Adaptive Immunity Flashcards
Inflammation vs adaptive immunity
inflammation: relatively rapid, nonspecific, short-lived (first responder)
adaptive immunity: slower acting, specific, very long-lived (long-term security)
Protective response to active infectious agents
neutralize or destroy pathogenic microorganisms (e.g., Ab response against viral infections)
Vaccination against infectious agents
induce safe and protective immune response (e.g., recommended childhood vaccines)
Diagnosis of infectious agents
measure circulating Ag from infectious agents or ab (e.g., Dx of Hep B ifxn)
Therapy for infectious agents
Passive Tx with Ab to treat or prevent infection (e.g., admin of Ab against hep A)
Protection against active cancer
Prevent tumor growth or spread (e.g., immune surveillance to prevent early cancers)
Vaccination against cancers
Prevent cancer growth or spread (e.g., vaccination w/cancer antigens)
Diagnosis of cancer
measure circulating antigen (e.g., circulating PSA for Dx of prostate cancer)
Therapy for cancer
Immunotherapy (e.g., Tx of cancer w/Abs against cancer Ags)
Protection against active dz d/t environmental substances
Prevent entrance into body (e.g., secretory IgA limits systemic exposure to potential allergens)
Vaccination against environmental substances
No clear example
Dx of environmental subtance dz
Measure circulating Ag or Ab (e.g., Dx of allergy by measuring circulating IgE)
Therapy for Dz d/t environmental substances
Immunotherapy (e.g., administration of Ag for desensitization of individuals w/severe allergies)
Protection against active self-antigens
Immune system tolerance to self-antigens, which may be altered by an infectious agent leading to autoimmune dz
Vaccination and self-antigens
Some cases of vaccination after tolerance to self-antigens leading to autoimmune dz
Dx of dz d/t self-antigens
Measure circulating Ab against self-antigen for Dx of autoimmune dz
Therapy for dz d/t self-ag
No clear example
Serum proteins and blood cells involved in adaptive immune response (general)
Proteins: Immunoglobulins/antibodies
Blood cells: lymphocytes
3 groups of cells must cooperate to make an immune response
APCs w/subpopulation of T cells that facilitate immune responses (Th cells) and immunocompetent **B or T Cells **resulting in differentiation of B cells into active Ab producing cells (plasma cells) and T cells into effector cells (e.g., T-cytotoxic cells)
Generation of clonal diversity (general)
- lymphoid stem cells from bone marrow migrate to central lymphoid organs (thymus or regions of bone marrow), where they undergo a series of cellular division and differentiation stages resulting in either immunocompetent T cells from thymus or immunocompetent B cells from bone marrow (driven by hormones)
- all necessary receptor specificities produced!
- in fetus - begins in liver, not bone marrow. Most done as fetus, some as adult
immunocompetent B and T cells: what are they, where do they go
cells that have gone through clonal diversity in lymphoid organs
Still naive - have never encountered a foreign antigen
Enter circulation and migrate to secondary lymphoid organs where they take residence in B and T cell rich areas
Central lymphoid organs
Thymus and bone marrow
secondary lymphoid organs
e.g., spleen, lymph nodes
Clonal diversity & selection
Clonal selection: how initiated, what happens (general)
- initiated by exposure to foreign antigen
- immunocompetent B and T cells already in secondary lymphoid organs
- Ag usually processed by APCs for presentation to Th cells
- Intercellular cooperation among APCs, Th cells, and immunocompetent B and T cells results in second stage of cellular proliferation and differentiation
Clonal selection: how many cells?
Small population of B and T cells - b/c Ag has “selected” those w/compatible Ag receptors
Result of clonal selection
- active cellular immunity or humoral immunity, or both
- Ag selects those lymphocyes w/compatible receptors, expands their population, causes differntiation into Ab secreting plasma cells, or mature T cells
Who mediates cellular immunity?
