Autoimmunity

Question 1

Define the following terms:

• Auto Antigen
• Genome wide association study
• Epitope Spreading
• Molecular Mimicry

Answer 1

• Auto antigen - An antigen or complex on normal tissues of the host triggers an autoimmune disease.
• Genome wide association study - Observational study of genome-wide polymorphism in different individuals that are linked to disease risk or a trait.
• Epitope spreading - The recognition of new and additional epitopes on the same or different antigen
• Molecular mimicry - Sequence similarity between a self foreign peptide or complex that leads to activation of auto-reactive B and T cells.

Question 2

Define autoimmune diseases and autoantigens

Answer 2

• Autoimmune diseases are chronic diseases resulting from adaptive immune responses directed towards autologous (self) components of the body.
• Autoantigens are subsets of self-proteins (T-cells and B-cells) or other cellular components (B-cells) that are the targets of adaptive immune responses in an autoimmune disease.

Question 3

Characteristics of Autoimmune Disease (AD)

Answer 3

Autoimmune responses persist chronically.
Unlike clearance of infetious material, self-proteins are not eliminated.

Question 4

References Table of ADs

Answer 4

Question 5

What are the immune effector mechanism that can cause autoimmunity?
(Hypersensitivity types)

Answer 5

• Type 1 - IgE allergy
• Type 2 - CD8 mediated
• Type 3 - Antibody complex & complement
• Type 4 - CD4 - cytokine mediated

Question 6

How antobodies can act in autoimmunity?

Answer 6

Antagonist - Blocking or lessening fuction
Agonists - Acting as ligand
Biomarkers - The antibody itself does not contribute, but B cells have important roles and/or are a biomarker for CD4 T-cell reponses.
Other - Competing with tight junctions, soaking up hormones.

Question 7

How autoimmune I disease are grouped?

Answer 7

1. Organ specific - Restricted to specific organs
2. Systemic - Affect many tissues of the body

Question 8

What triggers autoimmunity?
(Heavily Debated)

Answer 8

• Generally they are more common in women.
• Genetics (largely HLA) may account for 20-70% of autoimmunity
• Other causes may be infectious triggers that break tolerance, microbiota and enviroment

Question 9

Define what is molecular mimicry and epitope spreading?

Answer 9

• Molecular Mimicry - Cross reactive immune response to viral protein.
• Epitope Spreading - During inflammation or damage, antigen presenting cells (APC- mainly B cells) will take up secondary target. The APC presents new antigen to naive T-cells, spreading the autoimmune response.

Spread can be:
* New molecule autoantigen
* New epitope on existing autoantigen

Question 10

Why autoimmunity is largely genetic?

Answer 10

• Because is dominated by HLA genetics.
• Genetic basis has been revealed by twin studies - Risk in indentical twins is larger than non-identical.
• Autoimmune genes have discovered by genome- wide association studies - large population studies that detect common variants that associate with disease.
• HLA alleles usually account for most disease risk.

Question 11

Outside HLA, AD traits are dominated by?

Answer 11

AD traits are dominated by antigen targets and many lowrisk immune alleles.

Question 12

Recap of AD

Answer 12

• Autoimmune diseases can be classified into hypersensitivity reactions (Type I, II, III and IV only). While they hypersensitive classification indicates the dominant mechanism of the disease, tissue damage in autoimmune disease is caused by complex immune response.
• The adapative immune mechanism that control infections are the same mechanisms that cause tissue damage in autoimmune diseases.
• Autoimmune disease can be organ specific (tissue restricted antigens) or systemic (antigen in all or many tissues).
• Initiatin cause for many autoimmune diseases are unknown. Age, gender, genetics (mostly HLA type), and infection are all risk factors for the development of autoimmunity.

Question 13

In addition of HLA, risk alleles for Crohn’s disease can be characterized as targeting the ____ T-cell polarization, which includes the genes for IL23, RORTC (RorgT), IL-27, JAK2, IL-22 and AHR.

Answer 13

Th17

Question 14

Sjogran’s syndrome involves an antibody mediated targeting of exocrine tissues. Because it is mediated by ____ B cells that normally form the germinal center response but become chronically activated during disease, a secondary complication of Sjogren’s may be ____ lymphoma.

Answer 14

Follicular, Follicular

Question 15

Risl alleles for Graves’ disease include the antigen target (in this case the TSH receptor), and immune checkpoint receptors (e.g. CTLA4). However, the greatest risk is determined by the ____ locus, like most autoimmune diseases.

Answer 15

HLA

Question 16

Do autoimmune diseases involves just one immune component?
True or False

Answer 16

False
* AD rarely involves just one immune compoment.
* A disease may be “T-cell mediated” or” B-cell mediated” but immunity is never that simple, which is critical for therapeutic design.

Question 17

How does Multiple Sclerosis (MS) works and why type of hypersensitivity type is?

Answer 17

• Demyelinating disease of the central nervous system, believed to be initiated by myelin-reactive CD4+ T-Cells (Type IV).
• Loss of myelin causes decreased conduction along axons.
• Symptoms are diverse and vast - numbness, paralysis, vision loss, bowel, and bladder incontinence, etc.
• Age of onset: 20-40 years
• Women:Male 3:1
• Relapsing-remitting, chronic disease

Question 18

Are B-cell are important for MS?

Answer 18

We know B-cell mediated antibodies are relatively unimportant in MS
Unlike a true antibody mediated disease (e.g. Graves’ or optic neuritis), no risk to the fetus in MS.

