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Local immune response
- Macrophages secrete cytokines, dilate local blood vessels.
- Leukocytes recruited as a result of increased expression of adhesion molecules
- Leukocytes extravasate at site of infection
- Blood clotting in microvessels
Cytokines that cause fever
IL-1b (induces the production of IL-6), TNF-a, IL-6
Cytokines and chemokines by macrophages
IL-1b: Activates vascular endothelium & lymphocytes; Local tissue destruction; Increases access of effector
TNF-a: Activates vascular endothelium and increases vascular permeability; increased entry of lgG, complement, and cells to tissues; increased fluid drainage to lymph nodes
IL-6: Lymphocyte activation; Increased antibody production
CXCL8: Chemotactic factor recruits neutrophils, basophils, and T cells to site of infection
IL-12: Activates NK cells; Induces the differentiation into TH1 cells
The adaptive (acquired) system is based on ________ of lymphocytes bearing ________, and has memory.
- clonal selection
- Ag-specific repertoire
MHC Class I vs. MHC class II
- on all cells except RBCs
- on all antigen presenting cells
Generation of diversity in BCR and TCR:
V(D)J recombination (aka. Somatic gene recombination) by enzymes, mainly RAG1&2 (recombination activating genes)
The adaptive immune system is induced when an infection has overwhelmed the _________.
innate immune mechanisms
T cells that mature in the _____ enter the bloodstream, reach the peripheral lymphoid organs, and recirculate via the lymphatics between the blood and peripheral LNs.
To participate in the adaptive immune response T cells must ____________. They then differentiate into ________, capable of ________.
- encounter their specific Ag, presented to them as MHC-peptide complex on antigen presenting cells (APCs)
- Effector T cells
- removing the Ag
__________ are called Naïve T cells
Mature recirculating T cells that have not encountered their specific Ag
- comprise the cell-mediated arm of the adaptive immune system.
- must dock with an APC that bears the correct Ag peptide presented by an MHC molecule.
- function only in the context of intimate cell-cell contacts.
T cells function:
- helper functions, such as control of Ab responses via contacts with APCs and B cells
- cytolytic functions, i.e. recognition and lysis of virally infected cells (requiring cell-cell contact)
CMI reactions occur in response to:
- Intracellular bacteria
- Fungal infections
- Parasitic infections
- Tumor immunity
- Allograft rejection
Activated functions of myeloid cells in innate and adaptive immunity
Dendritic cell - Ag uptake in peripheral sites; Ag presentation
Macrophage - Ag presentation; Phagocytosis & activation of bactericidal mechanisms
Neutrophil - Phagocytosis & activation of bactericidal mechanisms
Eosinophil - Killing of antibody-coated parasites
Basophil - augmentation of anti-parasitic immunity; Promotion of allergic responses
Mast cell - Release of granules containing histamine and active agents
- Dendritic cells - low MHC expression when immature
- macrophages - low MHC but induced quickly
- B cells - constant high MHC expression
_________ are immature DCs that take up Ag in the skin, migrate to LNs to present foreign Ag to T cells.
Can transfer Ag to ________, too.
In LNs, LCs differentiate into DCs that can no longer ingest Ag (no more phagocytosis), but have _________ activity, enhancing activation of naive T cells.
- Langerhans cells
- resident DCs
- co-stimulatory (B7)
Examples of co-stimulatory molecules
- B7 (7.1/7.2; CD80/CD86), DC -> CD28, T, enhance, naive
- B7 (7.1/7.2; CD80/CD86), DC -> CTLA-4 (CD152), T, inhibitory, upregulated in activated T cell, thus down-regulate T cell proliferation, binds more avidly than CD28
- CD40 (B) -> CD40L (T), enhance
APC deliver three kinds of signals to naive T cells
- Activation: Ag presentation, carried by MHC II, binds to TCR and CD4 (binds to MHC II)
- Survival: B7.1/7.2 - CD28
- Differentiation: cytokines bind
CD28-dependent co-stimulation induces expression of T cell growth factor (IL-2) and its high affinity receptor (CD25)
- Naive T cells only have IL-2R β,γ chains w/ moderate affinity w/ IL-2.
- Activation of T cells induces expression of IL-2R α chain or CD25.
- Binding of this high affinity receptor by IL-2 leads to T cell proliferation.