- “Effector” T cells that can
- kill targets (cytotoxic T cells) or
- regulate the immune response (T-regulatory cells)
- memory cells (memory T cells) that can respond more quickly to a 2nd challenge w/same Ag
Who mediates humoral immunity?
population of
- soluble proteins (Abs) produced by plasma cells and
- memory B cells that can produce more Ab rapidly to second challeng w/same Ag
Result of Ab binding to antigen on infectious agent
direct inactivation of microorganism OR activation of variety of inflammatory mediators (e.g. complement, phagocytes)
Domain of antibodies - which organisms
Primarily bacteria and viruses
Tc Cells - what and who target
cytotoxic T cells - attack and kill targets directly
Target cells infected by variety of viruses and cancerous cells
Active acquired immunity/active immunity
produced by individual either after natural exposure to an antigen or after immunization
long-lived
Passive acquired immunity/passive immunity
not involve host’s immune response at all - occurs when preformed Abs or T lymphocytes are transferred from donor to recipient
e.g., maternal Abs across placenta, immunotherapy, preformed immunoglobulins post-exposure in unvaccinated
short-lived b/c donor stuff destroyed
CD
Cluster of differentiation
label for very large family of proteins found on surface of many cells. Many have alternative names.
CD1: location and function
location: APCs
function: presents lipid Ags
CD4: location and function
location: Th cells
function: Binds to MHC class II as co-receptor w/the TCR
CD8: location and function
Location: Tc cells
Function: binds to MHC Class I as co-receptor w/TCR
CD28: location and function
Location: T cells
Function: adhesion molecule that binds to CD80 to provide co-stimulatory signal for Tc cells
CD80 (B7-1): location and function
Location: APCs
Function: Adhesion molecule that binds to CD28 to provide a co-stimulatory signal
Antigen
molecule that can react w/antibodies or antigen receptors on B or T cells. Can be immunogenic, i.e., cause an immune response (production of Abs or functional T cells)
Epitope
portion of Ag configured for recognition & binding. Aka antigenic determinant
paratope
“antigen binding site” on Ab or lymphocyte that matches epitope
how many Abs against a molecule?
Depends on number of epitopes - usually a mixture of specific Abs
What influences immunogenic degree of Ag?
- being foreign
- size
- chemical complexity
- quantity
Central tolerance
in which lymphocytes w/receptors against self-Ags are eliminated
Peripheral tolerance
in which immune system actively prevents recognition of self-Ags by lymphocytes or Abs
who may regulate response to self-ags?
T-regulatory cells, (Treg cells)
(some pathogens mimic self-Ags in order to survive)
haptens
Antigens that are too small to make an immune response, but can be immunogenic if combined w/larger carrier molecules
e.g., PCN & poison ivy - must bind to large molecular weight proteins in blood or skin
allergens
Ags that induce allergic response
Molecules that directly recognize Ags
3 molecules: Circulating Ab and Ag receptors on surface of B lymphocytes (B-cell receptor or BCR) and T lymphocytes (TCR)
Antibody
serum glycoprotein produced by plasma cells in response to a challenge by an immunogen
Classes of immunoglobulins
Five:
IgG, IgA, IgM, IgE, IgD
IgG
- most abundant
- account for most protective activity against infection
Maternal Ab
Maternal IgG in blood of fetus/newborn
subclasses of IgG
IgG1, IgG2, IgG3, IgG4
IgA subclasses
IgA1, IgA2
where is IgA1 found?
mostly in blood
Where is IgA2 found?
Mostly in normal body secretions (predominant class in secretions)
IgA & secretory piece
IgA2
They are dimers anchored through a J chain and “secretory piece”
Secretory piece is attached to IgAs inside mucosal epithelial cells - may protect IgA2 against degradation by enzymes in secretions
IgM: characteristics
largest immunoglobulin
usually a pentamer stabilized by J (joining) chain
FIRST Ab produced during initial/primary response to Ag
IgD
limited info
low concentrations in blood
primarily on surface of developing B lymphocytes, function as one type of B cell Ag receptor
IgE
- least concentrated of any immunoglobulin class in circulation
- apparently very specialized functions:
- mediator of many common allergic responses
- defense against parasitic infections
Who are the Ag binding molecules?
soluble antibody & cell surface receptors
Ab molecule makeup
2 identical heavy chains and two identical light chains connected by interchain disulfide bonds (- between bonds in figure)
Ab heavy chain
divided into three regions w/relatively constant amino acid sequences (CH1, CH2, CH3) and a region w/a variable AA sequence (VH)
Ab light chains
Each light chain is divided into a constant region (CL) and a variable region (VL).
The hinge region (Hi) provides flexibility in some classes of Ab.
