 Adaptive Immunity: Humoral (Extracellular) & Cellular (intracellular)

 Induction of immunity can be either Active (infection/Vaccine, lifelong but

takes time) or Passive (Ab/Lymphocyte transfusion, provide immediate
protection but transient)
 After immunization, 1ry response takes 1-3 weeks, and 2ry response takes 2-7
days
 Phagocytes: Neutrophils and Monocytes
 Ab is a BCL membrane receptor which recognizes Ag and initiate process of
activation (either attached or soluble)
 All lymphocytes arise from stem cells in BM, TCL mature in thymus, BCL in BM
 Effector BCL called plasma cells. Those cells found in the blood called
plasmablast. Naïve BCL express IgM and IgD
 Memory cells: functionally inactive, long-lived
 FDC present Ag to BCL
 LN for Lymph born Ag, Spleen for blood born Ag
 Mucosal Lymphoid tissues: tonsils, Payer’s patch
 In the LN: BCL+FDC concentrate in follicles in periphery/cortex. Where TCL+DC
in Paracortex
 In the spleen: BCL concentrate in the follicles, where TCL in PALS
 This segregation of BCL and TCL is because of chemokines which act on BCL
receptor “CXCR5” and TCL receptor “CCR7”. The chemokines are produced
from cells in the same area (FDC in the follicle for BCL, and cells in the
paracortex and PALS for TCL)
 TCL must migrate to act on Ag where BCL can secrete Ab which enter the
blood
 Spleen doesn’t contain HEV
 Two principle ways of innate immune system: Inflammation “kills extracellular
microbes” + Antiviral Mechanism “mediated by NK which kill virus infected
cells, and IFN-1 which blocks viral replication within the cell”
 CD4 cells can recruit WBC, activate macrophages, help BCL, where CD8 only kill
reservoir of infection
 Non-protein Ag is able to bind multiple BCR and activate appropriate response,
where protein Ag are folded and doesn’t contain multiple epitopes, so
appropriate immune response can’t be achieved without help of CD4, that’s
why BCL ingest protein Ag, degrade it, and display it to CD4
 Non-protein Ag lead to production of Ab with the same Ag binding site (low
affinity), where protein Ag produce high affinity Ab + memory cells+ long-lived
plasma cells
 Humoral Immunity: produce Ab to prevent microbes from infecting cells,
opsonize microbes for phagocytosis, and active complement system
 Innate immune system recognizes structures that are shared by various classes
of microbes and not present on normal host cells. These structures are
essential for survival and infectivity of microbe (so if the microbe tries to evade
immune system by mutating this structure, then the microbe loses its
infectivity and survival)
 Innate immune system has identical receptor for different microbes (PAMP
and DAMP “for damaged cells)
 TLR are either located on cell surface (TLR1,2,4,5,6) (TLR 4 for bacterial LPS,
TLR 5 for bacterial flagellin) or endosomal (TLR 3+7+8 for viral RNA, 9 for CpG
DNA)
 Once engagement of TLR occurs>induction of transcription factors: NF-kB
which promote expression of various cytokines + adhesion molecules, and IRF”
interferon regulatory factors” which promote production of antiviral IFN 1
(alpha and beta)
 NLR are cytosolic receptors, consist of NOD1, NOD2, and NLRP-3 they sense
PAMP and DAMP
 NOD1+NOD2” associated with IBD”, both have the same CARD “Caspase
related domain”, they recognize bacterial peptidoglycan
 NLRP-3: gets activated by microbial structure, and by pathological changes in
cytosol (efflux of K+, increased UA, ATP, FFA and cholesterol deposition).
 NLRP-3 + adaptor protein + inactive caspase= Inflammasome which contribute
gout, atherosclerosis, DMII, and insulin resistance. Inflammasome cleaves pro
IL-1β to active IL-1β which mediate all these pathological effects. Mutation in
NLRP-3 leads to autoinflammatory syndrome (Rx is IL-1 antagonist)
 Rig-like receptor “RLR”: cytosolic, recognizes viral RNA leading to type I
interferon production
 Cytosolic DNA sensors “CDS”: cytosolic, recognizes Viral DNA leading to type I
interferon production
 Lectin: carbohydrate recognizing receptors on cell membrane. Those which
recognize fungal glycans are called Dectins, and those which recognize
mannose are called mannose receptors.
 Epithelial cells provide immunity through different ways: Mechanical Barrier,
Keratin on surface+mucous prevent microbes from contacting, Chemicals
(defensins, and cathelicidins), and Intraepithelial T-Lymphocyte (γ δ)
 Neutrophils: PMN, most abundant, stimulated by CSF which is secreted by
many cell types, multilobed nucleus with faint cytoplasmic granules. They’re
1st responder, live for few hours
 Monocyte: horseshoe-shaped nucleus, once it enters the tissue it becomes
macrophage “survive longer”
 Microglial cells in Brain, Kuppfer cells in liver, sinusoidal macrophages in
spleen, alveolar macrophages in lung, are specialized tissue-resident
macrophages from precursors in yolk sac and fetal liver as well as the BM
 Phagocytosis is mediated by mannose and scavenger receptors
 Macrophage activation:
o Classical M1: in destroying microbes, induced by signals from TLR+IFN γ
o Alternate M2: in tissue repair, induced by absence of strong TLR
signals+ (IL-4+IL-13)
 Innate lymphoid cells, lack TCR, named based on the cytokine they produced,
Th1, Th2, or Th17
 NK cells, lack BCR+TCR, kill infected cells + stressed cells, stimulate classic
macrophage activation by producing IFN γ
 NK activating cytokines “produced by DC + macrophages that have
encountered a microbe”:
o IL-15 for the development of NK
o IL-12 “produced by macrophages” + Type 1 IFN (α, β) for enhancing the
killing ability of NK
 NK receptors:
o Activating:
  NKG2D: recognizes molecules that resemble MHC I molecules
which are expressed in response to many types of cellular stress
 CD16: recognizes ab coated cells leading to their death “ADCC”
 Activating receptors have ITAM>phosphorylation and activation of
TK> exocytosis of cytotoxic granules and production of IFN γ
o Inhibiting:
 Killer cells Immunoglobulin-like Receptor “KIRs” “resemble Ig”
 NKG2 “consist of CD94 and lectin subunits” > have ITIM>block
activation of NK.
 All cells expressing MHC1 molecule are inhibitors for NK

