Autoimmunity

Question 1

3 ways autoimmunity can occur

Answer 1

1. immune regulation dysfunction: loss of Treg activity
2. normal self-antigens become modified by drugs, environmental chemicals, viruses, mutations
3. molecular mimicry: exposure to antigen very similar to self antigen

Question 2

what are the 3 possible outcomes for immature lymphocytes that recognize self-antigen in central and peripheral tolerance, respectively?

Answer 2

central tolerance: either apoptosis, receptor editing (B cells), or development of Treg (T cells)

peripheral tolerance: either anergy, apoptosis, or suppression

Question 3

how does anergy of T cells occur?

Answer 3

when TCR binds MHC on DC, but there is no signal 2 (B7 on DC binds CD28 on T cell)

Question 4

natural vs induced Tregs

Answer 4

natural Tregs exist in the thymus already (most Tregs)

induced Tregs are a subset of immature T cells that recognized self-antigen, so are converted to Tregs

Question 5

_____ is a transcriptional activator that is turned on only in Tregs

Answer 5

Foxp3+

key marker of Tregs

Question 6

Foxp3+

Answer 6

transcriptional activator turned on only in Tregs, key marker of Tregs

Question 7

you find a cell that expresses the following:
- CD4+
- IL-2 R
- IL-7 R
- Foxp3+
- GITR+

what kind of cell is it?

Answer 7

Treg

in particular, Foxp3+ is a key marker

Question 8

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)

Answer 8

caused by Foxp3+ mutation —> nonfunctional Treg cells

• early onset T1 diabetes (insulin dependent)
• watery diarrhea
• failure to thrive - most affected children die within 2 years

Question 9

mutation in Foxp3 causes what autoimmune disease

Answer 9

Foxp3 is critical transcriptional activator for Tregs

mutation —> IPEX
(immune dysregulation, polyendocrinopathy, enteropathy, X-linked)

Question 10

APC or APECED

Answer 10

APC = autoimmune polyglandular syndrome
APECED = autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy

AR autoimmune disease
- yeast infections
- hypoparathyroidism
- Addison’s disease

mutation in AIRE gene (AutoImmune REgulator), which turns on expression of tissue-specific proteins in the thymus so immature T cells are exposed to them during negative selection

Question 11

what occurs from a mutation in AIRE gene?

Answer 11

AIRE = AutoImmune REgulator

mutation —>

APC = autoimmune polyglandular syndrome
APECED = autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy

AR autoimmune disease
- yeast infections
- hypoparathyroidism
- Addison’s disease

[remember that AIRE is responsible for turning on expression of tissue-specific proteins in thymus so immature T cells are exposed to them, and won’t react to them when they are released throughout the body]

Question 12

how does negative selection of T cells ensure that developing T cells don’t react to proteins found in other body systems/organs?

Answer 12

AIRE (AutoImmune REgulator) transcription regulator turns on expression of tissue-specific proteins/ antigens (TRAs) from all over the body in the thymus, so immature T cells are exposed to them

Question 13

it is more common for MHC [I/II] genes to be associated with autoimmune disease

Answer 13

more autoimmune diseases are associated with specific MHC II alleles, because most autoimmune diseases are driven by antibodies, and CD4+ T cells are required to induce B cell class switching

Question 14

citrullination and its relevance to autoimmunity

Answer 14

arginine is modified to have an oxygen, which makes it become citrulline (via PAD/ peptidyl-arginine-deiminase)

citrullinated proteins are recognized by HLA

*note that PAD is upregulated by cigarette smoking

Question 15

T/F: most human autoimmune diseases are polygenic

Answer 15

TRUE

Question 16

how does molecular mimicry play a role (potentially) in rheumatic fever? (hint - requires a specific infection)

Answer 16

molecular mimicry: autoimmune response triggered by an antigen that looks like self antigen

group A streptococcal M protein is similar to antigen found in cardiac muscle —> rheumatic fever

(potentially - no definitive evidence yet)

Question 17

by-stander immune activation

Answer 17

infection induces an environment that promotes lymphocyte activation

a DC carrying a pathogen, but also expressing its own antigens, may by chance run into a self-reactive T cell and induce autoimmunity

[remember that autoimmune diseases are often associated with/triggered by infection]

Question 18

2 types of drug-induced autoimmunity (DIA)

Answer 18

1. immunological response (majority of cases) - drug hypersensitivity, usually reversible on drug withdrawal
2. true autoimmune process - requires immunosuppressive treatment, progresses independently of drug withdrawal

Question 19

2 factors that contribute to chronic nature of autoimmune diseases

Answer 19

1. immune system has amplification mechanisms to proliferate “useful” cells for combatting infection (in autoimmunity, though, these are self-reactive cells)
2. epitope spreading: immune response starts with one antigen but quickly spreads to others

*both of these processes lead to increased number of self-reactive clones

Question 20

epitope spreading

Answer 20

immune response starts with one antigen but quickly spreads to others

Question 21

2 major patterns of autoimmune diseases

Answer 21

1. organ-specific (ex- Type 1 diabetes, Hashimoto’s thyroiditis, Graves’ disease, Addison’s disease)
2. systemic (ex - Rheumatoid arthritis, systemic lupus erythematosus, scleroderma)

Question 22

what organs are affected in the following organ-specific autoimmune diseases?
a. Type 1 diabetes
b. Hashimoto’s
c. Graves’
d. Addison’s

Answer 22

a. Type I diabetes - pancreas (insulin, beta cells)
b. Hashimoto’s - thyroid
c. Graves’ - thyroid (autoantibodies activate thyrotropin receptor)
d. Addison’s - adrenal

Question 23

Rheumatoid arthritis, systemic lupus erythematosus, and scleroderma are common in that they are all examples of _____ autoimmune disease

Answer 23

systemic

Question 24

what occurs in SLE and what are the treatment strategies that currently exist?

Answer 24

SLE = systemic lupus erythematosus

immune complex mediated systemic autoimmune disease —> too much Type I IFN production leads to high-level anti-nuclear IgG production

treatment:
- anti-IFNa antibody (Type I IFN) - Sifalimumab
- TLR inhibition
- B cell deletion (Rituximab)
- anti-BAFF anitbody (Tabalumab)

Question 25

Sifalimumab, Rituximab, and Tabalumab are all used in treatment against SLE

what do they do

(note they can also be indicated for treatment of other diseases)

Answer 25

remember that SLE is due to too much Type I IFN that leads to high levels of anti-nuclear IgG (systemic autoimmune disease)

Sifalimumab: anti-IFNa (Type I IFN) antibody

Rituximab: B cell depletion (also used in treatment for non Hodgkin lymphoma)

Tabalumab: anti-BAFF antibody

Question 26

what occurs in rheumatoid arthritis

Answer 26

citrillination (altered arginine) of self protein leads to

T and B cell response to self antigens in joint tissues —> synoviocyte activation, cytokine production, inflammation —> destruction of cartilage and bone

Question 27

what are current treatments for rheumatoid arthritis?

Answer 27

remember that rheumatoid arthritis is destruction of cartilage and bone due to T/B cells recognizing citrullinated arginines in self-antigens

• TNF inhibitors, anti-TNF antibodies (Etanercept, Infliximab, Adalimumab, Golimumab, Centolizumab)
• IL-1 antagonist (Anakinra)
• anti-IL-6 receptor antibody (Tocilizumab)
• CTLA-4 fusion protein (binds B7, prevents it binding to CD28)
• anti IL-17 antibodies (Secukinumab)
• B cell deletion (Rituximab)