Effector T cells can respond to target cell ______ co-stimulation signal.
activated T cells proliferate and differentiate w/ the action of IL-2 to form effector T cells
The roles of effector T cells in cell-mediated and humoral immune responses
- CD8 cytotoxic T cells - Kill virus-infected cells
- CD4 TH1 cells - Activate infected macrophages; Help B cells' Ab production; IFN-γ
- CD4 TH2 cells - Help B cells' Ab production, esp IgE; against parasites; IL-4,5,13
- CD4 TH17 cells - Enhance neutrophil response; Promote barrier integrity (skin, intestine); fungi; IL-17,22
- CD4 regulatory T cells (various types) - Suppress T-cell responses; TGF-β, IL-10
- TFH cells - Help B cells' Ab production and lsotype switching; found in follicular centers; IL-21
Naive T cells encounter antigen during their recirculation through peripheral lymphoid organs
- T cells enter lymph node cortex from blood via high endothelial venules (HEVs)
- T cells not activated by Ag presented by dendritic cells exit LN via cortical sinuses
- T cells activated by Ag presented by dendritic cells start to proliferate and lose the ability to exit LN
- Activated T cells differentiate to effector cells and exit LN
Dendritic cells reside in ________ when immature. They take up ____ and migrate to ________ via _______. Mature dendritic cells activate _________ thus initiate ________.
- peripheral tissue
- regional LN
- lymphatic vessels
- naive T cells
- Adaptive immune response
Lymphocyte entry into a lymph node from the blood
- Rolling - selectins; naive T cells have CCR7
- Activation - chemokines, CCL21; activated T cells lose CCR7 and acquire CCR9
- Adhesion - integrins, LFA-1
- Diapedesis - chemokines, CCL21, CXL12
Activation of naive and effector T cells by antigen
- Activate naive T cells:
- - Dendritic cell takes up Ag, presents it
- - Naive T cell recognizes Ag
- - Binding, enhanced by costimulatory molecules like B7 (dendritic) and CD28 (T)
- - T cells activated
- Activate naive B cells:
- - naive B APC binds to effector T cells, enhanced by CD40L (T) - CD40 (B) binding
- - B cells activated
- Activation of effector T cells at site of infection
- made up of variable Ag-recognition proteins and invariant signaling proteins
- ITAM (Immunoreceptor Tyrosine-based Activation Motif) - intracellular signaling component of both TCR and CD3
- Ag-binding TCRα:β heterodimer
- 4 signaling chains (2 ε, 1 γ, & 1δ) collectively called CD3; required for the expression of TCRα:β and for signaling.
- A homodimer of ζ associated w/ TCRα:β.
- Each CD3 chain has one ITAM, ζ chain has three.
- cell-surface Ig for Ag binding
- non-specific Igα and Igβ (together linked to the heavy chain) both of which contains intracellular signaling tail, ITAM signaling proteins
ITAMs recruit signaling proteins that have ______ domains, which connect to _______.
Cell adhesion molecules of the Ig-super-family stabilize interactions between APCs : T cells
- ICAM-1/2/3 : LFA-1
- CD58 : CD2
Transient adhesive interactions between T cells and Ag-presenting cells are stabilized by specific antigen recognition
- ICAM-1:LFA-1 loose binding initially
- Ag-specific binding of TCR signals LFA-1 for conformational change
- ICAM-1:LFA-1 binding strengthened
The area of contact between an effector T cell and another cell forms ____________.
- an immunological synapse
- outer ring - pSMAC (supramolecular adhesion complex); LFA-1:ICAM-1, etc.
- inner ring - cSMAC; TCR, CD4, etc.
- collision and non-specific binding w/ target cell
- specific binding -> redistribution of cytoplasmic matter and cytoskeleton
- release of granules at site of contact
Activation of T cells changes the expression of several cell-surface molecules
- CD45RA -> CD45RO
- L-selectin disappears
- VLA-4 appears
- CD4, TCR stay
- LFA-1, CD2, CD44 increase
- secretion IFN-γ or binding to APCs containing microbes
- APCs secrete IL-12
- IL-12 converts naive CD4 T cell to TH1
- activated TH1 secrets IFN-γ, activating macrophage killing
- binds B cell, secrete IgG & IgE (enhanced by IL-4)
- - IgE -> degranulation of mast cells
- secrete IL-5, activates eosinophil against parasite
- secrete IL-5, IL-13, alternative activation of macrophage -> suppression of inflammation
CTL-mediated cell lysis
- exocytosis of granzymes, perphorin -> endocytosis -> perforin-dependent entry of granzymes -> caspases activated, leading to apoptosis
- FasL on CTL binds to Fas on target cell -> apoptosis activated
Cytotoxic effector proteins released from cytotoxic T cells
- Perforin - helps delivering
- Granzymes & Granulysin - activate apoptosis
Critical cytokines for CD4 T cells differentiation
B cell Development
- Derive from hematopoietic stem cells in the bone marrow.
