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156 Cards in this Set
- Front
- Back
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Sites of Ag entry
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skin barriers
oral UG tract |
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Sites of Ag capture in skin barriers
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breaching --> Langerhans cells in epidermis
injection --> spleen or tissue-specific macrophages |
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Sites of Ag capture with oral entry
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respiratory --> alveolar macrophage
GI --> M cell |
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Sites of Ag capture with UG entry
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urinary tract --> DC
reproductive organs --> DC |
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3 types of dendritic cells (DC)
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Langerhan
follicular DC thymic DC |
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most competent APC
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DC
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5 steps: DC presenting to T cells
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Localized DC take up Ag
activated DC migrate to LN via lymphatics DC mature during migration DC enter LN via afferents DC meet naive T cell in paracortex |
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Receptor that recognizes MHC-peptide as a whole entity
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TCR
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MHC stands for...
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Major Histocompatability Complex
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sole function of MHC
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display peptides
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MHC restriction
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T cells can only recognize peptides displayed by MHC
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MHC I expresses on...
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all nucleated cells
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MHC II expresses on...
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APCs only
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APC expresses which MHC on their surfaces
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MHC I & MHC II
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Structure of MHC I
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alpha (1, 2, 3) - peptide binding cleft (alpha1:alpha2)
- alpha3 binds CD8 beta2 microglobulin |
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Structure of MHC II
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alpha (1, 2)
beta (1, 2) peptide binding cleft (alpha1:beta1) beta2 binds CD4 |
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peptide length for MHC I
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8-10aa
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peptide length for MHC II
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10-30 aa
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MHC peptide features (5)
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peptide-binding stabilizes surface MHC expression
only linear and processed peptides bind to MHC only one peptide per MHC at a time different peptides can bind to the same MHC MHC binds to self & non-self peptides |
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Haplotype
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unit on which MHC is transmitted genetically
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In one individual, MHC is inherited on...
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two haplotypes, one from each parent
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Co-dominancy of MHC
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both paternal and maternal copies of MHC genes express on all nucleated cells in one person
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Exogenous Ag processing
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synthesized outside APC
processed and presented on MHC class II |
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Endogenous Ag processing
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synthesized or modified w/in APC
presented on MHC class I |
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primary mechanism for APC to take up exogenous Ag
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phagocytosis
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phagocytosis receptor on CD & Mphages
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PRR
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phagocytosis receptor on B cells
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Ab-Ag complex
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In Mphages, endogenous proteins come from...
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microbes that evade phagosomes
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In DC & Mphags, proteins taken up by phagocytosis can generate
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endogenous peptides (Cross presentation
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Cross presentation
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exogenous Ag processed thru MHC I path & presented to CD8+ T cells
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Primary source for endogenous Ag via cross presentation in DC
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viruses in host cells
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MHC II
process ____? present to... |
MHC II:
process exogenous Ag present to CD4+ T cells |
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MHC I
process ____? present to... |
MHC I:
process endogenous Ag present to CD8+ |
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MHC II pathway events
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look up in textbook
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MHC I pathway events
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look up in textbook
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Ag presentation in CMI - MHC II pathway (2 arms)
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Ab production
Mphages activation via T-helper cells Both targeted to extracellular pathogens |
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Ag presentation via CMI - MHC I pathway
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CTL
targeted to intracellular pathogens (esp. viruses) |
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PAMPs recognized by TLR-1,2,6
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lipoproteins
glycoplipids peptidoglycan zymosan |
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PAMPs recognized by TLR-3
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dsRNA
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PAMPs recognized by TLR-4
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LPS
fungal mannans viral envelope protein |
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PAMPs recognized by TLR-5
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flagellin
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PAMPs recognized by TLR-7.8
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ssRNA
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PAMPs recognized by TLR-9
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UM CpG
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Human MHC gene name
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HLA
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MHC gene loci are on chromosome ___
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6
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three MHC I genes
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HLA - A, B, C
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three MHC II genes
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HLA - DP, DQ, DR
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How was HLA initially discovered
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graft rejection
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HLA-DM
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MHC II assembly
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Genes found in "Class III" MHC locus
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complement: C2, C4, factor B
cytokines: TNF, LT |
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Genes for MHC I components found in MHC II locus
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TAP1 and TAP2
proteasome (both involved in MHC I assembly) |
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Internalized antigens =
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exogenous antigens
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Cytosolic antigens =
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endogenous antigens
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Exogenous antigens do not have direct contact with...
