PHYSIOLOGY

AfTo.To.fTeeh.eom
Table of Contents
Immune System 1
Introduction 1
Vaccines 4

B & T Cells
Antibody Classes 6
B Cell Activation & Differentiation 7
B Cell Development 10
Cell Mediated Immunity of CD4 Cells 12
Cell Mediated Immunity of Natural Killer & CD8 Cells 13
Cytokines 14
MHC Class I & MHC Class II Molecules 15
Somatic Hypermutation & Affinity Maturation 18
T Cell Activation 19
T Cell Development 20
VDJ Rearrangement 22

Contraction of the Immune Response 24

Anergy, Exhaustion & Clonal Deletion 24
B & T Cell Memory 25
Contracting the Immune Response 28

Innate Immunity 29
Innate Immune System 29
Complement System 31
NOTES

NOTES
• IMMUNE SYSTEM

INTRODUCTION TO THE
IMMUNE SYSTEM
osmsJl:/immune-s14s-l:em-in-l:Todue-l:ion
• Includes organs, tissues, cells, molecules CELLS OF THE IMMUNE SYSTEM
• Protects from microorganisms, removes
Leukocytes (white blood cells)
toxins, promotes inflammation, destroys
tumor cells • Formed by hematopoiesis in bone marrow
• Two branches o Starts with multipotent hematopoietic
stem cells
• Innate, adaptive
° Cells develop into myeloid/lymphoid
progenitor cells
INNATE IMMUNE RESPONSE • Myeloid cells: contribute to innate response
• Nonspecific cells: phagocytes, natural killer o Neutrophils: phagocytes, granulocytes,
(NK) cells; no immunologic memory polymorphonuclear cells (nucleus
• "Feverishly" fast (minutes to hours) segmented into 3-5 lobes); stain light
pink/reddish-purple; most numerous
Noncellular components
leukocyte
• Physical, chemical barriers (e.g. lysozymes O Eosinophils: phagocytes, granulocytes,
in tears, cilia in airways)
polymorphonuclear cells (nucleus
• Inflammation: stops spread of infection, usually bilobed); stain pink with eosin;
promotes healing larger cells fight parasites
• Four cardinal signs: redness. heat, O Basophils: nonphagocytes.
swelling, pain granulocytes. polymorphonuclear cells
• Complement system: cascade of proteins; (nucleus bilobed/segmented); stain blue-
triggers inflammation, kills pathogens by purple with hematoxylin; aid in fighting
cytolysis, tags cells for destruction parasites; granules contain histamine.
heparin; involved in inflammatory
ADAPTIVE IMMUNE RESPONSE response; least numerous leukocyte
O Mast cells: non phagocytes.
• Highly specific cells; immunologic memory,
granulocytes; involved in inflammatory
need priming
response
• Significantly slower, esp. initially (weeks)
O Monocytes: phagocytes. antigen-
• Clonal expansions: cells replicate
presenting cells; release cytokines to
• Clonal deletion: cells die off after immune recruit other cells; only circulate in blood;
response; some survive as memory cells differentiate into macrophages/dendritic
cells
O Dendritic cells: phagocytes. antigen-
presenting cells; release cytokines to
recruit other cells; circulate in lymph,

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 afratafreeh.com exclusive
blood, tissue; consume large proteins , B cells: contribute to adaptive response;
in interstitial fluid; break bloodborne complete development in bone marrow;
pathogens into small amino acid chains bind to specific antigens (antigen
- move to lymph node - present presentation not needed); capable of
antigens to T cells phagocytosis, antigen presentation; load
O Macrophages: phagocytes, antigen- antigens on major histocompatibility
presenting cells; release cytokines to complex (MHC) II, display to T cells;
recruit other cells; stay in connective T-cell activation - B cells mature into
tissue, lymphoid organs; not in blood plasma cells; secrete lots of antibodies/
• Lymphoid cells: contribute to the adaptive immunoglobulins (8 cell receptors in
response (except NK cells) secreted-form, mark pathogens for
destruction - "humeral immunity")
O NK cells: contribute to innate response;
complete development in bone marrow; , T cells: contribute to adaptive
large, contain granules; primarily target response; complete development in
infected, cancer cells; kill target cells thymus; responsible for cell-mediated
with cytotoxic granules (punch holes immunity; bind to specific antigens
in target cell membranes by binding (antigen presentation needed); naive
T cells primed by antigen presenting
to phospholipids - enter cell, trigger
apoptosis, programmed cell death) cells (usually dendritic cells); generally
categorized into CD4+, CD8· T cells;
CD4- (helper) T cells secrete cytokines
to coordinate immune response,
only see antigens on MHC II; CD8·
(cytotoxic) T cells kill target cells, cells
with antigens on MHC I

multlpotent
hemofopoletlc
STEM CELL

(Q)
--~~--~- -----~-----.
~
MYELOID LYMPHOID
pTogenitoT cell pTogenihT cell

(Q) (Q)
.----.....-~-?~~-r-~----- ,.> ~
~
NEUTR~IL .I,. 8AS!PHIL l M~CVTE "'-
8 CELL
NATURAL
KILLER CELL T CELL

@ © (6) (Q)
EOSINOPHIL 1MAST CELL
©
__)._ Q complete
e 9 completes
POLVMORPHONVCLEAR CELLS ~ ,l.. development ln development ln
[, 80NE MARROW THYMUS
GRANULOCVTES ~·~GE

(Q)
DENDRITIC PLASMA
CELL CELL

Figure 44.1 Family tree of immune system cells.

2
CLASSIFICATION OF IMMUNE Granulocytes
CELLS • Contain granules in cytoplasm
• All cells (except mast cells)
Phagocytes
polymorphonuclear
• Reach around pathogens with cytoplasm,
swallowing whole (phagosome) Antigen-presenting cells
• Destroy some pathogens with cytoplasmic • Present antigens to T cells
granules (phagosomes fuse with granules
- phagolysosomes; pH in vesicle drops
killing pathogens)
• Continue to swallow pathogens before
oxidative burst - produces highly reactive
oxygen (e.g. Hp2; destroys proteins,
nucleic acids, killing pathogens, phagocyte)

t. PHAGOCYTOSIS

ANTIGEN-PRESENTING
CELL

a. CYTOPLASMIC GRANULES Figure 44.3 Antigen-presenting cell

(depicted here as dendritic cell) presenting an
antigen to a T cell.

3. OXIDATIVE BURST

Figure 44.2 Phagocyte activities.

