Causes, types of immunosuppression and immune tolerance

1. IMMUNOSUPPRESSION
&
IMMUNE TOLERANCE
HEMA T
MSc BIOCHEMISTRY
BHARATHIAR UNIVERSITY
2018-2020

2. IMMUNOSUPPRESSION
• Immunosuppression is defined as “ A state of temporary or
permanent dysfunction of the immune response resulting from
insults to the immune system and leading to increased
susceptibility to disease” .
• The suppression of the body’s innate ability to ward off disease
and infection is known as immunosuppression.

4. IMMUNOSUPPRESSION CAUSES
• Immunosuppression may result from certain diseases, such as AIDS or
lymphoma.
• Immunosuppression may also be deliberately induced with drugs, as in
preparation for bone marrow or other organ transplantation, to prevent the
rejection of a transplant.

5. IMMUNOSUPPRESSION TYPES
• Cancer and haematological malignancies
• Chronic infections- HIV
• Chronic diseases- diabetes, COPD, auto immune diseases
• Asplenia
• Physiological- pregnancy
• Stem cell/ solid organ/ bone marrow transplant
• Drug induced
steroids
immunosuppressive drugs
cancer and haematological malignancy treatments
• Immuno therapies
monoclonal antibodies
immune checkpoint inhibitors

7. ORGAN TRANSPLANTATION
• people who receive organ transplants take medications to suppress the
immune system so the body won’t reject the organ.
• These "immunosuppressive" drugs make the immune system less able to
detect and destroy cancer cells or fight off infections that cause cancer.
• Solid organ and hematopoietic stem cell transplantation are definitive
therapies for a variety of end-stage diseases.
• Immunosuppression has improved graft survival but leaves the patient
susceptible to infectious complications.
• Of these, pulmonary infections are the leading cause of morbidity and
mortality in the transplant recipient. Depending on the transplant type,
rejection can be hyperacute, acute, or chronic.

8. IMMUNOSUPPRESSIVE DRUGS

9. ACTION OF IMMUNOSUPPRESSIVE DRUGS
DURING PREGNANCY

10. IMMUNE TOLERANCE
• Normally we do not make immune responses against our own
tissue, a concept known as "self-tolerance".
• Determining how the immune system distinguishes between self
and foreign antigens to make the decision between tolerance and
immunity has been a subject of detailed investigation during the
past 50 years.
• In 1945, R.D.Owen made a crucial observation that suggested that
tolerance to self-antigens occurred because the immune system
was exposed to these antigens during early development.

11. TYPES OF TOLERANCE
• Natural or "self" tolerance. This is the failure (a good thing) to attack the
body's own proteins and other antigens. If the immune system should
respond to "self", an autoimmune disease may result.
• Induced tolerance. This is tolerance to external antigens.
Examples:
• deliberately manipulating the immune system to protect us from unpleasant, even
dangerous, allergic reactions to such things as food (e.g. peanuts), insect stings, grass
pollen (hay fever).
• Preventing the immune system from mounting an inflammatory attack against the vast
numbers of harmless (even beneficial) bacteria living in the intestine.

12. • Both B cells and T cells can be made tolerant, but it is more
important to tolerize T cells than B cells because B cells cannot
make antibodies to most antigens without the help of T cells.

13. THEORIES PROPOSED FOR IMMUNOLOGICAL
TOLERANCE
• Clonal Deletion theory, proposed by Burnet, according to which self-reactive
lymphoid cells are destroyed during the development of the immune system in
an individual. For their work Frank M. Burnet and Peter B. Medawar were
awarded the 1960 Nobel Prize in Physiology or Medicine "for discovery of
acquired immunological tolerance.
• Clonal Anergy theory, proposed by Nossal, in which self-reactive T- or B-cells
become inactivated in the normal individual and cannot amplify the immune
response.
• Idiotype Network theory, proposed by Jerne, wherein a network of antibodies
capable of neutralizing self-reactive antibodies exists naturally within the body.

14. MECHANISMS OF IMMUNOLOGICAL TOLERANCE
T-cell Tolerance
• Central Tolerance
• T cells develop in the thymus. As they mature, recombination of gene
segments creates the two chains that make up the T-cell receptor for
antigen (TCR).
• Although the receptors on a single T cell are all alike, there is a virtually
unlimited repertoire of receptor specificities created in the population of T
cells within the thymus.

15. • In the thymus, the epitopes recognized by these receptors consist of a small
molecule, usually a peptide of 6–8 amino acids derived from body proteins; that
is, "self" proteins
• a histocompatibility molecule (encoded by the MHC)
• class II for CD4+ T cells
• class I for CD8+ T cells
• T cells whose receptors bind these epitopes so tightly that they could attack the
cell displaying them are deleted by apoptosis. The T cells that survive
this negative selection leave the thymus and migrate throughout the immune
system
• AIRE stands for autoimmune regulator. Knockout mice and those rare humans
who have no functioning AIRE gene suffer from severe autoimmune disease
especially of their various endocrine organs.

16. Peripheral Tolerance
• The T cells that leave the thymus are relatively — but not
completely — safe. Some will have receptors (TCRs) that can
respond to self antigens that are present in such high
concentration that they can bind to "weak" receptors;
• that they may not have encountered in the thymus.

17. B-CELL TOLERANCE
• The problem of B-cell tolerance is not so acute because B cells
cannot respond to most antigens unless they receive help from T
helper cells.
• Nevertheless, B cells become tolerized to self components and,
like T cells, this occurs both in the bone marrow (central
tolerance) and elsewhere in the body (peripheral tolerance)

18. Central Tolerance
• B cells are formed and mature in the bone marrow. In humans,
over half of the developing B cells produce a BCR able to bind self
components.
• Any cells that produce a receptor for antigen (BCR) that would
bind self components too tightly undergo a process of receptor
editing. They dip again into their pool of gene segments that
encode the light and heavy chains of their BCR and try to make a
new BCR that is not a threat. If they fail, they commit suicide
(apoptosis).

19. • Despite these mechanisms, some of the B cells that migrate out of
the bone marrow continue to express self-reactive BCRs and may
still be able to produce anti-self antibodies. So a mechanism is
needed to tolerize them out in the tissues ("peripheral
tolerance").

20. Peripheral Tolerance
• B cells with a potential for attacking self can be kept in check by
the absence of the T-helper cells they need; that is, T-cell
tolerance is probably the most important (but not the only)
mechanism for maintaining B-cell tolerance.

22. AUTOIMMUNE DISEASES
• Autoimmune diseases like Type 1 diabetes mellitus
• multiple sclerosis (MS)
• systemic lupus erythematosus (SLE)
• some forms of hyperthyroidism
and others represent a failure of self-tolerance.

23. INDUCED TOLERANCE
• Tolerance of Commensal Bacteria
• Treating Allergies
• Transplant Tolerance

24. TOLERANCE OF THE FETUS
• The human fetus is also an allograft, but the mother makes no
attempt to reject it

25. THANK YOU