Immunoreactivity and Immunotolerance

DEPARTMENT OF
PHYSIOLOGY
Saturday, December 5, 2020 1
Presenter:
Dr. Aishee Pal
Junior Resident (Acad)
Moderator:
Dr. Nasreen Akhtar
How we avoid attack on
our own cells and
tissues?

Overview
• Introduction
• Overview of Adaptive Immune System
• Major Histocompatibility Complex
• T and B cells: Types, Receptor, Structure, Activation
• Immunological Synapse
• Antigen Presenting Cells (APCs) and Dendritic Cells (DCs)
• Immunotolerance : Overview
• Central and Peripheral Tolerance: Mechanisms
• Applied Aspects
• Summary

A Historical Perspective of Immunology
Saturday, 05 December 2020 3
In
, the great historian of the PeloponnesianWar
college.columbia.edu
TIMELINE SCIENTIST RESEARCH FIELD
430 BC Thucydides • Described a plague in Athens
• Those who had recovered from the plague could nurse the sick
because they would not contract the disease a second time.
In 15th
Century
Chinese and Turks
1718 Lady Mary Wortley
Montagu
• Observed POSITIVE effects of variolation on the native Turkish
population and had performed the technique on her own
children.
1798 Edward Jenner
Father of Immunology
• Observed milkmaids not contracting smallpox infection apparently as
they were exposed to a similar form of disease-cowpox.
• He inoculated Master Phillips with fluid from cowpox pustule
later infected intestinally with small pox NO SMALL POX

1890: Emil von Behring and Shibasaburo Kitasato
• Nobel Prize in Physiology or Medicine in 1901 for giving first insights into the mechanism of
immunity)
• Tetanus antitoxin

1930: Elvin Kabat
Because immunity is mediated by antibodies
contained in body fluids (known at that time as humors),
called as humoral immunity
Merrill Chase
• 1940: Transferred immunity against - WBC from immune guinea pigs
• 1950s - lymphocyte - cellular and humoral immunity
Bruce Glick
• Using chickens - two types of lymphocytes
• T lymphocytes - thymus - cellular immunity
• B lymphocytes - bursa of Fabricius - humoral immunity

Early theories to explain specificity of Antigen-Antibody interaction
Selective theory Instructional theory
• Given by Paul Ehrlich in
1900
• Cells in blood expressed
receptors:“side-chain
receptors”
• React and bind with infectious
agents: “lock and key
mechanism”
• Induce cell to produce and
release more similar
receptors
• Specificity of Receptor-
Predetermined
• Antigen select the appropriate
Receptor
• Given by Friedrich Breinl and Felix
Haurowitz
(1930s and 1940s)
• A particular antigen - template
• Antibody would fold around template - assume
complementary configuration
Redefined by Niels Jerne, David
Talmadge, F. Macfarlane Burnet:
The clonal selection
theory

The clonal selection theory-underlying
paradigm of modern immunology
Antigen interacting with a receptor on a
lymphocyte
Division and Differentiation of that
lymphocyte
Formation of
clone of
identical
daughter cells
bearing the same
receptor as the
stimulated cell
Immature stage of cloned B cells meeting
antigen during development are eliminated
Antibodies produced by
B cells stimulated by
clonal selection will share
the
antigen-binding site with
the membrane receptor of
the stimulated cell
Representatives of the stimulated clones remain
in the host as “immunological memory”
Antigen Elimination
Kuby et al, Immunology, 7th ED

Macfarlane Burnet
1. HSC
2. Immature lymphocytes with Ag receptors
3. Those that bind to self Ag - destroyed
4. Rest mature to inactive lymphocytes
5. Encounter foreign antigen- activated
6. Produce many clones of themselves
The Clonal Selection Theory
Hypothesis

DEFINITIONS
• Immunoreactivity:
Immune reaction caused by an antigen
• Immunotolerance:
It is the phenomenon of indifference or non-reactivity or unresponsiveness towards a
substance/antigen that would normally be expected to elicit an immunological response
induced by exposure of lymphocytes to that antigen.
Kuby, Immunology, 8th Ed, 2019
Robbins, Pathologic Basis of Disease, 10th Ed, 2020