3
 Granulocytes

Phagocytes

Antigen-presenting
Agranulocytes
cells

VACCINES
osmsJl/ vecclnes
• Generate protective adaptive immune INACTIVATED VACCINES
response against microbes by exposure • Pathogen killed using heat/formalin
to nonpathogenic forms/components of • Response humoral/antibody-mediated; no
microbes cellular immunity - ! response
O Differs from passive immunity (body • Hepatitis A; polio; rabies; influenza
creates own antibodies)
• Administration: intramuscularly,
intradermally, intranasally, subcutaneously, SUBUNIT VACCINES
orally • Contain immunogenic portions of
pathogens (polysaccharides/proteins)
• lmmunoglobulin response depends on
route, type of vaccine • Combination of proteins from different
pathogens - conjugate subunit vaccines
O Intramuscular vaccinations - lgG
• Polysaccharide vaccines
O Rotavirus vaccine (oral) - lgA
, T cell independent (only respond to
• Four main types of vaccines
protein antigens)
O Live attenuated, inactivated (whole cell
, Not effective in children< two years old
vaccines)
O Subunit, toxoid (fractionated vaccines) , Memory B cells never formed -
repeated doses needed
, Haemophifus inf/uenzae type B;
LIVE ATTENUATED VACCINES hepatitis B; HPV; Bordetelfa pertussis
• Attenuated - pathogen weakened (but still (pertussis); Streptococcus pneumoniae;
replicates) Neisseria meningitidis; Varicelfa zoster
• Measles, mumps, rubella, varicella (MMRV);
rotavirus; smallpox; yellow fever

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 afratafreeh.com exclusive
TOXOID VACCINES
• Against specific toxins (main cause of
illness)
• Toxoid fixed/inactivated using formalin
• Often combined with subunit vaccines
• Tetanus, diphtheria, and pertussis (TDaP),
diphtheria, tetanus, and pertussis (DTap)
vaccine

CONTRAINDICATIONS
• Moderate/severe infection
• Allergy to eggs/previous vaccines
• Guillain-Barre syndrome (vaccines against
influenza, DTaP)
• Weakened immune system
O Pregnant (live attenuated vaccines)

5
 NOTES

NOTES
• B & T CELLS

ANTIBODY CLASSES
osmsJl/ o.n-li\>od14-elo.sses
• B cell receptor, major component of • Main immunoglobulin in mucosal sites;
humoral immunity sometimes occurs as dimer (valence: 4)
• Heavy, light chain; fragment antigen- • Two forms
binding region; constant region (Fe) , lgAl, lgA2 {differ in constant regions)
• B cell develops into plasma cell ----> B cell
receptor secreted as antibody lmmunoglobulin E (lgE)
• Antibodies: monomers, polymers • Monomer (valence: 2)
O Valence: number of antigen-binding • Production primarily induced by interleukin
fragments 4 (IL-4)
• Triggers granule release from mast cells,
eosinophils, basophils
FIVE TYPES
• Responds to nonpathogenic targets (e.g.
• Coded by heavy chain genes
peanuts) ----> allergies
lmmunoglobulin M (lgM)
lmmunoglobulin D (lgD)
• 1st antibody response
• Monomer (valence: 2)
• Monomer as B cell receptor (valence: 2)
• Found alongside lgM antibodies, signals
• Penta mer as antibody held together by maturation of B cells
joining (J) chain (valence: 10)
• Works against carbohydrate, lipid antigens
• Most effective at activating complement H£AVV DISULFIDE: FM6M£NT-
pathway UGHT C.HAl,~80fol
~ANTl61~tDING.
D
C.HAIN ""
~
lmmunoglobulin G (lgG) ~ ANTIG,f.N-BINDING,
• Monomer (valence: 2) B ce. L srre
L C.ONSTANT
• Four subclasses RECEPTOR -{ }- """"'NT 1•1
O lgG 1, lgG2, lgG3, lgG4 {differ in
constant regions)
• Serves as opsonin
• Activates classical complement pathway

lmmunoglobulinA (lgA)
• Monomer (valence: 2)
Figure 45.1 B cell receptor components.
• Serves as opsonin (eosinophils, neutrophils,
some macrophages)

6
 8 CELL RECEPTORS

b)
-ACTIVATES
C.OMPlEMENT - l3D HELPS MATURE.
8 C.E.LLS LEAVE
- DOESN'T REQUIRE the BONE MAP.ROW
TCELL HELP
VALENCE: 10

- MOST A8UNDMJT ANTIBOD'r' l'\UC.OSA

- AC.TS as.,, OPSONIN
ATOPIC DERMATITIS.
SEASONALALLERG,1£S.

~,~
·:.
. ::· v
0
0 ·-
- O
...
- PREVENTS PATHOG,ENS
~ 8.ASTHMA

fr,,.. ENTEP.INGr BODI(

Figure 45.2 Summary of the five classes of antibodies. lgM and lgD can act as B cell receptors.

8 CELL ACTIVATION &

DIFFERENTIATION
osms.i'l/\,-eell-o.etivo.-lion-o.nd-diffeTentio.-lion
• Developing B cell receptor expresses µ DIFFERENTIATION
heavy chain c- B cell receptors lgM • B cells stimulated by cluster of
• Alternative splicing---'> lgM, lgD expressed differentiation 21 (CD21)/complement
on surface e- mature, naive B cell receptor Type II (CR2) (receptor for C3d
explores lymphatic system - B cells enter complement fragment)
paracortical region of lymph nodes. migrate • Activated B cells differentiate into plasma
to cortical region ---'> form primary follicle cells. secrete antibodies
, Plasma cells initially secrete lgM, remain
ACTIVATION mainly in bone marrow. safeguard
against future encounters with same
• On activation (antigen-binding), B cell
antigen
forms germinal center - secondary
lymphoid follicle Activated CD4" T cell ---'> class switching
• Cross-linkage of two B cell receptors ---'> lg-
• B cells: antigen-presenting cells; present
alpha. lg-beta, CD19 cluster antigens on major histocompatibility
O Blk, Fyn, Lyn phosphorylate tyrosine complex (MHC) class II to helper T cells
residues on immunoreceptor tyrosine • CD40 ligand on T cell binds to CD40 on B
based activation motif (ITAM) units
cell ---'> cytokines instruct B cell on type of
---'> transcription factors nuclear antibody to produce (by activation-induced
factor kappa-light-chain-enhancer of cytidine deaminase)
activated B cells (NF-kB), nuclear factor
, IL-4. IL-5---'> lgE
of activated T cells (NFAT)---'> gene
expression of cytokines. upregulation of , Interferon (IFN) gamma - lgG
antiapoptotic cell surface markers
7
• Activation-induced deaminase removes
constant regions during differentiation to
leave desired antibody region

ANTIGENS
{;}

If. If ca 8 CELL :,cts

ACTIVATED, it lol"l'ls
ca 6EP.t11NALCENTER
z::::~ -----
S. 8 C.ELLS lol"""
PRIMAP.V FOLLICLE

a, 8 CELLS l"li:,ratc t,
(OTG kG;C
t. B & T C.E.LLS c11tcr
PARAGORTIGALllEGION

Figure 45.3 Mature, naive B cells form a primary follicle in the cortical region of a lymph node.
When the B cell binds an antigen, it activates and forms a germinal center. The follicle is now
called a secondary lymphoid follicle.

