LG 1.10 - Autoimmunity

Question 1

what is immunologic tolerance?

Answer 1

1. Lack of a response (antibody or cell-mediated) to an antigen which normally is immunogenic
2. can be tolerant to self antigens or foreign
3. we need self-tolerance to prevent autoimmunity disorders!

Question 2

Name the 2 Central T cell tolerance mechanisms.

Answer 2

positive tolerance and negative tolerance

Question 3

(2) With regard to T lymphs, what is ‘positive selection’?

Answer 3

1. one method to produce viable T cells.
2. when the double positive T cell has the ability to weakly recognize either MHC 1 or MHC 2.
3. double positive T cells that fail to recognize MHC are doomed to “death by neglect” aka apoptosis

Question 4

(2) With regard to T lymphs, what is ‘negative selection’?

Answer 4

1. one method to produce viable T cells.
2. In - selection, the CD4/CD8 cell binds too strongly to the MHC II or MCH I.
3. These cells that bind too tightly are not wanted and doomed to apoptosis

Question 5

(2) What criteria are required to produce Viable T lymphocytes?

Answer 5

One that undergone + selection but NOT - selection:
eg #1. a mature CD8 cell that binds weakly to a MHC I
eg #2. a mature CD4 cell that binds weakly to a MHC II
(~95% of T Cells fails to meet these criteria and are eliminated)

Question 6

(3) Do B cells exhibit + and - selection?

Answer 6

yes. analogous to T cells
1. recognizing flagged antibody is + selection
2. binding too strongly to antibodies is - selection
3. Note: B cell tolerance is not as complete as is T cell tolerance

Question 7

What is the AIRE gene? What is its role in T cell tolerance?

Answer 7

1. AutoImmuneREgulator=AIRE gene: codes for a transcription factor expressed in the thymus.
2. this factor controls synthesis of self-peptides employed in negative and positive selection.
3. Mutations in the AIRE gene result in peripheral release of self-reactive T cells
4. This could result in the development of multiple autoimmune diseases.

Question 8

List the 5 proposed mechanisms for how self-tolerance is broken and autoimmune diseases are induced.

Answer 8

1. Release of sequestered antigen
2. Imperfect tolerance
3. Drugs and other environmental factors
4. Infections
5. Genetic mutations/polymorphisms

Question 9

List 2 examples of diseases caused by release of sequestered antigens.

Answer 9

1. Testis – autoimmune orchitis post-vasectomy (antibodies produced against male’s own sperm)
2. Eye – sympathetic ophthalmia

Question 10

List 3 examples of imperfect tolerance induction mechanisms

Answer 10

1. Self-reactive B cells present
2. Rheumatoid factor (IgM anti-IgG)
3. Anti-idiotypic antibodies (antibodies that are specific for the binding site of other antibodies)

Question 11

For meds, I would just know that several can cause:

Answer 11

autoimmune diseases

Question 12

Which environmental toxins may cause autoimmune disorders?

Answer 12

heavy metals

Question 13

Infections can induce autoimmune problems. How does polyclonal activation do this?

Answer 13

Infections trigger production of antibodies. Occasionally, B cells produce antibodies that attack self.

1. Epstein Barr virus - infect B cells
2. Bacterial enterotoxins (LPS)

Question 14

Infections can induce autoimmune problems. How does cytokine stimulation do this?

Answer 14

IFN-gamma can up regulate HLA-II molecules in tissues.

Question 15

(4) Infections can induce autoimmune problems. How does the induction of inflammatory response do this?

Answer 15

Induction of co-stimulatory molecules. APC could express and present costimulatory molecules to T cell which would subsequently target self tissue.

Question 16

What dictates extent of autoimmune disorder?

Answer 16

1. the target antigen.
2. is the target antigen widely distributed? systemic (blood vessel endothelium),
3. a specific cell type in a specific organ? targeted, but could have wide-ranging effects (DM1)
4. a particular molecule? systemic (DNA, enzymes)

Question 17

Name the 3 types of pathogenic hypersensitivities involved in autoimmunity.

Answer 17

1. type II hypersensitivity
2. type III hypersensitivity
3. type IV hypersensitivity
   (NOT type I)

Question 18

BRIEFLY describe type II hypersensitivity

Answer 18

Antibodies to cell surface antigens

Question 19

BRIEFLY describe type III hypersensitivity

Answer 19

Immune complex disease

Question 20

BRIEFLY describe type IV hypersensitivity

Answer 20

T cell mediated

Question 21

Define autoimmunity

Answer 21

1. Inappropriate immune response to self antigens.
2. Can be benign or pathogenic
3. Etiology - unknown

Question 22

list some Systemic Autoimmune Diseases

Answer 22

Systemic lupus erythematosus
Rheumatoid arthritis
Sjögrens syndrome
Systemic sclerosis
Inflammatory muscle diseases
Small and medium vessel vasculitis
Large vessel vasculitides

Question 23

list some Organ-specific autoimmune disease

Answer 23

Thyroiditis (Grave, Hashimoto), 
Multiple sclerosis 
Myasthenia gravis 
Type 1 diabetes 
Pernicious anemia 
Autoimmune hemolytic anemia 
Autoimmune thrombocytopenia
Post-streptococcal glomerulonephritis 
Rheumatic fever, etc.

Question 24

Is self-tolerance inherited? When can tolerance most easily be induced?

Answer 24

• Not inherited, Must be learned.

- Most easily induced during maturation.

Question 25

How are autoimmune diseases initiated?

Answer 25

Requires:

• genetic susceptibility
• presence of self-reactive lymphocytes
• failure of immunologic tolerance
• an immunologic stimulus: inflammation or infection.

Question 26

(4) Infections can induce autoimmune problems. How does molecular mimicry/cross-reactivity do this?

Answer 26

antigens on invading organisms cross-react with self tissue
1. eg, post-strep rheumatic fever. antibodies attacks heart valve because of cross-reactivity between heart valve with strep bacteria antigens.

Question 27

Besides the AIRE gene, how does genetics affect B and T cell production?

Answer 27

1. provides LOTS of diversity!
2. -recombination of V,D,J gene segments (happens in T and B cells),
   - junctional diversity (happens in T and B cells) and
   - somatic hypermutation (mentioned in B cell section only)
3. variation gives huge T and B cell repertoire of 10^16 and 10^11, respectively.