 Lymphocyte with limited diversity:

o NK-T cells express TCR with limited diversity, present in epithelial and
lymphoid organs, they recognize microbial lipids attached to MHCI-
related molecule CD1
o B1 cells in peritoneum. Most of the circulating IgM ab “natural Abs” are
from B1 cells, specific for carbohydrate in wall of some bacteria
o Marginal zone B cells, involved in rapid response to blood born
polysaccharide rich microbes
o NK-Tcell, B1 cell, and Marginal zone B cells, display features of both
Adaptive (cytokines, and Ab secretions) and innate immunity (limited
diversity, rapid response)
 P.44
 CRP involved in opsonization
 TNF+IL-1 induce fever by acting on hypothalamus
 TNF+IL-1+IL-6 stimulate liver to produce CRP+Fibrinogen which enhances
bacterial killing
 High concentration of TNF leads to thrombus formation, reduced BP (VD+
reduced myocardial contractility)
 TNF+IL-1 induce WBC recruitment and adhesion by inducing expression of
selectin on the endothelium which will bind selectin ligand on WBC leading to
its rolling
 Under effect of chemokines produced by phagocytes, WBC will express LFA-1
and VLA-4 Integrins which will bind VCAM-1 and ICAM-1 (TNF+IL-1 will induced
their expression) integrins ligand on the endothelium leading to firm adhesion
 When microbe is phagocytosed>formation phagolysosome> microbial killing
through different ways:
o Phagocyte Oxidase: converting O2 to ROS, free radicles “Oxidative
Burst”
o INOS: converting Arginine to NO
o Lysosomal protease: break down microbial protein
o Neutrophil can die and release its contents forming Neutrophil
Extracellular Traps “NET”> killing of microbes and injuring host tissue
 Plasmacytoid DC and virus infected cells secret Type 1 IFN (α, β)>> Inhibit viral
protein synthesis, produce RNAase, inhibit expression of viral gene, and
increase susceptibility to CTL.
 Regulation of innate immunity:
o Macrophages + DC produce (IL-10) and (IL-1 receptor antagonist)
o IL-10 decreases microbicidal and inflammatory function of macrophages
 o TLR stimulate expression of Suppressors of Cytokine Signaling “SOCS”
which blocks the action of cytokines.
 Examples of evasion of innate immunity by microbes:
o Listeria produce enzyme which enables it to escape phagocyte
o Mycobacterial has lipid wall which inhibit fusion of phagosome to
lysosome
o Pneumococci has capsular polysaccharide which inhibits phagocytosis
o Staph. Produces catalase which breakdown ROS intermediates
o Pseudomonas synthesize modified LPS which resist action of Abx
o Neisseria and Strep resist complement activation:
 Neisseria express Salic acid which inhibit C3, C5 convertase
 Strep has M protein which blocks C3 binding to organism

 DC: Recognize and present Ag + induce expression of costimulators (signal 1+2)