Figure 45.4 Series of events following antigen binding that lead to B cell activation. lg-alpha, lg-
beta, and CD19 are intracellular side chains of the B cell receptors that cluster when two B cell
receptors are cross-linked by an antigen.

8
 8 CE.LL
ACTIVATION

O'I" CR:I.

Figure 45.5 Complement fragment C3d can bind an antigen and then be bound by molecule
CD21/CR2 on a B cell. B cells can also be activated when they have a B cell receptor that is
bound to an antigen, and a CD21 that's bound to an antigen.

t.

8 CELLS .,. .. ANTI<:.£N CP'I' T CELL

l'RESEIJTINC:o GEU.S

a,

AC.TIVAn1>
BGELL CPlf• TCELL

s.

BGELL
"cvTOICINE
RECEPTOR~
AC.TIVAn1>
CP'I• TC.ELL
s
CYTOklNES

Figure 45.6 B cell differentiation. 1: B cell presents an antigen to a CD4+ T cell. 2: If the T cell
activates, it expresses CD40L on its surface, which binds to CD40 on the B cell. 3: CD40L and
CD40 binding causes the B cell to express a cytokine receptor and the T cell to release cytokines.
The type of cytokine determines what type of antibody the B cell will produce.
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8 CELL DEVELOPMENT
osms.i"l/\,-eell-developme,rl
• Lymphopoiesis: development of diverse Early pro-B cell
set of lymphocytes with unique antigen • Common lymphoid progenitor cell
receptors expresses recombination activating gene
(RAG) 1, RAG2 - early pro-B cell
CREATION OF SUITABLE RECEPTOR Late pro-B cell
• B cell receptor contains two chains
• Heavy chain D. J gene segments spliced
o Heavy, light together (allelic exclusion: P1 chromosome
• Antigen-binding site made of variable (V), to complete splicing suppresses 2nd) - late
diversity (D). joining (J) protein segments pro-B cell
coded by genes of same name
o Heavy chain: all three segments Large pre-8 cell

o Light chain: V, J segments • Late pro-B-cell attaches D-J gene segment

to V gene segment via V(D)J recombinase
- binding site (heavy chain) recombined
with mu gene - large pre-B cell
ANTl&£N BINDING. SITE , Mu gene codes for lgM constant region
- VARIABLE protein
- DIVERSITV
- l'OINING Small pre-B cell
• Functionality of heavy chain tested by
LIGMT C.MAIN MEAVY C.MAIN
binding to surrogate light chain (VpreB,
:r V D
l J s lambda 5) - if successful, cells proliferate
V, \ - small pre-B cell

Immature B cell
• Light chain rearranged - functionality of
light chain tested by autoimmune regulator
(AIRE). identifies self-reactive cells by
expressing bodily antigens in lymphoid
organs - immature B cell
• Central tolerance/negative selection:
elimination of self-reactive cells
Figure 45.7 Antigen binding site on heavy , Strong binding to self-antigen - cell
chain is composed of V, D. and J segments. undergoes apoptosis
while antigen binding site on light chain has , Intermediate binding to self-antigen -
only V and J segments. light chain repeatedly rearranged with
kappa gene on Pt. 2nd chromosomes.
lambda gene 1 '\ 2n° chromosomes
STAGES OF DEVELOPMENT , Failure to eliminate self-reactive cells -
• Six stages: common lymphoid progenitor autoimmunity
cell - early pro-B cell - late pro-B cell
• Immature B cells finally undergo alternative
- large pre-8 cell - small pre-B cell - splicing on constant region - lgD constant
immature B cell
region replaces lgM constant region - cells
released into blood

10
 COl'll'ION
LYl'IPHOID
PROG,ENITOR
s RAG,-1
RA&-2

lsi CHROl'IOSOl'IE. 2o4 CHROMOSOME

EARL'/ v.1 V,?. V,l> v.'114 0.1 0,.2 0,.21 :r.1 :r,.:t :r., v.1 v,.2 v,;1> v.'114 0.1 0,.2
PR0-8 -000-··D··OO··D··OO·O- -000-··D-·DO·
C.E.LL
ALLELIC.
SPLICED D L J'
SEG.t\ENTS \ j EXC.LUSION

v,1 v,2 v,3 v,'l'I o,,:r,s

LATE
PR0-8 -DDD-··D··CD-
C.E.LL
\., ./ V(DlJ' RECOMBlt'ASE.
v,n o,, :r,s
V-D-J' BOUND -j I I ~ VDJ' REAP.Mt'G.E.l'IENT
*• rue:Ne.

LAl'G,£
PRE-8
C.E.LL

5URP.OuATE. UG.HT C.HAIN

-:
..._Vpre8

"'"'• 5
prc-8 CE.LL ~ ll'll'IUNOG,LOBULINBETA
REC.EPTOP. I -ll'll'IUt'OG,LOBUUN ALPHA

SMALL
PRE-8
CE.LL
LIG.HT C.HAIN (LC.l P.EARRANu£ME.NT

I t'OT
ITERATE
~ SeLF-P.EAC.TIVE
or
DIE
ll'IMATURE
8 CE.LL
0
Figure 45.8 B cell development stages and the changes that move them to the next stage.

11
 CELL MEDIATED IMMUNITY OF
CD~ CELLS
osms.i"l/eell-medio.-led-immuni-l:14-C,Dll-eells
• CD4 cells = T helper cells (support other ----> transcription factors signal transducer
immune cells) and activator of transcription 1 (STATl).
• T cells initially naive STAT2
• In response to antigen, T cell primed ---->
T helper Type II
effector T cell
• Fights parasites
O Two signals: antigen (MHC molecule on
• Eosinophils, basophils, mast celts-« IL-4,
antigen-presenting cell), costimulation
IL-4, IL-10----> transcription factors STAT6,
(CD28 binds to 87 on antigen-
GATA-binding protein 3 (GATA3)
presenting cells)
• Activated T helper cell-> IL-2----> up- T helper Type XVII
regulates IL-2 alpha receptor • Fights fungal, bacterial infections
• T helper cell binds to IL-2 (autocrine • Fungi, bacterie -e Ill. IL6, IL23,
stimulation)----> clonal expansion transforming growth factor (TGF)~---->
transcription factors ROR-y, STAT3
FOUR TYPES OF T HELPER CELL
T follicular helper (Tfh)
• Depends on cytokines in environment
• Establishes memory 8 cells
T helper Type I (Thl) • Antigen-presenting cells e- IL6, IL21, IL27
• Fights intracellular infections ----> transcription factors 8 cell lymphoma
• Macrophages----> IL-12, natural killer (NK) protein 5 (8CL-5), cMaf
cells v- IFN-y, infected cells=-. IFNa, IFN~

PRIMING
l'EQUIRES 2 SIC:.NALS
1.ANTIGi€N I

CVTOl:.INE.
RECE.PTOP.
\.___

r;;). NAIVE T CELL

\:.:_)
ANTIGEN-
PRESENTING
CELL
0 ' -

Figure 45.9 T helper cells require two signals to be primed and become effector T cells:
presentation of an antigen and binding of CD28 on T cell to 87 on antigen-presenting cell.