W/in each VL are three highly variable complementary determining regions (CDR1, CDR2, CDR3) separated by relatively constant framework regions (FRs)
3 important portions of Ab molecule revealed by limited digestion w/enzyme papain
Fc and 2 identical Fab fragments
Both Fab fragments bind Ag
What happens to structure when andibodies fold?
CDRs are placed in proximity to form the antigen binding site
Structure of Antigen receptor on surface of B cells (BCR complex)
monomeric Ab w/a structure similar to that of circulating Ab.
Additional hydrophobic transmembrane region (TM) anchors molecule to cell surface
Igalpha & Igbeta
Molecules on active BCR complex that are responsible for intracellular signaling after the receptor has bound antigen
T cell receptor (TCR) structure
- alpha chain and beta chain joined by a disulfide bond.
- Each chain consists of a constant region (Calpha and Cbeta) and a variable region (Valpha and Vbeta)
- variable regions contain CDRs and FRs in a structure similar to Ab
Active TCR associated w/several moleucules responsible for intracellular signaling
- CD3 (complex of gamma, epsilon, and delta subunits)
- Complex of two zeta molecules attached to a cytoplasmic protein kinase (ZAP70) that is critical to intracellular signalling
Fab
“Antigen binding fragment”
part of Ab that binds to Ag
confers specificity toward Ag
Fc
- “crystalline fragment”
- part of Ab. Crystallizes when separated from Fabs.
- responsible for 1) biologic functions of Ags, 2) activation of complement cascade, 3) opsonization by binding to Fc receptors on surface of cells of innate immune system
How is Antibody class determined?
By which heavy chain is used:
- IgG - gamma
- IgM - mu
- IgA - alpha
- IgE - epsilon
- IgD - delta
light chains of Ab
kappa or lambda
how are light and heavy chains held together?
noncovalent bonds and disulfide linkages
Constant regions of light and heavy chains
AA sequences should be relatively stable across Abs of same class & subclass
Variable regions of light and heavy chains: structure
- vary widely across Abs of same class and subclass
- 3 areas called complementary determining regions (CDRs) - where most of variability is localized
- 4 regions separating CDRs: Framework regions (FRs) w/relatively stable AA sequences
Variable regions of light (VL) and heavy (VH) chains: purpose
determine conformation of Ag binding site and thus antigenic specificity of immunoglobulin
3CDRs of light and 3CDRs of heavy. FRs control accuracy of folding
Ab valence
- how many functional Ag binding sites
- Heavy & light chains identical, so the two binding sites have specificity for same Ag
Valence of specific Abs
- IgG, IgE, IgD, circulating IgA: valence of 2
- secretory IgA: valence of 4
- IgM: theoretical valence of 10, but can only bind 5 b/c sites get blocked
BCR
on surface of B lymphocytes. unlike Ab, purpose is for intracellular signalling.
BCRs on immunocompetent B cells: mIgM and mIgD - these recognize the Ags, but the signals are sent to nucleus via Igalpha and Igbeta heterodimers
APCs
antigen presenting cells - highly specialized for certain types of Ags
most Ab and immune responses dependent on them
MHCs
- major histocompatibility complex
- primary role of this molecule is antigen presentation
- found on surface of every cell but RBCs
- classes I and II
3 molecules primarily responsible for antigen presentation
MHC I, MHC II, CD1
Which chromosome encodes MHC molecules?
chromosome 6
info for class I, class II, and several other molecules involved in innate or immune response: complement proteins (C’), cytokines (cyto), aka MHC class III
3 principal class I molecules
HLA-A, HLA-B, HLA-C
(but region contains info for alpha chains of several others, e.g., HLA-E, HLA-F, HLA-G)
MHC Class one structure & Ag presentation
- MHC class I products complex w/Beta 2 microglobulin (B2M) (encoded on chrom 15)
- present small peptide Ags in a pocket formed by the alpha1 and alpha2 domains of the alpha chain. The conformation is stabilized by B2M as well as by intrachain disulfide bonds (-S-S-)
MHC class II structure & Ag presentation
- alpha and beta chains of class II encoded in same regions as class I (HLA-DR, HLA-DP, HLA-DQ).
