3. First
*Positive and negative thymic selection ensures that mature T cells
recognize self MHC I or II molecules (positive selection) but are not
overtly self-reactive against self peptides (negative selection).
*Thymocytes that are unable to make these distinctions meet an
apoptotic death.
*The efficiency of negative selection is greatly increased by the action
of the AIRE (Autoimmune ruglator) gene. This gene operates in the
thymic cells that are responsible for negative selection of developing
thymocytes, (as well as in other cells and tissues). AIRE causes the
thymic epithelial reticular cells to express a large number of
molecules normally associated with non-thymic cells and tissues. As a
result, negative selection can induce central tolerance to a range of
both thymic and non-thymic self peptides.
*Rare individuals lacking a normally functioning AIRE gene develop
autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
(APECEO), an autoimmune syndrome also known as autoimmune
polyendocrinopathy syndrome type I, that results in
hypoparathyroidism, adrenal cortical dysfunction, and chronic
mucocutaneous candidiasis.
Second
*Not all self peptides are presented within the
thymus, and some self peptides arise after the
waning of thymic function.
*Some peptides are restricted to anatomic sites
that are not easily accessible to the immune
system .
*Consequently, some potentially autoreactive T
cells slip through positive and negative
selection . As a result, the adaptive immune
system must use additional means to avoid self
reactivity.
*Selective non responsiveness or tolerance
requires that when the adaptive immune
system does recognize self, it should adopt a
nondestructive strategy.
*Several tolerance mechanisms have evolved to
minimize potential harm caused by
postdevelopmental selection autoreactive cells.
INTRODUCTION
4. Immunologic Tolerance
* Is a state of unresponsiveness of the immune system to substances or tissue
that have the capacity to elicit an immune response in given organism. It is
induced by prior exposure to that specific antigen and contrasts with
conventional immune-mediated elimination of foreign antigens.
5. Central T-Cell Tolerance
* Refers to death (deletion) of self-
reactive T- and B-lymphocyte
clones during their maturation in
the central lymphoid organs (the
thymus for T cells and the bone
marrow for B cells).
* Transgenic animal models
demonstrate that central
mechanisms are indispensable for
induction of self-tolerance
CD4-CD8- (double negative) T-
cell progenitors enter the thymic
cortex and rearrange their
receptors to become CD4+CD8+
(double positive) thymocytes
Positive and negative selection
occurs in the thymus
6. T-cell Peripheral Tolerance
1- T-cells that escape intrathymic
negative selection can cause tissue
injury unless they are deleted or
muzzled in the peripheral tissues.
2- “back up” mechanisms that
silence such potentially autoreactive
T-cells are:-
A- Clonal deletion by activation-
induced cell death
B- Clonal anergy
C- Peripheral suppression by T-cells
7. A- Clonal deletion by activation induced
cell death
* Mechanism to prevent uncontrolled T-cell
activation during normal immune response
involves apoptotic death of activated Tcells
by Fas-Fas ligand system.
* Expression of Fas (CD95) is upregulated in
antigen activated T-cells.
* Engagement of Fas by Fas L, coexpressed
on activated T-cells, dampens the immune
response by inducing apoptosis of
activated T-cells.
*The self antigens that are abundant
in the peripheral tissues cause
repeated and persistent stimulation
of self-antigen-specific T-cells
leading eventually to their
elimination via Fas mediated apoptosis.
8. B- Anergy
This is a major mechanism inactivating peripheral
autoreactive T-cell clones
Anergic T-cell clones cannot respond to cognate
antigenic stimuli: they do not produce IL-2 or
IL-2R .Multiple proposed mechanisms explain this
block in T-cell activation :
1- Disruption of the interaction between the T-cell
co-receptor CD28 and APC co-stimualtory
molecules CD80/86
2- Interaction of CTLA-4 with CD80/86, negatively
regulating T-cell activation
3- T-cells displaying CD28 tend to be activated by
APC, while T-cells displaying CTLA-4 tend to
become anergic
4- Under physiologic conditions, T-cells express
CD28 on initial encounter with APC Shortly after
such stimulation, they start displaying CTLA-4,
which has a higher binding affinity than CD28 for
CD80/86 than does CD28
5- CTLA-4 knockout mice develop profound
lympho-proliferative disease
9. APC APC
T Cell
CD28
B7
Costimulation
T cell activation
B7
CTLA-4
T cell (activated
T cell or Treg)
CTLA-4 blocks and removes B7
lack of costimulation T cell
inhibition
CTLA-4 competitively inhibits B7-CD28 engagement
10. Clinical Significance of CTLA-4
* CTLA-4 is used as a biologic response modifier to treat these patients, significantly
reducing joint inflammation like RA
*A fusion protein consisting of CTLA-4 and immunoglobulin (abatacept, belatacept) is
used clinically in arthritis and after transplantation.