12
 CELL MEDIATED IMMUNITY OF
NATURAL l(ILLER & CDS CELLS
osms.i"l/eell-medio.-led-immuni-l14-Nk-CDl-eells
NATURAL l(ILLER (NI<) CELLS CD! CELLS
• Identify target cells; deliver perforin, • CD8 cells = cytotoxic T cells
granzymes • T cells initially naive
• Part of innate response - no need for • In response to antigen, T cell primed -
specific antigen effector T cell
• Activation receptors recognize surface , Two signals: antigen (MHC molecule on
molecules on infected cells; inhibitory antigen-presenting cell), costimulation
receptors recognize molecules (e.g. native (CD28 binds to 87 on antigen-
MHC class I molecules) presenting cells)
• Also activated by antibody-dependent cell- • Activated T helper cell - IL-2 - up-
mediated cytotoxicity regulates IL-2 alpha receptor
O lgG binds to virally-infected cell - • T helper cell binds to IL-2 (autocrine
CD16 on NK binds to antibody stimulation) - clonal expansion
• Needs to see antigen in context of MHC I to
kill cell (doesn't need CD28)
MHC, I A85£NT FOREIGN MHC I • Binds nonspecifically to multiple cells with
adhesion molecules - fails to bind to MHC
I - disengages
• If antigen binds, cytoskeletal rearrangement
~ - forms supramolecular activation cluster
(SMAC)

d
ANTISODI/ DEPENDENTCELL
, Includes central SMAC (cSMAC) for
antigen recognition, peripheral SMAC
(pSMAC)
• Cytotoxic cell releases granules with
perforin, granzymes (caspases -
apoptosis)
MEDIATED OffOTOXIC,ITV (ADC,C,)
-19G

Figure 45.10 NK cells recognize cell surface

molecules like MHC I to determine whether or
not to kill a cell. They can also kill via ADCC.
In this process, the NK cell is stimulated
by binding to the constant chain of an lgG
antibody attached to a virally infected cell.

13
 INCORRECT ANTIGEN FORMS SMAG
COi CELL
,. - . T C.ELL DISENC':aAGiES
,r-"'-.
pSMAC cSMAC

CORRECT ANTIGEN
ENGiAC':aESMORE
STRONGiU,'
~ 0
01'TOSKEL£TAL
.o
R£ARRAN(;.£M£NT

APOPTOSIS

Figure 45.11 CDS cells weakly bind a variety of cells with adhesion molecules. However, they
only destroy cells with antigens on their MHC I molecules that allow the CDS cells to bind tightly.

CYTOl(INES
osms.i-1:/e14-l:oklnes
• Proteins secreted by all types of cells to messenger RNA (mRNA), inhibit protein
communicate (bind to receptors, trigger synthesis, express MHC
response) • Type II
, Interferon-gamma - promotes anti-
FIVE TYPES viral state, activates macrophages, CD4-
helper T-cells
Interleukins (lls)
• Act as communication between leukocytes, Colony stimulating factors (CSFs)
nonleu kocytes • Bind to surface receptors on hematopoietic
• Promote development, differentiation of T. stem cells - proliferation, differentiation
B cells Transforming growth factors (TGFs)
• Mostly synthesized by helper T cells • Control proliferation, differentiation of cells
Tumor necrosis factors (TNFs)
• Bind to cell receptors. cause cells to die MAIN FUNCTIONAL RESPONSES
(induce apoptosis)
Pro-inflammatory
• Heavily involved in inflammatory response
(up-regulate expression of adhesion • Enhance innate, adaptive immune
molecules. increase vascular permeability, responses
induce fever) • IL-1. IL-12, IL-lS, TNF, IFN-y

Interferons (IFNs) Parasite/allergy

• Type I • Help immune system handle large
O Produced by virally infected cells - parasites, induce allergic responses
affect surrounding cells: degrade • IL-4. IL-5, IL-10. IL13
14
Regulatory stimulating factor (GM-CSF), macrophage
• lmmunosuppressive colony-stimulating factor (M-CSF), IL-7
• IL-10, TGF-13 Chemotactic
Growth and differentiation • Help cells move towards site of
• Replenish immune cells inflammation

• Granulocyte-macrophage colony- • IL-17,IL-8

MHC CLASS I & MHC CLASS II

MOLECULES
osms.i-l/MHC-elo.ss-1-MHC-elo.ss-1 I
• Major histocompatibility complex (MHC), Structure
AKA "human leukocyte antigen" • Contains alpha, beta-2-microglobulin
° Cell surface proteins, present antigens chains
to T cells • Alpha chain: peptide binding groove,
transmembrane region
MHC CLASS I , Binding groove binds peptides 8-10
• Found on all nucleated cells, presents amino acids long; hydrophobic peptide
antigens from inside residues - hydrophilic groove amino
acids
• Bound by CD8 molecules on cytotoxic T
cells • Three extracellular domains: alpha-1,
alpha-2, alpha-3
• Includes HLA-A, HLA-B, HLA-C

MHC CLASS I MOLECULES

PE.PTIDE BINDING GROOVE

-ALPHA 1

ALPHA
C.HAIN
ALPHA 3-

TRANSME.M8RANE-{
REGION

Figure 45.12 Structure of an MHC class I molecule.

15
Function move peptide chains to endoplasmic
• Allows immune cells to sample cellular reticulum
proteins (via endogenous pathway of , TAP loads peptide onto MHC class I
antigen presentation) using tapasin
O Marked protein sent to proteasome , MHC class I loaded into exocytic vesicle,
O Proteasome degrades protein----> short sent to cell surface
peptide chains , Cytotoxic T cells, NK cells interact with
O Transporters of antigenic peptides (TAP) peptide (if necessary)

CYTOTOXIC.TC.ELL NATURAL .iL: CELL f/3

:,.
ENDOPLASMIC.
RETIC.ULUM --®--
"~---- EXOC.YTIC.
VESICLE

TRANSPORTERS of MHC. CLASS I

ANTIGENIC. PEPTIDES J
(TAP)

Figure 45.13 Endogenous pathway of antigen presentation.

MHC CLASS II presentation)

• Found on antigen-presenting cells, , Antigen-presenting cell ingests antigen
presents antigens from outside ----> endosome
• Bound by CD4 molecules on helper T cells , Lysosome + endosorne e-
• Includes HLA-DP. HLA-DQ, HLA-DR phagolysosome; degrades protein ---->
short peptide chains
Structure , MHC class II binding groove
• Contains alpha. beta chains filled temporarily with invariant
O Both penetrate cell membrane chain (degrades during vesicular
O Binding groove binds peptides 14-20 transportation)
amino acids long , Vesicle fuses with phagolysosome
, MHC class II binds peptide, sent to cell
Function surface
• Engulfs, destroys pathogens; presents , CD4- helper T cells interact with peptide
antigens to CD4· T helper cells (via (if necessary)
exogenous pathway of antigen

16
 MHC. GLASS II MOL£C.UL£

ALPHA 1
OO~AIN--

Figure 45.14 MHC class II molecule structure.