- IN some cases, multiple genes for alpha and beta chains are available
- present peptide Ags in a pocket formed by the alpha 1 domain of the alpha chain and the beta 1 domain of the beta chain
CD1 - chromosome
chromosome 1
contains genes for 5 alpha chains (CD1A-E) and the alpha chain complex with beta2 microblobulin
CD1 Ag presentation
Presents lipid Ags in a pocket formed by the alpha1 and alpha2 domains.
commonly important factors in infections w/bacteria of Myobacterium spp. (e.g. in tuberculosis and leprosy b/c these bacteria got lots o lipids in their cell membranes)
How are Ag presenting molecules anchored to plasma membrane?
by hydrophobic regions of on ends of alpha and beta chains
Transplantation and antigen presenting molecules
MHC!
different set of MHC surface Ags in different people = mount immune response
why we call them “human leukocyte antigens”
Also why we “tissue type” to try to match HLA tissue types
Cytokine source and function: IL-1
source: APCs
Function: stimulate T cells to proliferation and differentiation; induce acute-phase proteins in inflammatory response; endogenous pyrogen
Cytokine source and function: IL-2
Source: Th1 cells, NK cells
Function: Stimulates proliferation and differentiation of T cells and NK cells
Cytokine source and function: IL-4
Source: Th2 cells, mast cells
Function: Induces B cell proliferation and differntiation; up-regulates MHC class II expression; induces class-switch to IgE
Cytokine source and function: IL-5
Source: Th2 cells, mast cells
Function: induces eosinophil proliferation and differntiation; induces B cell proliferation and differentiation
Cytokine source and function: IL-7
Source: Thymic epithelial cells, bone marrow stromal cells
Function: major cytokine for induction of B and T cell proliferation and differntiation in central lymphoid organs
Cytokine source and function: : IL-8
Source: macrophages
Function: Chemotactic factor for neutrophils
Cytokine source and function: IL-10
Source: Th cells, B cells
Function: Inhibits cytokine production; activator of B cells
Cytokine source and function: IL-12
Source: B cells, APCs
Function: Induces NK cell proliferation, increases production of IFN-gamma
Cytokine source and function: IL-13
Source: Th2 cells
Function: IL-4 like properties; decreases inflammatory response
Cytokine source and function: IL-17
Source: Th17 cells
Function: increases inflammation; increased influx of neutorphils and macrophages; increased epithelia cell chemokine production
Cytokine source and function: IL-22
Source: Th17 cells
Function: increases inflammation; increased epithelial cell production of antimicrobial peptides
Cytokine source and function: IFN-alpha & IFN-beta
Source: macrophages, some virally infected cells
Function: antiviral, increases expression of MHC class I molecule, activates NK cells
Cytokine source and function: IFN-gamma
Source: Th1 cells, NK cells, Tc cells
Function: Increases expression of MHC class II, activates macrophages and NK cells
Cytokine source and function: TNF-alpha (cachectin)
Source: Macrophages
Function: IL-1 like properties, induces cellular proliferation
Cytokine source and function: TNF-beta (lymphotoxin)
Source: Tc cells
Function: kills some cells, increses phagocytosis by macrophages and neutrophils
Cytokine source and function: TGF-beta
source: lymphocytes, macrophages, fibroblasts
Function: chemotactic for macrophages, increases macrophage IL-1 production, stimulates wound healing
class I receptor Dimers (alpha and beta chains): ligand and additional info
Ligand: IL-3, IL-5, IL-6, IL-11, IL-12, IL-13
info: IL-3 and IL-5 share a common alpha chain; IL-6 and IL-11 share a common beta chain
Trimers (alpha, beta, and gamma chains): ligand and additional info
Ligands: IL-2, IL-4, IL-9, IL-15
info: all share a common gamma chain
Class II receptors: ligand and additional info
LIgand: IFNalpha, beta, and gamma
info: two chains
TNF receptors: ligand and additional info
ligand: TNFalpha, beta, CD40, Fas
info: single chain
Immunoglobulin-like receptors: ligand and additional info
ligand: IL-1
info: single chain w/immunoglobulin-like characteristics
When does clonal diversity occur
primarily as fetus
When does clonal selection occur
primarily after birth throughout life
Where does clonal diversity occur?
central lymphoid organs: thymus for T cells, bone marrow for B cells
where does clonal selection occur
Peripheral lymphoid organs, including lymph nodes, spleen, other lymphoid tissues
Is foreign Ag involved in clonal diversity?
