - fixes complement C3b CR1 on RBC recog and binds C3b-tagged immune complexes --> carries to spleen or liver --> macrophage picks up w/ Fc receptors for phagocytes --> macrophages stim by C3a or C5a --> bind and engulf microbe w/ C3b on surf |
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C1 inhibitor (C1INH)
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binds irreversibly to C1r and C1s (c1qrs complex) --> fall off complex
- blocks classical pathway initiation |
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Factor I
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degrades C3 converteases in combo w/ other cofactors
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C4BP (c4 binding protein)
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binds C4b and serves as cofactor for FActor I
- factor I splits C4b --> destroys convertase activity |
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DAF
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decay accelerating factor
- inserted into host membranes can interact w /alternative C3 convertase - displaces Factor B fragment --> inactivate C3 convertase - blocks alternative pathway |
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membrane cofactor protein
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cofactor for factor I
- generation of iC3 --> destroys C3 convertase activity |
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CD59
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inhibits MAC formation
- sim structure as C9 --> binds C5b, C6, C7, C8 nascent attack complex |
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paroxysmal nocturnal hemoglobinuria
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DAF and CD59 defect
- absence on RBCs results in hemolysis - release Hb excreted in urine |
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Hereditary angioneurotic edema
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C1INH defect
- extreme increase C2b --> acted on by plasmin, and releases C2 kinin --> massive tissue swelling |
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what do the immunoglobulin isotypes differ by?
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all on H chain constant region
- differ by AA seq and amt of glycosylation |
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hypervariable regions
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3 hotspots of variability on Ig's that comprise Ag-binding site, closely opposed to each other
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somatic hypermutation
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additional mech for creating antibody diversity after antigen contact
- random mutations generated in CDR regions of molecules - result = affinity maturation of Abs |
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what are the different IgM structures?
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pentameric = secreted form --> joined through constant regions via covalent bonds, allows mult attachment pts
monmeric- transmembrane form |
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isotype switching
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changing the effector fn of ab (ex IgM --> IgG)
- intronic switch signals after VDJ combo --> depends on where they are---looping out (loop won't be included) - occurs after Ab formed |
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what adhesion molecules initiate B cell differentiation?
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VLA-4 on progenitor w/ VCAM-1 on stromal cell
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What are the different cell stages of B cell differentiation?
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1. early pro-B cell - induction of prolif via Kit/SCF interaction
2. Late pro-B cell - expression of IL-7 receptor on B cell, responds to IL-7 generated by stromal cells 3. Pre-B cell = 1st expression of Ag receptor on cell (terminates mu chain rearrangements) - dependent on IL-7 for survival 4. Immature B cell - non-dividing - not dep on IL-7 for survival - IgM expression on surface |
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when in B cell dev are RAG genes and TdT expressed?
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RAG genes - early proB to pre-B
Tdt - through late pro-B (N nucleotide genes) |
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how many rearrangements are allowed of H and L chain genes during B cell differention?
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H chain - only 1 chance of producing productive H chain - due to germline config - have 3 gene segmeents recombining to produce entire variable region of H chain
L chain - no intervening D segment, so can have multiple rearrangments |
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what are the checkpoints in B cell development?
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1. expression of pre-B cell antigen receptor (as rearrangements take place)
2. expression of B cell receptor on surface after H and L chain rearragments |
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pre-B cell receptor
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occurs after H chain rearrangement
- surrogate light chain of VpreB and lambda5 bind to terminus of H chain to allow it to be expressed on surf - ligand in env recog surrogate light chain in combo w/ H chain --> signal transduced through accessory molecs (IgB and Igalpha) - signal to start rearranging L chains and stop H chains |
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What does B cell expression in immature B cell signify?