PHAGOlYSOSOME
d-1~.:s'.''r GRANULES
PATHOGEN/PROTEIN

MHC CLASS II ~-

@?
..... INVARIANT
\
__ . _ _CMAl/7

1 r>' PATHOGEN/PROTEIN

@ . PEPTIDES

Figure 45.15 Exogenous pathway of antigen presentation.

17
 SOMATIC HYPERMUTATION &
AFFINITY MATURATION
osmsJl/ somo.-lie-h14pel9mu-lo.-lion-o.ffini-l:14-mo.-l:u,-o.-lion
SOMATIC HYPERMUTATION , Base excision: uracil-DNA glycosylase
• Intentional mutation of antibody genes to removes uracil from uridine - next
create new antigen specificities - stronger, round of replication, random nucleotide
more specific response to antigen inserted - mutations
• Occurs in activated B cells (germinal • Only some mutations increase affinity
centers, spleen) , Low affinity B cells die naturally with
• CD40L on T cell binds to CD40 on B cell - time
cytokines instruct B cell to produce specific , High affinity B cells live on (affinity
type of antibody maturation)
• Activation-induced cytidine deaminase
(AID) turns cytidine into uridine (not usually AFFINITY MATURATION
found in DNA) - mismatch/base excision
• Process by which B cells increase affinity
repair to remove uridine
for antigen during an immune response
O Mismatch repair proteins MSH2, MSH6
• Somatic hypermutation. clonal selection
use nucleases to remove uridine; DNA
(only high affinity cells activated - only
polymerase replaces nucleotides -
high affinity cells replicate)
mutations

SOMATIG HYPERMUTATION AFFINIT~ MATURATION

lowt.rl

AFFINIT'l

STRONC.EST

Figure 45.16 Somatic hypermutation only occurs in B cells which express enzyme AID. AID
makes small mutations directly in antigen binding site of B cell receptor, which get expressed in
daughter cells of a rapidly proliferating cell. These changes in the variable region change affinity
(strength) that B cell receptor has for its antigen. As antigen becomes limited, B cells with lowest
affinity will die off first. so only B cells with strongest affinity for their antigen remain.
18
 T CELL ACTIVATION
osmsJl:/-1:-eell-o.e-livcnion
• Priming: T cell begins differentiation when , Zeta-chain-associated protein kinase 70
exposed to antigen (ZAP-70) phosphorylates LAT, SLP-76
O Two signals: antigen (MHC molecule on ----> activation of transcription factors
antigen-presenting cell), costimulation NF-kB, NFAT----> gene expression of
(CD28 binds to 87 on antigen- cytokines, upregulation of antiapoptotic
presenting cells) cell surface markers
• Signal sent to nucleus by CD3 peptide • Activated T cell-« IL-2----> up-regulates IL-2
chains alpha receptor
O Lymphocyte-specific protein tyrosine • T helper cell binds to IL-2 (autocrine
kinase (LCK) phosphorylates tyrosine stimulation) ----> clonal expansion
residues on immunoreceptor tyrosine
based activation motif (ITAM) units

ANTIGEN-PRESENTING CELL
MHC II with
ANTIGEN
).,
CDS~ Jr_ ..
T CELL---.. ~ jj{-cD2&
R<G<PTCO "-._./{

r0 ~· G
.._.. - ~ B i;,-IL-2 ~ PRODUCES IL-2
~ for CD& T CELLS

\.. IL-2 ~ MAkES & EATS ~ CLONAL

RECEPTOR ITS OWN IL-2 EXPANSION
HELPER T CELL

Figure 45.17 Summary of T cell activation. T cells need two signals to activate: first, presentation
of its antigen by MHC class I (cytotoxic C cells) or class II (helper T cells), and costimulation,
which is when CD28 and 87 bind. In helper T cells, this triggers a series of steps that lead to
upregulation of the IL-2 alpha receptor and production of IL-2 for itself, causing clonal expansion,
and CD8 T cells.

19
 afratafreeh.com exclusive

T CELL DEVELOPMENT
osms.i"l/-l-eell-developmen-l
• Lymphopoiesis: hematopoietic stem cell STAGES OF REARRANGEMENT
- common lymphoid progenitor cell - • Tracked by CD3, CD4, CDS cell surface
immature B cell (bone marrow) markers

Double negative/ON stage

CREATION OF SUITABLE RECEPTOR • Common lymphoid progenitor initially CD3-,
• T cell receptor contains two chains: alpha, CD4-, cos- (double negative/ON stage;
beta broken down into ON 1, DN2, DN3, DN4)
O Alpha: comparable to B cell's light chain
, ON 1 cell expresses RAG 1, RAG2 -
O Beta: comparable to B cell's heavy chain DN2 cell
• Antigen-binding site: V, D, J protein , Beta chain D, J gene segments spliced
segments coded by genes of same name together (allelic exclusion) - DN3 cell
O Beta chain: all three segments , V gene segment combines with DJ
O Alpha chain: V, J segments gene segment by V(D)J recombinase -
V-0-J gene segment bound toµ gene
segment - DN4 cell
T GELL , Functionality of beta chain tested by
REG£PTO" binding to invariant pre-T alpha chain -
if successful, cells proliferate

Double positive/DP stage

• Daughter cells express CD3, CD4, CDS
(double positive/DP stage)

Single positive/SP stage

• Central tolerance: eliminates potentially

~ -, self-reactive cells by positive, negative

ALPHA BETA selection
CHAIN CHAIN , Self-reactive cell elimination failure -
I \ autoimmunity
- V i. ~ SEGMENTS - V: VARIABLE SEC"aMENT
- D: DIVERSITV SEC:aMENT • Positive selection
- ~: J'OINING SEGMENT , T cells recognize/bind to self-MHC
molecules
ALPHA C,HAIN , Binding failure - apoptosis
V,.1 V,.:>. V,.3 V,.10 :r,t :r,:>. :J13 :r,,t
• Negative selection
,:::::JDO···D····D-DD···D- , Autoimmune regulator gene (AIRE):
allows primary lymphoid organs to
express antigens normally found
throughout body; aids in testing self-
reactivity
BETA CHAIN:Vl-1>3-J'S BETACHAIN: V'l'l-l>IO-J'1 , Excessively strong binding to self-
ALPHACHAIN: V7-:J2 ALPHACHAIN: V2-:J3 antigens - apoptosis

Figure 45.18 Structure of T cell receptor.