 DC+Macrophages: secrete IL-1, IL-6, IL-12 which lead to proliferation and
differentiation of TCL
 DCs are 2 types:
o Classical: located in the tissue including lymphoid tissues, in skin they’re
called Langerhans, major cytokines include TNF, IL-6, IL-12
o Plasmacytoid: resemble plasma cells, located in the blood and tissue. It
is a major source of type 1 IFN (α, β)
 Ag enter DC either by phagocytosis or receptor mediated endocytosis
 Some microbial Ag bind different innate receptors on various cells including DC
which induce production of TNF + IL-1, these cytokines induce expression of
 CCR7 receptor on DC which is specific for chemokines produced by lymphatic
endothelium and by stromal cells in TCL zones, this will lead to their migration
to lymphocytes. During migration DC mature from cells designed to capture Ag
to APC (this maturation is reflected by increase number of expressed MHC on
DC, and by costimulators) (keep in mind naïve TCL also express CCR7 which
lead to meeting of TCL and DC)
 TCL response to antigens begin in the draining LN within 12-18 hours
 MHC protein is called HLA. P.63. MHCI (on all nucleated cells) MHCII (DC,
macrophages, BCL, thymic epithelium and endothelium, and its expression on
other cells can be induced by IFN γ)
 MHC haplotype is set of MHC allels on each chromosome
 MHC molecule can present one peptide at a time
 Only stable (loaded) MCH molecule can be expressed on cells
 MHC I (Cytosolic) MHCII (Extracellular)
 P.63 explain the structure of MHC molecules, Important to known what
constitute the peptide binding cleft, and what constitute the binding site for
CD4/CD8
 MHC II Ag Processing:
o Internalization of extracellular microbial protein>enter lysosome which
may bind to phagosome> breakdown into peptide> binding of peptide
to the newly synthesized MHCII in vesicle
o MHCII is being synthetized in ER of APC, the newly synthetized MHCII is
attached to Invariant Chain “Ii” which contain CLIP “CLIP prevent MHCII
from binding to peptide in ER which meant to bind to MHCI”
o MHCII+CLIP enter vesicle where peptide is located, Ii is degraded
 o MCHII like protein “DM” exchange peptide by CLIP> MHCII is loaded
“Stable”>expressed on cell surface
 MCHI Ag Processing:
o Source of Ag: Viruses, microbes which escaped phagosome, or mutated
host genes
o They are unfolded and tagged by ubiquitin and then degraded into
peptides by proteasome
o TAP “Transporter associated with Ag Processing” on membrane of ER
actively pump peptide into ER
o MHCI is attached to Tapsin which link MHCI to TAP, thereby peptide
which enters ER through TAP will directly bind to MHCI and then the
stable “loaded” MHCI will be expressed on cell membrane.
 Cross-Presentation: DC ingest infected/damaged cells, transport them to
cytoplasm, undergo action of proteasome to generate peptides, then present
them MHC1. (one type of cells can present antigens of other cells “infected
cells/dying cells” & prime “Activate” naïve TCL specific for that Ag)

 Variable region of the receptor is for Ag recognition, where Constant region

mediate effector function by binding to other molecules “phagocyte,
complement…etc.”
 CDR “Hypervariable region” part of the V region of Lymphocyte receptor
where Ag bind
 BCR “Ig”:
o 4 polypeptide chains, 2 H, 2 L, each L chains is attached to H chains, H
chains are attached by disulfide bound.