Overview of Adaptive Immune System
Saturday, December 5, 2020
12
T cell TCR Ag
B cell
BCR

Types of Receptor Binding
 The ratio of the time spent in the “on” versus the “off” state determines:
• AFFINITY of the receptor-ligand interaction
• AVIDITY - the strength of the noncovalent binding between receptor and ligand
 Antigen recognition by T cells is qualitatively different from that of B cells
MONOVALENT
BINDING
T cell Receptor
BIVALENT BINDING
B Cell Receptor

T cells: Types, Functions and Secretions
Th1 • Promotes production of opsonizing antibodies (IgG),
cytotoxic T cell development and delayed-type
hypersensitivity (DTH)
• Transcription Factor: T-Bet positive
IFN-gamma
IL-2
Th2 • Stimulate eosinophil development via IL-5
• Mediate immunity against parasitic infestations AND Chronic
eosinophilic inflammation via IgE
• Transcription Factor: GATA-3 positive
IL-4, IL-5, IL-13, and IL-10
Th9 • Antitumor immunity, allergy, and autoimmune disease IL-9 and IL-10
Follicular
Helper T
cell
• Recruits neutrophils: early involvement against extracellular
pathogens
• Chronic inflammatory responses in chronic infection, allergy,
autoimmunity
IL-17A: induces production of
proinflammatory cytokines &
chemokines
Treg cell • Establishment and maintenance of peripheral tolerance
suppressing (Negative Selection Process) the immune
response
• Transcription Factor: FOX-P3 positive
IL-12, IL-23, CD-4/45/
FOX-P3, TGF-beta
Cytotoxic
T cell
• Kills infected cells by damaging the target cells or inhibiting
microbial replication
T cell/target cell adhesion
molecule interactions
(eg: CD2 with CD58,
CD11a/CD18 with CD54CD54Saturday, December 5, 2020 14
CD4/
MHC II
CD8/
MHC I

Function of B and T cells
Robbins, Pathologic Basis of Disease, 10th Ed

Major Histocompatibilty Complex
• Tightly linked cluster of genes in chromosome 6p
16Saturday, 05 December 2020
GENES Associated:
• Class I: (HLA A, B, C)
• Class II:(HLA DQ, DR,
DP)
• Class III :Complement
system: C4, C2, and Bf
• Class IV : Tumor
Necrosis Factor (TNF)-
α and β, genes like
B144, AIF1, and the
MIC family.
MHC Class I MHC Class II
Source of Antigen Intracellular Extracellular
pathogens
Antigen Binding Groove Closed Open
Degraded in Cytosol Endocytic vesicles
Expression All nucleated cells Professional APCs
Antigen Presented to CD8 T cells CD4 T cells
Effect Cell death Pathogen is killed

T Cell Receptor : Structure
• (TCR) alpha-beta (TCR2) or gamma-delta (TCR1) heterodimer.
• αβ TCR: recognizes peptide antigens that are presented by MHC
molecules on the surfaces of APCs.
• γδ TCR: recognizes peptides, lipids, and small molecules, without
presentation to MHC proteins.
• The α and β chains of TCR lack cytoplasmic extensions, thus
communicate with the interior of the cell through a single-span
transmembrane, CD3 family
• TCR-CD3 Complex: Initiates signal transduction by
Phosphorylation of ITAM motifs and regulation of catalytic activity
via protein tyrosine kinases: Lck and ZAP-70Chromosomal location of TCR chains
Alpha, Delta 14q11
Beta 7q35
Gamma 7p15
Immuno-receptor Tyrosine Activation Motif

