AUTOIMMUNITY

Dr. Andrew Nyerere

Email-knyerere@jkuat.ac.ke
Self/Non-self Discrimination

Autoimmunity is
a problem of
self/non-self
discrimination.
 Autoimmunity
• 5 % to 7% adult affected.

• Two third women.

• More than 40 human diseases

autoimmune in origin.
AUTOIMMUNITY & LEFT-
HANDEDNESS
• LEFT handed individuals more affected.
• 11% of left handed & 4% of right
handed.
• Reasons for this are obscure.
• left-handedness & immune malfunction
may both result from abnormal endocrine
function in fetal life.
 Effects of autoimmunity
1) Tissue destruction
Diabetes: CTLs destroy insulin-producing b-cells in
pancreas
2) Antibodies block normal function
Myasthenia gravis: Ab binds acetylcholine receptors
3) Antibodies stimulate inappropriate function
Graves’ disease: Ab binds TSH receptor
Mimics thyroid-stimulating hormone
Activates unregulated thyroid hormone production
4) Antigen-antibody complexes affect function
Rheumatoid arthritis:
IgM specific for Fc portion of IgG
IgM-IgG complexes deposited in joints inflammation
 Causes of autoimmunity
• 1) Release of sequestered Ag
• Smoking can trigger Goodpasture’s syndrome
• Alveolar basement membrane normally not exposed to
• immune system
• Smoking damages alveoli, exposes collagen
• Anti-collagen Ag damages lung and kidney
• Anti-sperm Ab produced in some men after vasectomy
• Injection of myelin basic protein (MBP) produces MS-
like EAE
• in mice
• May be triggered by injury or infection
 Causes of autoimmunity
• 2) Immune stimulation

• Microbial infection stimulates APCs carrying self Ag

• High level of APCs with “second signal” breaks anergy

Mechanisms of autoimmunity
• Ag released from hidden location.

• Antigen generated by molecular changes.

• Molecular mimicry.

• Alteration in Ag processing.

• Infection.

• Genetic factors.
Mechanisms of autoimmunity
• Lymphocytes abnormalities.

• Failure of central tolerance.

• Overcome of peripheral tolerance.

• Polyclonal lymphocytes activation.

Ag related from hidden location
Many self Ag are found in hidden location eg. C N S ,TESTES ,EYE
(CORNEA)
organ damage

Hidden Ag released

Reaches blood stream

Encounter Ag sensitive cells

Stimulate autoimmunity
Antigen generated by molecular changes
• Development of completely new epitopes on normal protein. eg RF immuno
conglutinine.

Mech of formation of RF :
Ab + Ag

new epitopes exposed on Fc region of Ab

Stimulate the formation of Rf

Establishment of disease like rheumatiod

artheritis and SLE
 Molecular mimicry
• Sharing of epitopes between an infectious
agent and its host.

• Antibodies directed against the infectious

agents starts reacting with normal self Ag.

• Triggers autoimmunity.
 Alteration in Ag processing
• A T cell may fail to develop tolerance to
an self Ag simply because it is not
efficiently procured.
• If something happens to improve the
processing, an autoimmune disease may
be triggered.
• This usually happens at the site of
inflamation resulting in modified Ab.
• Eg. Thyrotoxicosis , diabetese.
 Infection
• Here autoimmunity is not due to infectious
agent itself ,but results from dis regulation of
host immune response by the microbes.
This may be due to :
• Polyclonal lymphocyte activation.

• inhanced stimulation of co stimulator.

• Alteration of self Ag(cross reactive neo-Ag)

 GENETIC FACTORS
• The important genes that regulate the development of autoimmunity
are located within MHC.
• MHC have got critical role in maturation of T cell & induction of IR .
• MHC ll genes are directly responsible for auto antigen processing and
presentation.
• The structure of Ag binding groove will determine , if specific Ag
will trigger an AU response.
• Eg. Diabetes mellitus in dog:
DLA-A3, A7, A10 and DLA-B4

SLE: DLA- A7

POLYARTHRITIS: DLA- A7
 Lymphocytes abnormalities
• Primary abnormalities either in B cell or T cell.
• Since these cells are critical regulators of all IR.

• MHC presentation of all antigenic peptide to these

cells will be defective, in case the cells are
abnormal.

• Abnormalities in lymphocytes could affect any one

of the mechanism that normally maintains self
tolerance.
 Failure of central tolerence
Inside primary lymphoid organ;
 positive selection

 negative selection (Deletion of self reacting T

cells in thymus apoptosis).

 Failure of central tolerance starts AU diseases.

 POLYCLONAL LYMPHOCYTE ACTIVATION

• Stimulation of non deleted self reacting

lymphocytes. These are activated by some
activators-
• LPS- POLYCLONAL B CELL ACTIVATOR

• BACTERIAL SUPER ANTIGEN-

POLYCLONAL T CELL ACTIVATOR
Damage to immunologically
privileged sites can lead to
autoimmunity
 Rheumatiod Arthritis
• Auto-immune disorder which results in
inflammation of the synovial lining of the joint
and cartilage destruction.

• This result in loss of function.

• Affects 1% of adults.
 Treatment for autoimmunity

• Immunosuppression (e.g., prednisone, cyclosporin A)

• Removal of thymus (some MG patients)
• Plasmapheresis (remove Ab-Ag complexes)
• T-cell vaccination (activate suppressing T cells??)
• Block MHC with similar peptide
• anti-CD4 monoclonal Ab
• anti-IL2R monoclonal Ab