Chp. 2 AutoImmune Disorders Overview

Question 1

What are autoimmune diseases characterized by?

Answer 1

Immune mediated damage of self tissues.

Prevalence in the US is 1%-2%

Question 2

What does autoimmune diseases involve?

Answer 2

They involve a loss of self tolerance

Question 3

What is loss of self tolerance due to?

Answer 3

Self reactive lymphocytes (B or T).

Normally lymphocytes develop central (in thymus for T cells or bone marrow for B cells) or peripheral tolerance.

Question 4

How is central tolerance developed in the thymus?

Answer 4

Central tolerance leads to apoptosis of self reactive T cells and generation of regulatory T cells (T-regs).

T cell made in bone marrow, travels to and enters thymus as a stem cell. Undergoes two rounds of selection, + and -.

It undergoes + selection as a double + thymocyte (CD4/CD8). It is then asked, “do you recognize Ag on MHC I or II). Takes place in cortex.

Next as either a CD4 or CD8 (single positive) it undergoes - selection where it is asked, “ do you bind self Ag? This takes place in medulla

During this time, it is presented peripheral self Ag on dendrites or medullary epithelial cells (MEC) on MHC.

MEC cells require a fully functional AIRE gene in order to express the entire subset of self Ag.

Question 5

What is AIRE and what happens if there is a mutation in this gene?

Answer 5

It is a transcription factor in MECs that allow it to present self Ag to single positive thymocytes. If there is a mutation, some of the self Ag won’t be expressed and those thymocytes that would react to the Ag not expressed will “escape” out of the thymus, possibly causing autoimmune disease.

Question 6

What do AIRE mutations result in?

Answer 6

Polyendocrine Syndrome:

HypoPTH
Adrenal Failure
Chronic Candida Infections

Question 7

What does central tolerance in the Bone Marrow lead to?

Answer 7

It leads to B cell receptor editing or B cell apoptosis

Question 8

How is central tolerance in the bone marrow developed?

Answer 8

B cells are produced in the bone marrow as stem cells. In the bone marrow they undergo - selection.

• selection: B cells presented peripheral self Ag by a dendrite (not an MEC, those are only in the medulla of the thymus). Does it bind?

If yes, then 1 of 2 things will happen:
1. RECEPTOR EDITING. Rag genes will be activated to rearrange. This will edit the light chain, and hopefully the B cell will no longer bind self Ag.

2. Apoptosis via mitochondrial pathway.

Question 9

What are T-regs and what is their functional role?

Answer 9

T-regs actively suppress the activation of the immune system and prevent pathological self reactivity (autoimmune disease). Their role is evidenced when they are not around. An example is IPEX, a severe autoimmune disease characterized by a genetic deficiency in T-regs

Question 10

What cells do T-regs suppress and what cytokines do they secrete? What effect do these cytokines have?

Answer 10

They suppress T cell activation (thereby suppressing autoimmunity). It does this by cock blocking the B7-CD28 connection by binding to B7 with CTLA-4

AND secretes:

IL-10:
-Inhibits MHC II and B7 on APCs

TGF-B:
-Inhibits macrophage activation

Generally these two cytokines are anti-inflammatory. Suppresses the immune system.

Question 11

What does IL-10 from T-regs do? TGF-B?

Answer 11

It inhibits MHC II and B7 on APCs. This is the way it suppresses the immune system.

TGF-B decreases macrophage activity

Question 12

How do T-regs suppress T cell activation?

Answer 12

Interferes with the auto reactive T-cell’s CD28 binding to B7 on APCs by using its CTLA-4 to bind to B7.

Question 13

What two processes does peripheral tolerance lead to? Meaning what happens to a lymphocyte in the body (periphery) that has been found to be auto reactive?

Answer 13

Anergy or Apoptosis

Question 14

When would a lymphocyte undergo anergy?

Answer 14

It would undergo anergy when it becomes activated by the first signal only - which is Ag presented on MHC II. The other signal (B7-CD28) is not present. When the the lymphocyte does this, it undergoes anergy which is functional inactivation rather than death, and it can no longer respond to Ag. B cells can also become anergic if they react to Ag in the absence of specific T-Helper Cells.