T cell Receptor Activation: The three-signal model of T cell
activation
18
Antigen binds weakly to TCR
SIGNAL 1: ALLORECOGNITION
TCR-CD3-Peptide-MHC complex activated by
phosphorylation of ITAMs and Lck protein on
APC
CD4/CD8 coreceptors on T cells
binds to MHC class II/I on APCs
SIGNAL 2: COSTIMULATION
CD28 co-receptor provides another signal
upon binding to costimulatory molecules
CD80 (B7-1)/CD86 (B7-2)
Sayegh et al, N Engl J Med 1998; 338:1813-1821
Kuby et al, Immunology, 8th Ed
SIGNAL 3: CYTOKINE
SIGNALING
Autocrine and Paracrine
Stimulation

Leiden JM et al, Annual Rev Immunol 1993; 11:539
Organization of human TCR Gene locus: V(D)J
recombination
TCR chain is encoded by multiple rearranging gene segments:
Alpha locus: Three gene clusters:
49 V; 61 J; 1 C
Beta locus: Four gene clusters:
75 V; 2 D; 2 C; 6 Jβ1; 7 Jβ2
V (variable); J (joining) ; C (constant); D (Diversity)
• TCR genes undergo recombination of the V,D,J genes
called V(D)J recombination.
• This event is dependent upon the function of recombinase-
activating genes 1 and 2 (RAG1 and RAG2)

AP
C
T-
Cell
MHCICAM-1/3
or CD54
LFA-1
TCR
CD4/8
B7-1/B7-2
or CD80/86
CD28
Processed antigen
ICAM : Intercellular adhesion molecule
LFA : Lymphocyte function associated antigen 1
Immunological synapse/Steps of antigen presentation
Adhesion

Functions of Different APC

Dendritic cells
• Dendritic cells (DCs) : "professional" APCs
• Most Important APC: located at the
MOST COMMON SITE to capture
antigens
• Development of immature DCs: Pattern
recognition receptors, such as "Toll-like"
receptors (TLRs), lectins
• APCs constitutively express high level of
MHC molecules class I/ II molecules
• Types: 1. Plasmacytoid
2. Conventional
3. Follicular
Patente TA at al, 2019, Front. Immunol. 9:3176

Differentiation of Dendritic cells
2
5
HSC:Hematopoietic Stem Cell; MP:Myeloid Precursors; LP:Lymphoid Precursors; MDP:Macrophage-
DCprecursors; CDP:Common DC precursors; pre-Cdc:pre-classical dendritic cells; FLT3, Fms-Related
Tyrosine Kinase 3.
pDC, plasmacytoid dendritic cells; cDCs, conventional dendritic cells; Patente TA at al, (2019). Front. Immunol.
9:3176

Functions of Dendritic cells
antigens are presented to T-cells
without the activating co-stimulatory
signals
Development
into Treg cells
AnergyT cell
apoptosis
2. Immature DC : An essential role In the
induction and maintenance of immuno tolerance:
“Tolerogenic DC” express:
1.LESS co-stimulatory
molecules &
proinflammatory cytokines
2. UPREGULATE the
expression of inhibitory
molecules (PD-1 & CTLA-
4)
3. SECRETE
anti-inflammatory
cytokines (IL-10)
1. Critical for the initiation of the immune response: Processing and presenting antigen to T cells by several
means like:
a. engulfment by phagocytosis,
b. internalization by receptor-mediated endocytosis, or
c. imbibition by pinocytosis

Types of Dendritic cells
Plasmacytoid
DCs
Conventional DCs Follicular DCs
anti-tumor and anti-
virus immunity
• Potent inducers of regulatory T cells in
intestine
• Maintaining tolerance in the liver
• Produce retinoic acid upon stimulation with
vitamin D3,
Stimulating CD4+ naïve T cells to express
gut-homing molecules and Th2 cytokines
• Fc receptors for IgG
and C3b receptors
• Presenting antigens to
B cells in the germinal
center
• They play a role in
humoral immune
responses
Kuby et al, Immunology, 8th Ed,2019

B Cell Receptor: Structure
Constituents:
• A heterodimer : 2 invariant
proteins, Igα (CD79a) and Igβ
(CD79b)
• CD40: Receives signals from Th
cells.
• Complement receptor: CR2/
CD21
• Signal
transduction
in response
to antigen
recognition,
• Generate
innate
immunity.
• CR2 is also used by EBV as a receptor to enter, infect B
cells.
• Development of B cell memory
Abbas et al, Cellular and Molecular Immunology, 9th Ed, 2017