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termination of light chain gene rearrangements
- L chain displaces lamda 5 and VpreB surrogate chains -links up w/ H chain and expresses B cell receptor on surf |
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allelic exclusion
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controls gene rearrangements
- doesn't allow add'l B cell receptors to be encoded or translated on surf - explains clonal selection hypothesis where B cell clones are monospecific |
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receptor editing
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process of rescuing self-reactive B cell clones
- rearrange L chain genes producing IgM w/ different specificity --> try again w/ self-Ag |
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Elimination of self reactive B cells
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in bone marrow
- if reacts w/ self antigen, retained in marrow, could undergo receptor editing--> if goes through all options will apoptose - if doesn't reaction w/ self ag --> moves to blood and expresses IgM and IgD |
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b cell anergy
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B cell clones reacting to soluble self Ags --> not deleted
- soluble self Ag binds but doesn't crosslink (in bone marrow, would cross-link receptor) - B cell signaled to make IgD and unresponsive to Ag - enters periph circ but doesn't last long |
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What happens to immature non self-reactive B cells once they enter circ?
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- must enter primary lymphoid follicles to mature
- CCL21 attracts them to HEV's (stromal cells) - CCL21 and 19 attract them into LN (DC's) - CXCL13 (FDCs) attract them to primary follicle - BAFF-BAFF-R interaction --> mature B cell co-expressing IgM and IgD |
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HLA Class I structure
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- polymorphic heavy chain - alpha 1, 2, 3 domains
- B2m nonpolymorphic light chain - peptide binding cleft = alpha 1 and 2 - CD8 T cell binds alpha 3 |
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Transactivators
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restrictive TF's that need to be in cells to get MHC2 Transcroption
- MHC only |
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What induces MHC I expression?
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Type I interferons
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Bare Lymphocyte syndrome
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mutation of transactivator
- no MHC2 --> no CD4 response - SCID |
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what chromosome are MHC on?
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6
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HLA Class II structure
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dimers
- a chain --> alpha 1 and alpha 2 EC domains - b chain --> B1 and B2 EC domains - peptide binding = B1 and a1 - CD4 binds B2 - peptide binding domain is larger than MHC I and can accomomdate larger peptides |
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MHC restriction
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recognition by TCR is restricted to 1 MHC and peptide combo
- any change in either peptide or MHC molec will result in loss of recog - NO ADOPTIVE TRANSFER |
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What are the differences in MHC binding between class I and II?
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class I - requires amino and carboxyl groups at end of peptide (not necessary for MHC II because ends are more open)
- 8-10 AAs in length (10-30 for MHC II) - anchor residues in peptide complementary to cleft - always have hydrophobic/basic AA at carboxyl residue will have either Tyr or Phe at another position |
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LMP 2 and 7
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involved in producing peptide for MHC I molecules
- substitute for other consituent proteins in proteosome and change catalytic activity --> immunosome |
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TAP 1 and 2
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mediate transport of peptides for MHC I to ER
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What viruses have subverted MHC binding to peptide antigen?
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1. herpes simplex --> block tap binding to peptide
2. adenovirus - competitive inhibitor of tapaisin (one of loading complex proteins) 3. CMV - makes own tap molec that puts in ER, but opp direction |
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Where are peptides for MHC I and II made?
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1. proteosome
2. acifiied endocytotic vesicles |
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What mechanism prevents MHC II molecs from binding TAP peptides in ER (for MHCI)?
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invariant chain - blocks binding of peptides to MHC II in ER
- shuttles MHC II closer to endosome - invariant chain cleaved --> leaves clip fragment bound --> blocks binding of MHC II to peptides in vesicles - HLA-DM facilitates release of CLIP --> peptides bind |
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what cells do not have MHC? (even type I)
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RBCs
placental cells |
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How do placental cells evade NK cells?
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HLA-G inhibits NK cells
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Cross-Presentation
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- proteins/peptides from endocytotic pathway find way into cytoplasm/ER and bound by MHC I molecs
- ex. Hep C --> only infects hepatocytes - macrophage engullfs apoprtotic part of hepatocyte --> endocytotic pathway --> retrotranslocation to cytosol --> MHC I pathway CD8 |
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haplotype (HLA)
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total constellation of MHC molecs you're have on your chromosome
- most of us have diff HLA haplotypes (imp for transplatnation) |
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co-dominance
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Expression of HLA class I and II molecs is co-dominant
- both haplotypes expressed in all indiv (1 from each parent) |
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what does polymorphism in MHC result in?
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heterozygosity
- can present 6X as many molecs thatn if only had 1 |
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Where do MHC molecs differ from each other?