Question 15

What is the genotype of T reg cells? What cytokine is needed for their generation and survival?

Answer 15

Usu it is CD4, CD25, FoxP3. FoxP3 is a unique transcription factor that is necessary for the development of CD25 T-regs.

The cytokine needed is IL-2. This is required for T-reg generation and survival.

Question 16

What is FoxP3 and if its mutated, what effect would this have on immunity?

Answer 16

It is a transcription factor expressed by T-regs that is responsible for their development.

Mutations in FoxP3 will lead to the severe autoimmune disease Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked Syndrome or IPEX. This is disease is characterized by a decrease in T-regs

Question 17

What are CD25 polymorphisms associated with?

Answer 17

Polymorphisms associated with CD25 lead to

AUTOIMMUNITY

Namely, Multiple Sclerosis and DM Type I

Question 18

What would a self reactive lymphocyte have to do to be programmed to undergo apoptosis?

Answer 18

They would have to become activated w/o the signal AGAIN!! They violated a second time. Now they undergo cell death. They are out of there

Question 19

What apoptotic pathways can auto reactive lymphocytes undergo?

Answer 19

Ok, so they have to undergo apoptosis. Let me count the ways?

1. The Death Receptor FAS.
   - Fas is a member of the TNF receptor family. When its engaged by its ligand coexpressed on the same cell or neighboring cells, it spells death for the cell. Self reactive B cells are deleted this same way with Fas LIGAND ON T CELLS
2. Mitochondrial Pathway: This does not depend on the death receptor, but is involved with deletion of auto reactive lymphocytes

Question 20

If there is a mutation if the Fas Pathway, what is the resulting disease?

Answer 20

The disease is called Autoimmune Lymphoproliferative Syndrome. This disease is characterized by lymphadenopathy and autoAbs (i.e. IgG twd cells) including anti-DNA

Basically this is mostly a mutation in the Fas receptor, but it could be the ligand This is where there is a buildup of auto reactive lymphocytes bc they can’t undergo apoptosis bc the Fas or death pathway isn’t working. These auto reactive lymphocytes proliferate and develop IgG toward cells SO LOOK FOR CYTOPENIAS!!! i.e. anemias, thrombocytopenias.

Also bc they proliferate there will be a ton of them so the tissue where they chill in (reticulo-endothelial) will be enlarged. i.e. lymph nodes and spleen. This is LYMPHADENOPATHY AND HEPATOSPLENOMEGALY.

WILL EVENTUALLY LEAD TO LYMPHOMA (blood cell tumor from lymphocytes)

Question 21

Who are autoimmune disorders more commonly seen in?

Answer 21

Women, usu of childbearing age. Estrogen is thought to be the culprit bc it is thought to reduce apoptosis of self reactive B cells.

Question 22

What is the likely cause of autoimmunity?

Answer 22

Likely a trigger in a genetically susceptible person. There’s a high incidence in twins having the same autoimmune disease

Question 23

What are AI diseases associated with?

Answer 23

Associated with certain HLA subtypes, especially HLA-B27 and PTPN22.

HLA-B27 associated with ankylosing spondalitis

Non HLA genes would be PTPN22 which is a tyrosine phosphatase. Any polymoprphisms or mutations will cause a decrease in the signal necessary for T and B cell responsiveness.

Question 24

What do environmental triggers, well, trigger?

Answer 24

Bystander activation or molecular mimicry

Question 25

What is epitope spreading?

Answer 25

When the immune reaction changes from only targeting the primary epitope to targeting other epitopes. In contrast to molecular mimicry, the other epitopes need not be structurally similar. (epitope is part of an Ag that is recognized by the immune system)

Question 26

How are overlapping features of autoimmune disorders explained?

Answer 26

EPITOPE SPREADING

Question 27

What is molecular mimicry?

Answer 27

It is when an exogenous Ag shares structural similarities with certain host Ags, and thus amplify the immune response. The immune response is now attacking the host tissues. ex is rheumatic fever with GAS.