CH. 12: Tolerance and Autoimmunity

Question 1

Describe mechanisms of central tolerance.
- Deletion, anergy, receptor editing

Answer 1

T and B cells:
- deletion: autoreactive T and B cells are eliminated from repertoire via apoptosis

B cells:
- anergy: functional inactivation of lymphocyte, resulting in unresponsiveness upon further contact with antigen; does not proliferate and differentiate when activated; important for prevention of autoantibody-specific B cells from secreting autoantibodies
- receptor editing: allows immature B cells expressing a BCR specific for a self-antigen to replace it with a BCR specific for a nonself-antigen

Question 2

Describe importance of receptor avidity in tolerance.

Answer 2

Avidity (strength) of interaction of BCR or TCR with its autoantigen influences cell fate:
- high avidity for autoantigen = receptor editing
- moderate avidity = anergy
- weak avidity = B cell become clonally ignorant

Question 3

Describe mechanics of peripheral tolerance.
- Anergy, regulatory T cells, Fas-FasL interactions

Answer 3

Anergy:
- B cells = lack of T cell help; anergic B cells cannot compete with non-anergic B cells and eventually die by apoptosis
- T cells = lack of co-stimulatory signal; T cell fails to be activated

Regulatory T cells:
- ability to downregulate T cell function; require specific TCR, but once activated, their suppressive function is nonspecific
- suppresses autoreactive effector CD4+ and CD8+ T cells, B cells, dendritic cells, NK cells

Fas-FasL interactions:
- ligation of Fas initiates apoptosis in cell expressing Fas
- FADD (Fas-associated death domain)
- T cells can express Fas and FasL (may be both a target and perpetrator)

Question 4

What are immune privilege sites? Name the sites (5).

Answer 4

• sites in body that don’t develop immune responses to pathogens, tumor cells, or histoincompatible tissue implants
• eye, testis, brain, ovary, placenta
• IL-10, TGF-beta, and FasL establish immune privilege

Question 5

Describe genetic susceptibility of autoimmunity.

Answer 5

• no individual gene is sufficient to elicit the disease; products of many genes are needed to interact with one another
• HLA complex; even if u possess the HLA allele, it doesn’t mean you will develop the disease

HLA = “human leukocyte antigen”

Question 6

Describe environmental susceptibility of autoimmunity.

Answer 6

Some environmental factors (either infectious or noninfectious) can trigger autoimmunity:
- inducing release of sequestered (found in immune privileged sites) antigens
- molecular mimicry
- polyclonal activators may nonspecifically activate all B or T cells; some may be autoreactive and trigger autoimmunity; PAMPs

Question 7

Describe drug and hormonal triggers of autoimmunity.

Answer 7

• certain drugs can chemically alter epitope of self-antigen to render it immunogenic, resulting in autoimmunity
• drug-induced autoimmune diseases are self-limiting, so disease disappears when drug is discontinued

Question 8

Describe therapeutic strategies (4) for autoimmune diseases.

Answer 8

• cytotoxic or immunosuppressive drugs
• anti-cytokine therapies
• mAb that block co-stimulatory interactions or induce cell depletion
• activation of suppressor T cells (regulation of balance between subsets of T cells)