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- ag binding cleft usually
- diff alleles bind diff sets of proteins |
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gene conversion
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generates sequence diversity in MHC genes
- nonreciprocal transfer of genetic info - 1 gene converts, the other receives - short recombination events - alleles begin to look like mosaics of other MHC genes |
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What are the comparisons between the TCR and BCR?
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- diversity created by recombination in both
- TCR's structure beta chain ~ H chain of Ig alpha chain ~ L chain of Ig - once TCR made on surf, no other changes take place due to Ag binding (B Cell --> somatic hypermutation and isotope switching after Ag binding) |
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What will happen w/ defective RAG?
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- SCID
- no gene recomb non functional T and B cells - prone to mult infections |
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omenn syndrome
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missense mutation in RAG genes, partial activity
- patial adaptive immune resp - bright red rash - high eosinophilia and IgE due to Th2 phenotype |
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TCR functional complex
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TCR w/ S cytoplasmic chain (for signal transduction)
- 3 invariant chains/peptides interacting w/ TCR alpha beta chain - help to stabilize TCR on cell surf = CD3 (2 epsilon, gamma, delta) |
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what thymic cells mediate positive T cell selection?
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cortical epithelial cells
- present MHC-peptide complex from degrad of self protein - T cells taht recog given signal to proliferate - if recog MHC II/peptide --> CD4 T cells - if recog MHC I/peptide --> CD8 |
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at what differentiation stage are T cells at when they undergo positive and negative selection?
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double positive mature
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What are the different steps in differentiation of an alpha beta T cell?
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1. uncommitted progenitor (CD34)
2. committed double negative progenitor (CD2) 3. beta rearrangment done 1st (instead of gamma delta)--> uncommitted double + thymocyte 4. alpha and beta rearrangements --> committed double positive T cell |
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Notch1
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important regulator of T cell differentiation on thymic epithelium
- upon binding to thymocyte, IC domain of Notch1 cleaved --> nucleus - activates gene transcription for prolif and diff of t cell type |
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what are the checkpoints in T cell diffferentiation?
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1. after rearrangment of beta genes to become uncommitted double + thymocyte
2. after alpha gene rearrangments to become mature double positive cells |
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Selection of T cells in thymus
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1. postiive
2. negative - DC and macrophage mediated - if don't interact w/ self peptide presented by DC/macro, move out of thymus via blood venules |
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where are DC's and macrophages located in the thymus?
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medulla (inner)
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what is another mechanism of eliminating autoreactive T cells besides negative selection?
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suppression by Treg cells (CD4 and CD25 positive) --> secrete cytokines that suppress activity of CD4 T cells by interacting w/ same APC
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in what APCs is MHC constitutively expressed?
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B cells
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in what APCs are co-stimulatory molecules constituively expressed?
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DC's
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what molecules allow T cells to initially bind APC as first step in T cell activation?
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LFA-1 on T cell w/ ICAM on APC
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Signals required for T cell activation
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1. interaction of TCR w/ MHCII
2. Co-stimulatory molecules on APC surface - B7 molecule on APC binds CD28 of T cell (Co-stim molecs only expressed by APC when recog pathogenic/foreign products, not self-peptide) - binding of MHC ligand (via APC) to TCR sets off signal cascade to activate T cell |
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What process down-regulates T cell activation?
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CTLA4 w/ CD28 ---> 20X stronger than B7-CD28 --> activation downregulated (occurs after effector cells genearted)
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T cell anergy
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- major mech of periph T cell tolerance against tissue spec Ag's (haven't encountered these in thymus)
- T cells tolerated in this way wont be able to respond to same Ag even if presented by an APC |
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autoimmune lymphoproliferative syndrome
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- defect in apoptosis mech --> lack of removal of effector T cells after cessation of immune actviation
- usually a Fas or FasL defect - enlarged LN's, splenomegaly, autoimmune disease, hemolytic anemia |
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what factors responsible for the differentiation of effector CD4 T cells into the different CD4 cells?
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1. Treg --> induced by TGF-B and FoxP3
2. Th1 --> induced by IL-12, IFN-gamma, and T-bet 3. Th2 --> induced by IL-4 and GATA3 |
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What cytokines do the diff CD4 cells secrete?
