Autoimmunity

Question 1

What is autoimmunity?

Answer 1

breakdown in self-tolerance

Tcell activation (CD4, CD8, DCs, macrophages, etc) outweigh the regulatory cells action (Treg, Breg, regulatory DCs)

Question 2

What is immunological self-tolerance?

Answer 2

-a specific unresponsiveness to a self antigen

(an individual’s immune system does not attack the normal tissues of the body)

-a breakdown or failure in the mechanisms that mediate self-tolerance leads to autoimmunity

Question 3

What is central tolerance?

Answer 3

selection of B cells (BM) and T cells (thymus)

Question 4

What is peripheral tolerance?

Answer 4

ignorance,
anergy (functional unresponsiveness),
deletion (apoptosis),
suppression (block in activation

Question 5

How is anergy mediated?

Answer 5

functional unresponsiveness due to multiple mechanisms,

Question 6

How is deletion mediated?

Answer 6

apoptosis (activation-induced cell death) due to Fas/FasL pathway; increased expression of pro-apoptotic proteins

Question 7

What are the two fates of lymphocytes that recognize self?

Answer 7

1) principal fate: death

2) some T cells in thymus and periphery differentiate into regulatory T lymphocytes;
Treg generation also happens in periphery (T cells see antigen on APC surface that triggers them to become a Treg)

Question 8

What do Treg cells upregulate?

Answer 8

The master regulator of Treg cells = FoxP3 (Transcriptional upregulator protein)

Question 9

What do Treg cells inhibit?

Answer 9

• T cell activation (at level of DC binding to native T cells)
• T cell effector functions (effector T cells)

Question 10

What is the phenotype of Treg cells?

Answer 10

CD4+; 
IL-2 receptors (CD25) high
IL-7 receptor (CD127) low;
FoxP3+ (transcriptional activator);
GITR+
and other markers

Question 11

What is the consequence of FoxP3 mutations?

Answer 11

IPEX: most commonly manifests with early onset, insulin-dependent DM1; severe watery diarrhea; failure to thrive; dermatitis;

most die w/in 2 yrs of birth

Question 12

What do Tregs use?

Answer 12

inhibit cytokines;
target dendtric cells (make them supressive);
cytolysis (granzyme B);
metabolic disruption (Tregs pull IL-2 away from Teff cells so T effector cells can’t survive)

Question 13

AIRE

Answer 13

“autoimmune regulator” - essential for self-tolerance

aka: you need AIRE to make sure most of the T cells that are self reactive are purged

Transcription Factor in thymus that mediates transcription of ectopic genes in thymus (promotes ectopic expression of peripheral tissue restricted antigens in the thymus)

Question 14

Mutations in AIRE are found in pts with what disease?

Answer 14

APS/APECED

Question 15

What are the 2 major classifications of autoimmune diseases?

Answer 15

organ specific;
systemic
(~34min)

Question 16

Genetic Basis of Autoimmunity

Answer 16

-MHC related

• RA: frequently associated with citrullinated proteins (associated with smoking):
• amine group changed to oxygen = Arg –> citrulline
• the citrullinated group becomes a target of the immune system for both T cells and B cells

Question 17

What is molecular mimicry in having infection trigger autoimmunity?

Answer 17

By accident, pathogens can look somewhat like self so the response to pathogen triggers an autoimmune response.

Activated T cells and Ab from B cells cross-react with self-antigens, leading to autoimmunity

Question 18

How can infection trigger autoimmunity?

Answer 18

1) molecular mimacry
2) infection provides environment that promotes lymphocyte activation (by-stander activation): infection –> disruption of cell or tissue barrier –> release of sequestered self antigen –> activation of non-tolerized cells –> autoimmunity

EX: severity of DM1 exacerbated by Coxsackie Virus infection
Coxsackie B4 nuclear Protein is a mimic of human GAD

Question 19

What two types of immunological responses can be triggered by drugs?

Answer 19

1) immunological response: metabolite or complexed with host protein
2) true autoimmune process induced by drug: progresses initially independently of drug withdrawal

Question 20

Abacavir Hypersensitivity Syndrome (AHS)

Answer 20

Abacavir: anti-retroviral (reverse transcriptase inhibitor)

AHS: true autoimmune process induced by a drug bc binding to HLA-B*57:01 doesn’t let peptide bond as usual so –>drug+peptide binding results of in presentation of novel self

Question 21

Why do autoimmune diseases tend to be chronic?

Answer 21

the initiating trigger cannot be eliminated

1) amplification of the response –> increased # of self-reactive clones
2) epitope spreading –> increased # of self-reactive clones