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your cytosol (stay inside macrophage)
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3 types of endogenous antigens
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Microbes evading phagolysosome fusion
microbial proteins cross presented by DC viral proteins generated during viral infection |
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Non-polymorphic MHC genes
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DM: MHC II assembly
proteasome & TAP: MHC I assembly complement proteins cytokines |
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MHC II Pathway Events (7 steps)
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Antigens taken up by phagocytosis
endosomal antigens digested by proteases MHC II molecules synthesized in ER CLIP occupies peptide binding cleft in exocytic vesicle, processed peptides contact MHC-II-li DM removes CLIP & peptide replaces it Peptide-MHC II translocates to the cell surface |
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Invariant chain
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bound to MHC II in the ER in order to keep random peptides from binding
cleaved --> li --> CLIP |
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MHC I Pathway Event
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microbes in cytoplasm
peptides go thru TAP to get to ER peptides assembled with MHC I in ER and travel to cell surface |
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Processing enzyme for MHC I
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proteasome
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Processing enzyme for MHC II
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protease
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Which MHC class has a transporter and what is it?
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MHC class I - TAP
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Which MHC class has an accessory protein and what is it?
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MHC class II - invariant chain
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2 receptors determine NK-mediated killing
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ITIM - inhibitory (as in self-Ag)
ITAM - activating (as in viral-infected cell) |
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receptors mediating Ag recognition in ADAPTIVE immunity (2)
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BCR (mlg)
TCR |
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3 types of BCR
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mlg
Ig-alpha Ig-beta |
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3 types TCR
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TCR
CD3 zeta |
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Ig is composed of how many chains?
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4 - 2 heavy & 2 light
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In an Ig molecule, each L chain has one ____ and one _____
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In an Ig molecule, each L chain has one Variable and one Constant region
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In an Ig molecule, each H chain has one _____ and 3-4 _____ regions
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In an Ig molecule, each H chain has one Variable and 3-4 Constant regions
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The antigen binding site on an Ig is made of ___ and ____
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The antigen binding site on an Ig is made of variable-heavy and variable-light chains
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How many antigen epitopes can each Ig monomer bind to?
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2
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CDR =
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complementarity determining region: hypervariable
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most variable CDR
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CDR3
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Papain-mediated cleavage of Ig results in...
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Fab (VhCh1-VLCL)
Fc (Ch2Ch3Ch4) |
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Pepsin-mediated cleavage of Ig results in...
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F(ab')2 (VhCh-1-CLCL)x2
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5 H chains for Ig's
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mu, delta, gamma, alpha, epsilon
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2 L chains for Ig's
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kappa, lambda
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Antibodies that have different H chains belong to different _____ (or _____)
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Classes (or Isotypes)
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Class Switching
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IgM <--> IgG
constant region of H chain changed; variable region of the heavy chain stays the same. Ig retains affinity for the same antigens, but can interact with different effector molecules. |
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5 Ig isotypes
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IgM
IgD IgG IgA IgE |
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Ig allotype
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same class of Ig from different individual
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Idiotype
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unique structure present in Ag-binding region of the Ab produced by a single clone of lymphocyte
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In tissue, ____ is the most abundant Ab
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IgA
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Function of IgM
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major surface Ig on BCR
first isotype of Ab secreted by any B clone pentameric secreted form makes it very competent in complement activation neutralizing Ab |
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Most abundant isotype in serum
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IgG
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Only Ab to cross placenta via neonatal Fc receptor
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IgG
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ADCC
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Ab-dependent cell-mediated cytotoxicity
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4 functions of IgG
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ADCC
activation of complement neutralization regulation on B cell |
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IgA
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major player in mucosal immunity
major Ab in colostrum and milk - neonatal immunity can cross gut epithelial via FcRn neutralizing Ab secreted IgA dimer activates complement |
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IgE
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major player in allergic rxn
dominant force in clearing parasite infection functions together with eosinophils or mast cells |
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Do TCR complexes class switch?
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no
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How many chains do TCR have?
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2: alpha & beta
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lymphocyte receptor that is membrane anchored and does not have a secreted form
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TCR
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90% of T cells have TCR =
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alpha/beta
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10% of T cells have TCR =
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gamma/delta
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which TCRs are MHC restricted (adaptive immunity)?
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alpha/beta
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which TCRs are not MHC restricted & recognize phospholipids or glycolipids?
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gamma/delta
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TCR binding to peptide is >100x ______ than Ig binding to Ag
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TCR binding to peptide is >100x WEAKER than Ig binding to Ag
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Co-receptors
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CD4 and CD8
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TCR binds to peptides and CD4/CD8 binds to ____
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MHC
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V, D, & J segments are found on which receptor chains?
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BCR heavy-variable chains
TCR beta chains |
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BCR light-variable and TCR alpha chains include which 2 segments
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variable (V)
joining (J) |
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Allelic exclusion
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only one allele (maternal or paternal) expresses in each cell
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Allelic exculsion ensures:
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one cell, one antigen specificity
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VDJ recombination occurs in the development of which cell types?
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B and T
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Purpose of VDJ recombination
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diversity of antigen recognition
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VDJ recombination is mediated by...
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recombinase RAG1/RAG2 at somatic DNA level
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RAG1/RAG2 only express in which cells?