 o Ag binding site: one V(H) and one V (L). Each V region contain 3 CDRs’,
the most variable is CDR3
o Each Ig has:
 2 FAB (whole L chain + V(H) and 1st Constant(H))
 1 Fc (Remaining Constant H chain) which mediate effector
function
o Hinge allows the two FAB to move independently
o Ig named according to heavy chain
o Serum half-life: E-D-M-A-G: 2-3-5-6-23 Days
o All are monomer (2 Ag binding sites) except IgA dimer (4 binding sites)
and IgM is Pentamer (10 Ag binding sites)
o P.88
 TCR:
o Heterodimeric protein contains two chains (α, β) each chain has one V
and one C regions
o TCR complex: TCR+ (CD3+ ζ, they transmit signals)
o No affinity maturation
o Some TCR express γ δ chains “in epithelium” recognize non-protein Ag
and doesn’t require MCH presentation
 P.80+91
 Survival and proliferation of lymphocyte precursors depend on IL-7 produced
by stromal cells in BM/Thymus
 Positive selection: Only TCL capable of recognizing MHC in thymus are selected
to survive
 Negative selection: self-reactive BCL and TCL will be eliminated
 Immature BCL express IgM, where mature ones express IgD with IgM
 Immature TCL/thymocyte/pro-TCL: is double negative “-CD4 -CD8”. Double
positive is the mature one (?wrong statement, should be single positive either
4 or 8)
 Types of intracellular microbes:
o Inside the phagocyte: Mycobact. Leigonella, Listeria,
[Link], Lishmania, Trypanosoma cruzi
o Inside other cells: All viruses, All Rickettsiae, Plasmodium falciparum,
[Link]
 P.106
 TCL differ in their TCR but not in the signaling generated upon activation (CD3+
ζ)
 TCR binds MHC with low affinity, to stabilize it Integrin LFA-1 binds its ligand
on APC ICAM-1
 Costimulators on APC B7-1 “CD80” B7-2 “CD86” is recognized by CD28
receptor on TCL
 CD 40 Ligand (CD154) expressed on activated TCL binds CD40 on APC” DC,
Macrophages, BCL”>>enhancing expression of costimulators+IL-12 which is
important for TCL differentiation
 Adjuvant “product of killed bacteria, mimicking microbes” used with
vaccination to induce expression of costimulators
 CD69 is a marker of T cell activation involved in cell migration
 P.112 + P.116
 Immune synapse: contact between TCL and APC
 IL-2 is an example of autocrine cytokine as it is produced from activated TCL
and act as TCL growth factor
 IL2- receptor consists of 3 chains, naïve TCL express only 2 chains. Only after
TCL activation the third chain is produced
 During clonal expansion: the expansion of CD4 is much less than CD8
 Effector lymphocyte appear with 3-4 days after exposure to microbes
 Memory cells survive even after microbe is eliminated. This is due to the
action of IL-7+IL-15 “produced by stromal cells”
 Memory cells:
o Central: in Lymphoid organ, Rapid clonal expansion upon re-exposure to
the microbe
o Peripheral: Rapid effector function re-exposure to the microbe
 Naïve TCL express adhesion molecules: CD62L+CCR7 on which chemokines
produced by HEV act. CCR7 then transduce signals to activate LFA-1 to bind to
ICAM-1 on HEV> resulting in firm adhesion rolling and entering of Naïve TCL to
TCL zone
 Once TCL is activated it stops expressing CD62L+CCR7 will migrate out of LN
 Fingolimod (Rx for MS) binds S1P (Sphingosin 1-phosphate) receptor
preventing the exit of TCL from LN… role of S1P in migration of TCL is explain in
P.123
 Naïve TCL don’t express E, P Selectin. *P124 VERY IMPORTANT

