Al-Nahrain University

College of Pharmacy
Immunology
Lecture:7 Tolerance and autoimmunity
By
Dr. Noor Adil Abood
Tolerance is specific immunologic unresponsiveness (i.e., an
immune response to a certain antigen [or epitope] does not occur,
although the immune system is otherwise functioning normally)
In general, antigens that are present during embryonic life are
considered “self” and do not stimulate an immunologic
response (i.e., we are tolerant to those antigens).
The lack of an immune response in the fetus is caused by the
deletion of self-reactive T-cell precursors in the thymus. On
the other hand, antigens that are not present during the process
of maturation (i.e., that are encountered first when the body is
immunologically mature) are considered “nonself” and usually
elicit an immunologic response
T-Cell Tolerance
• The main process by which T lymphocytes acquire the ability to
distinguish self from non-self occurs in the fetal thymus. This
process, called clonal deletion, involves the killing of T cells
(“negative selection”) that react against antigens (primarily self
major histocompatibility complex [MHC] proteins) present in the
fetus at that time.
• The self-reactive cells die by a process of programmed cell death
called apoptosis. Tolerance to self acquired within the thymus is
called central tolerance, whereas tolerance acquired outside the
thymus is called peripheral tolerance.
• For negative selection and clonal deletion to be efficient, the
thymic epithelial cells must display a vast repertoire of “self”
proteins. A transcriptional regulator called the autoimmune
regulator (AIRE) enhances the synthesis of this array of self
proteins.
• Mutations in the gene encoding the AIRE protein result in the
development of an autoimmune disease called autoimmune
• Peripheral tolerance is necessary because some antigens are not
expressed in the thymus and therefore some self-reactive T cells
are not killed in the thymus. There are several mechanisms
involved in peripheral tolerance: Some self-reactive T cells are
killed, some are not activated, and others are suppressed by
regulatory T cells producing inhibitory cytokines.

• Clonal anergy is the term used to describe self reactive T cells

that are not activated because proper costimulation does not
occur.