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1. Treg = TGFB and IL-10
2. Th1 - IL-2, IFN-gamma 3. Th2 - IL4, IL5 |
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What are the different effector fn's of Th1 cells?
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look in T cell activation notes
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what are the different TH2 cytokines?
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IL4, IL5, IL10, IL13, TGFB
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CD8 T cell activation
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receptor recognition (MHCI and peptide)
- redistribution of cytoskeletal and cytoplasmic contents of T cell - target destruction via lytic granules (w/ perforin, and granzymes) - perforin forms pores, granzymes are serine proteases that activate nucleases --> induce FasL --> apoptosis |
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B cell receptor complex for B cell activation
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Ig + in association w/ accessory molecs
- Ig alpha, Ig beta - signal B cell to begin diff and prolif after Ag contact and cross-linking |
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What is first step in activation of mature naive b cells?
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receptor crosslinking of Antigen receptors --> initiations signal transduction by Tyr kinases --> phosph of IC domains
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B cell receptor complex
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increases signalling greatly
- very imp for b cell activation 1. CR2 - binds C3d on cells 2. CD19 - signaling domain 3. CD81 - C3d fragments gen from C3b by Factor I interaction w/ CR1 on B cells --> bound by CR2 of B cell co-receptor |
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characteristics of plasma cell
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abundant RER in cytoplasm
surface Ig expression lost terminally differentiated, unable to prolif most end up in bone marrow |
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T-independent Ag's
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activate B cells in absence of Th
- ellicit only a primary, IgM response (need T cells for isotype switching) - no memory |
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What are the different TI antigens?
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1. TI-1 - act as B cell mitogens
- ex. LPS --> elicits spec and non-spec response SPECIFIC - LPS recog by complex of CD14, TLR4, MD2 on macrophages and B cells - Naive B cell binding to LPS through BCR-TLR4 complex --> LPS specific antibodies NONSPECIFIC (polyclonal) - 2 mechs 1. LPS bound TLR4 complex polus BCR binding to diff surf Ag on LPS 2. BCR binding to surf Ag on LPS --> internalized, activation through TLR-9 --> IgM Ab to surf Ag 2. TI-2 Ags (ex polysaccharides) - comprised of repeating epitopes, elcicit ag-spec IgM - BCR crosslinking to mult repeated epitopes --> B cell activation and IgM resp |
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Why do infants need an adjuvant for polysaccharide vaccines?
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TI-2 cells not funciontaly mature till 2yo
- can link vaccine to tetanus toxoid or another T-d protein - will be taken up, recog and internalized by B cells that get T cell help |
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T-dependent antigens
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- predominant type of immune response initiator
- requires APC and activation of Th cells to activate and differentiate to Ab-secreting plasma or memory cells |
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What is the 2-signal activation of T-cell dep Ag's w/ B cells?
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1. Ag binding
2. CD40-CD40L binding w/ cognate T cell elaboration of cytokines |
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what occurs in the medullary cords of the lymph nodes?
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plasma cells produced, IgM released into lymp circ.
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where does somatic hypermutation, isotype switching, and clonal expansion of B cells occur?
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germinal centers of lymph nodes
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What does somatic hypermutation of B cells require?
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T cell cytokines and ligation w/ CD40
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What is the role of follicular dendritic cells in somatic hypermutation of B cells
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- present native unprocessed Ag to B cells on iccosomes --> taken up by B cells undergoing SHM --> B cells compette in GC's for Ag bound on FDC's
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What is the result of affinity maturation of B cells
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high affinity BCR --> bind ag and crosslink --> Form CD40/CD40L w/ Th cell --> upregulates Bcl-xl --> inhibits apoptosis
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What determines the isotype that a particular B cell switches to?
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cytokines
1. IL-4 induces IgG1 or IgE 2. IL-5 --> augments IgA production 3. IFN-gamma --> induces IgG3 and IgG2a 4. TGFB --> IgG2b and IgA |
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What determines the fate of B cells as plasma or memory cells?
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IL-10 ---> plasma cells
IL-4 ---> memory B cells occurs after B cells have been Ag-selected |
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Brambell receptors
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2 component receptors that bind Fc portion of IgG --> brings it into EC tissue space from circ via active transport
- also transports IgG to fetal from maternal circ |
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how are antigens processed in gut associated lymphoid tissue?