Different combinations of V, D, and J
segments provide T cell receptors with a
wide variety of antigen specificities.
20
 DN = DOUBLE NEGATIVE C.ELL (C.D3-, cos-. C.Di-)
DP = DOUBLE POSITIVE C.ELL (C.D3+, C.Dll+. C.Di+)
SP = SINGLE POSITIVE C.ELL (C.D3+, C.Dll+/C.D3+, C.Di+)

l _P.AC:a-1
P.AGr-2
8£TA CHAIN
DN:2

1- SPUC£D Di.
S€Gl'\€NTS
s
V.1 v...a V.•
-00-··D····DD··D···DD··D-

V.t V.:l
-00-··D···OCD··D-
Q..t Q.a

'(.111
~
Q.,, J,t :1,2.

~
Q.t Q..2.7,? :r,..
:r,"'

C,Ol'\81Ne: D-J" SEGl'\Ef'ITS

DN3 \. ~ COl'IBINE. V-D-J" SE.G,l'IENTS

V."\Q..2.J",?

DN'i
1 -VDJ" COl'\BINE.D
with CONf, TANT
P.€(:alON
-cxrr-
! C-ONSlAHT
V.,. -i ~J',l lEGWlH
ANTie.EN BINDING, SITE.

ADD CONSTANT REC:,ION

l --t • I

HOMODIMER
r \
INVARIANT
pra-T ALPHA
8£. TA"' \ f'C,D'l
>')

REARRANC.E.
CELL D1V1S10N ALPHA C,HAIN

DN'i \
...-DP C.ELLS
1. POSITIVE SELECTION
:I.. NEGATIVE SELECTION
3. DOWNREGULATION
of CD~/CD&

SP GD4' T GELL SP C,08' T GELL

P£RIPH£RII
?
Figure 45.19 T cell development summary.
21
• DP cells recognize self-MHC but do not
recognize self-antigen presented in MHC
molecule - downregulate either CD4/CDS
receptor - further development into single
positive (SP) cell
O Strong binding to MHC - CD4
downregulated - SP CDS- T cell
O Weak binding to MHC - CDS
downregulated - SP CD4- T cell

VDJ" REARRANGEMENT
osms.i"l/VD:f -Teo.TTo.ngemen-l
• Mechanism used to generate range of B, T HEAVY/BETA CHAIN
eel I receptors REARRANGEMENT
• Antigen-binding sites: V, D, J protein • Recombination signal sequence
segments coded by genes of same name , Heptamer 5'-CACAGTC-3',
O Each cell inherits multiple V, D, J 12, 23 nucleotides, nonamer
segments - randomly recombine - 5'-ACAAAAACC-3'
recombinational inaccuracy, random , DNA loops to bring together two
assortment of two chains (heavy/ recombination signal sequences
beta chain rearranged first) - new , RAGl, RAG2 cut DNA at recombination
specificities signal sequence
• V(D)J rearrangement only affects V region , Recombinases (e.g. ku, artemis)
(creates variability in hypervariable regions) reattach, recombine DNA
• Error-prone process
, Cut end placed onto terminal
H'IP£1tVARIAIL£ lt£610til deoxynucleotide transferase (TdT)
C.OMPLEME.NTAP.IT\I-DET£P.MINING.P.£G.IONS to add random nucleotides - alters
antigen specificity
• Functionality of heavy chain tested -
random assortment of chain

LIGHT CHAIN REARRANGEMENT

• Rearranged into kappa/lambda light chain
(kappa rearranged before lambda)

IC.R TC.It

Figure 45.20 Locations of hypervariable

regions on BCRs and TCRs affected by V(D)J
rearrangement.

22
 1. VD:J REARRANGEMENT oJ BETA/HEAVY CHAIN
RECOMBINATION
SIGNAL SEQUENC.£
v I o

EXTRACHROMOSOMAL
D
t DNACUT t
REATTAC,H

--ar?MIS
i RECOMBINE
CIRCULAR DNA

) --qµ
i NUCLEOTIDES ADDED 'o11 T ar

-1.._ ..~N N NON NN-D-

i DNA is LluATEI>

--c::IIJ-
CK.
BETA i KEAV~
CKAlg
( TGEU 8 CE.LL

a. BINDING TEST S. PAIRED WITH VARIETY

SURl'.OGATE"""\
CHAIN
(p,.-T
ALPHA)
~
,;
SURl'.OGATE""'-
LIG.HT
C.HAIN
(Vp,el)
O • - •
oJ LIGHT/AlPHA CHAINS

t
s. PROLIFERATION ------. 'I. AlPHA/LIGHT CHAIN
REARRANGEMENT
Figure 45.21 Summary of the process by which B and T cell receptors are made.

23
 NOTES

NOTES
CONTRACTION OF THE IMMUNE
• RESPONSE

ANERGY, EXHAUSTION, &

CLONAL DELETION
osms.i"l/ eon-lTo.e-ling-immune-Tes onse
CLONAL ANERGY START of IMMUNE RESPONSE: C,028 > CTLA-'-1
• Functional unresponsiveness to self
antigens
• Lymphocytes can bind to antigens, without
costimulation
• T cells: costimulation involves CD28
binding to 87 on antigen-presenting cells
(A PCs) T CELL
OT regulatory cells reduce 87 expression LATER In IMMUNE RESPONSE: C,TLA-'-1 > C,028
on antigen presenting cells
O Later in immune response, T cells begin
to express cytotoxic T-lymphocyte
associated protein 4 (CTLA-4) - binds
to 87

Figure 46.2 T cells express much more

CTLA-4 later in immune response. 87 binds
to CTLA-4 more strongly than it does to
CD28 and inhibits T cell - T cell inactivation.

CLONALEXHAUSTION
TCELL
• Later in immune response, T cells begin to
express program death 1 (PD-1)
• Program death ligand 1 (PD-Ll) on
antigen-presenting cells bind to PD-1 - T
cells shut down

CLONALDELETION
• Recognition of self antigens - T cell
apoptosis (programmed cell death)
Figure 46.1 T regulatory cells reduce • Later in immune response, T cells express
costimulation by releasing cytokines that Fas
reduce 87 expression on antigen-presenting • Fas ligands on CDS+ T cells. NK cells bind
cells (APCs). to Fas - activate enzymes called caspases
- apoptosis 24
 CD&+
T CELL

Figure 46.3 Clonal deletion. T cells express

Fas----> bind to Fas ligand on CDS+ T cell/NK
cell=- caspases activated-» apoptosis.