B Cell Receptor: Activation
IgM/IgD: Transmit
signals
Phosphorylation of tyrosine residues in ITAMs motifs
Facilitated by LYN-Src kinase protein
CD21, co-receptor
associated with CD19,
binds to the complement
molecule: C3d
Antigen binds weakly to
BCR
Immuno-receptor Tyrosine Activation Motif ; TAPA-1 (Target of the Antiproliferative
Antibody 1)
Facilitates signal transduction CD19 along with
CD81/TAPA-1
Annu Rev Immunol. 2014;32:283-321
Saturday, October 31, 2020

IMMUNOLOGICAL TOLERANCE
• Self-tolerance refers to lack of
responsiveness to an individual’s
own antigens, and it underlies our
ability to live in harmony with our
cells and tissues
Protection from
infections
Prevention of
excess activation
Immunity
Lymphocytes
APC
Central and
Peripheral
tolerance
Robbins, Pathologic Basis of Disease, 10th Ed, 2020

FACTORS DETERMINIG IMMUNOGENICITY AND TOLEROGENICITY OF
ANTIGEN
Factors Stimulation of Immune
Response
Induces Tolerance
Time of exposure Short lived (Eliminated by Immune
Response)
Prolonged exposure
Route of exposure Subcutaneous, Intradermal Intravenous, mucosal
Structural
characteristics of
allergen and antigen
Antigens with ADJUVANTS;
Stimulates Th cells
Antigens without ADJUVANTS;
Non-Immunogenic/Tolerogenic
Co-exposure with
stimulators
Low Level of costimulators High Level of costimulators
Saturday, December 5, 2020 31Kuby et al, Immunology, 8th Ed, 2019

Overview of Tolerance
Saturday, December 5, 2020 32Male D, Textbook of immunology , 8th ED
Types Central Tolerance Peripheral
Tolerance
Site Primary or Central lymphoid organs
eg THYMUS or BONE MARROW
Peripheral refers to the
secondary or peripheral
lymphoid organs
Cells Involved During development of T and B
lymphocytes
Induced in mature
lymphocytes
Process Involves Immature self-reactive T and B
lymphocyte clones recognizing self
antigens are killed/rendered
harmless
Prevent auto-reactive
mature lymphocytes from
attacking self antigen

IMMUNOLOGICAL TOLERANCE
CENTRAL TOLERANCE
PERIPHERAL TOLERANCE
T cells
1. Receptor Editing
by V(D)J
Recombination
2. Negative
selection or
clonal deletion
B cells
1. Negative
selection or
clonal
deletion
2. Clonal Arrest
3. Clonal Anergy
4. Clonal editing
5. Development
of Treg cells.
B cells
1. Anergy
2. Suppressio
n by Treg
cells
3. Deletion by
Apoptosis
1. Anergy:
2. B cell
Intrinsic
Mechanisms
T cells

Central T Cell Tolerance
Kuby, Immunology, 8th Ed, 2019; Robbins, Pathologic Basis of Disease, 10th Ed, 2020

Central tolerance in Thymus
Role of Positive & Negative selection
Male D, Textbook of immunology , 8th ED
Negative Selection of
cTEC

36
Role of AIRE (AUTOIMMUNE RESPONSE ELEMENT) in
mTECs
mTECs: Medullary Thymic Epithelial Cells
Kuby, Immunology, 8th Ed, 2019;

AIRE (AUTOIMMUNE RESPONSE
ELEMENT)
• AIRE encoded on: Chrom 21; region 22q.3, Autosomal Recessive
• Location: Medullary Cortical Thymic Epithelial Cells (mTECs)
• Component of multiple protein complex that
binds to chromatin and regulate the process
of gene transcription
• AIRE comprises (From the N-terminus
moving to the C-terminus ):-
1. CARD : Caspase-Activation and
Recruitment Domain
2. NLS : Nuclear Localization Signal
3. SAND
4. PHD1 and PHD2: 2 zinc fingers Plant-
Homeodomains.
5. PRR : proline-rich region
Schematic representation of human autoimmune regulator
(AIRE).
Perniola R (2018) Twenty Years of AIRE. Front. Immunol. 9:98.

