immuno12 &13 tolerance & autoimmunity
TRANSCRIPT
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
1/35
Pharm-Immuno 12&13
Immunologic Tolerance &
AutoimmunityDr. Saber Hussein
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
2/35
Objectives
1.Define and explain the concept of immunologictolerance
2.Categorize the conditions that influence tolerance
induction3.Know the mechanisms that induce self-tolerance
4.Know the benefits & disadvantages of tolerance
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
3/35
Tolerance & Anergy
Tolerance: The acquisition of a specific nonresponsiveness to a
molecule recognized by the immune system as nonself
Tolerogen:
An otherwise immunogenic substance that, because of itschemical composition, dose, or route of introduction,induces immunologic tolerance rather than immunity
Anergy:
An absence of cell-mediated immune reaction in supposedly
sensitized animals or individuals. No allergic response to an
immunogen or allergen
In advanced cases of TB, infections withMycobacterium
tuberculosis, the tuberculin test becomes negative
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
4/35
Central & peripheral
tolerance to self Ags
Central tolerance
Immature lymphocytes
specific for self Ags
may encounter these
Ags in the generative
lymphoid organs (bone
marrow & thymus) andare deleted
Peripheral tolerance
Mature self-reactive
lymphocytes may be
inactivated ordeleted
by encounter with self
antigens in peripheral
lymphoid tissues
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
5/35
Consequences of the lymphocyte-Ag encounter Naive lymphocytes may be activated to proliferate and differentiate
by immunogenic antigens Tolerance is induced when tolerigenic antigens induce
functional anergy (unresponsiveness) or
apoptosis, leading to an inability of the cells to again respond to the sameAg even in an immunogenic form
Some Ags are ignored
by lymphocytes,
resulting in no
response, but the
lymphocytes arecapable of responding
to the same antigen in
an immunogenic form
Fig 9-1
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
6/35
Tolerance
induction
Tolerance is a
secondary
"nothing"
response
Conditions that influence tolerance induction:
1. The immunologic maturity of an animal & its immune cells
2. The dose of Ag
3. The physico-chemical nature of the Ag
4. Immunogenicity of an Ag
5. Route of Ag administration
6. Kind of recipient
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
7/35
Mechanisms that induce self-tolerance
Three principal mechanisms that induce self-tolerance:
[1] Physical elimination or clonal deletion
[2] Functional inactivation, anergy
[3] Regulated inhibition of Ag-reactive T & B cells Induction of self-tolerance can occur at three levels:
i. The T-cell level
ii. The B-cell leveliii. The T-cell-B-cell cooperative level
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
8/35
T Cell Positive & Negative Selection in the Thymus
MHC-restriction is not preprogrammed into T cells
It is acquired
(a)by contact with humoral factors and
(b)by physical interaction of TCR-expressing cells
with MHC molecule-expressing cells during T-celldevelopment in the thymus
Positive and negative thymic selection is a life or
death process for the developing T cell:
Positive selection for self-MHC-restricted cells Negative selection of autoreactive T cells
Mature T cells are self-MHC-restricted and self-
tolerantbecause all thymocytes whose TCRs show
strong recognition of self Ags are eliminated
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
9/35
IL-2 synthesis is controlled by
costimulatory signals CTLA-4 is a CD28
homologue that issynthesized after the
activation of T cell.
When CTLA-4ligates B7 it blocksactivation signals
that is No more IL-2is synthesizedleading to cell death
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
10/35
Ags can induce any of the following:
1. Clonal abortion:1. multivalent antigen can, when given in appropriate
concentrations, cause immature B cells to abort by
preventing their further differentiation
Tolerizability ofpre-B cells is high Clonal deletion:
very strong negative signals (missing Ag; absence of TH)
can cause deletion of mature B cells
Clonal anergy: intermediate concentration of multivalent antigen allows
pre-B cells to develop into morphologically normal B
cells, with normal numbers of immunoglobulin receptors,
but renders them profoundly anergic
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
11/35
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
12/35
T cell & B cell tolerance Because the thymus activity decreases into adulthood most T cell lines
are present after birth
The clone that dies or becomes tolerant will not or only slowly be
replaced with active T cells T cell tolerance stays for long time
B cells are made life long in the bone marrow
Later encounter with immunogenic Ag would activate the new B cells
B cell tolerance
is shorter
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
13/35
Advantages & disadvantages of tolerance
Advantages1. Self-tolerance is essential for the function of the immune
system
2. Tolerance to foreign tissue grafts
3. Gene therapy4. Control of damaging immune responses such as:
i. Hypersensitivity
ii. Autoimmune diseases
Disadvantages1. Tolerance to certain foreign antigens that cause disease such
as bacterial infections
2. Tolerance to some self-antigens associated with cancer
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
14/35
Autoimmunity/Objectives Define autoimmunity
Know the multiple etiologies for autoimmune diseaseand the central role of helper T cells
Describe
cell-mediated autoimmunity leading to autoimmune
disease antibody-mediated autoimmunity leading to
autoimmune disease
List other factors that may lead to autoimmune
disease Discuss some of the approaches used in the
treatment of autoimmune diseases; appreciate thepreventive approaches to specifically eliminate the
causes
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
15/35
Autoimmunity, definition, mechanism
Autoimmunity:
The immuneresponse of the
body with
antibodies or
cell-mediatedimmunity
to self-tissues or
antigens,
resulting inpathological
consequences
and
autoimmune
disease
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
16/35
Etiologies of autoimmune diseases Genetic factors:
Involvement of genetics is evidenced by the fact that monozygotictwins, dizygotic twins and family members have increased
predisposition for certain diseases. Such inheritance is polygenic.