No?
is foreign Ag involved in clonal selection
yes - determines which clones of cells will be selected
what hormones/cytokines involved in clonal diversity
thymic hormones, IL-7, others
Cytokines involved in clonal selection
many produced by Th and APCs
Is tolerance induced in clonal diversity?
Central tolerance as autoreactive cells are deleted
tolerance induced in clonal selection?
peripheral tolerance as autoreactive cells are regulated
Final product of clonal diversity
immunocompetent T and B cells that can react w/antigen but have not seen Ag, and migrate to secondary lymphoid organs
Final product clonal selection
plasma cells that produce Ab, effector T cells that help (Th), kill (Tc), or regulate immune responses (Treg); memory B and T cells
T cell development in thymus: who controls stages of cellular division and differentiation?
hormones
What characterizes the differentiation process of the T cells in the thymus?
up-regulaton of many important surface molecules and random development of huge number of different T-cell receptors against all possible Ags that adult may encounter
T cell development in thymus: where does lymphoid stem cell enter?
subcapsular region of thymus, where it begins differentiation
T cell development in thymus: one of first changes after entrance
appearance of molecule CD2, a marker for all T cells
T cell development in thymus: which cells guide most of the early differentiation process and where do they do it?
epithelial cells, in cortex of thymus
T cell development in thymus: what IL does pre-T cell begin expressing and why?
IL-7, produced by epithelial cell along w/other thymic hormones to drive T cell differentiation process
T cell development in thymus: how does T cell begin constructing the T-cell receoptor (TCR)?
by first rearranging and expressing the TCR beta chain and expressing CD3 molecules
TCR alpha chain not yet produced, but beta chain is expressed on surface of pTCR using a protein that acts as a surrogate for the alpha chain
T cell development in thymus: Clonal deletion
- Some pTCRs are produced w/specificities toward self-antigens (b/c of randomness of process of developing TCRs on preTcells cells).
- Many undergo negative selection and are deleted by apoptosis induced through interactions w/self-antigens presented by epithelial cells.
- more than 95% of T cells undergo apoptosis in thymus! and still some get through and need to be controlled via peripheral tolerance
T cell development in thymus: Where do survivors of negative selection (no clonal deletion) go and what do they do there?
move towar thymic cortex and begin expressing TCR alpha chain, the normal TCR, and both CD4 and CD8 on their surfaces = “double positive”
T cell development in thymus: what happens to “double positive” cells?
- Have both CD4+ and CD8+, encounter medullary epithelial cells that express both MHC class I and MHC class II molecules.
- Phenotype of dvping T cell is positively selected so that interaction btwn CD4 and MHC class II selects for retention of CD4 expression
- and interaction btwn CD8 and MHC class I favors CD8 phenotype
T cell development in thymus: how many populations of “single postive” immunocompetent T cells leave the thymus?
two -
- one is CD4+, CD8- (destined to be a Th cell)
- one is CD4-, CD8+ (destined to be Tc cell)
B cell clonal diversity: where to lymphoid stem cells go?
portions of bone marrow that serve as central lymph organ for B cell dvpt
What guides proliferation and differntiation process of lymphoid cells during B cell clonal diversity?
interactions w/series of bone marrow stroma cells - guides them through direct cell-to-cell contact and production of cytokines and hormones by the stromal cells (but w/o foreign antigen)
What characterizes B cell differentiation?
As w/T cell - up regulation of surface molecules (we don’t even learn all) and the random development of a huge number of B cell receptors
B cell diversity: what happens to pro-B?
- binds to a membrane bound cytokine (stem cell factor)
- initiates expression of surface molecule CD45R
- CD45 will push dvpt forward
- begins to rearrange DJ regions of Ab heavy chain gene
B cell diversity: what happens to Pre-B?
- concludes rearrangement of heavy chain (VDJ)
- begins expressing cytoplasmic mu heavy chain
- Mu chain is incorporated into pCR using surrogate protein in place of light chain
- up-regulates IL-7R
- environmental IL-7 (from stromal cells) drives remaining steps
- if presented self-Ag by stromal cell and shows specificity –> clonal deletion
B cell diversity: what happens to immature B cell?
- passed self-Ag test, now an immature B cell
- rearrange light chain DNA (VJ) and expresses BCR w/light chain and mu heavy chain (surface IgM)
B cell diversity: what happens to Mature B cell?
