Autoimmunity I, II, Immunotherapeutics, Grayson

Question 1

___ - autoreactive T cells against antigens of joint synovium. Consequence - ___ inflammation and destruction causing ___

Answer 1

Rheumatoid arthritis - autoreactive T cells against antigens of joint synovium. Consequence - joint inflammation and destruction causing arthritis.

Question 2

____ - autoantibodies and autoreactive T cells against thyroid antigens. Consequence - destruction of thyroid tissue leading to hypothyroidism: underproduction of thyroid hormones.

Answer 2

Hashimotos

Question 3

___ - auto-antibodies and auto-reactive T cells against DNA, chromatin, proteins and ubiquitous ribonucleoprotein antigens Consequence - glomerulonephritis, vasculitis, and rash

Answer 3

SLE - auto-antibodies and auto-reactive T cells against DNA, chromatin, proteins and ubiquitous ribonucleoprotein antigens Consequence - glomerulonephritis, vasculitis, and rash

Question 4

___ - autoreactive T cells against pancreatic islet cell antigens. Consequence - destruction of pancreatic islet beta cells leading to non-production of insulin

Answer 4

Type I DM

Question 5

Genetic factors and infection environmental determine immune regulation and can lead to ___

Answer 5

autoimmunity.

Question 6

Mechanisms for preventing self-reactivity:

CAP FAR

Answer 6

Central tolerance - deletion editing which occurs in thymus or bone marrow

Antigen segregation - physical barrier to self-antigen access to lymphoid system. You keep the antigens sequestered.

Peripheral anergy - If you don’t get signal 2 –> cellular inactivation by weak signaling without co-stimulus

Functional deviation

Activation induced cell death - if you stimulate a t cell over and over and over again, it will undergo apoptosis. This makes sense because the only time you will get stimulated continueously for many many weeks, is if you are reacting against self.

Regulatory T cells - supression of cytokines and intercellular signals. They release TGF-beta and IL-10.

Question 7

Although not all self-antigens are expressed in the thymus, a mechanism is in place to express a broad range of self-antigens. What is the gene that drives this mechanism?

What happens if you have a mutation in this gene?

Answer 7

AIRE controls the expression of a wide variety of non-lymphoid self-antigens in the thymus, and thus allows for selection against many self-reactive thymocytes.

If you have a mutation in AIRE, then you get:

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), an autoimmune disease that is due to a mutation in the autoimmune regulator gene (AIRE).

AIRE controls the expression of a wide variety of non-lymphoid self-antigens in the thymus and thus allows for selection against many self-reactive thymocytes.

Question 8

Central ___ or ___ of Newly Formed Lymphocytes Is The First Checkpoint of ___

Answer 8

Central Deletion or Inactivation of Newly Formed Lymphocytes Is The First Checkpoint of Self-Tolerance

Question 9

APECED = mutation in ____.

What happens then?

Answer 9

APECED = mutation in AIRE. In the absence of AIRE, T cells reactive to tissue-specific antigens mature and leave the thymus.

Question 10

What are the immunologically privileged (sequestered) sites in the body?

Answer 10

BETU

BET University

Brain, Eyes, Testis, Uterus

Lets say you punch someone in the eye. Now you will get some damage there. The little red circles are intraocular antigens (not expressed by AIRE), but now it goes to the lymph nodes, and activates T cells. Now it will go back and damage your T cells.

Question 11

Only professional APCs express ___ and ___.

If a T cell interacts with an antigen presenting cell lacking_____/___, the T cell will become anergic, i.e., non-responsive.

This prevents potentially autoreactive T cells from responding to self-antigens in the absence of a professional APC.

Answer 11

Only professional APCs express CD80 and CD86.

If a T cell interacts with an antigen presenting cell lacking CD80/86, the T cell will become anergic, i.e., non-responsive.

This prevents potentially autoreactive T cells from responding to self-antigens in the absence of a professional APC.

Question 12

IPEX = decreased ___ = no ___ cells

Answer 12

IPEX = decreased FOX3P = no Treg cells

Question 13

Which cytokines does the Treg cell release?

T cells can also give the “kiss of death” to __ and __ cells.

Tregs can also disrupt ____ events in ___ via secretion of molecules that disrupt specific pathways.

Tregs can also disrupt ability of ___ ___ to activate T cells

Answer 13

Which cytokines does the Treg cell release?

T cells can also give the “kiss of death” to T and B cells.

Tregs can also disrupt metabolic events in T cells via secretion of molecules that disrupt specific pathways.

