immune tolerance mechanisms

1. Tolerance
Sally Elfishawi
Associate professor of clinical pathology
Imcert

2.  Immunological tolerance is defined as
unresponsiveness to an antigen that is induced
by previous exposure to that antigen
 Antigens that induce tolerance are called
tolerogens, or tolerogenic antigens, to
distinguish them from immunogens, which
generate immunity
 Tolerance to self antigens, also called self-
tolerance, is a fundamental property of the
normal immune system

4. A processed antigen in an MHC is seen by
a TCR.
The TCR asks the MHC, “Are you me?” and
receives an affirmative answer, “Yes.”
The TCR asks the processed antigen, “Are
you me?” and receives the negative
answer, “No!”
Thus, the processed antigen is seen as
“not-self,” i. e., “foreign.”

5. A processed antigen in an MHC is seen by a TCR.
The TCR asks the MHC, “Are you me?” and receives an
affirmative answer, “Yes.”
The TCR asks the processed antigen, “Are you me?” and
receives the negative answer, “No!”
But what if the TCR asks the processed antigen,
“Are you me?” and receives the answer, “Yes.” TCR’s
which can see “self” are eliminated in a process called
clonal deletion.
Clonal deletion assures that TCR’s don’t see “self.”

7.  Immunological tolerance is important for
several reasons:
 Normal individuals are tolerant of their
own (self) antigens because the
lymphocytes that recognize self antigens
are killed or inactivated, or change their
specificity
 Foreign antigens may be administered in
ways that inhibit immune responses by
inducing tolerance in specific lymphocytes
 Induction of immunological tolerance may
be exploited as a therapeutic approach for
preventing harmful immune responses

8.  Self-tolerance may be induced in immature self-reactive lymphocytes in the
generative lymphoid organs (central tolerance) or in mature lymphocytes in peripheral
sites (peripheral tolerance)
 Central tolerance occurs during the maturation of lymphocytes in the central
(generative) lymphoid organs, where all developing lymphocytes pass through a stage
at which encounter with antigen may lead to cell death or replacement of a self-
reactive antigen receptor with a new one
 Peripheral tolerance occurs when, as a consequence of recognizing self antigens,
mature lymphocytes become incapable of responding to that antigen, or are induced
to die by apoptosis, or mature T cells are actively suppressed by regulatory T cells
 Foreign antigens in the absence of costimulatory signals may inhibit immune
responses by inducing tolerance in specific lymphocytes

9. Nguyen el al 2021

10. Central tolerance occurs in the
thymus and relies on self-
antigen expression on medullary
thymic epithelial cells (mTEC)
under regulation of the
transcription factor AIRE. CD4
+ T cells that recognize self-
antigens in the context of HLA
class II proteins undergo
positive or negative selection.
The selection process is based on
the nature of the interaction
between TCR and HLA-peptide
complex. T cells that are
positively selected go on to
populate the periphery where
they are controlled by
peripheral tolerance
mechanisms acting directly on
the self-reactive T cells
(intrinsic) or indirectly via
additional cells (extrinsic).

13. T LYMPHOCYTE TOLERANCE

15.  The thymus also has an unusual mechanism for expressing protein antigens that are typically present
only in certain peripheral tissues, so that immature T cells specific for these antigens can be deleted
from the developing T cell repertoire. Some of these peripheral tissue antigens are expressed in
thymic medullary epithelial cells under the control of the autoimmune regulator (AIRE) protein.
Mutations in the AIRE gene are the cause of a multiorgan autoimmune disease called the autoimmune
polyendocrine syndrome (APS). This group of diseases is characterized by antibody and lymphocyte-
mediated injury to multiple endocrine organs, including the parathyroids, adrenals, and pancreatic
islets

22.  Regulatory T cells produce IL-10 and TGF-β both of which inhibit immune responses
 Regulatory T cells inhibit the ability of APCs to stimulate T cells

23.  Inhibits the proliferation and effector functions of T cells and the activation of macrophages
 Regulates the differentiation of functionally distinct subsets of T cells
 Stimulates production of IgA antibodies by inducing B cells to switch to this isotype
 Promotes tissue repair after local immune and inflammatory reactions subside

24.  The biologic effects of IL-10 result from its ability to inhibit many of the functions of activated
macrophages and dendritic cells
 Inhibits the production of IL-12 by activated dendritic cells and macrophages
 Inhibits the expression of costimulators and class II MHC molecules on dendritic cells and
macrophages

25. APOPTOSIS

26.  T lymphocytes that recognize self antigens without inflammation or that are repeatedly stimulated by
antigens die by apoptosis
 The mitochondrial (or intrinsic) pathway is regulated by the Bcl-2 family of proteins antiapoptotic proteins
(Bcl-2, Bcl-XL)
 proapoptotic effector proteins of the Bcl-2 family called Bim, Bax and Bak,
 In the death receptor (or extrinsic) pathway, cell surface receptors homologous to tumor necrosis factor
(TNF) receptors are engaged by their ligands
 Repeated stimulation of T cells results in the coexpression of death receptors and their ligands, and
engagement of the death receptors triggers apoptotic death. In CD4+ T cells, the most important death
receptor is Fas (CD95), and its ligand is Fas ligand (FasL)

29. Thank you
‫شكرا‬