- Rearrangement of the heavy-chain locus.
- The pre-B-cell receptor tests for successful production of a complete heavy chain and signals for the transition from pro-B cell to pre-B cell.
- Pre-B-cell receptor signaling inhibits further heavy chain locus rearrangement and enforces allelic exclusion.
- Pre-B cells rearrange the light-chain locus and express cell-surface immunoglobulin.
- Immature B cells are tested for autoreactivity before they leave the bone marrow.
Gene segments for light and heavy chains
- Leader, Variable, (Diversity), Joining, Constant
- D is only for heavy chain
- All have multiple functional segments except κ light chain only has 1 Constant.
The early stages of B-cell development are dependent on ________.
- bone marrow stromal cells
- stromal cells release CXCL12
- FLT3 of multipotent stem cell binds to FLT3 ligand on stromal cells
- stromal cells release IL-7, binds to IL-7 receptors on common lymphoid progenitor, which develops through pro- and pre-B-cell stages
- pre-B cell puts IgM on the surface, becomes immature B cell
Transcription factors during early stages of B-cell development:
- ikaros - functioning throughout
- Pax5 - from the beginning of pro-B cell on
The development of a B-lineage cell vs. the rearrangement of Ig genes
- early pro-B: H chain, D-J
- late pro-B: H chain, V-DJ
- Pre-B: L chain, V-J
Suface Ig on B cells
- immature - IgM
- mature - IgD and IgM
The development of a B-lineage cell vs. protein expression
- RAG-1/2 - during time of rearrangement
- lambda5 - surrogate light-chain; disappears at the end of pre-B
- Iga/b - throughout B cell development
- CD19 - from late pro-B on
- IL-7R - growth factor receptor; mid-stem to mid pre-B
Genes can be recombined contains sequence called
- recombination signal sequence (RSS)
- RAG-1/2 randomly pick two segments, cleave off RSS, and the remaining segments are eventually connected w/ the help of many proteins, including TdT
Selective expansion of TH1 leads to ______ & production of ________;
Selective expansion of TH2 provides ________ (especially production of ________).
- cell mediated immunity
- opsonizing Ab classes (IgG)
- humoral immunity
- IgM, IgA & IgE
CD-4 T cells' fate-speficying and secreting cytokines
- TH1: by IFN-γ, IL12. Produce IFN-γ
- TH2: by IL-4. Produce IL-4, IL-5, IL-13
- TH17: by TGF-β, IL-6, IL-23. Produce IL-17, IL-22
- TFH: by IL-6. Produce IL-21
- iTReg: by TGF-β, IL-2. Produce TGF-γ, IL-10.
Blocking of _______ can induce Th1
Blocking of _______ can induce Th2
The subsets of CD4 T cells each produce cytokines that can negatively regulate the development or effector activity of other subsets
- TReg produces TGF-b, inhibits TH1 & TH2
- TH2 produces IL-4, inhibits TH1 & TH17
- TH1 produces IFN-c, inhibits TH2 & TH17
Transcription factors for
TH1 vs. TH2 ____ can affect disease outcome
Intracellular parasites (Mycobacterium leprae & M.
tuberculosis) – macrophage vesicles
Tuberculoid leprosy – Predominantly ___ response (_______): __________.
- little Ab production
- survival with few bacteria, but inflammatory skin and peripheral nerve damage
Lepromatous leprosy – Predominantly ____ response (): _________.
- Mainly humoral response
- Ab cannot reach the intracellular bacteria in macrophages; gross tissue destruction; fatal
_______ are critical for keeping the immune response in check:
X-linked _____ mutation in humans – multiorgan autoimmunity
_____ - mouse model; autoimmunity
Course of acute infection that is cleared by adaptive immune response
- 1. Establishment of infection: from entry of microbes to threshold Ag level (to activate adaptive response) is reached; microbe level increases.
- 2. Induction of adaptive immune response: microbe level keeps rising until the peak.
- 3. Adaptive immune response: in effect; microbe level decreases until cleared.