Tregs can also disrupt ability of dendritic cells to activate T cells

Question 14

T/F: T regs can also be used to treat disease

Answer 14

True

This is an animal example. Basically, people grew up Tregs from a patient, and injected them in, and inhibited autoimmunity.

Question 15

Th17 T cells:

• Are induced in the presence of two cytokines— ___ and ____

These cells are highly____ via the release of ____ cytokines and chemokines.

Mice lacking the ability to generate Th17 T cells are more/less susceptible to a number of induced autoimmune diseases

Answer 15

Th17 T cells:

• Are induced in the presence of two cytokines—TGF-beta and IL-6
• Are highly pro-inflammatory via the release of pro-inflammatory cytokines and chemokines.

Mice lacking the ability to generate Th17 T cells are less susceptible to a number of induced autoimmune diseases

Question 16

Which two cytokines induce Th17?

Answer 16

IL-6 and TGF-B

Question 17

Mice lacking the ability to generate Th17 T cells are ___ susceptible to a number of induced autoimmune diseases.

Why?

Answer 17

Mice lacking the ability to generate Th17 T cells are less susceptible to a number of induced autoimmune diseases.

Th17 releases cytokines that are highly pro-inflammatory. If Th17 is inhibited, these proinflammatory cytokines will not be released, and thus make the mice LESS susceptible to autoimmune diseases.

Question 18

Lots of autoimmune diseases have associations with __ gene mutations.

Answer 18

HLA

Question 19

How might HLA antigens serve as risk factors for autoimmune disease?

1. Certain HLA alleles may be more _____ in presenting self-antigens.
2. ____ may be present in the ___ at very ____ levels or bind ____ to HLA, and thus thymocytes expressing TCRs for such self-antigens may be _____ selected, but not negatively selected –> autoreactivity to self-antigens

Answer 19

How might HLA antigens serve as risk factors for autoimmune disease?

1. Certain HLA alleles may be more effective in presenting self-antigens.
2. Self-antigens may be present in the thymus at very low levels or bind poorly to HLA, and thus thymocytes expressing TCRs for such self-antigens may be positively selected, but not negatively selected –> autoreactivity to self-antigens

Question 20

___ - autoreactive T cells against brain antigen

Consequence - formation of sclerotic plaques in brain with destruction of myelin sheaths surrounding nerve cell axons, leading to muscle weakness, ataxia and other symptoms.

Answer 20

MS (Type IV HSR)

Question 21

Enhanced level of Th17 can cause __ disease. Why?

Answer 21

Enhanced levels of Th17 can cause autoimmune diseases.

Why?

Because Th17 releases IL-6 and IL-17, which are pro-inflammatory cytokines.

Question 22

Myasthenia gravis is a disease that is a compbination of Type __ HSR and Type __ HSR.

Answer 22

Type II and IV

Question 23

Immune Compex-mediated Immunopathy

• Immune complex deposition in glomeruli or joints may result in tissue damaging inflammation
• Occurs in ____ and rheumatoid arthritis
• Anti-____ and ____ antibodies are diagnostic for ___
• ____ antibodies (rheumatoid factors) in rheumatoid arthritis.

Answer 23

• Immune complex deposition in glomeruli or joints may result in tissue damaging inflammation
• Occurs in systemic lupus erythematosus (SLE) and rheumatoid arthritis
• Anti-double stranded DNA and Sm antibodies are diagnostic for SLE
• Anti-IgG antibodies (rheumatoid factors) in rheumatoid arthritis

Question 24

T cell mediated immunopathology (Type___ HSR)

• Important contributions to SLE, rheumatoid arthritis, insulin-dependent diabetes mellitus, and multiple sclerosis
• Involvement of __ and ___ T cells

Answer 24

T cell mediated immunopathology (TypeIV HSR)

• Important contributions to SLE, rheumatoid arthritis, insulin-dependent diabetes mellitus, and multiple sclerosis
• Involvement of CD4 and CD8 T cells

Question 25

Rheumatoid arthritis and myasthenia gravi is a combo of what two HSR?

Answer 25

II and IV

Question 26

SLE, Type 1 DM, Myasthenia Gravis, MS are all a combo of Type __ and IV

Answer 26

II and IV

Question 27

Hashimoto’s thyroiditis, Pernicious anemia and Rheumatoid arthritis all involve _____ AND ___-______effector mechanisms

Question 28

T/F: Rheumatoid arthritis is also a type III immune-complex disease

Answer 28

True

Somehow, after a viral infection, the imune system will recruit CD4 T cells and B cells, which then release anti-IgG antibodies (Rheumatoid factors). This stimulates the complement system.

