Conditions that Predispose to Autoimmunity & Tx Strategies

Question 1

What are genetic risk factors for autoimmunity?

Answer 1

1. gender: greater numbers in women for most conditions
2. defects in genes encoding immunoregulatory proteins: AIRE, FoxP3, CTLA-4
3. inheritance of particular HLA alleles

Question 2

How can FoxP3 and CTLA-4 defects lead to autoimmunity?

Answer 2

Due to loss of Treg fxn

Question 3

What are environmental risk factors for autoimmunity?

Answer 3

1. exposure to altered self-Ags
2. molecular mimicry
3. sequestered self antigens
4. hygiene hypothesis

Question 4

Explain the genetic risk factor of inherited HLA alleles

Answer 4

Some HLA alleles are strongly correlated with certain autoimmune diseases. It’s hypothesized that these alleles may be best able to present the particular self Ags to autoreactive T cells.

Question 5

Explain the environmental risk factor of altered self antigens with an example

Answer 5

Ex. smoking sig. increases risk of developing RA in individuals who express MHC class II allele: HLA-DRB104. Smokers have elevated levels of modified proteins due to conversion of arginine to citrulline. It’s hypothesized that HLA-DRB104 presents these altered self antigens to T cells, inducing an autoimmune response

Question 6

Explain the environmental risk factor of molecular mimicry

Answer 6

Prior exposure to antigens may induce memory B and memory T cells, whose Ag-specific receptors cross react with self antigens.

Question 7

Give an example of molecular mimicry

Answer 7

It is well established in rheumatic fever: antibodies induced in response to infection with streptococcal bacteria can cross react against heart tissue epitopes that are structurally similar to the bacterial cell wall epitopes

Question 8

Explain the environmental risk factor of exposure to sequestered self antigens

Answer 8

Trauma to tissues may expose immune system to sequestered Ags derived from normally immune privileged sites.

Question 9

Give an example of exposure to sequestered self antigens

Answer 9

Sympathetic ophthalmia: an eye injury can allow for previously immune privileged ocular Ags to be released. which can lead to an autoimmune attack

Question 10

What is a potential explanation for MS?

Answer 10

Exposure to sequestered self Ags: trauma to BBB causing a breach, allowing T & B cells access to “new” Ags to which they’ve never been exposed, including those from the myelin sheath, causing an immune response

Question 11

What are other risk factors for autoimmune diseases and disorders?

Answer 11

1. Chronic inflammation - when nonhematopoietic tissue cells may be inappropriately induced to express MHC molecules.
2. Aging - progressive decreased ability to generate new T cells
3. hygiene hypothesis - absence of chronic parasite exposure
4. Tregs - commensals role in maintaining tolerance may activate Treg

Question 12

Treatments of autoimmune diseases

Answer 12

1. immunosuppressive and anti-inflammatory agents
2. humanized monoclonal antibodies - aim to block effects of anti-inflammatory cytokines, block activation and infiltration of T cells or that can target B cells

Question 13

Goal of tx for autoimmunity

Answer 13

Inhibit actions of immune response or alleviate symptoms

Question 14

Risks of autoimmune treatment

Answer 14

1. More susceptible to opportunistic infections

2. Side effects