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part of mucosal immunity
- M cells take up antigen from lumen by endocytosis and phagocytosis - Ag transported across M cells in vesicles and eleased at the basal surface - Ag bound by dendritic cells --> activate T cells |
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How does the antigen determine whether there will be a Th1 or Th2 response?
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1. If tight binding of Ag w/ TCR --> Th1
2. If binding less tight --> Th2 |
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What Th response predominates in helminth infections?
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Th2 --> produces IL-13 --> induces ep cell repair and mucous
- attracts lg amt of mast cells and eosinophils (IgE-driven) |
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original antigenic sin
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occurs when dealing w/ a highly mutable pathogen
- whenever there's a memory response, and a primary response needs to be elicited against a new Ag epitope on same Ag --> memory respolnse inhibits the primary response - ex) in primary infection, virus has 4 diff epitopes --> primary response to THOSE epitopes --> virus cleared - 2nd infection w/ same virus but one of epitopes has been mutated --> will be a memory respolnse to the 3 epitopes that stayed same, which will inhibit a primary respolnse to the 1 mutated epitope |
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What are the differences in surface molecules between a memory and naive T cell?
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1. CD45RO --> 30X more in memory cell
2. LFA-3 --> 8X more in memory cell (ligand for CD2 involved in adhesion and signaling) |
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How does cancer evade the immune system?
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1. most of Ag's are self-abberant proteins, therefore not recognized as foreign (T cell anergy/tolerance to tissue-specific proteins)
2. TGF-B secreted by Treg cells inhibits Th1 and cytotoxic T cell activity |
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how can an immune response be developed to cancer?
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- mutant peptides can be presented in context of MHC
- reactivation of embryonic genes not normally expressed in differentiated cell - overexpression of normal self protein by tumor cell changes the density of self-peptide presentation --> allowing recog by T cells |
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HSPs and cancer
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-heat shock proteins (chaperones)
- in cancer cells, will chaperone peptides coming from aberrant proteins --> source of immune response induction - HSPs taken up by DC's in assoc w/ aberrant peptide --> induce cytotoxic T resp and Th2 resp |
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Toxic Shock syndrome
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due to S. aureus
infection that subverts specific cellular immune response and produces generalized immune activation --> so generalized that it causes septic shock |
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How does S. aureus subvert the immune system?
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secretes superantigen
- proteins that interact w/ V-beta region of TCR - intercalate w/ both MCR and TCR --> doesn't go through Ag processing and presentation - as result, all T-cell clones containing V-beta region get activated - massive cytokine secretion and septic shock |
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What cytokines are involved in TSS?
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1. IL-1 and TNF-alpha --> acute phase response - fever
2. IL-6, IL-8, TNF-alpha --> activate vascular endothelium 3. IL-2 --> increases vascular permeabolity |
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How does AIDS subvert immune response?
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- targets CD4 co-receptor on T cells
- enters into T cells and apoptotic mechanism |
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what changes occur in lymph nodes of AIDS patients?
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follicular hyperplasia --> suggest ongoing B cell response to virus
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What is the drug therapy for AIDS?
|
AZT - pyrimidine analog
- incorporation blocks DNA synth of virus |
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2 different types of leprosy, manifestations, cytokine profile
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1. tuberculoid - Th1 response
- granulomas, periph nerve damage - normal serum Ig levels - normal T cell responsiveness cytokines = IL2, IFNgamma, TNF-B 2. Lepromatous leprosy - Th2 type response - hypergammaglobulinemia - disseminated infection (bone cartilage diffuse nerve damage) - low or absent T cell responsiveness - cytokines = IL4, 5, 10 |
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What are the different ways pathogens can evade/subvert Immune Defenses?
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1. antigenic variation
2. Latency (eg herpesvirus) 3. Subversive tactics 4. Activation by bacterial superantigens --> deplete T cells |
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What are the different types of antigenic variation pathogens use to evade IR?