 Th1 development/function:
o Entry of microbes will stimulate DC to produce IL-12, NK cells to produce
IFN γ, Viral infected cells to produce type 1 IFN
 o These produced cytokines “IL-12, IFN γ, and Type 1 IFN” will act on
activated TCL, through transcription factors “STAT1, STAT4, and T-bet”
to produce Th1
o Th1 then starts producing IFN γ which act on macrophage enhancing its
bactericidal effect “Classical activation M1” leading to:
 Production of ROS, iNOS, and lysosomal enzymes leading to killing
of the microbe
 Production of TNF, IL-1: for leucocyte recruitment
 Production of IL-12 leading to Th1 differentiation and more IFN γ
production
 Increase expression of costimulatory leading to more TCL
activation

 Th2 development/function:
o When mast cells or eosinophils or even CD4 encounter Helminth they
produce IL-4 which will act on the activated TCL through transcription
factors GATA3, STAT6 and results in development of Th2
o Th2 then release its signature cytokines:
 IL-4: class switching to IgE which will coat mast cells
 IL-5: stimulate eosinophils
 IL-4+IL-13: peristalsis, alternative macrophage activation “M2”
this will stimulate macrophage to secrete IL-10 and TGF-β >>>
Tissue repair + Fibrosis
 Th17 development/function:
o Extracellular bacteria and fungi will stimulate DC to secrete IL-1, IL-6, IL-
23, TGF-β
o These cytokines will act on activated TCL through transcription factors
RORγt and STAT3 to develop TH17
o Th17 then starts to secrete:
 IL-22: which help maintaining integrity of epithelium
 IL-17: stimulate production of TNF, IL-1, IL-6, CSFs (leucocyte
recruitment and inflammation) and definsins (local antimicrobial)
o TGF-B is powerful inhibitor of immune response, but when it presents
with IL-1 or IL-6 it promotes the development of Th17
 CTL mechanism of killing:
o Perforin: disruptsb integrity of target cell plasma membrane, facilitating
entry of Granenzyme
o Granenzyme B: it cleaves Caspase which is found on the target cell
cytosol, inducing its death
o Fas ligand on CTL binds death receptor called Fas(CD95) on target cell
inducing its apoptosis
 Mechanism of pathogen resisting cell-mediated immunity:
o CMV: Inhibit proteasome activity, and removes newly synthesized MHC I
molecule from ER
o HSV: Interfere with TAP transporter
 o EBV: Inhibit proteasome activity, and increase production of IL-10 which
inhibits macrophage activation
o Pox virus: produce soluble cytokine receptor which neutralizes cytokines
o Intracellular bacteria: inhibit phagolysosomal fusion, and create pores in
phagosome
o HIV: directly kills CD4 cells
o Some viruses: increase expression of PD-1 receptor “TCL exhaustion:
initial immune response then prematurely terminated”
 Naïve BCL express IgM, and IgD Antibodies, repeated exposure increases the
affinity
 T-dependent (Follicular BCL) BCL activation has advantage of increase affinity
and increase class switching compared to T-independent (marginal zone +B1
cells)
 1ry response takes 5-10 days, where 2ry response takes only 1-3 days
 Innate immune system activates BCL through different ways :
o Complement system: C3D bind to (CR2, CD21 on BCL) and activate BCL
o TLR on BCL recognizes microbes and activate BCL
 Although BCL receptors (IgM, IgD, for naïve BCL) recognize Ag, they themselves
cannot transduce signals as they have short cytoplasmic tails. BCL receptors
are attached to two proteins Igα and Igβ to form BCR complex. Each protein is
attached to ITAM” Immunoreceptor Tyrosine-based Activation Motif”
 Migration of TCL, and BCL:
o Activated CD4 express more CXCR5 and less CCR7>>migrate out of T-
Zone
 o Activated BCL express more CCR7 and less CXCR5>>migrate out of
follicle
o CD4+BCL meet in the parafollicular area
 BCL can activate previously differentiated TCL but not naïve TCL
 Hapten is a small chemical recognized by BCL, it stimulates Antibody
production only if it is attached to a protein carrier (Conjugated
Vaccines...[Link].)
 T-B interaction at the edge of the follicle results in production of low level of
AB, with low affinity. Plasma cell generated in these extra-follicular foci are
short lived
 CD4 which express high CXCR5 and enter B-rich follicle are called follicular
helper TCL (Tfh)
 Generation and function of Tfh depends on receptor of the CD28 family (called
ICOS) which bind BCL and other cells. Tfh may secrete cytokines signature of
Th1, Th2, Th17
 Germinal Center consist of:
o Dark Zone: is the area of follicle where BCL undergo proliferation,
somatic mutation, affinity maturation, and isotype switching
o Light zone: is the area of the follicle where selection of high affinity AB
occurs. In addition to production of memory cells and long-lived plasma
cells
 IgG is able to bind to (FcRn) on endothelium of placenta, and phagocyte. This
prevents its degradation, and mediates its transportation to fetus.
 Tfh secrete IL-10 which promotes production of IgG which functions to
neutralize microbes/toxins, opsonize microbes, ADCC, complement activation,
neonatal immunity, and in feedback inhibition.
 BCL produces heavy chain determined by “C” region of Ab, while maintaining
the same specificity b/c “VDJ” sequence didn’t change
 Activation Induced Deaminase “AID” is important for class switching (converts
cytosine to uracil) and somatic mutation
 Isotype switching is also affected by the site of immune response
(mucosa>>>IgA)
 Affinity maturation occurs by mutation in V region of antigen binding site
 Somatic hypermutation: mutation of Ig’s in germinal center
 In germinal center BCL will undergo apoptosis unless rescued by Ag
recognition and TCL help.
 Ag/Ab complexes activate complement system, these complexes are displayed
by FDC which reside in light zone. Therefore, BCL has two choices to ensure its
survival: they either bind free Ag, or bind complexes displayed by FDC.