- was immature cell, then changes in processing of heavy chain precursor RNA –> coexpression of sIgM and sIgD
- Leaves bone marrow to go to secondary lymphoid organs as immunocompetent B cell
Professional APCs
dendritic cells, macrophages, B lyphocytes
B: to Th cells that facilitate humoral response
Macrophages: to memory Th cells to initiate rapid response (secondary immune response)
Dendritic: to naive immunocompetent Th cells
required for initiation of most immune responses
Ag processing & presentation
Is a foreign antigen endogenous or exogenous?
Could be either: endogenous (cytosolic protein) or exogenous (eg., bacterium)
-
*endogenous include
- viruses b/c viruses infect cells and use normal cellular protein synthesizing machinery to translate viral genes into viral proteins
- Ags produced by cancerous cells
How is an endogenous antigenic determinent (antigenic peptide) produced and what happens to it?
by cellular proteasomes
it’s transported by TAP (Transporter assoc w/Ag Processing) proteins into the endoplasmic reticulum (ER) where MHC and CDL molecules are being assembled.
Antigen processing: what happens to antigenic peptide in ER?
it binds to the alpha portion of the MHC Class I molecule and then is transported to cell surface
MHC Class II and antigenic peptide
- alpha and beta chains of mhc class II are being assembled, but the antigen binding site is blocked by an invariant chain (small molecule) to prevent interactions w/endogenous antigenic peptides
- MHC II invariant chain complex is transported to lysosomes
- lysosome digests invariant chain
- encounter exogenous antigenic fragments have been generated as a result of phagocytosis - bind
- MHC II-antigen complex inserted into cell membrane
CD1 and ER/antigenic peptides
- CD1 assembled in ER, but Ag binding site is specific to lipid epitopes, so will not bind to endogenous antigenic peptides
- Transported to lysosomes - may encounter & bind to antigenic lipids produced by phagocytic digestion of engulfed bacteria
- CD1-Ag complex transported to cell membrane & presents lipid Ags
who presents endogenous Ags?
MHC I
MHC I are on all cells but RBCs, so any change d/t viral infxn or malignancy can be expressed by MHC I on a cell’s surface
Who presents exogenous Ags?
**MHC II **& CD1
Unlike MHC I, MHCII are only expressed on a limited number of cells w/APC function. Co-expressed w/MHC I. - e.g., macrophages, dendritic cells, B lymphocytes, activated T lymphocytes, some endothelial cells
and CD1 - but only lipid containing Ags
Most important step in clonal selection
production of a population of Th cells - Th1, Th2, Th17 and Treg cells
necessary for dpt of cellular and humoral immne response
Model in book: Role of APCs in clonal selection
may influence whether a precursor Th cell (Thp) will differentiate into Th1, Th2, Th17, or Treg
What 3 events initiate differentiation of Thp cell?
- Ag signal produced by intereraction of TCR & CD4 w/Ag presented by MHC II
- Co-stimulatory signals produced from interations between adhesion molecules CD80 and CD28 (e.g.,)
- Signal via Interactions of cytokines - esp IL-1 w/IL-1R on Thp
T cell clonal selection: What happens after 3 clicks initiate differentiation?
Thp up-regulates IL-2 production and expression of IL-2R, which act in an autocrine fashion to acceplerate Thp-cell differentiation and proliferation
T cell clonal differentiation: how is phenotype decided?
- D/t relative concentrations of other cytokines
- IL-12 and IFN-gamma produced by some APCs favor Th1 cell (cellular immunity)
- IL-4, produced by variety of cells, favors Th2-cell phenotype (humoral immunity)
- IL-6 and TGF-beta (T cell GF) facilitate differentiation into T17 (inflammation)
- IL-2 and TGF beta –> Treg (suppress immune response)
effect of Th1 (T cell differentiation)
- characterized by production of cytokines that assist in differentiation of Tc cells, leading to cellular immunity
- supposedly more for viral, bacterial, and cancer cells
- IL-12 and IFN-gamma produced by some APCs favor Th1 cell
Effect of Th2 (T cell differentiation)
- produce cytokines that favor B cell differentiation and humoral immunity (B cells) (also needed for class switch)
- supposedly more for multicellular parasites and allergens
- IL-4, produced by variety of cells, favors Th2-cell phenotype
Th1, Th2, and Th17 together (T cell differentiation)
- produce inhibitory cytokines - IFN gamma will inhibit the development of Th2 & Th17 cells and IL-4 will inhibit the dvpt of Th1 and Th17 cells
- Some antigens (e.g., tetanus vaccine) produce humoral and cell-mediated responses simultaneously
effect of Th17 (T cell differentiation)
- produce cytokines that affect phagocytes and increase inflammation
- esp neutrophils and macrophages and production of antimicrobial proteins and chemokines by epithelial cells = controls many aspects of inflammation, including chronic
- IL-6 and TGF-beta (T cell GF) facilitate differentiation into T17
effect of Treg (T cell differentiation)
produce immunosuppressive cytokines that prevent immune response from being excessive
IL-2 and TGF beta –> Treg
What 2 classes of immunoglobulins dominate Ag response?