• Clonal ignorance refers to self-reactive T cells that ignore self

antigens. These self-reactive T cells are either kept ignorant by
physical separation from the target antigens (e.g., the blood–brain
barrier) or ignore self antigens because the antigens are present in
such small amounts.
Clonal anergy outside the thymus. A: B7 protein on the
antigenpresenting cell interacts with CD28 on the helper T cell,
and full activation of the helper T cell occurs. B: B7 protein on the
antigen-presenting cell is not produced; therefore, CD28 on the
helper T cell does not get a costimulatory signal. Anergy of the
helper T cell occurs despite interaction of the T-cell receptor (TCR)
with the antigen.
B-Cell Tolerance
B cells also become tolerant to self by two mechanisms: (1) clonal
deletion, probably while the B-cell precursors are in the bone
marrow, and (2) clonal anergy of B cells in the periphery. However,
tolerance in B cells is less complete than in T cells, an observation
supported by the finding that most autoimmune diseases are
mediated by antibodies.
B cells bearing an antigen receptor for a self protein can escape
clonal deletion (apoptosis) by a process called receptor editing. In
this process, a new, different light chain is produced that changes
the specificity of the receptor so that it no longer recognizes a self
protein. This reduces the risk of autoimmune diseases and increases
the repertoire of B cells that can react against foreign proteins. It is
estimated that as many as 50% of self-reactive B cells undergo
receptor editing. T cells do not undergo receptor editing.
Autoimmunity
• The term autoimmunity refers to a failure of the body’s immune system to
recognize its own cells and tissues as “self”, Instead immune responses are
launched against these cells and tissues as if they were foreign or invading bodies.
• It occurs when mechanism of self-tolerance fail.
Mechanisms of autoimmunity
* Ag released from hidden location.
* Antigen generated by molecular changes.
* Molecular mimicry.
* Alteration in Ag processing.
* Infection.
* Genetic factors.
* Lymphocytes abnormalities.
* Failure of central tolerance.
* Overcome of peripheral tolerance.
* Polyclonal lymphocytes activation.
Factors contributing in initiation of autoimmune diseases
• Genetic Factors
Many autoimmune diseases exhibit a marked familial incidence,
which suggests a genetic predisposition to these disorders. There
is a strong association of some diseases with certain human
leukocyte antigen (HLA) specificities, especially the class II genes.
For example, rheumatoid arthritis occurs predominantly in
individuals carrying the HLA-DR4 gene. Ankylosing spondylitis is 100
times more likely to
occur in people who carry HLA-B27, a class I gene, than in those
who do not carry that gene.
• Hormonal Factors
Approximately 90% of all autoimmune diseases occur in women.
Although the explanation for this markedly unequal gender ratio is
unclear, there is some evidence from animal models that estrogen can
alter the B-cell repertoire and enhance the formation of antibody to
DNA. Clinically, the observation that systemic lupus erythematosus
either appears or exacerbates during pregnancy (or immediately
postpartum) supports the idea that hormones play an important role
in predisposing women to autoimmune diseases.
Environmental Factors
There are several
environmental agents that
trigger autoimmune
diseases, most of which are
either bacteria or viruses. For
example, pharyngitis caused
by Streptococcus pyogenes
predisposes to rheumatic
fever.
Members of the normal flora
of the bowel are thought to
play a role in the genesis of
inflammatory bowel
diseases, such as Crohn’s
disease and ulcerative colitis.
Some important autoimmune diseases:
Autoimmune Hemolytic Anemia
• In autoimmune hemolytic anemia, antibodies specific for blood group antigens
(including Rh) expressed on the surface of RBCs are responsible for destroying these
RBCs. This results in anemia, a reduced number of RBCs or decreased hemoglobin
level in the circulation.
The destruction of the red cells can be attributed to several mechanisms:-
• One involves the activation of the complement cascade and lysis of the cells. The
result release of hemoglobin may lead to its appearance in the urine
(hemoglobinuria).
• The second mechanism is the opsonization of RBCs facilitated by antibody and the
C3b component of complement .In the latter case, the RBCs are bound to and
engulfed by macrophages with receptors for Fc and C3b that attach to the antibody-
coated RBCs.
• A third mechanism is the destruction of RBCs through antibody-dependent cellular
cytotoxicity (ADCC), mediated by NK cells and other effector cells .This mechanism
does not require complement.
Graves’ Disease.
• Graves’ disease is an example of an autoimmune disease in which
antibodies directed against a hormone receptor act as agonists and
activate rather than interfere with the activity of the receptor.
• patients with this disease develop autoantibodies against receptors
for thyroid-stimulating hormone (TSH) that are expressed on the
surface of thyroid cells.
• the interaction of autoantibodies with the TSH receptor activates the
cell in a manner similar to TSH activation, thereby stimulating excess
production of thyroid hormone. Normally, TSH produced by the
pituitary binds to TSH receptors on the thyroid, activating the gland to
produce and secrete thyroid hormones.
• When the level of thyroid hormones gets too high, the production of
TSH and thus the production of thyroid hormones is shut down via a
negative feedback loop.
• Graves’ disease the autoantibodies continuously stimulate the TSH
receptors, resulting
Systemic Lupus Erythematosus (SLE)
• The disease gets its name (which literally means “red wolf”) from a
reddish rash on the cheeks (“malar”), a frequent early sign.
• The term systemic is quite appropriate, because the disease affects
many organs of the body. It is mediated mostly by autoantibodies and
immune complexes, which often deposit in the skin, joints, lungs, blood
vessels, heart, kidney, and brain.
• The origin of this disease is still a mystery, but details of the
immunologic mechanisms responsible for the pathology are partially
known.
• Patients with SLE produce antibodies mostly against components of the
cell nucleus (antinuclear antibodies [ANAs]), notably against native
dsDNA. Antibodies may also be produced against denatured, single
stranded DNA, ribonucleoproteins, and nucleo-histones
• It is generally believed that nuclear autoantigens become available
during the process of apoptosis.
• Normally, The phagocyte system removes such potentially
immunogenic autoantigens swiftly. There is evidence in human lupus that
Rheumatoid Arthritis (RA)
• Is an autoimmune disease that causes chronic inflammation of
the joints.
• signs & symptoms: Resulting in pain, swelling, stiffness, and
deformity. Other symptoms include fatigue, low-grade fever, and
loss of appetite.
• RA is characterized by chronically inflamed synovium (soft tissue
that lines the joints).
• Most patients produce IgM antibody specific for a determinant on
the Fc portion of IgGs. This anti-IgG antibody is called rheumatoid
factor (RF). When RF binds to IgG, the resulting immune complexes
can deposit in the joints, where the complement and establish an
inflammatory process.
• Joint damage is due to invasion of inflammatory cells such as
neutrophils, and macrophage.
• Proliferation of fibroblast, macrophages and mast cells result in
the formation of a pannus, an organized mass of cells that grow into
Type I Diabetes Mellitus. (TIDM)
• Is a form of diabetes that involves chronic inflammatory destruction of the insulin
producing β cells in the islets of Langerhans of the pancreas.
• The results in little or no insulin production. Insulin facilitates the entry of glucose into
cells, where it is metabolized for energy production.
• In TIDM, the major contributors to β-cell destruction are cytotoxic CD8+ T cells.
However, inflammatory infiltrates in the islets of Langerhans include CD4+ T cells and
macrophages, along with the cytokines they secrete, such as IL-1, IL-6, and IFN-α. Many
patients with TIDM also develop autoantibodies to insulin and other antigens such as
glutamic acid decarboxylase (GAD). It is thought that these autoantibodies arise as a
consequence of β- cell destruction. Also genetic factors predisposing to TIDM include
several genes in the HLA class II region, the insulin gene on chromosome 11.