Tolerance/autoimmunity

Front 1

Summary of CMI response:

Back 1

Front 2

Which form of IgM is a pentamer?
Which is a monomer?

Back 2

Membrane-bound form is a monomer.
Secreted IgM in serum is a pentamer.

Front 3

Summary of the humoral immune response:

Back 3

Front 4

What is immunological tolerance?
two levels?
describe them.

Back 4

-UNRESPONSIVENESS TO SELF ANTIGENS

1. Central Tolerance: serves to delete self-reactive clones of lymphocytes before the cells are allowed to mature if they possess receptors that recognize self antigens with high affinity.

2. Peripheral Tolerance: inactivates or regulates self-reactive lymphocytes that survive the initial screening process, complete their maturation and enter peripheral tissues.

Front 5

3 MECHANISMS OF TOLERANCE INDUCTION (peripheral):

Back 5

Clonal Deletion

Clonal Anergy

Suppression

Front 6

Describe the process of central tolerance in T cells:

Back 6

Front 7

What determines if a developing thymocyte will become a nTreg cell?

Back 7

-Must have intermediate affinity for self antigen
-FoxP3

Front 8

Why do we need Peripheral Tolerance processes?

Back 8

-Central tolerance is not a foolproof process; 100% of possible self-reactive T cells are not deleted.

-Peripheral tolerance prevents T cell responses to self antigens in peripheral tissues.

Front 9

3 steps in the activation of T cells:

Back 9

Front 10

How is clonal anergy promoted?

Back 10

When APCs are presenting self-antigen to a T cell, the costimulatory response occurs via the CTLA-4 receptor on the T cell interacting with the CTLA-4L receptor on the APC. This is an INHIBITORY interaction.

The T can't respond; it becomes "anergic" to the self-antigen.

Front 11

IMMUNE SUPPRESSION BY REGULATORY T CELLS (Treg):
-where do they arise?
-what important transcription factor is needed?
-what cytokine is needed?

Back 11

-Most Treg cells are generated in the thymus, but may also arise after induction in the periphery, by self antigens.
 
-The development and function of these cells are dependent on the transcription factor Foxp3 (forkhead box P3)
 
-Most are CD4+ and are dependent on the cytokine IL-2 for survival and function.

Front 12

What are the steps in making Tregs?

Back 12

Front 13

How do Tregs function in peripheral tolerance? 4

Back 13

*Tregs have high expression of IL-2Rs
*More of low-affinity alpha chain of IL-2R
1) Denies other T cells IL-2, thus inhibiting their function against self-antigen.
2) They secrete inhibitory cytokines like TGF-ß.
3) Interfere with APC function (unknown mechanism)
4) Can directly kill T cells if needed.

Front 14

CLONAL DELETION BY ACTIVATION INDUCED CELL DEATH (AICD):

Back 14

-T cells in the periphery can be triggered to die by apoptosis in response to recognition of self antigens. This mechanism is called AICD.
*Fas/FasL are key in this process.
*There's a lack of IL-2 in AICD.

Front 15

Describe CENTRAL TOLERANCE IN B CELLS: 2

Back 15

When immature B cells strongly interact with self antigens in the bone marrow, the B cells either change their receptor specificity (receptor editing) or die by clonal deletion (negative selection).

Front 16

Describe peripheral anergy induction in B cells:

Back 16

-B and T cells require cooperation in the lymph nodes to keep each other stimulated.
-A mature B cell that recognizes a self antigen without T cell help is functionally inactivated (anergic).

Front 17

What happens when central and peripheral tolerance fails?

Back 17

Autoimmunity

Front 18

What is autoimmunity?

Back 18

-Autoimmunity is an immune response against autologous or self antigens.

-It results when central and peripheral tolerance mechanisms fail!
 
-Autoimmune disease arises when autoimmunity causes clinical damage or destruction of self proteins, cells, and organs by the activation and effector functions of autoreactive T and B cells.

Front 19

What events are required for autoimmune disease? 4

Back 19

Front 20

2 key factors in development of autoimmunity:

Back 20

The principal factors in the development of autoimmunity are the inheritance of susceptibility genes and environmental triggers, such as infections, inflammation, or injury.

Front 21

Most important genes in autoimmunity?

Back 21

The most important genes conferring predisposition to autoimmunity are the MHC (HLA) genes.

Front 22

One example of genetic involvement in developing an autoimmune disorder?

Back 22

Ankylosing spondylitis has a really high identified risk with the B27 HLA allele.

Front 23

Non-HLA genes involved in autoimmunity? 5

Back 23

AIRE
Fas/FasL
Foxp3
IL-2
IL-2R alpha/ß

*Failure of peripheral tolerance is the key level in developing autoimmunity.

Front 24

Discuss influence of external factors in developing autoimmunity:

Back 24

-inflammation, infection, etc.
-molecular mimicry

Front 25

2 main mechanisms by which external factors promote autoimmunity:

Back 25

Mechanisms by which pathogens may promote autoimmunity include:
  1. Inflammation
2. Molecular mimicry

Infections may activate self-reactive lymphocytes, thereby triggering the development of autoimmune diseases.

Front 26

How does inflammation promote autoimmunity?

Back 26

The inflammatory microenvironment induced by infection “breaks” peripheral tolerance and promotes activation of self-reactive lymphocytes.

-xs cytokines --> xs activation of APCs

Front 27

How does molecular mimicry promote autoimmunity?

Back 27

Occurs when microbial antigenic determinants cross-react with host self antigens.

Front 28

Good example of molecular mimicry in autoimmunity?

Back 28

Infection by Streptococcus pyogenes and development of Rheumatic fever.

-M PRO similar to cardiac tissue PROs

-It's suspected this is happening with MS/EBV.

Front 29

Two broad classes of autoimmune disease based on the clinical manifestations of the disease:
2 examples of each

Back 29

1) Organ-specific autoimmunity
Hashimoto thyroiditis
Myasthenia gravis

2) Systemic autoimmunity
Ankylosing spondylitis
Systemic lupus erythematosus

Front 30

Briefly list the pathologies that can be results of autoimmune disorders:

Back 30

Self-reactive antibodies, leading to type II and type III hypersensitivity responses.
 
Cell-mediated injury (type IV hypersensitivity). These may include cytotoxic T cell responses or macrophages driven by DTH responses.
 
May result from both humoral and cell-mediated injury.