*There is also interest in blocking CTLA-4 using monoclonal antibodies (e.g.
ipilimumab) to inhibit tumor tolerance
*Insufficient production of key transcriptional activators (e.g. AP-1, NF-kB, NFAT-1)
during T-cell activation reduces IL-2 production
*Transcription suppressors (e.g. CREM) can also decrease transcriptional activity of the
IL-2 gene promoter, leading to T-cell anergy
*Alterations at multiple levels of regulation (e.g. activity of key kinases such as MAPK, or
stability of IL-2 mRNA) can contribute to reduced IL-2 production in anergic T-cells
11. C- Immune Regulation
* Immune regulation is achieved by the action of Treg’s
Treg are important in the maintenance of peripheral
tolerance
* When they are depleted from mice, autoimmunity
results
* A human patient with genetic Treg dysfunction
develops lymphadenopathy and inflammatory
infiltrates consisting of autoreactive T-cells in multiple
organs
*Naturally-occurring thymus-derived Treg display
anergic properties in vitro, but can also suppress
CD4+CD25- T-cells in vivo, via direct cell-cell contact,
or secretion of cytokines
*During active inflammation (e.g. infection), Treg do
not prevent protective immune function
*Induced CD4+CD25+ Treg can also be activated in
peripheral lymphoid organs (e.g. by TGFβ) and
suppress immune responses via anti-inflammatory
cytokines (e.g. TGFβ and IL-10) rather than direct
contact
12. Regulatory T cell
Costimulation and preventing the activation
of T cells One theory to explain how T cells
choose CD28 or CTLA- 4, with these very
different outcomes, is based on the fact that
CTLA-4 has a higher affinity for B7 molecules
than does CD28.
Thus, when B7 levels are low (as would be
expected normally when APCs are displaying
self antigens), the receptor that is
preferentially engaged is the high-affinity
CTLA-4, but when B7 levels are high (as in
infections), the low affinity activating
receptor CD28 is engaged to a greater extent
13.
14.
15.
16.
17. 1- Allograft tolerance:
there are two general cases in which an allograft may be accepted.
A; when cells or tissue are grafted to an immune-privileged site that is sequestered from immune surveillance
(like in the eye or testes) or has strong molecular signals in place to prevent dangerous inflammation (like in
the brain).
B; when a state of tolerance has been induced, either by previous exposure to the antigen of the donor in a
manner that causes immune tolerance rather than sensitization in the recipient, or after chronic rejection.
2- Women who have borne multiple children by the same father typically have antibodies against the father's
red blood cell and major histocompatibility complex (MHC) proteins. However, the fetus usually is not rejected
by the mother, making it essentially a physiologically tolerated allograft. It is thought that the placental tissues
which interface with maternal tissues not only try to escape immunological recognition by downregulating
identifying MHC proteins but also actively induce a marked peripheral tolerance.
Placental trophoblast cells express a unique Human Leukocyte Antigen (HLA-G) that inhibits attack by
maternal NK cells. Maternal T cells specific for paternal antigens are also suppressed by tolerogenic DCs and
activated iTregs or cross-reacting nTregs.
