Immunological Tolerance

Question 1

Describe immunological tolerance

Answer 1

We become immunologically tolerant to auto-antigens (self-antigens) and intolerant to foreign antigens (pathogenic). Specific immunological tolerance prevents undesirable immune responses to auto-antigens. Auto-immune pathology arises due to immunological intolerance to auto-antigens.

Question 2

What is central tolerance?

Answer 2

Immunological tolerance in location of lymphocyte maturation site; thymus and bone marrow.

Question 3

What is peripheral tolerance?

Answer 3

Outside bone marrow and thymus

Question 4

Why does the IS focus more on T cell tolerance rather than B cells?

Answer 4

Because helper T cells help B cell make antibody and mediate Tc activation. Many types of adaptive immune responses will not occur in the absence of T helper cells.

Question 5

Describe the structure of the Thymus

Answer 5

It is a primary lymphoid organ, located in the thoracic cavity. Lobulated, with an outer cortex and an inner medulla of each lobule. It has a collagenous capsule with depressions marking the septum. It is the site of T cell maturation and T cells of different stages of development can be found here.

Question 6

What is a thymocyte?

Answer 6

It is an early T cell; the majority of T cellsin the thymus

Question 7

Describe the process of T cell development.

Answer 7

Haematopoietic stem cells in the bone marrow begin lymphoid differentiation pathway and some lymphoid precursor cells then leave the bone marrow and enter the thymus via the circulation; lymphoblasts. Genetic recombinatioon of T cell receptor genes occurs initiating T cell development.

Question 8

What cells, other than T cells are present in the thymus?

Answer 8

cortical epithelial, medullary epithelial cells, nurse cells

Question 9

What do nurse cells do?

Answer 9

they are in intimate contact with thymocyte and produce cytokines and growth factors to aid thymocyte development.

Question 10

Which structures of the thymus facilitate the large degree of death in the thymus?

Answer 10

Hassal’s corpuscles, they remove dead and dying T cells

Question 11

Describe the negative selection that occurs in the thymus

Answer 11

The recombination of TCR genes is random and TCR need to recognise peptides presented by MHC; TCRs produced that cannot recognise MHC are removed by phagocytosis. T cells which have recombined their TCR genes into a conformation which can recognise auto-immune antigens are removed, failure to do this results in autoimmune disease. Negative selection occurs via induced apoptosis in T cells with a high affinity for self MHC or for self MHC+peptides.

Question 12

Describe the positive selection that occurs in the thymus

Answer 12

There is positive selection for T cells which can recognise MHC by thumic epithelial cellswhich express both MHC-I and II, which rescue T cells recognising self MHC.

Question 13

What is thymic education?

Answer 13

The positive and negative selection of T cells. Positive selection via apoptosis by neglect (default is to die without stimulation) of T cells that fail to recognise self MHC. Thymic education results in a single positve T cell. During T cell development, MHC-II interaction = CD8 gene switched off. MHC-I interaction = CD4 gene switched off. T cells then leave the thymus.

Question 14

What are double negative T cells?

Answer 14

Those that do not have CD4 or 8, they become double positive in the thymus.

Question 15

What is the net migration pathway in the thymus?

Answer 15

Is via the corical-medullary junction, deeper into the cortex and then enter the medulla and leave the thymus.

Question 16

What molecules and process do T cell precursor cells undergo?

Answer 16

Rearrangement of TCR gene, double positive + CD3. It is an immature thymocyte.

Question 17

What is AIRE?

Answer 17

The autoimmune regulator; a transcription factor that causes thymic expression of tissue-specific self antigens (such as insulin) to faciliate negative selection. Thyroglobin (synthesised in the thyroid) also enters the thymus for negative selevtion. Many genes are switched on and expressed in the thymus however not all. Tolerance via negative selection results. Deficiency of AIRE transcription factor; some autoimmune disorders.

Question 18

Where does peripheral tolerance occur?

Answer 18

Outside the thymus or bone marrow and deals with any self-reactive lymphocytes that escape central tolerance.

Question 19

What is anergy?

Answer 19

Inactivation of specific lymphocytes, and is induced if antigen is encountered in the absence of co-stimulation. Anergy can be reversed if infection is present; APCs upregulation of costimulatory molecules, enable activation.

Question 20

What to Treg do?

Answer 20

They mediate the downregulation of inappropriate immune responses; can be natural or induced. They can suppress dendritic, T and B cells by increasing the expression of CTLA-4. Treg can produce cytotoxic granules and immunusuppressive cytokines such as IL-10 and TGFbeta.

Question 21

How do natural Treg arise? (nTreg)

Answer 21

They express Foxp3 transcription factor with cD25 present on the cell surface of the T cell. Foxp3+CD25+T cells develop in the thymus and when they leave they will be readily able to suppress immune responses.

Question 22

How do induced Treg arise? (iTreg)

Answer 22

A thymic cell not expressing Foxp3 or CD25 but when they leave the thymus (in the periphery) they can act as a regulatory T cell by encountering an antigen which induces expression of Foxp3 and CD25.

Question 23

What does Foxp3 do?

Answer 23

modifies the expression of genes with immunoregulatory function, such as acetylases and are upregulated causing an increase in CD25, CTLA4 and GITR (glucocorticoid-inducing TNG-related receptor). Other genes are deacetylases which decrease the expression of IL-2 and IFNgamma. CD25 is a component of IL-2 receptor; downregulation via IL-2 deprivation.

Question 24

What are the mechanisms of immunological tolerance?

Answer 24

Silence (isolation) vie no Ag receptors (BCR/TCR) 
Deletion
Anergy
Helplessness - no T helper cells
Suppression of activated cells.