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1. multiple serotypes (eg. S. pneumoniae --> changes surface Ag's)
2. Mutation and Recombination (ex. influenza virus) a. antigenic drift - alter hemagluttinin in diff person and then infect person who had antibodies to the original hemagluttinin b. antigenic drift - coinfection of 2 different strains in a host, recombination to produce virus w/ diff hemagglutinin (H1N1 virus) 3. Gene conversion - ex. trypanosomes --> have 1000s of VSGs in genome, can undergo gene conversion to allow org. to vary VSG expressed |
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Latency
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way to avoid T cell mediated killing
ex) herpes virus traveling up to trigeminal ganglion and slowing down rep to avoid detection by T cells |
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X-linked hyper IgM
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- T cell deficiency caused by defective CD40-CD40L signaling
- results in lack of IL-4 secretion (needed for isotope switching, affinity maturation of B cells) - also results in defective macrophage response - signaling req for macrophages to mount inflam response and produce cytokines |
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deficiency in C1, 2, 4
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immune complex disease
- no activation and deposition of C2b then clarance through receptors on RBC's passage through spleen and liver |
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Wiskott Aldrich syndrome
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X-linked T cell deficiency
- defect in WASP --> req for rearrangment of cytoskeletal elements when B and T cells recog Ag's through TCR and MHC II presentation by B cells - prevents effective B and T cell interactions or cognate recognition |
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Leukocyte adhesion deficiency
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- defect in phagocyte fn
- defect in B chain of CD18 in 3 key receptors 1. LFA-1 --> ligand for ICAM-1 --> important for transendothelial adhesion and trafficking --> allows PMN's to get out of circ into tissue 2. CR3 3. CR4 - recog iC3b --> impaired phagocytosis |
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what is contained w/in the granules of mast cells
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1. enzymes - tryptase, chymase, carboxypeptidase
2. toxic mediators - histamine and heparin (cause immed resp) 3. pre-formed cytokines - IL4 and IL13 - IL3, 5, GM-CSF -TNF-alpha - - leukotrienes (lipid) |
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what are late-acting inflammatory mediators (type I hypersens)
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PGD2 and LTC4
- mediate late phase respose |
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What are the actions of the different pre-formed mast cell cytokines in type I hypersensitivity
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1. IL4 and IL13 --> mediate Th2 response and differentiation of T cells into Th2 cells; IL-4 mediates class switching to IgE
2. IL-3, GM-CSF, IL-5 --> help mobilize eosinophils from bone marrow and support their release 3. TNF-alpha --> activates endothelium (increases perm) 4. |
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what are the different toxins and cytokines released by eosinophils to coop w/ mast cells in producing allergic resp?
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1. enzymes
a. eosinophil peroxidase - triggers His release from other mast cells that havent yet b. eosinophil collagenase - remodels tissue 2. toxic proteins a. major basic protein - toxic to parasites and tissues when rel b. eosinophil cationic protein - toxic to parasites 3. cytokines --> IL3, 5, GM-CSF - IL-8 --> chemotactic for macrophages 4. lipid mediators a. leukotrienes --> increase perm, mucous secretion, sm muscle contraction b. platelet activating factor - chemotactic for leukocytes |
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How can eosinophils have bystander effect on host tissue?
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promotes hypereosinophilia --> can cause heart damage
- fibrous exudate in endocardium |
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What is the role of basophils in type I hypersensitivity?
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- consitutively express FCeRI receptors to IgE --> respond to IgE Ab's bound to Ag's in circ
- play role as APC's in type I response --> secrete IL4 to recruit Th2 cells |
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properties of inhaled allergens in type I hypersensitivity
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1. mostly proteins that induce T cell response
2. often are proteases- can loosen junction bet ep cell 3. low MW (easy diffusion) 4. Highly soluble and can be eluted from particles 5. high stability 6. Maintain high antigenicity even in dessicated form |
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Properties of systemic anaphylaxis
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due to allergens reaching blood stream
1. Heart and vasc --> leakiness of BVs 2. Resp tract --> contraction of smooth muscles (difficulting breathing and swallowing 3. GI tract --> contraction of sm muscles, fluid outflow lose fluid into tissues (hypovolemia), decreased O2 perfusion, irreg heartbeat, shock |
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How can systemic anaphylaxis be stopped/reversed?
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Epinephrine restores decreased blood pressure
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what do type II hypersensitivity rxns result from?