(explained in. P165)
 Ab response to T-independent antigens:
o Cross linking of multiple epitope of the Ag to multiple Ag receptor on
specific BCL eliciting strong BCL response
o Complement system activation through TLR
o Marginal zone BCL in spleen, and B1 cells in peritoneum make up
important T-independent Ab response to Ag.
 FCRγIIB “contain ITIM”: is an inhibitory receptor involved in Ab feedback
 Activated BCL:
 o Plasmablast “Blood” + Plasma cells “BM”
o Memory cell “product of T-dependent”: long-lived, either circulate or
reside in tissues
o Memory cell “product of T-independent”: short lived
o P.166
 Ig consist of:
o Fab: Ag binding site
o FC: effector function through receptors called Fc receptors on
macrophages, Complement, and other cells
 The long half-life of IgG is due to its ability to bind FcRn in endosome of
phagocyte, endothelium, and placenta
 When microbe binds an Ig, the Fc portion will bind FcγRI (CD64) on
phagocyte>>activation of phagocytic activity
 Ab mediated phagocytosis is the major mechanism of defense against
encapsulated organisms “Pneumococci”
 IVIG can be useful in some inflammatory b/c because of its effect through
FcγRIIB “inhibitory receptor”
 Fc Receptors:
o FcγRI: High affinity, on macrophages + neutrophils + eosinophils,
phagocyte activation
o FcγRIIA: Low affinity, on macrophages + neutrophils + eosinophils + Plt,
weak phagocyte activation
o FcγRIIB: Low affinity, on BCL + DC + mast cells + macrophages +
neutrophils, feedback inhibition of BCL
 o FcεRI: High affinity, on mast cells + basophils + eosinophils,
degranulation of mast/basophils
 Complement system:
o Lectin + Alternative >> Innate immune system
o Classical>> Ab
o P.178
 Membrane Attack Complex “MAC”: C6-C9: forms pores in cell membrane of
the microbe through which water and ions enter causing death of microbes
 Function of Complement system:
o Opsonization: C3d act on CR1 on phagocytes
o Cell Lysis: Through MAC “but only for microbes with thin membrane like
Neisseria”
o Inflammation: C3a, C5a, are chemotactic for WBC and stimulate release
of mediators
o Enhance humeral immunity:
 C3d act on CR2 on BCL to enhance response
 Ag-Ab-Complement complex will be displayed by FDC to BCL to
produce high affinity Ab
 Regulation of complement system:
o C1 inhibitor (C1 INH) inhibits C1r, C1s protease activity, thereby
prevents formation of C2a, C4b from C1. “Stops complement system
early at stage of C1 activation”
o Decay Accelerating Factor “DAF”: inhibits C3b binding to Bb. Also, it
inhibits C2a+C4b binding. The result is inhibition of C3 convertase
 terminating classical and alternative complement activation. DAF
defect associated with PNH disease.
o Factor I and its cofactors “Factor H + MCP” cleave C3b into inactive form
o Factor H mutation is associated with atypical HUS and age-related
macular degeneration
 The propensity of BCL in mucosal tissues to produce IgA, could be due to
cytokines which induce switching to this isotype including TGF-β which is
produced in high levels in MALT
 BCL in lamina propria of the intestine/respiratory tract, secrete IgA attached to
poly Ig Fc receptor, this complex will be endocytosed and secreted to lumen
while attached to the same receptor (to prevent its degradation) >>> the
concept of oral polio vaccine.
 Neonatal immunity is mediated by IgG FcRn in the placenta, and IgA in breast
 P.186/187
 Central tolerance takes place in BM, Thymus, Generative lymphoid organs
 Peripheral tolerance takes place in peripheral lymph nodes
 Central tolerance mechanisms include: Apoptosis, BCL Receptor editing, and T-
reg development
 Peripheral tolerance mechanisms include: Apoptosis, Anergy, and Suppression
 Central tolerance: lymphocytes that strongly recognize self Ag either undergo -
ve selection “Apoptosis” or develop into regulatory TCL
 AIRE “Autoimmune Regulator”: responsible of thymic expression of peripheral
self Ag. Defects in AIRE results in Autoimmune Polyendocrine Syndrome
 In resting state, APC continuously presenting self Ag to TCL but with little or no
costimulators
 Anergy: Functional Unresponsiveness this occur as a result of:
o TCL recognize self Ag without costimulatory>>TCL loose it ability to
transmit activating signals, this could be due to activation of ubiquitin
ligase enzyme which modifies signaling proteins targeting them for
intracellular destruction
o Engagement of inhibitory receptor part of CD28 family (PD-1, CTLA-4)
upon recognizing self Ag
 CTLA-4:
o Expressed transiently on activated CD4 and continuously on T-reg.
o Works by blocking and removing B7 from APC
o During rest state high affinity CTLA-4 binds to B7 costimulator (as B7 is
low in this state)
o During infection low affinity CD28 activating receptor binds B7
costimulator (as B7 level is high during infection)
 PD-1 expressed on activated CD4, CD8. It has ITIM
 T-reg:
o Majority are developed in thymus
o Mostly are CD4
o Express CD25 “α chain of IL-2 receptor” + FOXP3 “important for T-reg
development/function”. Mutation in FOXP3 >> IPEX
o Survival and function of T-reg, depends on:
 IL-2, which is also important for proliferation of TCL
 TGF-β, as it stimulates expression of FOXP3
o Function of T-reg:
  Secrete cytokines “TGF-β + IL-10” which inhibit lymphocyte, DC,
and macrophages
 Express CTLA-4
 Consume IL-2 (so less is available for development of other TCL,
which leads to less inflammation)
 Apoptosis:
o Upon recognizing self Ag>>production of pro-apoptotic proteins>>cause
proteins to leak out of mitochondria and activate cytosolic enzyme
“caspase” which induces apoptosis
o Fas (CD95) on many cells will bind to Fas ligand on activated TCL>>
activation of caspase.
o Mutation of Caspase 8, 10 which are downstream of fas activation>>
Autoimmune Lymphoproliferative Syndrome
 P.201