Examples:
SLE (anti-dsDNA Abs)
Type 1 diabetes (>14 genes are involved)
HLA genes are associated with several autoimmune diseases
Environmental factors:
They trigger autoimmune diseases. There are Ags that aresequestered from the lymphoid system. Examples:
Lens and uveal proteins of the eye
Spermatozoa.
Accidents might end the sequestration of such Ags leading toautoimmunity
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
17/35
Tolerance Autoimmunity1. Absence of TH cells:
Low dose of Ag T-cell
tolerance
B cells are not affected
but because TH is
lacking No auto-Abproduction
2. Control by Ts
3. Absence of MHC II on
potential target cells
1. Bypass of TH absence
leads to autoimmunity
2. Impairment of Ts can
lead to autoimmune
response as result of
primary
immunodeficiency or
anti-Ts Abs
3. Gaining the ability ofpresenting their Ag to
TH They become
APC
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
18/35
Mechanisms of bypassing the
absence of TH cells1. Provision of an altered determinant capable
of activating TH cells
2.
Polyclonal activation of B cells3. Bacterial & viral infections:
Streptococcal infections elicit Ab that cross-reacts with normal tissue of the heart
leading to autoimmune disease4. Bacteria and EBV can act as adjuvant leading
to polyclonal activation and autoimmuneresponse
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
19/35
Postulated mechanisms of autoimmunity
In this proposed model of an
organ-specific T cell-mediatedauto-immune disease, variousgenetic loci may confersusceptibility to autoimmunity,
probably by influencing the
maintenance of self-tolerance Environmental triggers, such as
infections and
other inflammatory stimuli
promote the influx of lymphocytes
into tissues and
the activation of self-reactive T cells,
resulting in tissue injury
Fig 9-3
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
20/35
Central T cell tolerance
Negative selection, or deletion Strong recognition of self antigens by immature T cells in the
thymus may lead to death of the cells
Development of regulatory T cells that enter peripheral tissues
May result from self-antigen recognition in the thymus
Fig 9-4 (CD4 & DC8)
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
21/35
T cell
anergy
An antigen presented by costimulator-expressing antigen-presenting cells (APCs) induces a normal T cell response.
If the T cell recognizes antigen without costimulation, or
in the presence ofCTLA-4-B7 interactions,
the T cell fails to respond and is rendered incapable of respondingeven if the antigen is subsequently presented by costimulator-
expressing APCs
Fig 9-5
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
22/35
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
23/35
Activation-induced
death of T cells
1. T cells respond to Ag presented bynormal APCs by
secreting IL-2,
expressing anti-apoptotic proteins,
and undergoing proliferation and
differentiation.
2. Restimulation ofrecently activated Tcells by Ag leads to:
coexpression ofFas and FasL,
engagement of Fas, and apoptotic death of the T cells
FasL on one T cell may engage Faseither
on a neighboring cell or
on the same cell
3. Fas-independent activation-induced celldeath ofimmature T cell results fromexpression of intracellularpro-apoptoticproteinsbecause of
Ag recognition by T cells withoutcostimulation or
innate immunity
Fig9-61
2
3
Death R.