- 4. Immunological memory
Both the ____ and the ______ of Ab increase with repeated immunization.
- isotype switch IgM -> IgG
- stronger effect on IgG than IgM [seemingly]
secondary Ab response from memory B cells is distinct from generation of primary response
- higher frequency of Ag-specific B cells
- IgG, IgA vs. IgM>IgG
- high affinity
- high somatic hypermutation (discuss later)
Function of Ab isotypes
- - Opsonization
- - classical pathway of complement activation
- - Ab-dependent cytoxicity of NK and macrophages
- - neonatal immunity via gut and placenta
- - feedback inhibition of B activation
- - classical pathway of complement activation
- - surface Ab-receptor for naive B cells
- - mucosal immunity - GI & respiratory tracts
- - Ab-dependent cytotoxicity of eosinophils - parasites
- - mast cell degranulation (immediate hypersensitivity)
- - surface Ab-receptor for naive B cells
Different cytokines induce switching to different antibody classes
- IL-4 induces IgG1, IgE
- IFN-γ induces IgG3, IgG2a
- TGF-β induces IgG2b, IgA
- IL-21 induces IgG3, IgG1, IgA
Activate complement system
- IgM and IgG3
- IgG1,2,3,4 and IgA
IgA is transported across epithelium as _______ and diffuses into extravascular sites as _______.
IgG2 can act as opsonin in presence of an FcR of appropriate allotype in ~ 50% of whites
Effector functions of Ab
- neutralize microbes and toxin
- macrophage - opsonization and phagocytosis
- NK - Ab-dependent cytolytoxicity
- Complement activation - C1q
- - Lysis of microbes
- - phagocytosis of opsonized microbes
- - inflammation
Bound Ab is distinguishable from free Ig by _______:
- its state of aggregation
- Free Ig does not cross link FcR on macrophages, no action
- Bound Ig aggregate and causes FcR crosslink, activates macrophage, phagocytose and kill.
- antibody dependent cell-mediated cytotoxicity, through which Ab-coated target cells can be killed by NK cells
- Fc region of IgG binds to FcγRIII (CD16) on NK
- NK activate and cause apoptosis of the target cell
- multivalen Ag cross-link IgE
- activates mast cells
- rapid release granule contents, inflammatory mediators
thymus independent antigens
Response of bacterial Ags with intrinsic ability to activate B cells do not require T cell help
TI-1 antigens: At high concentrations, these molecules cause ______, regardless of their ______. Also called ___. E.g. LPS which binds LPS binding protein and CD14, and associates with TLR4 of B cells.
- proliferation and differentiation of most B cells
- B cell mitogens
High concentration of TI-1 Ag causes __________.
polycolonal B cell activation and nonspecific Ab response
Low concentration of TI-1 Ag causes __________.
TL-1 Ag-specific Ab response
consist of molecules such as bacterial capsular polysaccharides that have repetitive structures
Whereas TI-1 Ags can activate _________, TI-2 Ags can _________.
- both immature and mature B cells
- only activate mature B cells
Response to TI-2 Ags occur predominantly in _______ B cells (aka _____).
- a subclass of B cells called B-1
- CD5 B cells
TI-2 Ag induce _________ production. However, with help from _______, B cells _________.
- DCs and cytokines such as BAFF
- switch their class of Ig to IgG
Antibody neutralization of toxins
- Toxin binds to membrane receptor
- Toxin dissociates, poisons the cell
- Ab binds to toxin and block its binding to the host cell
Cell receptor for Ab
- NK -> IgG1: FcγRIII (CD16), low affinity
- mast cell -> IgE: FcεRI, high affinity
The major class of Ab present in the lumen of the gut is _____________, the transcytosis of which is facilitated by ________.
- secretory dimeric IgA
- pIgR (polyIg)
Secretary Component (SC)
- binds part of the Fc of IgA containing binding site for FcαRI, so that FcαRI cannot bind IgA
- Protects the Ab from proteolytic cleavage
- Binds mucins in mucus – “glues” IgA to mucus layer
Neonatal Humoral Protection
- Fetus – passive IgG; only Ab isotype in fetus
- FcRn (neonatal)
- - Placental IgG transport from mother to fetus
- - Neonatal transporation - Transports IgG from gut lumen of neonate into circulation
- - Adult recyle - gut, liver & epithelium of adults – endocytose and recycle IgG to blood, prevents excretion from the body
- Colostrum – IgG, IgA