IgM, IgG
IgM predominates initial exposure to antigen in primary response. IgG appears later.
after host’s immune system primed, another challenge by same Ag induces secondary response w/some IgM and more IgG
lag phase in immune response
after initial exposure to most Ags - necessary for clonal selection, including processing and presentation of Ags, induction of Th cells, interactions btwn immunocompetent B cells and Th cells, maturation and proliferation of the B cells into plasma and memory cells
Vaccines and secondary immune response
- vaccine and natural infection both are antigenic challenges that result in a level of protective IgG that may remain elevated for decades
- It is the prolonged and protective secondary immune response that provides protection
B cell clonal selection: definition
Immunocompetent B cells undergo proliferation and differentiation into Ab secreting plasma cells
B cell clonal selection: 3 signals
- MHC II presenting Ag interacts w/TCR and CD4 on Th2 cells
- Co-stimulatory signals through adhesion molecules, esp CD40 and CD40L (CD154) (necessary for class switch)
- Cytokine signal via Th2 cytokines –> esp IL-4 binding to IL-4R on B cell
- additional cytokines influence switch to particular classes or subclasses of Ab
How does B cell recognize Ag?
can recognize soluble Ag directly through B cell receptor and co-receptors
e.g., complement receptors (CD21) which usually involve accessory molecules e.g., CD19
Tc clonal selection - what happens?
3 players: abnormal cell, Tc, Th1
- TCR binds to Ag presented by MHC I of abnormal cell; CD8 binds to MHC I (Ag signal)
- CD80 on abnormal cell interacts w/CD28 on Tc cell (costimulatory signal)
- IL-2 from Th cell binds to IL-2R on Tc
cell will proliferate and differentiate through multiple stages into functional Tc cells
Tc clonal selection: where does antigen usually come from?
endogenous antigen expressed on cell infected w/virus or malignant
Result of Tc cellular differentiation
production of active Tc cells w/capacity to id Ags on surface of infected or malignant cells and destroy those cells
As w/B cells, some activated cells will not be killers, but will be memory cells that can rapidly respond in future
Direct function of Ab
Antibody works alone - before toxins bind to receptors on surface of hosts cell. They intercept the bacterial or viral toxins, cover the portion that needs to bind to host cell
Indirect function of Ab
- Work by activating other components of innate immune response (usually through Fc region)
- Can be done in 2 ways:
- classical complement pathsay through C1 –> MAC
- increased phagocytosis of bacteria opsonized w/Ab and complement components bound to appropriate surface receptors (FcR and C3bR).
- Ag reacts w/Fab of Ab, and Fc portion of Ab is recognized by inflammatory cells
Flu Vaccination and Ab: direct or indirect?
give inactivated or weakened/attenuated virus – to induce neutralizing ab production at site of typical viral entrance (direct effect)
Viruses like polio and flu spread through blood and thus are susceptible to circulating Abs, can be controlled even after initial infection
(some infections like measles and herpes don’t circulate, so they are inaccessible to vaccines after initial infection)
Toxoids - how do they work?
We make Abs to particular toxins, antitoxins
we can induce these but chemically inactivate them so they won’t harm the host, just keep immunogenic effects (e.g., for diptheria and tetanus)
Cell killing mechanisms: examples
Tc, NK, ADCC (Ab dependent cellular cytotoxicity)
How do Tcs initiate apoptosis?
- Bind TCR to Ag, CD8 to MHCI
- BInd CD28 to abnormal cell’s CD80
- Bind FasL to Fas on cell - stimulates apoptosis
- secrete perofrin that creates pores for entrance of granzymes into cell - apoptosis
What do NK cells do if they find an MHC I?