.
Functions of AIRE
• Acts as transcriptional regulator, promoting expression of selected tissue-restricted antigen in thymus by
Translation and Chromatin Packing
• Embodies the essence of thymic self-representation
• Promiscus Gene Expression:
Allows mTECs to express proteins not ordinarily found in the thymus
present them using MHC molecules Promotes Self Tolerance
• Formation of scaffold-like meshwork of the intermediate filaments or microtubules
• CARD domain: Homomerization into oligomers, binding to specific oligonucleotide motifs.
• SAND region: Anchorage to heterologous proteins (DNA phosphate group binding)
• CARD, NLS, and SAND domain: Lysine residues, sites of acetylation, key for protein localization
• PHD fingers: 4 cysteine, 1 histidine, 3 Cysteine residue motifs, coordinates two zinc ions.
“Read” the chromatin marks, Degree of methylation at the tail of histone H3.
Perniola R (2018) Twenty Years of AIRE. Front. Immunol. 9:98.

Role of Dwell time in T cell selection
Alpha CPM : α-chain
connecting peptide motif
LCK : lymphocyte-specific
protein tyrosine kinase
ITAM : Immune-receptor-
Tyrosine-based-Activation-
Motif
Palmer et al, Nature Reviews Immunology 2009; 207-213

Mechanism of Central B cell Tolerance: Receptor editing
A process whereby ongoing antibody gene recombination promotes a change in the
specificity or expression of the antigen receptor of a B cell..
V CD JVV V
BB
Receptor
recognises
self antigen
B Apoptosis
or anergy
BB
Edited receptor now recognises
a different antigen and can be
rechecked for specificity
CD JVV VV
Arrest development of immature B cells:
And reactivate Recombinase Activated Genes:
RAG-1 and RAG-2
Saturday, December 5, 2020 40Nat Rev Immunol. 2017 May ; 17(5): 281–294

1. Allelic exclusion promoting Genetic diversity
2. Assembles genes that encode potentially autoreactive antibodies
Central tolerance as a barrier to immunity
• Hinder immune reactions to foreign antigens to which reactivity might be desirable, such as vaccines.
Against HIV
• Neutralizing HIV antigen by IMMUNOTOLERANCE
Nat Rev Immunol. 2017 May ; 17(5): 281–294
UTILITY OF V(D)J COMBINATION

Other Mechanism of Central B cell Tolerance

T regulatory –cells (Treg)
• Approximately 10% of all CD4
• CD25+ CD4+ cells
• Expressions on Treg Cells:
1. Express FOXP3, a transcription factor: For
development and function
2. CD28 expressed on resting- T cells,
CTLA-4 expressed on T-cell surface after initial
TCR activation
3. High levels of IL-2 receptor alpha chain
(CD25)
Kuby J et al, Textbook of Immunology, 8th Ed, 2019
Hypothesis for generation of Treg cells:
Thymic / Natural Treg
cells
(nTreg)
Peripheral / adaptive / inducible
(iTreg)
specific for self-peptides required for environmental
antigen/ allergen specific T cells

Regulatory T Cells (Treg)
Nature Reviews Immunology, Volume 8, July 2008
Male D, Textbook of immunology , 8th ED, 2013
Functions:
• Suppresses Immune responses against pathogens, allergens, tumors, and allografts :
Peripheral Immunotolerance
• Protect fetus (semi-allografts): during pregnancy from immune rejection
Pivotal role in prevention of:
• autoimmune diseases like type 1 diabetes,
• chronic inflammatory diseases such as asthma and inflammatory bowel disease (IBD)
• Loss of function of Treg Cells: severe autoimmune inflammation in patients: IPEX Syndrome
(immunodysregulation, polyendocrinopathy, enteropathy, X-linked)

