Tolerance

Question 1

What does tolerance prevent?

Answer 1

adaptive immune system responses to self-antigens and innocuous environmental antigens

Question 2

Describe immune tolerance

Answer 2

• failure to attack self-antigens
• not a failure to recognise an antigen
• active response to a particular antigen
• just as specific as an immune response

Question 3

What are the 2 types of tolerance and what defines them?

Answer 3

• central - primary lymphoid organs
• peripheral - secondary lymphoid organs
  defined by where the state of tolerance is induced for the specific cell

Question 4

Describe central tolerance in T cells

Answer 4

• occurs in thymus
• selection process of cells via TCRs
• during early development of T cells before they are mature and able to influence immune response

Question 5

Describe bone marrow and tolerance

Answer 5

• pre-T cells aka Haematopoietic stem cells migrate through bloodstream to thymus
• pre-T cells: CD4-, CD8-, TCR-

Question 6

Describe tolerance in the thymus cortex

Answer 6

• TCR+ TCR gene rearrangements have occurred
• CD8+ and CD4+
• cortical epithelial cells present self antigen via MHC class I and II to thymocytes
• no interaction = apoptosis ‘death by neglect’
• high affinity interaction - apoptosis, negative selection
• low affinity interaction - positive selection

Question 7

Describe what occurs when TCR interacts with MHC class I and class II

Answer 7

• MHC class I - CD8+ only
• MHC class II - CD4+ only

Question 8

Describe tolerance in the thymus medulla

Answer 8

• medullary epithelial cells and/or dendritic cells interact with thymocytes
• medullary epithelial cells express proteins from everywhere in body
• high affinity interaction - apoptosis, negative selection
• mature T cells migrate to periphery

Question 9

Describe B cells and Central Tolerance

Answer 9

• occurs in bone marrow
• selection process of cells via immunoglobulin
• during early development of B cells
• before they are mature and secreting antibodies

Question 10

Describe bone marrow and B cells in regards to tolerance

Answer 10

• immature B cells - surface IgM+
• also stromal cells
• no interaction with self-antigen

Question 11

Describe receptor editing of B cells in bone marrow

Answer 11

• auto-reactive B cells signalled to reattempt Ig receptor rearrangement
• negative selection

Question 12

Describe clonal deletion

Answer 12

• in bone marrow
• strong interaction with self antigen
• <10% immature B cells leave bone marrow
• negative selection

Question 13

Describe B cells in the spleen in tolerance

Answer 13

• continual production of immature B cells
• even after leaving bone marrow - most do not last
• survival signs required from FDCs present in spleen
• not central tolerance entirely but related

Question 14

Describe how central tolerance is less stringent for B cells

Answer 14

• limited - not all proteins expressed on stromal cells
• likely due to requirement for Th cell help to activate most B cells
• antigen-receptor binding and activation of B cell by T cell leads to proliferation and differentiation of B cell to acquire effector function

Question 15

Why is peripheral tolerance needed?

Answer 15

• innocuous environmental agents
• pregnancy
• failure of central tolerance
• somatic hypermutation

Question 16

Describe somatic hypermutation

Answer 16

• generates novel B-cell specificities within germinal centre
• some of these B cells may now be able to bind self antigens
• encounter of autoreactive B cell with self antigen within germinal centres causes apoptosis

Question 17

What are the different sections within peripheral tolerance?

Answer 17

• clonal anergy
• active regulation
• clonal ignorance

Question 18

Describe clonal anergy

Answer 18

• process for immature B cells in spleen can lead to anergy or deletion
• dependent on co-stimulatory molecules (cytokines, Th cells), type of antigen

Question 19

Describe active regulation

Answer 19

• Treg cells: natural and induced
• natural formed in thymus
• induced formed in periphery

Question 20

Describe clonal ignorance

Answer 20

• self-antigen presented in too low a concentration
• change can occur in diseases such as cancer
• active anti-inflammatory, anti-lymphocyte mechanisms

Question 21

Describe chances in immunoprivileged sites in clonal ignorance

Answer 21

• stimulation of immune responses against immunoprivileged sites can occur
• appears to be antigens are targets for immune response but need to be activated elsewhere
• e.g., reactive sympathetic ophthalmia

Question 22

Describe reactive sympathetic ophthalmia

Answer 22

• inflammation of uveal layer of the eye (uveitis)
• injury allows access to previously hidden ocular antigens
• autoimmune (hypersensitivity type IV) response damages eyes