Immunological Tolerance and Autoimmunity

Question 1

What are the two mechanisms of tolerance and where do they occur?

Answer 1

Central tolerance: takes place in developing lymphocytes in the central lymphoid organs

Peripheral tolerance: mature lymphocytes within the peripheral tissues

Question 2

What are the only cells in the body which express autoimmune regulator (AIRE) proteins?

Answer 2

Thymic epithelial cells

Question 3

What are AIRE proteins used for?

Answer 3

It stimulates thymic epithelial cells to express tissue-restricted Ags (Ags normally expressed in other areas of the body)

Question 4

What happens if a developing T cell has high affinity for a tissue-restricted Ag?

Answer 4

It will either undergo apoptosis or develop into a Treg cell.

Question 5

What could defects in AIRE lead to?

Answer 5

Autoimmune polyendocrinopathy (autoimmunity against more than one endocrine organ)

Question 6

Explain the steps to T cell maturation and the possible outcomes

Answer 6

Stem cell → double negative pro-T cell → pre-T cell → double positive immature T cell

From here if it has weak recognition for MHC class I or II + peptide, it will develop into a CD8+ or CD4+ T cell, respectively. 
If there is no recognition of MHC + peptide, then it results in death by neglect
If there is strong recognition of either MHC I or II + peptide, we get either apoptosis (negative selection) or Treg differentiation

Question 7

What type of cell is allowing peripheral T cell tolerance? How is this done?

Answer 7

Treg cells

If a Treg cell in the periphery binds to a self-cell it starts to upregulate CD25 (AKA IL-2Rα) which starts to bind IL-2 (thought to be able to outcompete naive T cells IL-2Rs), and secrete IL-10 and TGF-β in order to start inhibiting B cells, NK cells, effector T cells, and Naive T cells from continuing with their immune response.

Question 8

What cells carry CTLA-4, and how does it induce tolerance?

Answer 8

Both activated T cells and Treg cells express CTLA-4

Upon CTLA-4 binding to B7 on an APC, the CTLA-4+ cell removes the B7 from the surface of the APC and undergoes endocytosis. Now upon APC binding of T cells, it will result in T cell unresponsiveness (anergy) since there is no costimulator

Question 9

What are two ways a self reactive T cell can undergo apoptosis?

Answer 9

Cell death caused by Ag recognition w/o costimulation leading to the release of apoptotic proteins from the mitochondria

Cell death caused by engagement of death receptors

Question 10

What are 3 ways B cells can undergo central tolerance if it is self-reactive?

Answer 10

It can undergo receptor editing which leads to the expression of a new Ig variable region

It can undergo deletion triggering apoptosis

Or it can have reduced receptor expression and signaling leading to . an anergic B cell floating around

Question 11

What are 3 days a B cell can undergo peripheral tolerance?

Answer 11

We can have functional inactivation leading to an anergic B cell

It can trigger apoptosis leading to deletion

Or it can be regulated by inhibitory receptors (FcγRs) found on the surface of the B cell which are attached to ITIMs within the cytosol in order to downregulate the response

Question 12

What is commensal tolerance?

Answer 12

The idea that specialized cells in the lymphatics of mucosal tissue which recognize normal microbiota, but do not respond.

Cells involved in this include B-1 cells, ẟ/γ T cells, DCs, and a large population of Tregs

Question 13

If DCs localized in the mucosa involved in commensal tolerance are capable of transporting epitopes from the lumen into the submucosa, why does it not lead to an immune response?

Answer 13

They secrete IL-10 and TGF-β while this is done.

Question 14

Why are fetuses known as semi-allogeneic grafts?

Answer 14

Since a baby has both Dad and Mom DNA, only half of the baby is seen as “self” to the moms immune system.

This doesn’t generate an immune response since the mother starts building tolerance w/ Ags present in the seminal fluids

After implantation, Mom will establish a population of Tregs specific for paternal Ags

Question 15

What is autoimmunity?

Answer 15

A misdirection of the adaptive immune response towards healthy cells of the body and a failure to maintain self-tolerance

Question 16

What are some factors that contribute to autoimmunity?

Answer 16

Genes, infections, and environmental factors

Question 17

What are some principle factors in development of autoimmunity?

Answer 17

Inheritance of susceptibility genes PLUS environmental triggers

Question 18

What are some effectors mechanisms of autoimmunity?

Answer 18

Immune complexes, circulating auto-Abs, and auto-reactive T cells

Question 19

What are some clinical manifestations of autoimmune diseases?

Answer 19

Could be organ-specific or systemic

Could be acute or chronic AND progressive

Question 20

What causes autoimmunity to be chronic AND progressive?

Answer 20

Chronicity is due to the many amplification loops since you are reacting to tissue that is always going to be there

Persistence and progression due to epitope spreading where response against one self-Ag causes damage that leads to the release of other Ags (e.g., PAMPs)

Question 21

What are some environmental causes of the development of autoimmune diseases?

Answer 21

Infection (rheumatic fever).
Physical trauma where you introduce immune cells where they shouldn’t be (sympathetic ophthalmia).
Drug-induced (SLE)

Question 22

What are a couple mechanisms that have been postulated into how infection may lead to autoimmunity?

Answer 22

Activation of APCs: A self Ag may be bound to the MHC of an APC while at the same time a microbe is taken up leading to the expression of B7 causing accidental activation of T cells against the wrong Ag (self).

Molecular mimicry: Where a microbe may cause activation against an Ag that happens to look a lot like self-Ags