8 & T CELL MEMORY

osmsJl:/B-e1nd- T -eell-memoTIJ
• Ability of B, T cells to "remember" particular MEMORY B CELLS
antigen • Only B cells that have undergone class
, B, T cells multiply when receptors detect switching become memory B cells
particular antigen , Memory response limited to peptide
, After immune response mounted, antigens (not lipids/carbohydrates)-
excess cells undergo apoptosis follicular T helper cells needed for
, Memory B. T cells contain same class-switching only respond to peptide
receptors after immune response antigens
• Immunologic memory----> secondary , Memory B cells don't produce lgM/lgD
(anamnestic) response • Live up to 10 years in lymph nodes
, Primary response: naive B. T cells • Often differentiate into lgG-producing
require activation before response to plasma cells when reactivated
pathogen ----> high pathogen burden • Due to somatic hypermutation, lgG created
(response can take days, weeks) late in immune response typically has
, Secondary response: memory B, T higher affinity than lgM created early
cells, antibodies needed to respond to in immune response----> lgG binds to Fe
pathogen already exist-» low pathogen gamma receptor II on lgM-producing B
burden (response occurs right away) cells. prevents differentiation into plasma
cells ----> ! lgM production. j lgG production

25
 PRIMARY IMMUNE RESPONSE
g CELL ACTIVATION & CLASS SWITCHING

STEP t ANTIGEN BINDS

~o.

FOLLICULAR • •
DENDRITIC ~
CELL • **
\** • •(
11,. STIMUATORY CYTOKINES *
RELEASED

STEP~

STEPS
(Q\
~-l9G

. J
3e. MEMORY g CELL

.~~~ .
SWITCHING ~

Figure 46.4 B cells are activated through interactions with other immune cells. Step la: follicular
dendritic cell traps antigens and lb: sends out stimulatory cytokines. Step 2: the B cell presents
the antigen to a follicular T helper cell. Step 3a: the follicular T helper cell expresses CD40L on its
surface and produces IL-21. 3b: together, they induce the B cell to undergo class switching (shift
from expressing a B cell receptor with lgM and lgD to expressing lgG, lgE, or lgA. 3c: some of
these B cells become memory B cells.

26
 PRIMARY IMMUNE RESPONSE
START---------------- END
l9M 1:,6
y
LOWER
y HIGHER
AFFINITY AFFINITY
Fi. GiAMMA
RE.CE.PTOR II
~

NEWLYACTIVATED MEMORY B CELL

B CELL

t
-~~~/*'
(;] ... ft
•:!.'.,;:~.
'.::)
_,
~~
©'·'

PLASMACELL

LOW AFFINITY lgM HIGH AFFINITY lgG

PRODUCTION HAlTEO PRODUCTION PROMOTED
Figure 46.5 Process by which higher affinity lgG production is favored over lower affinity lgM
production. Memory B cells differentiate into high affinity lgG-producing plasma cells. lgG binds
to Fe gamma receptor II on newly activated B cells, which produce low affinity lgM. This prevents
them from differentiating into low affinity lgM-producing plasma cells, allowing the proportion of
high affinity lgG in the response to be greater.

MEMORY T CELLS cytotoxic cells, binding to, destroying target

• Cell surface ligand CD45 used to identify T cells)
cells • IL-7 receptors replaced with IL-2 receptors
O Naive T cells express CD45A during activation ----> cells die shortly after
O Memory T cells express CD450 immune response

Effector memory T cells Central memory T cells

• Move around body looking for pathogens • Live up to 25 years
• Respond as primary response (for CD4+ • Remain in lymphoid tissues
helper cells, secreting cytokines: for CDS+ • High levels of IL-7 receptors maintained---->
cells live on after immune response
27
 EFFECTOR MEMORY T C.E\.\.S
CD'l· HE.LP£R
T CE.LL

{C.VTOKINE.S
TMVE.L IN 2. OUT o o o o ------'!I. SUPPORT OTHER
of TISSUES o0 o ~ IMMUNE CELLS

MEMORY T C.E\.\.S ___/ coa· <VTOTO~<

~ TC.ELL
IL-1

~
~Cl BIND & DESTROY
~ TARGETCELLS

e RE.MAIN IN
LVMPHOID
TISSUE )

Figure 46.6 The two types of memory T cells (effector memory T cells and central memory T
cells) and their functions.
NEW EFFECTOR
T CELLS

CONTRACTING THE IMMUNE

RESPONSE
osmsJl/con-lTo.c-ling-immune-Tesponse
• Immune response termination B CELLS
• Peripheral tolerance to self antigens limits • Similar mechanisms to T cells
immune response (preventing autoimmune • Later in immune response, reduced
disease) presence of antigens, T cells prevent B cell
• Mechanisms directed primarily at T cells; activation - anergy
includes use of T regulatory cells, clonal • Surplus lgG binds to Fcyr II on B cells -
anergy, exhaustion, deletion prevent differentiation into plasma cells

T REGULATORYCELLS
• Inhibit antigen-presenting cells by releasing
specific molecules (e.g. indoleamine 2,3
dioxygenase)
• Release cytokines (e.g. IL-10, TGF-beta) -
antigen-presenting cells express inhibitory
ligand (e.g. PD-Ll)
• Express high levels of IL-2. adenosine
receptors (competing with other T cells)

28
NOTES

NOTES
• INNATE IMMUNITY

INNATE IMMUNE SYSTEM

osms.i"l/inno.-le-immune-s14ste m
• Comprises immune system along with • Phagocyte kills pathogen (post-
adaptive immunity identification)
• Includes barriers to repel pathogens , Phagosome binds with lysosome, forms
° Chemical barriers: lysozyme (tears), low phagolysosome
stomach pH , Specific phagolysosome granules
O Physical barriers: epithelium (skin/gut), (proteases, hydrolases) kill internal
cilia lining airways microorganisms while decreasing pH
, Azurophilic granules (hydrolases,
Key features oxidative enzymes) activate in acidic
• Nonspecific cells do not distinguish environment - more microorganisms
invaders killed
• Response occurs within minutes-hours , Nicotinamide adenine dinucleotide
• No memory phosphate (NADPH) oxidases oxidize
O Always responds to pathogen in same oxygen molecules - superoxide ion
manner creation
, Superoxide dismutase converts
Human microbiome superoxide into hydrogen peroxide,
• Included in innate immunity killing remaining microorganisms
• Bacteria, fungi, viruses in/on humans
Signalling PRRs response to pathogens
• May affect host response in own way
• Large amount of pathogens enter -
signalling pattern recognition receptors also
RESPONSE TO PATHOGENS activated
• Signalling PRRs - phagocytes to release
Phagocyte response to pathogens
cytokines
• Phagocytes eat, kill pathogens
• Toll-like receptors (TLRs) especially
• Phagocyte consumes pathogen important in signalling PRRs
O Phagocytic pattern recognition , PAMP activation - TLRs activate
receptors (PRRs) on phagocyte identify transcription factor NF-'KB -
pathogen-associated molecular patterns proinflammatory cytokines (e.g. TN Fa,
(PAMPs) on pathogens (e.g. bacterial- IL-1~. IL-6) secreted - vasodilation,
wall components) fever, recruiting leukocytes
O Phagocyte swallows pathogen, traps it , Intracellular pathogens: interferon
in phagosome alpha, beta may be secreted (prevents
pathogen multiplication)

29
 ····:: .
3o.. 3\,.
PHAGOLVSOSOME
(phogosome + l11sosome) .....
•;:.•...,.. . ..···-·.
•••••••
• • • ·-:.1 • ...... ,8.