Inactivation of Traditional T cells by Treg cells
TGF beta : Transforming growth factor beta
CTLA : Cytotoxic T cell lymphocyte associated protein
LAG : Lymphocyte-Activation gene
IDO : Indoleamine 2,3-dioxygenase
Vignali et al, Nature, 2008; 523-532
FOXP3
FOXP3
FOXP3
FOXP3
FOXP3

Mechanisms of Peripheral tolerance

1. Antigen sequestration
• Sequestered away from immunological system by physical and immunological barriers
• Breach in barrier elicits brisk response
– Sympathetic ophthalmia
– Formation of anti-sperm antibodies following vasectomy
Saturday, December 5, 2020 49Male D, Textbook of immunology , 8th Ed, 2013

2. ANERGY MODEL
Saturday,December5,2020
50
T cells that cannot be completely activated upon recognition of their cognate antigen are called anergic

Molecular Basis of Anergy Model
• Receptors suppressing T cell Activation Signal: CTLA-4,
PD-1
• Transcription factors mediating anergy signals: NFAT1
,p27kip1, Tob
Mechanism:
• Suppression of IL-2 gene expression: Signal Block
• Lack of Co-stimulation
TCR-CD3-
Antigen-MHC
Complex
Kuby J et al, Textbook of Immunology, 8th Ed, 2019

CTLA-4 (Cytotoxic T-Lymphocyte-Associated Antigen 4 )
Molecular Basis
IDO
End products of degraded tryptophan:
act directly on T-cells
IDO : Indoleamine 2,3-dioxygenase
• CTLA4 is a high affinity ligand for the costimulatory molecules CD80 and CD86
• Binds to B7-1/CD80 or B7-2/CD86 costimulatory molecules on APCs
• Critical Negative regulator of adaptive immune responses : Terminates T-cell
responses
APC
Treg
Molecular Basis of CTLA-4
Upregulation of IDO Catabolize tryptophan
Suppression of IL-2 gene expression
● Genetically engineered mice with deleted
CTLA4 :
Autoimmunity due to uncontrolled lymphocyte
activation with massive lymph node enlargement
● Polymorphism in CTLA-4 gene :
type 1 diabetes and Graves' disease
THERAPEUTIC APPLICATION
• Blocking CTLA-4 --> increased immune responses to
tumour
• Anti-CTLA-4 antibody(Cyclosporine, Tacrolimus,
Daclizumab, Basiliximab): approved for advance
melanomas
Schwartz JC et al, Nature. 2001;410(6828):604;Radvanyi LG et al, J Immunol. 1996;156(5):1788.

PD-1 (Programmed cell death 1)
• Site of Action: Peripheral tissues
• Cellular Expression: Activated T cell
• Cells inhibited: CD8+ > CD4
• Molecular Signals: Inhibits kinase-dependent signals from CD28 and TCR (by recruiting and
activating phosphatase following binding to its ligands PDL-1 or PDL-2)
Recognises 2 ligands
1. PD-L1 : expressed on APCs and many other tissue
cells
2. PD-L2 : expressed mainly on APCs
Engagement with ligand
Inactivation of T cells
Abbas et al, Cellular and Molecular Immunology, 9th Ed

3. Mechanism of Immune Suppression by Regulatory T cells
Regulatory T Cells Suppressor Mechanisms
Tr1, IL-10-induced IL-10, TGF-B, CTLA4, PDCD1
Th3 TGF-B, IL-10
CD4,CD25 (Negative)
Membrane TGF-B, CTLA4, PDCD1,GITR, IL-10
CD8,CD25,CD28 (Positive)
CD4 CD8 (Negative) Induction OF apoptosis
Γδ TCR IL-10, TGF-B
Inhibit lymphocyte activation
and effector functions
Regulatory T cells suppress
immune mechanism via
suppressor mechanism
Kuby J et al, Textbook of Immunology, 8th ED, 2018