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altered self antigens
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arthus reaction
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model of local immune complex disease
- result of direct injection of a soluble antigen you're sensitized to - local immune complex formation activates complement - C5a binds C5a receptor on mast cell --> induces degranulation - local inflamm, increased fluid and protein release, etc. |
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serum sickness
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when high load of Ag injected
- as ab response increased, starts being cleared (piont at which you experience symptoms) - As Ab increases, beings to clear complexes and you recover |
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What are the differnet types of Type IV hypersensitivity rxns?
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both due to effector T cells reacting to foreign proteins or altered self-Ag's
1. Delayed Type Hypersensitivity (DTH) - due to protein Ag's or microbial proteins 2. Contact hypersensitivity - due to haptens (by themselves not antigenic, but when boudn to protein or larger molec --> immune resp) |
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What is the pathogenesis of DTH response (Type IV hypersensitivty)?
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- Ag-specific Th1 effector cells recog Ag presented by APC's --> releases cytokines that mediate rxn
1. IFNgamma - activate macrophages, increasing rel of inflamm mediators 2. TNFa and LT - local tissue destruction, increased expression of adhesion molecs on BV's 3. IL-3/GM-CSF - monocyte production by bone marrow stem cells |
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How is contact dermattis caused? (type IV hypersensitivity)
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protein adducts formed with a hapten of the allergen
- recog as neo-Ag through T cell interactions |
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why is it generally easier to make female to male than male to female transplant?
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- HY minor histocompatibility antigens --> All Y chrom proteins recog as foreign minor histocomp molecs by female
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where do MHC molecs gernally differ from each other?
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antigen binding cleft
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alloreactivity
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reactivity against different peptides presented on surface of transplanted cells/tissues in context of MHC
- most of diff in MHC molecs is visible to TCR and bound to ALLO peptides - some surface differences in MHC peptides can also be recog as foreign |
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Hyper-acute rejection (target, mediators, therapy, etc.)
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targets = blood type Ag's and allo MHC
Effector resp = preformed Ab and complement therapy = none prevention |
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Where do pre-formed Ab's in Hyperacute rejection come from?
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1. ABO - most common; found in nature (food, bacteria)
2. HLA - wouldn't have them unless there's a mixing of blood (transfusion or pregnancy) |
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Acute rejection
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Target = allo-MHC and/or their peptides (direct allorecognition)
Effector Resp = Mostly CTL, but also Th1 inflamm resp Therapy = Steroids, cytotoxic , Specific calcineurin inhibitors (cyclosporin A, FK506, rapamycin, tacrolimus |
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direct allorecog
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Donor DC's stimulate CD4 and CD8 T cells --> CD8 T cells will kill before get chronic inflamm.
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tissue typing
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mixed lymphocyte rxn --> donor spleen cells or blood cells w/ APC, T, B cells
- irradiate so don't replicate - mix recipient T cells/B cells - measure T cell prolif and cytotoxicity |
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What are the 4 classes of drugs used for prophylactic/induction therapy for transplants?