Some maternal Treg cells also release soluble fibrinogen-like proteins 2 (sFGL2), which suppresses the
function of DCs and macrophages involved in inflammation and antigen presentation to reactive T cells
Tolerance in physiology and medicine
18. 3-The skin and digestive tract of humans and many other organisms is
colonized with an ecosystem of microorganisms that is referred to as the
microbiome. Though in mammals a number of defenses exist to keep the
microbiota at a safe distance, including a constant sampling and presentation
of microbial antigens by local DCs, most organisms do not react against
commensal microorganisms and tolerate their presence. Reactions are
mounted, however, to pathogenic microbes and microbes that breach
physiological barriers. Peripheral mucosal immune tolerance, in particular
mediated by iTreg cells and tolerogenic antigen-presenting cells, is thought to
be responsible for this phenomenon. In particular, specialized gut CD103+ DCs
that produce both TGF-β and retinoic acid efficiently promotes the
differentiation of iTreg cells in the gut lymphoid tissue. Foxp3 cells that make
IL-10 are also enriched in the intestinal lining. Break in this tolerance is
thought to underlie the pathogenesis of inflammatory bowel diseases like
Crohn's disease and ulcerative colitis
19. Autoimmune Response vs. Autoimmune Disease
A clear distinction must be made between an autoimmune response and an autoimmune
disease.
The term autoimmune response refers to the demonstration of an autoantibody or T cell mediated
reactivity directed to a self-antigen.
An autoimmune response may or may not be associated with autoimmune disease. For
example, many clinically well individuals, particularly women, exhibit an autoimmune response
by the presence of serum antinuclear antibodies (ANAs) and demonstrate no symptoms.
Although the presence of ANA may also be associated with the autoimmune disease SLE, the
diagnosis requires the presence of additional clinical features of the disease.
Although much progress has been made in understanding the pathophysiology of autoimmune
diseases, the underlying etiopathogenesis remains elusive for most of these disorders.
Autoimmunity affects ~5% of the population, predominantly women in their reproductive years,
with peak incidences during adolescence and the fourth through fifth decades
An understanding of lymphocyte physiology and tolerance mechanisms largely derives from
transgenic animal models, as well as genomics and proteomics research
There has been some success translating such observations to humans, but additional clinical
studies are required, including to better understand the pathogenesis of autoimmunity
Improved knowledge may be applied to generate more efficacious and safer autoimmune
therapies
24. 1. Autoimmune diseases are multifactorial
including age, genetics, gender, infections and the nature of the autoantigen.
2. Age and gender: Autoantibodies are more prevalent in older people and women have a greater risk than men for
developing a autoimmune disease.
Factors contributing to the development of autoimmune diseases
Sex-based differences in autoimmunity
Differences can be traced to sex hormones
-hormones circulate throughout the body and alter immune response by influencing gene
expression
-(in general) estrogen can trigger autoimmunity and testosterone can protect against it
Difference in immune response
♀ produce a higher titer of antibodies and mount more vigorous immune responses than ♂
♀ have a slightly higher cortisol secretion than ♂
-♀ have higher levels of CD4+ T-cells and serum IgM
27. 3- Polyphormism in
Non-HLA genes
• Associated with
various
autoimmune diseases
and may contribute to
failure of self tolerance
or abnormal
activation of
lymphocytes
• Combinations of
multiple inherited
genetic
polymorphisms
interacting with
environmental factors
induce the
immunologic
abnormalities that
lead to autoimmunity.
• Epigenetic changes
also affect the diseases
onset.
28. 4. Infections: Many infectious agents have been linked to
particlular autoimmune diseases and may be important in
their etiology.
5. Nature of the autoantigens: Target antigens are often
highly conserved proteins, such as heat shock proteins
(HSPs), stress proteins, enzymes, or their substrates.
6. Drugs and autoimmune reactions: Certain drugs can
initiate autoimmune reactions by unknow mechanisms, e.g.
patients receiving procainamide develop SLE-like
symptoms and have anti-nuclear antibodies.
29. 7-Molecular Mechanisms of Autoimmunity
Cross-reactivity (molecular and viral mimicry):Viral and nonviral peptides can mimic self- peptides and induce
autoimmunity
32. If B cells reactive to self-
peptides are activated,
autoimmunity can occur.
Example: Epstein-Barr virus,
which is the cause of infectious
mononucleosis.
8- Polyclonal B cell activation by
viruses and bacteria