4. Activation Induced Cell Death (AICD) of T-cells
Activated T-cell express both:
• Fas(CD95): member of the TNF-receptor family and,
• FasL: membrane protein structurally homologous to
cytokine TNF
Death of excessively activated lymphocyte thus,
maintains lymphocyte homeostasis throughout life.
Male D, Textbook of immunology , Eighth edition , 2013
• Express a pro-apoptotic PROTEIN: Bim
• Absence of antiapoptotic expression: Bcl-2 and Bcl-x Unopposed Bim triggers
apoptosis by the p38MAPK-dependent mitochondria pathway

1. Anergy: Internalisation of the BCR via reduced
expression of receptors for the cytokine B-cell
activating factor (BAFF)
2. B cell Intrinsic Mechanism: Dependence on T cell
help for high affinity isotype switched antibody
production

Clinical Aspects of
Immunoreactivity and Immunotolerance

Immunological tolerance in Pregnancy
Saturday, December 5, 2020 59Guleria et al, J Immunol.2007; 178:3345-3351
IMMUNE PRIVILEDGE : FETUS
• Express MHC derived from both parents
• Peripheral tolerance of mother to fetus --> fetal survival
• Expression of FasL and FOXP3 transcription factor at fetal-maternal interface:
• clonal deletion of immune cells that recognize paternal Ags
• Cells of villous trophoblast lack expression of MHC class I, Downregulation of MHC-I molecules, HLA-A
& HLA-B
• Increase expression of inhibitory non-classical MHC molecule: HLA Ib genes, HLA-E, HLA-F, and HLA-
G
• Binds to inhibitory immune cell surface receptors: IL-4
• HLA-G inhibits Cytotoxic T cell responses Regulatory T-cells
• CD8+ T cell apoptosis induced by soluble HLA-G through the Fas/FasL pathway
• Interaction of HLA-G with KIR-related leukocyte Ig-like and CD85: DCs become tolerogenic,
Anergic T cells

Clinical
Gene Mutation Associated Disorders
AIRE APECED Syndrome: Autoimmune Polyendocrinopathy,
Candidiasis, Ectodermal Dystrophy.
Autosomal Recessive, autoimmune adrenal failure (Addison's
disease), hypoparathyroidism and chronic mucocutaneous
candidiasis.
FOXP3 IPEX Syndrome: : Immune dysregulation, polyendocrinopathy,
enteropathy, X-linked
Defects of V(D)J
recombination
SCID Syndrome: Severe combined immunodeficiency
Defects in TCR itself Nonlethal Combined Immunodeficiency
Polymorphisms: CD25
gene promoter region
Type 1 Diabetes, Multiple Sclerosis
Fas or FasL ALPS Syndrome: Autoimmune Lymphoproliferative Syndrome

Immunology Is More
Than Just Vaccines and
Infectious Disease Saturday, December
5, 2020 61
Cytokine dysregulation;
Inappropriate MHC-expression;
Failure of Central/Peripheral
suppression

Dec Mar Jun Sep Dec Mar Jun Sep Dec Mar
1997
Jun
430 BC
15th
Century
1798 1881-
1885 1890
1940s
1950s:1900
1930s and
1940s
Thucydides:
Plague
Discovery
Chinese &
Turks:
Variolation
-small pox
crusts
Edward Jenner:
Protective effect
against smallpox
Pasteur:
Vaccines
against
Anthrax &
Rabies
Emil von
Behring &
Shibasaburo
Kitasato1st insights
into the
mech. of
immunity
Elvin
Kabat:
Used
Serum to
identify
γ-
globulins
Merrill
Chase:
Cellular
&
Humoral
Immunity
Paul
Ehrlich
Selective
Theory
Friedrich Breinl
& Felix
Haurowitz:
Instructional
Theory
A Historical Perspective of
Immunology
TIMELINE
Aaltonen &
Nagamene:
AIRE gene
discovery

Immunology: The Field of Research and Nobel Prizes

Summary

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Immunoreactivity and Immunotolerance

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