Lecture 1 - The making and breaking of tolerance to self- antigens

Question 1

what are roles of the immune system ?

Answer 1

defence against infection. a lower immunity leads to increased susceptibility to infections eg AIDS
Vaccination boosts immune defense and protects against infections

recognises and responds to tissue grafts and newly introduced proteins; immune responses are barriers to transplantation and gene therapy

Defense against tumours allows potential for immunotherapy of cancer

abnormalities of the immune system causing Allergic diseases, immunodeficiencies and autoimmune disorders

Question 2

What is tolerance ?

Answer 2

tolerance refers to the specific immunological non reactivity to an antigen such as the body tolerance to self antigens and tolerance to non-self antigens (pathogens)

Question 3

what are immunological features of tolerance ?

Answer 3

Tolerance is an active immune response, it is antigen specific, and it has immune memory. Tolerance is different from non-specific immuno-suppression and immunodeficiency

Question 4

how does the immune system distinguish between self and non-self antigens?

Answer 4

Immune system distinguishes self and non-self antigens through central and peripheral tolerance.

central tolerance is the control checkpoints of the immune cell development by non self reactive T cells development in the thymus and non self reactive B cells development in the bone marrow

peripheral tolerance is the control of the immune response in the peripheral organs such as the spleen, lymph nodes and other tissues

Question 5

describe how the process in central tolerance allows a functional immune system.

Answer 5

A functional immune system requires the selection of T lymphocytes expressing receptors that are major histocompatibility complex restricted but tolerant to self-antigens.

Positive and negative selections take place in the thymus.

Positive selection is the process that focuses the T cell receptor to recognise peptides bound to self- MHC molecules.

Negative selection refers to the process by which T cells that react stronly with self antigens are removed

Question 6

describe the process of T cell development

Answer 6

1. T cell progenitors develop in the bone marrow and migrate to the thymus
2. positive and negative selection takes place in the thymus.
3. mature T cells migrate to the peripheral lymphoid organs
4. activated T cells migrate to the sites of infection

Question 7

what does positive vs negative selection of t cells act on?

Answer 7

Positive selection acts on a repertoire of T cell receptors with inherent specifically for MHC molecules .

in negative selection, T cells that react strongly with self antigens are deleted in the thymus

The expression of the self-proteins in thymic medulla is controlled by a gene called AIRE

Question 8

what does AIRE do?

Answer 8

expression of self proteins in peripheral tissues is expressed by AIRE IN THE THYMUS

AIRE promotes the expression of self antigens in thymus, thus delete auto T cells

Question 9

describe the development of B cells

Answer 9

1. generation of B cells in the bone marrow
2. negative selection in the bone marrow
3. migration of B cells to the peripheral lymphoid organs and peripheral activation
4. antibody secretion and memory cells in the bone amaro and lymphoid tissue

An immature Bc that strongly recognize self-Ags (e.g. a multivalent one with several epitopes) either changes its Ag receptor (receptor editing) or dies by apoptosis (negative selection).

Question 10

what happens to majority f self reactive b and T cells ?

Answer 10

Majority of self-reactive T and B cells are deleted via central tolerance in the thymus and bone marrow. Some autoreactive T and B cells escape to the periphery

Question 11

describe peripheral tolerance

Answer 11

Lymphocytes that encounter large number of self-antigens for the first time in the periphery are eliminated or inactivated

methods of peripheral tolerance include;
Activation-induced cell death
Clonal anergy
Clonal ignorance
Suppression through regulatory cells

Question 12

what is clonal ignorance?

Answer 12

Clonal ignorance occurs when antigens are isolated d in the immune privileged sites such as brain, eye, testis, uterus, hamster cheek pouch

Question 13

describe how damage to immune privileged site can induce autoimmune response (sympathetic uveitis)

Answer 13

In the case of sympathetic uveitis, if one eye experiences trauma, the immune privilege of that eye may be compromised. The damaged tissue releases antigens that can trigger an immune response. Since the immune privilege is disrupted, the immune system may recognize these released antigens as foreign or harmful.

In sympathetic uveitis, the immune response can cause inflammation and damage to the uvea (the middle layer of the eye) in both eyes.

Question 14

what does the breakdown of self tolerance lead to?

Answer 14

autoimmunity.

Question 15

describe innate vs immune response

Answer 15

innate resposne -ce llualr and humoral components: Response is nonspecific, i.e. against foreign cells or substances without recognising their specific pathogen antigens
Response is fast (within minutes) – phagocytosis and inflammatory
Response is mediated by the important receptors on innate immune cells, which are activated and produce proteins (e.g. chemokines and cytokines).
The response does not have memory

adaptive immune response: Response is specific and diverse, i.e. against foreign cells or substances via recognising their specific pathogen antigens
Response is slow (within days) –
Response is mediated by the important receptors on T and B cells, which are activated, clonal expansion, and produce proteins (e.g. chemokines and cytokines) and antibodies
The response has memory

Question 16

describe the antigen recognition and a T cell function in adaptive immune response

Answer 16

Antigen presenting cells (APCs) such as dendritic cells and macrophages phagocytose pathogens and present pathogen antigens to the TCR in the context of Major Histocompatibility Complex (MHC) to activate CD8 T cells (MHC-I, expressed onall mammalian cells) or CD4 T cells (MHC-II, expressed on professional APCs).