 BCL tolerance: (I didn’t understand it well)

o Central:
 Anergy
 Deletion (-ve selection)
 Receptor editing: re-expression of RAG>>new light chain with the
old chain>>new BCR with different specificity
o Peripheral:
  Anergy
 Deletion
 T-reg effect
 Fas ??
 Gut tolerance to commensal microbes:
o Separation of some bacteria from intestinal immune system by
epithelium
o Abundance of IL-10 produced by T-reg
o Unusual type of DC, such that signaling from TLR leads to inhibition
rather than activation
 Fetal tolerance:
o Generation of peripheral FOXP3 T-reg specific for these antigens
o Poor Ag presentation by the placenta
o Exclusion of inflammatory cells from the placenta
o Inability to generate harmful Th1 responses in the uterus
 P. 205-207
 Infections may contribute to autoimmunity in different ways:
o APC with increased costimulatory may break TCL tolerance and promote
self-reactive lymphocyte
o Molecular mimicry: Ab against Strep. May cross react with myocardial
Ag
o Innate immune reaction may alter structure of self Ag (Enzymatic
conversion of arginine>citrullines in self-protein>> the citrullinated
protein recognized as non-self and elicit immune response
o Release of Ag which usually is hidden from immune system (eye, testis)
 Immune responses to tumors usually dominated by tolerance or regulation,
not by effective immunity
 Tumor Ag could be product of:
o Passenger mutation: not involved in tumorigenesis (radiation induced)
o Driver mutation: involve in tumorigenesis, mutated suppressor gene,
mutated P53 protein, mutated Ras, Bcr/Abl fusion proteins
o Aberrantly expressed self-protein: looks normal, but expression is
dysregulated (tyrosinase, gp100, cancer/testis antigens)
o Viral oncogene: HPV E6, E7 in cervical Ca, EBVNA in lymphoma
 Tumor evasion mechanisms:
o Stop expressing Ag, if it not in involved in tumorigenesis it’s called Ag
loss variant
o Stop expressing MHC molecule, but this will stimulate NK cells
o Express ligands for TCL inhibitory receptors
o Produce low costimulators which will stimulate TCL binding CTLA-4
inhibitory receptor rather than the activating receptor CD28
o Secretion of inhibitory cytokine: TGF—β
o Induce development of T-reg
 Cancer immunotherapy:
o Passive:
 Ab against tumor Ag (CD20>B-lymphoma, VEFG>Colon ca, anti
Her/Neu>Breast Ca)
 Adoptive cellular therapy: TCL isolated from
blood/tumor>>>expanded in vitro>>>injected back to patient
 Chimeric Ag receptor
 o Active:
 Vaccinating patients with their own tumor Ag, or DC+Ag which
were expanded in vitro
 HPV, HBV, vaccination (prevention of infection, and thus
prevention of cancer)
 Checkpoint Blockade: Ab against CTLA-4 for melanoma, and
against PD-1 for various tumors. The drawback is autoimmunity
 Cytokine therapy: IL-2 as it promotes lymphocyte activation, the
drawback is Capillary leak syndrome
 The chance that two siblings has identical MHC 1:4
 Direct allorecognition: CTL recognize Ag presented by Donor APC>> Acute
rejection
 Indirect Allorecognition: CTL recognize Ag presented by host APC>> Chronic
rejection
 Mixed Lymphocyte Reaction “MLR”: leucocytes of two individuals are mixed
and the degree of reaction corresponds to the outcome of graft exchange
 Graft rejection:
o Hyperacute:
 Occurs within minutes
 Features thrombosis and necrosis
 Occurs due to preformed Ab (from previous Blood transfusion or
organ transplantation, or pregnancy)
 It is not common due the utility of cross matching
o Acute:
 Days to weeks
  Either:
 TCL “CD4, CD8” mediated through direct damage or release
of cytokines
 Ab mediated complement activation>> injury to vessels of
graft
o Chronic:
 Months to years
 TCL mediated fibrosis and narrowing of blood vessels “graft
atherosclerosis”
 It could be also due to Alloantibodies
 Calcinurin inhibitors “Cyclosporin+FK”>> block calcinurin phosphatase>>block
NAFT activation>> inhibit transcription of cytokines
 Rapamycin inhibits kinase “mTOR” + IL-2 signaling required for TCL activation
 Blood groups Antigens are sugar, so they don’t elicit TCL response
 A+ has B Ab, B has A Ab, AB has no Ab, O has A+B Ab
 Rh Ag is a protein on RBC membrane, which may be the a target of maternal
Ab, when the fetus express paternal Rh and the mother lack that protein
 P.228 Figure 10-12
 Hypersensitivity Reactions:
o Type I Immediate hypersensitivity: IgE mediated release of mediatory
from mast cells, and eosinophils
o Type II Ab mediated: Ab other than IgE cause cellular damage either
through complement system, or Fc receptor mediated recruitment
o Type III Immune-Complex: Ab against soluble Ag form complex which is
deposited in blood vessels damaging them
 o Type IV Delayed hypersensitivity reaction: TCL mediated
 Most of the mast cells are coated by IgE with different specificity. However, in
atopic patient IgE Fc receptor of certain specificity “the allergen” is attached to
high affinity FcεRI receptor. This is called sensitization, which means repeated
exposure will lead to subsequent activation
 FcεRI is also found on basophils
 Mast cell action upon repeated exposure to same allergen:
o Degranulation and release of mediators: Histamine which cause small
vessels VD, increase vascular permeability, and transient smooth muscle
contraction
o Synthesis and release of arachidonic acid metabolites:
 Prostaglandin: causes VD
 Leukotrienes: causes prolong smooth muscle contraction
o Synthesis and release of cytokines which is responsible of late phase
reaction:
 TNF+IL-4 >> recruitment of neutrophils and eosinophils