Activation receptors notice abnormal cells BUT
MHC class Is inactivate NK cells via Inactivation receptors
NK and cells w/no MHC I
- Will detect abnormal surface w/activation receptor & kill
- Don’t have Ag specific receptors. Have Fc receptors for IgG and variety of NK specific cell surface receptors that ID protein changes (and inhibitory receptors to stop killing of MHC I cells)
ADCC
- Antibody dependent cellular cytotoxicity
- can be used by macrophages and NK cells
- IgG Ab binds to foreign Ag on target cell. Cells involved in ADCC bind IgG through Fc receptors (FcRs) and initiate killing.
Activation of a macrophage by a T cell: what kind of T cells do this and how?
helper T/Th1
they produce cytokines that activate macrophages
Activation of a macrophage by a T cell: what are the requirements?
- Th1 must produce cytokines (w/microbial products, e.g. LPS): IFN-gamma –> IFN-gammaR on macrophage
- optimal activation also requires close contact among the cells, mediated by a variety of adhesion molecules expressed on surface of cell (CD40L on Th1, CD40 on macrophage)
- *classical pathway: IFN-gamma; alternative - with ILs)
- ILs can also deactivate macrophages!
- all of the above mediated via cytokines!
transfer of immunity from mother to baby
- IgG transferred across syncytiotrophoblast - begins around 3 mths
- An active process
- Maternal IgG binds to Fc receptors on surface of syncytiotrophoblast and is internalized via endocytosis
- specific for IgG and do not bind others
- Interaction of IgG w/Fc receptors protects Ab from lysosomal digestion during transport across cell (transcytosis)
- on fetal sie, IgG released via exocytosis
Is fetus capable of IgM response?
Yes! And a little IgA. But not IgG challenge. That’s why gets it from mom
Which cells transport maternal IgG across placenta?
trophoblastic
Ab levels in umbilical cord blood and neonatal circulation
- at birth, fetal circulation contains nearly adult levels of IgG, almost exclusively maternal
- After delivery, maternal IgG is rapidly catabolized and neonatal IgG production increaes
- Maternal IgG gone around 10 mths
- Low levels around 4mths to 2 yrs
SEQUENCE OF EVENTS IN A BACTERIAL INFECTION
- Bacteria enters the body
- Innate response: inflammation – triggers adaptive response
- Adaptive response:
- Recognition of invasive organism by antibodies or receptors on B/T cells triggers a complex cascade: recognition is related to Clusters of Differentiation (CD) and Cytokines. Must not be a self antigen
- Antibodies/immunoglobulins recognize and bind to bacteria (eg. IgG, IgA, IgM, IgE, IgD, B Cell Receptor Complex, T Cell Receptor Complex)
- Antigen processing and presentation: MHCs & CD1 (not on RBCs) can occur in lymphoid organs: Antigen Presenting Cells: dendritic cells, macrophages and B cells are the best. Dendritic cells present to immunocompetent Th cells, macrophages present to memory Th cells- rapid response to antigens, B cells present to Th cells for the development of humoral immunity. This is also where B and T cells get activated.
- IgM- Primary immune response follow by IgG v secondary- seeing same antigen again
- Antibody fxn: direct- neutralization (inactivating/ blocking the binding of antigen to receptors), aggranulation (clumping insoluble particles that are in suspension), precipitation (making soluble antigen into insoluble participate). Indirect- activate inflammation, complement, phagocytes, opsonization, T cells, NK cells,
- From the bacteria’s perspective:
- i.Colonization: Infectious organisms usually exist in reservoirs then transmitted through indirect contact eg. Bites or direct contact eg food. Human to human transmission eg URIs. Organism is deposited in receptive environment eg vagina for colonization: microorganism stabilizes adherence to tissue
- ii.Invasion: It invades the surrounding tissue and other areas of the body
- iii.Multiplication: rapid replication either within cells or by themselves- may form multicellular masses called biofilms
- iv.Spread: Lymphatics, blood stream, internal organs- need adhesion molecules, toxins and protection against host’s inflammation and immune system
- v.Clinical process: incubation- initial exposure to first symptoms, prodromal- symptoms present, invasion- rapid multiplication and spread, convalescence- successful removal of organism of killing of host
