(L29) Immunological Tolerance and Autoimmunity

Question 1

Differentiate between central and peripheral tolerance.
How are each developed and where?

L29 S3-4

Answer 1

Central tolerance:
-occurs in primary lymphoid organs during development of immature lymphocytes
-caused by:
—deletion of self-reactive lymphocytes
—B cell editing
—Treg cell

Peripheral tolerance:
-occurs outside of primary lymphoid organs in mature self-reactive lymphocytes
-caused by:
—anergy
—deletion
—suppression by Treg cells

Question 2

Which transcription factor in the thymus is necessary for development of central tolerance and why?

L29 S6;31

Answer 2

AIRE (autoimmune regulator)

Allows expression of tissue restricted Ags in thymus epithelium where T cells are tested for self-reactivity

Question 3

What are the characteristic markers of Treg cells?

L29 S10

Answer 3

CD4+
CD25+
FOXP3+
CTLA-4+

Question 4

How are Treg cells developed?

L29 S10-11

Answer 4

T cells with strong TCR interaction with self-Ags but below threshold for negative selection

They produce anti-apoptotic factors that prevent negative selection

Express FOXP3, unique to Treg, following exposure to retinoic acid from DCs

Question 5

How do Treg cells function?

L29 S13;41

Answer 5

Inhibition of APC response:
-when presented Ag, they release anti-inflammatory cytokine (IL-10 and TGF-β) inhibiting APC activation and subsequent T cell activation

Inhibition of T cells (indirect):

• Tregs constitutively express IL-2Rα (CD25) which binds free IL-2, preventing it from activating other T cells while still activating Tregs
• Tregs constitutively express CTLA-4 which binds CD80/86 preventing it from being with other T cells

Question 6

How are immune complexes cleared from the blood?

L29 S36

Answer 6

Immune complexes consisting of Ag:Ab complexes activate complement.

C3b is deposited on complex and binds to CR1 on RBCs

RBCs carry immune complexes to the liver and spleen where they are picked up by Mφs by CR1 and FcγR

Question 7

How is T cell activation regulated by CTLA-4?

L29 S39-41

Answer 7

CTLA-4 is homologous with CD28 and also binds CD80/86, however, it has ITIMs and instead generates an inhibitory signal

CTLA-4 is expressed at low levels on resting T cells, but expression is proportionally increased by binding of Ag to TCR.

The stronger the Ag stimulation of TCR, the more CTLA-4 is produced. This attenuated T cell response preventing over activation

Question 8

What are immune privileged sites and how do they relate to autoimmunity?

What are examples of immune privileged sites?

L29 S47

Answer 8

Sites that T cells and Abs do not have access to.
Proteins of these sites are also not tested for autoimmunity so damage allowing T cells or Abs to enter can result in autoimmunity.

Examples:

• eye (retina and both chambers)
• brain
• pregnant uterus
• ovaries/testis
• adrenal cortex
• hair follicles

Question 9

What set of genes have the highest association with autoimmunity when mutated?

L29 S49-50

Answer 9

HLA genes, most commonly HLA-DR and HLA-DQ

Question 10

What mechanisms of microbial initiation of autoimmune disorders are there?

L29 S53

Answer 10

Molecular mimicry:

• microbial Ag is similar to self Ag
• Rheumatic fever: streptococcal Ag similar to cardiac myosin
• Multiple sclerosis: viral Ags similar to myelin basic protein

Polyclonal activation:
-robust inflammatory response results in activation of auto-reactive lymphocytes

Release of sequestered self-Ags:
-microbes kill host cells releasing self-Ags that are not tested for autoimmunity