Tolerance and

Autoimmune Disease
Dr. Mejbah Uddin Ahmed
 Autoimmunity and Tolerance

Tolerance:
Specific immunologic unresponsiveness to certain
antigen in spite of immune system is functional is
called tolerance.
Both T cells and B cells participate in tolerance.
But T cells play primary role in tolerance.
Tolerance is Two types:
a) Central tolerance.
b) Peripheral tolerance.
 T cell
Thymus
precursors Abnormal release of
autoreactive T cells

Selected T cells

Central
Tolerance

Peripheral
Tolerance
anergy /
deletion/
suppression
Bone marrow
 Autoimmunity and Tolerance

T cell tolerance:
Central tolerance: Central tolerance of T cell
acquire in the thymus by the process called clonal
deletion.
Clonal deletion: Killing of T cells that react against
self MHC proteins is called clonal deletion/
negative selection.
 Autoimmunity and Tolerance

Peripheral tolerance: Peripheral tolerance of T

cells acquire outside the thymus.
Mechanism of peripheral tolerance:
a) Some are killed.
b) Some are inhibited.
c) Some are suppressed by regulatory T
cells.
(Self reactive T cells die by a process of
programmed cell death called apoptosis).
 Autoimmunity and Tolerance

Peripheral tolerance:
Clonal anergy: Self reactive T cells are not
activated because proper costimulation
does not occur.
Clonal ignorance: This means self reactive T
cells ignore self antigen. May be due to
physical separation or antigens are very
small amount.
Costimulation: CD28, B7 and CD40L, CD 40

CD28 B7

T cell CD4 or 8 APC

TcR MHC

CD40L CD40
 Autoimmunity and Tolerance

B-cell Tolerance:
B cell Tolerance is less complete than T cell,
So most autoimmune disorders are antibody
mediated. B cells tolerance involves:
a) Clonal deletion: Probably in the bone
marrow.
b) Clonal anergy: In the periphery.
 Autoimmunity and Tolerance
Induction of Tolerance:
Whether an antigen will induce tolerance or
immune response, depends on:
a) Immunologic maturity of host.
b) Structure and dose of antigen.
c) T cell become tolerant rapidly and remain
longer than B cell.
d) Administration of cross reacting antigen.
e) Administration of immunosuppressive
drugs.
 Autoimmune
disease

• Autoimmunity is a
problem of self/ non-
self discrimination.

• Loss of self tolerance

to self antigen may
result in autoimmune
diseases.
 Autoimmunity and Tolerance
Factors causes autoimmune disease:
 Genetic:HLA-DR4 =›Rheumatoid Arthritis, HLA-
DR27 =›Ankylosing spondylitis.
 Hormonal factors.
 Bacterial and Viral infection.
Mechanism:
 Molecular mimicry.
 Tissue damage & release of sequestered antigen.
 Alteration of normal protein due binding of drugs.
 Autoimmunity and Tolerance

Autoimmune diseases occurs due the

following types of immune response:
a) Antibody to receptors.
b) Antibody to cell components other than
receptors.
c) Cell mediated.
 Autoimmunity and Tolerance

1. Antibody to receptors:

Disease Target of immune

response

Myasthenia gravis Acetylcholine receptor

Graves disease TSH receptor
 Autoimmunity and Tolerance
Antibody to cell components other than receptors:

Autoimmune diseases Target of immune response

SLE DNA, histones

Rheumatoid Arthritis IgG
Rheumatic fever Heart, Joints
Hemolytic anemia RBC membrane
AGN Glomerular basement
membrane
Guillain-Barre SyndromeMyelin protein
 Autoimmunity and Tolerance

 Cell mediated:

Autoimmune diseases Target of immune

system
Allergic Reaction to myelin
encephalomyelitis and protein causes
multiple sclerosis demyelination of brain
Celiac disease Enterocytes
 Autoimmunity and Tolerance

 Microbial infection associated with Autoimmune

diseases:
Bacteria:
Streptococcus pyogen=› Rheumatic fever
Campylobacter jejuni =› Guillain-Barre syndrome
Chlamydia trachomatis =› Reiter’s syndrome,
Shigella species =› Reiter’s syndrome
 Autoimmunity and Tolerance

Microbial infection associated with Autoimmune

diseases:
Viruses:
Hepatitis B virus =› Multiple sclerosis
Measles virus =› Allergic encephalitis
Cytomegalovirus =› Scleroderma