Question 19

Characteristics of MS

Answer 19

• Disease is caused by CD4+ T-cells and CD8+ T-cells.
• Antibodies are not important (mothers with MS can have babies without risk of fetal myelin damage).
• However, CD20+ B-cells (remember CD20 marks mature B-cell, but not antibody secreting B-cells) are the frontline therapeutic target in primary progressive MS.
• B-cells likely support CD4 killing due to antigen presentation, cytokine release, and/or being a viral reservoir.

Question 20

Is Graves’ disease is antibody mediated?
True or False

Answer 20

True
Fetus gets affected unlike MS disease.

Question 21

How does antibodies act during Graves Disease?

Answer 21

Antibodies act as an agonist.
When thyroid hormones are needed, thyroid stimulating hormone (TSH) binds to TSH receptor and is then broken down.

Anti-TSH receptor antibodies bind the TSH receptor causing iodinated thyroglobulin to breakdown into T3 and T4.

However there is a break in the feedback loop to stop TSH hormone production from the pituitary gland.

Question 22

Characteristics of Graves’ Disease

Answer 22

• 3 million americans, 1 in 90
• Sysmptoms - heat intolerance, nervousness, irritability, warm moist skin, weight loss, enlargement of the thyroid (hyperthyroid), bulging eyes (infiltrative opthalmopathy) and thickening of the skin (infiltrative dermopathy).
• Classical triad of Graves’ Disease - hyperthyroidism, infiltrative ophthalmophathy and infiltrative dermopathy.
• 7:1 Women:Men

Question 23

How does antibodies act during Myasthenia Gravis?

Answer 23

In contrast, in some diseases like myasthenia gravis, antibodies act as antagonists.
Muscle under your control get weak.
Antibodies block acethylcholine, which results in muscle weakness.

Question 24

What are the type of hypersensitive and what is the mechanism of Hashimoto’s thyroiditis?

Answer 24

• It is a diease mediated by autoreactive CD4 Th1 cells (hypersentsitive IV) and autoantibodies (IgG2A).
• Lymphocytes infiltrate the thryoid, resulting in progressive destruction of the tissues.
• Patientes develop hypothyroidism and eventually fail to produce thyroid hormones.

Question 25

What are the similiarities and differences between Hashimoto's thyroiditis and Graves' disease?

Answer 25

Similarities: Both are thyroid disease. Differences: GD - Agonist, and TSH- reactive B-cells. Hyperthyroidims. HD - Antagonist, B-cell and CD8 T-cells are autoreactive. Hypothyroidism.

Question 26

What is the mechanism of the systemic lupus erythematosus (SLE)?

Answer 26

* Mechanims - Almost every cells contains autoantigens (furniture, decorations and tools from the building) that are targeted by autoantibodies (security get confused). * Pathology is mediated by soluble immune complexes and have circulating IgG antibodies specific for molecules on the cell surface, cytoplasm and nucleus. * More common in women (10:1) * Relapsing-remitting disease ## Footnote Autoantigens - The normal parts of your cells that belong there. Autoantibodies - The immune system getting confused and attacking those normal parts.

Question 27

What type of hypersensitivity does SLE belongs?

Answer 27

* Type III - Antibody complex and complement. * Breakdown in clearing apoptotic cells results in development of anti-nucleat antibodies. * Deposistion of immune complexes in kidneys, joints, and blood vessels results in inflammation and organ dysfunction.

Question 28

With which diseases does Epstein-Barr Virus (EBV) is associated?

Answer 28

* Multiple Sclerosis * Rheumatoid arthritis * Sjögren's Syndrome * SLE

Question 29

Characteristics of Type 1 Diabetes?

Answer 29

Mechanism - Autoimmune diease that destroys pancreatic beta cells. Short term complications are diabetic ketoacidosis, long term are heart disease and stroke. 5-10% of all diabetes. 80,000 children diagnosed each year.

Question 30

What is the mechanism of Type 1 Diabetes?

Answer 30

Mechanism - T1D is a CD8 T-cell mediated disease of the beta cell. 1. B-Cells antigen present to CD4 cells 2. CD4 cells make IFN-gamma that upregulates MHC-I on Beta-Cells. 3. CD8 cells kill pancreatic beta cells.

Question 31

Is T1D is genetic?

Answer 31

TD1 is highly genetic. * Concordance between identical twins is 30-70% * Unidentical siblings is 6-7% Risk alleles relate to selection of CD4 cells * HLA type explains ~ 30% of genetics (right) * Insulin, explains an additional 3.3% * All non-HLA explains 9%

Question 32

What is the difference between low and high HLA-ABC?

Answer 32

* Low HLA-ABC is a mechanism of immune privilege * High HLA-ABC means an immune privilige break.

Question 33

What does CTLA4 causes?

Answer 33

CTLA4 induces immune exhaustion and suppression.

Question 34

Review of Autoimmune Diseases

Answer 34

For all cases, major risk is HLA. Three (MS, SLE, and T1D) likely have a viral cause, but the field has not ruled out an epiphenomenon. 1. Graves' syndrome and Myasthenia gravis demonstrate opposing roles antibodies can play as signaling agonists and antagonists. 2. MS is a CD4 T-cell mediated disease, but there are important contributions of CD8 and B-cells components 3. T1D is a CD8 T-Cell disease with important

Question 35

In type 1 diabetes, a ____ cell kills beta cells via antigen specific killing. Their killing is targeted by a ____ helper cell. The helper lymphocyte recognizes antigens presented on a HLA-D risk allele by a ____ lymphocyte, which also happens to make antibody biomarkers.

Answer 35

CD8, CD4 and B-cell