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
24/35
T cell-mediated
suppression of immune
responses
In a normal response, T cellsrecognize Ag and proliferate anddifferentiate into effector cells
A typical TH1 response APCs secrete IL-12, which stimulates
differentiation of the naive T cells intoTH1 effectors that produce IFN- andactivate macrophages in the effectorphase of the response
Some T cells may differentiate intoregulatory cells in the peripheraltissues or the thymus
Regulatory cells inhibit the
activation and differentiation ofnaive T cells
by contact-dependent mechanisms, or
they may secrete cytokines thatinhibit the effector phase of T cellresponses
Fig9-7
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
25/35
Tolerance or activation? Features of protein antigens that influence the choice between T
cell tolerance and activation
Why the self antigens induce tolerance and microbial antigensstimulate T cell-mediated immune responses?
Fig 9-8
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
26/35
Negative selection and receptor editing in
immature B lymphocytes
An immature B cell that strongly recognizes self antigens
E
.g. a multivalent self Ag with several epitopes in the bonemarrow is
killedby apoptosis or
Receptor editing:
changes its antigen receptor by making a new light chain with
different specificity
Fig9-9
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
27/35
Peripheral
tolerance in
B cells
A. A mature B cell that recognizes a self Ag without T cell help is
functionally inactivated & becomes incapable of responding to
that Ag
B. B cells that are partially activated by recognition of self Ags
without T cell help may be excluded from lymphoid follicles and
may die by apoptosis because they are deprived of survival
stimuli
Fig9-10
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
28/35
Autoimmune disease association with alleles of MHC locus
Several lines of evidence support such association:
Family and linkage studies show that individuals who inheritparticular HLA alleles are more likely to develop someautoimmune diseases than individuals lacking these alleles ("relativerisk").
Selected examples of HLA disease associations are listed. For
instance, individuals who have the HLA-B27 allele are 90
to100
times more likely to develop the disease ankylosing spondylitisthan B27-negative individuals; other diseases show varying degreesof association with other HLA alleles.
Breeding studies in animals have shown that the incidence of someautoimmune diseases correlates strongly with the inheritance of
particular MHC alleles (e.g., insulin-dependent [type 1] diabetesmellitus with the mouse class II allele called I-Ag7).
Genome scanning studies have also revealed the association of MHCwith autoimmune diseases in humans and mice (e.g., HLA-DR andtype 1 diabetes in humans). See next, Fig9-11:
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
29/35
Ankylosing spondylitis Progressive deformity due to ankylosing
spondylitis over a period of 26 years
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
30/35
Association of autoimmune diseases with alleles of the
MHC locus
MHC IIallele
Fig9-11
Skin disease characterized by
groups of itching blisters
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
31/35
The roles
of somenon-MHC
genes in
auto-
immunity
Some genes other than MHC genes may contribute to the
development of autoimmune diseases.
Lpr = Mouse mutation "lymphoproliferation"
gld = "generalized lymphoproliferative disease
AICD, activation-induced cell death
ALPS, autoimmune lymphoproliferative syndrome
AutoImmuneRegulator
polyEndocrine
Fig9-12
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
32/35
Mechanisms
by which
microbesmay promote
auto-
immunityA. Normally, encounter of mature T cells with self Ags presented by
resting APCs results in peripheral tolerance by anergy ordeletion
B. Microbes may activate the APCs to express costimulators; and
when these APCs present self Ags, the specific T cells are activatedrather than rendered tolerant.
C. Some microbial Ags may cross-react with self antigens (mimicry)
Therefore, immune responses initiated by the microbes may becomedirected at self cells and tissues
Molecular mimicry applies to T cells and self-reactive B cells
Fig.9-13
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
33/35
Autoimmune diseases1. Antibody-mediated autoimmunity
1. Autoimmune hemolytic anemia2. Myasthenia gravis
3. Graves' disease
2. Immune complex-mediated autoimmunity
1. Systemic lupus erythematosus (SLE)3. T-Cell-mediated autoimmunity:
1. Multiple sclerosis
2. Type I diabetes mellitus
3. Hashimoto's thyroiditis4. Antibody- & T-cell-mediated autoimmune
disease1. Rheumatoid arthritis
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
34/35
Myasthenia
gravis
-
8/7/2019 Immuno12 &13 Tolerance & Autoimmunity
35/35
Rheumatoid Arthritis
Chronic, inflammatory joint disease. Serum and synovial fluid of patients contain
Rheumatoid factor
IgM and IgG antibodies bound to Fc fragment of
normal IgG
Synovial membranes and blood vessels containrheumatoid factor and normal IgG, which attractPMN causing inflammation
In active disease the patients have
low titers of complement and
high titers of rheumatoid factor