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B & T precursors
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4 VDJ recombination steps that occur at the H chain locus
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one of D segments is ligated to J segment
DJ is ligated to V segment splicing machinery ligates VDJ with C-mu expression of VDJC-mu H chain combines with surrogate L chain on surface of pre-B cell |
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2 VDJ recombination steps that occur at the L chain locus
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V gene segment is ligated to a J gene segment
VJ ligated to C |
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VDJC-mu H chain associates with VJC L chain to make...
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an mlgM (or mlgD)
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mlgM (or mlgD) expresses on...
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B cell surface
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2 modes of junctional diversity
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nucleotides removed by exonucleases
N-region nt's are added by TdT |
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binding strength btw an epitope and the Ag-binding site
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affinity
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total binding strength of the affinity from each Ag-Ab binding site plus synergy from the multiple Ag-bindigns on the same antigenic particle
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avidity
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increase of the binding strength btw an epitope and the Ag binding site
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affinity maturation
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affinity maturation only occurs...
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in B cells via somatic mutation
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Definition of affinity maturation
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after Ag stimulation, somatic mutation and selection increase Ab affinity
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Adaptive CMI is mediated by ___ cells
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T cells
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Components of adaptive CMI include
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T cells, APC and cytokines
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Dominant mechanism for clearing infection of intracellular bacteria, fungi and parasites
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delayed-type hypersenstivity
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Dominant mechanism for clearing viral infection
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CTL mediated cytotoxicity
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2 types of Adaptive CMI
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DTH
CTL mediated cytotoxicity |
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Intracellular microbes in a vacuole replicate...
what type of antigen? |
inside membrane-bound vacuole, avoiding death by lysosome
exogenous antigen |
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intracellular microbes in the cytosol replicate...
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in the cytosol
endogenous antigens |
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5 steps in CMI
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naive T cells recognize APC in 2* lymphoid organs
activated T cells proliferate & secrete cytokines or differentiate effector T cells migrate in lymphatics to site of infection apoptosis and Treg regulate the effector population at end of infection clearance subset of T cells --> memory cells |
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4 groups of interaction
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Ab--Ag = specificity
coreceptor - recognition & signal transduction Adhesion - stabilizing recognition costimulator - second signal |
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Example of Ag-Ab receptor
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TCR - peptide
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Example of coreceptor interaction
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CD4 - MHC II
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Example of adhesin interaction
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LFA - ICAM
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Example of costimulator interaction
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CD28 - B7
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Function of adhesin binding
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stabilizes T cell-APC interaction
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During T cell activation, integrin avidity increase upon what event?
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cytokine signaling
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2 adhesion accessory molecules
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LFA-1 (APCs, endothelium)
VLA-4 (endothelium) |
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ITAM
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immunoreceptor tyrosine-based activation motif
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ITAM motifs are present on which molecules?
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CD3 complex molecules mediating signal transduction after Ag binding
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T cell Anergy
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In the presence of antigens, if the costimulator receptor on a T cell is not engaged with a costimulator on APC, the T cell goes into anergy
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what turns on signaling transduction wrt T cells
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when APC express costimulators during infxn, the engagement with costimulator receptors on T cells
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CMI Signaling transduction events lead to ...
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T cell proliferation and differentiation
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Outcome of signal transduction in T cells
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TFs activated
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What phosphorylates ITAM on CD3/zeta
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Lck on coreceptor
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ZAP-70 phosphorylates adatpor proteins and initiates which 3 signaling pathways
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Ca2+-NFAT pathway
PKC-NFkB pathway MAPK-AP1 pathway |
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Ca2+-NFAT pathway
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ZAP-70 --> PLC --> IP3 --> Ca2+ --> calmodulin --> calcineurin --> NFAT-P --> NFAT
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NFkB pathway
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ZAP-70 --> PLC --> DAG --> PKC --> NFkB-IkB --> NFkB
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AP1 pathway
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ZAP-70 --> adaptor --> Ras-GTP/Rac-GTP --> ERK/JNK --> C-fos/C-jun --> AP1
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Cytokine gene expression in activated T cells
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IL-2: T cell proliferation
IL-4: T cell differentiated IFN-gamma: activate Mphages |
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Membrane ligand gene expression in activated T cells
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CD40L: B activation
FasL: apoptotic protein |
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Membrane receptor gene expression in activated T cells
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IL-2R: T cell proliferation
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IL-2 binds IL-2R on T cells, leading to...
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cell proliferation
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Superantigens lead to....
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toxic shock syndrome
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Difference btw tosic shock and spetic shock
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Toxic shock caused by enterotoxin or Toxick Shock Syndrome Toxin 1
Septic shock caused by endotoxin/LPS with sepsis |
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Toxin shock mechanism
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superAg stimulates excessive T cell response, generating massive amounts of IL-1, IL-2, TNF-alpha
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Common effector in TOxin and Septic shock
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massive production of IL-1 and TNF-alpha
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Superantigen binds to what on TCR?
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MCH II and V-beta on TCR
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Example of superantigen
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Staphylococcal entertoxin
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