 Goal of immunotherapy: shift immune response away from Th2, and IgE. This
can be achieved either by inducing tolerance in allergen-specific TCL, or by
stimulating T-reg
 Mechanism of injury in type II, III allergic reaction
o Inflammation “recruitment”
o Opsonization
o Abnormal cellular response (activating/inhibitory) Ab
 Diseases caused Ag/Ab complex (Type II):
 o Deposition of Ag/Ab complex occurs in malaria, and hepatitis
o Ab against Srep. Ag is deposited in heart (Rheumatic fever) and kidneys
(PSCGN)
 Diseases caused by immune complex (Type III):
o Localized: Arthus reaction
o Systemic: SLE, and serum sickness
 Therapy for Ab mediated diseases (Type II, III):
o Limit inflammation and it injurious consequences with drugs such as
corticosteroids
o Plasmapheresis is used to reduce level of circulating Ab, or immune
complex
o IVIG might be helpful, postulated mechanisms of action include:
 By inducing expression of inhibitory Fc receptor “FcγRIIB” on
myeloid cells and BCL
 Compete against pathogenic Ab to FcnR >> decrease half-life of
Ab pathogen
 P. 243, 242
 Epitope spreading: initial immune response against one or a few self Ag may
expand to include responses against many more self Ag

 Genetic mutation of SCID (TCL+BCL):

o (what I understood, that numbers mentioned down are true for US, but
not for KSA):
 o X-linked:
 ½ of the cases of SCID
 99% due to common γ chain (also called IL-2R γ) signaling subunit
of cytokines (2,4,7,9,15,21)
 Pro TCL, cannot proliferate in response to IL-7>> decrease
TCL>>dysfunction of BCL. Also, NK cells are deficient b/c IL-15 isn’t
working
 TCL is decreased, BCL normal or increased, Low serum Ig level
o ADA mutation:
 Account for ½ of the cases of AR-SCID
 ADA is needed for breakdown of adenosine>>purine
accumulation “Toxic”
 Defect in TCL maturation, and dysfunction of BCL
 Decrease TCL and BCL (mainly TCL)
o PNP deficiency is similar to ADA
o JAK3 mutation is similar to X-linked
o RAG1, RAG2 which encode VDJ recombinase that is required for Ig and
TCL receptors recombination and lymphocyte maturation (decrease in
BCL, TCL and serum Ig)
 X-linked Agammaglobulinemia:
o Defect in Bruton Tyrosin Kinase (BTK) >> pre BCL in BM fail to expand
and mature
o ¼ has autoimmune disease (could be b/c BTK is needed for central
tolerance)
 o Absence/decreased BCL and Ig
 Digeorge:
o Due thymus incomplete development
o Selective defect in TCL maturation
o Improves with age
 Defective BCL responses:
o X-linked Hyper IgM syndrome: mutation in gene encoding CD40 ligand
which bind CD40 on BCL, DC, and macrophages>>> defect TCL
dependent humoral immunity “class switching and affinity maturation”,
and defect in macrophage activation
o AR Hyper IgM due to mutation affecting Activation Induced Deaminase
“AID” which is involved in class switching and somatic hypermutation
o CVID: defect in Ab response to infection and reduced Ig
o Defect in TCL response:
 Bare lymphocyte:
 No expression of class II MHC molecule
 Defect in maturation of TCL in the thymus
 Profound decrease in CD4
 P. 255

 Defect in innate immunity:

 o CGD:
 Mostly X-linked
 Defect in phagocyte oxidase

o LAD:
 Mutations in gene encoding Integrins
o C3 deficiency results in severe infections, where C2, C4 deficiency results
in increase bacteria/viral infection and SLE as well.
o Chediak-Higashi syndrome:
 Leucocyte lysosomal granules do not function
 Affects phagocyte and NK cells
 Increase susceptibility to infection
o Mutation in MyD88 (adaptor protein in TLR)>> risk of pneumococcal
pneumonia
o Mutation in TLR3>>>recurrent herpes encephalitis
 WAS:
o Defect in protein needed for various adaptors
o X-linked
o Characterized by small platelets, small leucocyte, eczema, and
immunodeficiency
 Ataxia Telangiectasia:
o Mutation in gene involved in DNA repair
o Defected DNA repair
o characterized by Ataxia, vascular malformation “telangiectasia” and
immunodeficiency
 Gene therapy was successful in X-linked SCID. However, it increased the risk of
leukemias
 HIV:
o Consists of two RNA strands
o Binds CD4 and chemokine receptors (CXCR4, CCR5) by its glycoprotein
gp120 (fusion membrane by membrane) >> virus enter host cytoplasm
o Under the action of viral protease >> viral uncoating> RNA release
o Through action of viral reverse transcriptase viral DNA copy of viral RNA
is produced
o Viral DNA integrates into host DNA through action of integrase
o The integrated viral DNA is called provirus
o When infection occurs> host cell produces more copies of Viral RNA
 Patients with mutation in CCR5 remain disease free for years, because HIV
cannot enter CD4 cells
 Major source on infection in HIV patient is infected CD4, macrophages, and DC
 Cancer associated with HIV: EBV>>>Lymphoma, Herpes>> Kaposi
 HIV decreases expression of class I MHC
 Presence of HLA-B57, HLA-B27 seems to be protective, perhaps because these
HLA molecules are particularly efficient at presenting HIV peptides to CD8
 Elite controllers, or long term non-progressors, are HIV patients who control
infection without therapy