·"':~··
SPECIFIC AZUROPHILIC
GRANULES GRANULES

"I. SUPER.OXIDE
NADPH SUPER.OXIDE DISMUTASE
OXIDASE ~~~
~~ ~
~ ~ -+ @+fob
elacfron ~ ~ HYDROGEN
~ @B) PEROXIDE

Figure 47.1 Overview of the phagocyte response to pathogens.

1. The phagocyte's pattern recognition receptors (PRRs) identify pathogen-associated molecular
patterns (PAMPs) on the pathogen.
2. The pathogen is phagocytosed and trapped in a phagosome, which then
3. binds with lysosomes, forming a phagolysosome.
3a. Specific granules from the lysosomes act first to kill pathogens and decrease pH.
3b. After the pH is sufficiently lowered, azurophilic granules are activated and kill more
pathogens.
4. NADPH oxidases oxidize oxygen molecules to create superoxide ions. The ions are then
converted by superoxide dismutase into hydrogen peroxide, which kill the remaining pathogens.

30
 COMPLEMENT SYSTEM
osmsJl/ eomplemen-l-s14s-lem
• Collection of plasma proteins called , Clr cleaves Cls (activating Cl
complement proteins molecule) - Cl cleaves C4 into C4a,
• Produced in liver, collectively destroy C4b - C4b binds to pathogen
pathogens , Cl also cleaves C2 into C2a, C2b -
C2a joins C4b on pathogen - C4b2a
(C3 convertase) formed
COMPLEMENT SYSTEM PATHWAYS
, C3 convertase cleaves C3 into C3a, C3b
• Acts fol low one of three pathways
, C3b binds to pathogen near C4b2a/
° Classical, alternative, lectin
C3 convertase, creates C5 convertase
Classical pathway (C4b2a3b)
• Features Cl-C9 proteins , C5 convertase cleaves C5 into C5a, C5b
• Cl , C5b binds to C6, C7, CS, many C9s -
forms membrane attack complex (MAC)
° Component proteins Clq, Clr, Cls
- penetrates pathogen cell membrane
(latter two-serine proteases)
• Cl consists of six Clq proteins
, Binds to six antibody-antigen
complexes
C.t PROTEIN
• Calcium ties together Cl
, Lack of calcium - lack of Cl

Alternative pathway
• Factor B, factor D proteins
• C3 cleaved spontaneously (small amounts)
C1Tl SERINE
Cts J PROTEASES • Pathway steps
, C3b binds to pathogen - factor B binds

r
le.=,"
-cr-:
to pathogen
, Factor D cleaves factor B - forms Ba,
Bb - C3bBb formed (C3 convertase)
, Follows classical pathway
• Constant activation prevention
Figure 47.2 Structure of a Cl protein. , Cl-inhibitor protein dissociates C3bBb
Each of the six Clq proteins can bind to an
antibody-antigen complex. Calcium ties the Lectin pathway
protein together. • Features mannose-binding lectin protein
(binds to bacterial man nose)
• Pathway steps
• Proteins inactive until "cleaved" (portion of
, Mannose-binding lectin protein
protein breaks off)
acts similar to Cl - cleaves C4, C2
• Pathway steps to eventually establish C4b2a (C3
° Clq proteins bind to Fe portion of convertase)
antibody when bound to antigen , Follows classical pathway
O Two Clq proteins bind - Cl changes
shapes (conformational change)
exposing Clr, Cls

31
 PATHOGEN Gl.ASSIGAI.. PATHWAY

... :( ):
OlbA,,~C'-a
(,%:la
= CS CONVERTASE s. I
I
'
\ ,'""'- C3
CONVERTASE
C.! rc3~
l_c3a

,. 11
~ C3b
I

'\,\,--,:,'·---'
'\i\---"
C,%:).a3b
= CS CONVERTASE

!II 11
To I
cs_/,~. .
CONVERTASE ... D
~
j C.S

I
(
\: -- . . _1 _ - .,
MEMBRANE ATTACI( C.OMP\.EX
(MAC.)

Figure 47.3 Overview of the classical complement pathway.

1. Clq binds to an antibody-antigen complex.
2. When two Clq proteins are bound, Cl undergoes a conformational change, exposing Clr
and Cls. Clr then cleaves Cls to activate Cl.
3. Cl cleaves C4 and C2.
4. C4 and C2 bind to the surface of the pathogen, forming C3 convertase.
5. C3 convertase cleaves C3.
6. C3b binds to the pathogen near the C3 convertase, forming C5 convertase.
7. C5 convertase cleaves C5.
8. C5b joins C6, C7, CS, and then multiple C9s to form the membrane attack complex,
penetrating the pathogen cell membrane.

32
 AlTERNATIVE PATHWAY lEC.TIN PATHWAY

C,3\,

C,3\, a ~~ 's
• FACTORB - •
/)i.
C3o.
FACTOR D

Figure 47.5 Overview of the lectin pathway.

Mannose-binding lectin protein binds to
mannose on the pathogen, then cleaves
C4 and C2. The rest follows the classical

D pathway (from step 4 in earlier figure).

C,3\, Bb

OTHER COMPLEMENT PROTEIN

S. ~C.1- INHIBITOR
ROLES
• In addition to MAC-formation
Figure 47.4 Overview of the alternative
complement pathway. 1. Small amounts of , C3b: opsonin - opsonizes pathogens,
coats them with molecules, encourages
C3 are cleaved spontaneously. 2. C3b and
factor B bind to the pathogen. 3. Factor D phagocytosis
cleaves factor B. 4. C3b and Bb form a C3 , C5a, C3a: chemotaxins - recruit
convertase and cleave more C3 proteins. neutrophils, eosinophils, monocytes,
The rest follows the classical pathway (from macrophages
step 6 in previous figure). 5. Cl-inhibitor , C5a, C3a: anaphylatoxins - cause
constantly prevents activation of this basophil, mast cell degranulation,
pathway by dissociating C3bBb. releases proinflammatory molecules

C,$\, C.SCl C.!Cl

0 =OPSONIN
pho.goe11te
CJ (l = C.HEMOTAXINS & ANAPHYLATOXINS
)_ @) ~
@
e neuhophlls eoslnophlls (: bo.sophils
pToinflo.mmo.toT'I
1noleeules

©
monoe11tes
~
1no.eTopho.ges
(Q)
1110.rt cells

Figure 47.6 Other roles of complement proteins. C3b acts as an opsonin; it coats pathogens to
facilitate phagocytosis. C5a and C3a act as chemotaxins; they recruit neutrophils, eosinophils,
monocytes, and macrophages. C5a and C3a also act as anaphylatoxins; they cause basophils
and mast cells to degranulate.

33