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1. corticosteroids
2. cytotoxic/anti-metab drugs 3. calcineurin inhibitors 4. anti T cell Ab's |
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Classes of drugs for maintenance immunosuppresion for transplants
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1. corticosteroids
2. cytotoxic/antibmetabolite 3. calcineurin inhibitors |
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treatment of acute rejection rescue therapy
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1st - lg doses of corticosteroids
2nd - adjust dosing of calcineurin inhbitors 3rd. anti-T cell antibodies |
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mechanism of corticosteroids
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- upreg production of IkBalpha --> prevents NFkB from entering nucleus --> cytokine production is inhibited
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Mycophenolate mofetil (MMF)
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inhibitor of purine salvage pathway
- new drug that cutes acute rejection rate in half vs. old drugs - replicating alloresponsive cells not able to make purine bses for DNA --> DNA synth inhibited, cell death |
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Importance of calcineurin in transplant rejection
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- after naive T cell recog of Ag --> IC Ca increased --> IP3 pathway activated --> activates calcineurin
- dephosph and activates NFAT - NFAT binds TF AP-1 in nucleus --> activates IL-2 transcription - IL 2 essential in activation of T cell and development of adaptive immune resp |
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rapamycin
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- binds to FK binding proteins but does not inhibit calcineurin like the other calc inhibitors do
- inhibits signal transduction from IL-2 receptor and blocks T cell activiation at later stage |
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Chronic Rejection
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Target = allo-MHC (years) Indirect
Effector Resp = chronic inflamm (cytokines and ab's) Therapy = immune suppresion |
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Indirect pathway of allorecognition (resp for chronic rejection)
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- continual stim of alloreactive T cells
- also stim B cell response - alloantibodies recruit inflamm cells to blood vessel walls of transplanted organ - increasing damage allows immune effects to enter tissue of BV wall and inflict increasing damage - result inadequate bl supply and ischemia |
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bone marrow transplant
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key = pluripotent stem cells that will replace recipients' entire immune system, platelets, RBCs
- 2-3 wks post transplant, new circ bl cells produced from transplanting marrow --> proves SC's have colonized bones (engraftment) |
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BMT HLA matching
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need positive selection of new T cells, so much have at least 1 HLA allotype match between donor and recipient
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pannus
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membrane of granulation tissue composed of inflamm cells that stars one area and migrates and beigns to cover and enzymatically dissolve/destroy the cartilage
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what type of T cell response is rheumatoid arthritis
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predominantly Th1 cell
- if get rid of TNF, disease process stopped |
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mutation in AIRE
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incomplete deletion of self-reactive T cells (plays role in negative selection)
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Mutation in FoxP3
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results in IPEX (x linked)
- due to defetive T reg cells - CD4 cells not controlled |
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linkage disequilibrium
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- some haplotypes that can't be separated --> are tightly linked
- Ex. DR3 linked to DQ2, and DR4 linked to DQ8 --> why DR3/4 heterozygotes are at risk for type I diabetes (which has assoc w/ Dq8 and Dq2) |
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molecular mimicry
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when ag from pathogen stimulates immune resp --> cross reacts to self tissue
ex.) streptococcus and rheumatic fever |
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molecular mimicry w/ T cells
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- same MHC molec presents both pathogen and self peptide that mimics it
- naive T cell binds to MHC-peptide complex of less affinity and w/o co-stim molecs --> self-tolerance broken - effector Th1 cell responds to self-peptide memiic and activates macrophage to destroy self peptide |
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Epitope spreading
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start w/ IR to 1 epitope on a mole, and as IR progresses, other epitopes included
- tissue injury caused by autoimmune or other cause exposes cryptic hidden epitopes --> presented to T cells in immunogenic form |
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What are the different treatments for rheumatoid arthritis
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1. TNF targetting
a.) soluble receptor (Enbrel/etanerept) b. antibody (Remicade/infliximab) 2. IL-1 receptor antagonist (Kineret) |
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why is a live attenuated vaccine better than killed vaccine?
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- take orally --> make IgA (natural infection)
- shot in arm is just IgG - attenuated induces CTL and Ab's, while killed is just Ab's |
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what type of vaccine is rabies virus?
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Inactivated/killed
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What vaccines are attenuated (live)
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measles, mumps, rubella, varicella, yellow fever, sabin polio (not in US), rotavirus, Tb (not in US)
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What vaccines are toxoid
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diptheria, tetanus
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what vaccines are subunit
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meningitis (neisseria), bacterial pneumonia, Hep A+B, HPV
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Why is it necessary to make a protein conjugate vaccine?
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needs T cell help for good AB respolnse ---> binds MHC II --> isotype switching, SHM
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How is linked recognition utilized i making vaccines for children?
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- link toxoid/protein carrier to polysaccharide
- B cell binds bacterial Polysacch - peptides from toxoid oare presented to T cell --> activates B cell - good for kids because their TI-2 cells are not fully developed yet |
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Why is pertussis killed bacteria added to diphtheria and tetanus vaccine
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supplies danger signal - something to initiate inflammation and induce co-stim molecules
- most of time won't respond to plain proteins |
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NOD2 and MDP interactions in vaccines
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MDP = degradation product of bacterial cell wall (repeating units)
NOD2 (TLR molecule) - in cytosole of enterocytes - respond to bacterial products by activating NFkB |