Question 29

In RA,

Cytokines are produced in the ____ and promote:

• Proliferation of ____ cells and thickening of the ___ membrane
• Infiltration of ____ into the synovial fluid
• Release of ___ that degrade connective tissue
• Recruitment of T and B lymphocytes
• Activation of T and B lymphocytes resulting in production of __ ___ that promote complement activation
• Osteoclast activation and associated bone resorption

Answer 29

Cytokines are produced in the synovium and promote:

• Proliferation of synovial cells and thickening of the synovial membrane
• Infiltration of neutrophils into the synovial fluid
• Release of proteases that degrade connective tissue
• Recruitment of T and B lymphocytes
• Activation of T and B lymphocytes resulting in production of rheumatoid factors that promote complement activation
• Osteoclast activation and associated bone resorption

Question 30

In type I diabetes, an effector T cell recognizes peptides from a ___-cell specific protein and kills the ___-cell. This is a done by the CTL cell and is a Type ___ HSR.

Answer 30

In type I diabetes, an effector T cell recognizes peptides from a beta-cell specific protein and kills the beta-cell. This is a done by the CTL cell and is a Type IV HSR.

Question 31

In MS, it is mostly a CD_ T Cell mediated Type ___ HSR.

Answer 31

In MS, it is mostly a CD4+ T Cell mediated Type IV HSR.

Question 32

Self reactive CTL’s are associated with what disease?

Answer 32

Type I Diabetes

Question 33

In ___ ____ an unknown trigger sets up an initial focus of inflammation in the BBB. The BBB becomes permeable to leukocytes and blood proteins. CD4 T cells specific for CNS antigen are activated in peripheral lymphoid tissues. Once activated, they re-encounter antigen presented on microglia or dendritic cells in the brain. This causes an inflammatory reaction in the brain due to mast-cell activation, antibodies and cytokines. Demyelination of neurons occur. This is a Type ___ HSR

Answer 33

In MS, an unknown trigger sets up an initial focus of inflammation in the BBB. The BBB becomes permeable to leukocytes and blood proteins. CD4 T cells specific for CNS antigen are activated in peripheral lymphoid tissues. Once activated, they re-encounter antigen presented on microglia or dendritic cells in the brain. This causes an inflammatory reaction in the brain due to mast-cell activation, antibodies and cytokines. Demyelination of neurons occur. This is a type IV HSR.

Question 34

• _____ – General immunosuppression
• _______s – e.g., Anti-TNFa (Remicade) or soluble TNFa receptor (Enbrel) in Rheumatoid Arthritis
• ______ – Multiple Sclerosis
• Antibodies against T cell homing receptors – Anti-integrin a4 in Multiple Sclerosis and inflammatory bowel disease (in Phase II clinical trials)
• ____ – Multiple Sclerosis (pilot studies); statins inhibit HMG-CoA reductase, blocking synthesis of cholesterol—a precursor for estrogens, etc.

Answer 34

• Corticosterioids – General immunosuppression
• Anti-Cytokine Antibodies or Soluble Receptors – e.g., Anti-TNFa (Remicade) or soluble TNFa receptor (Enbrel) in Rheumatoid Arthritis
• b-Interferon – Multiple Sclerosis
• Antibodies against T cell homing receptors – Anti-integrin a4 in Multiple Sclerosis and inflammatory bowel disease (in Phase II clinical trials)
• Statins – Multiple Sclerosis (pilot studies); statins inhibit HMG-CoA reductase, blocking synthesis of cholesterol—a precursor for estrogens, etc.

Question 35

Long Term Goal of Autiimmunity Therapeutics:

Tolerance to Autoantigen Triggering the Autoimmune Response

The problem:

__ ___ – As the autoimmune response becomes chronic, the number of autoantigens increases

Answer 35

Long Term Goal:

Tolerance to Autoantigen Triggering the Autoimmune Response

The problem:

Epitope spreading – As the autoimmune response becomes chronic, the number of autoantigens increases

Question 36

Conventional immunosupressive drugs in clinical use:

Corticosteroids - inhibit ___, inhibits many targets, including __ production by ___.

Azathioprine, cyclophosphamide, mycophenolate - inhibit proliferation of ___ by interfering with __ syntheiss

Rapamycin - inhibits proliferation of ____ cells by blocking ___-dependent ___ (important for growth) activation

Cyclosporin A - inhibit the ___-dependent activation of ___, blocks IL-__ production and proliferation by __ cells.

Answer 36

Conventional immunosupressive drugs in clinical use:

Corticosteroids - inhibit inflammation, inhibits many targets, including cytokine production by macrophage.

Azathioprine, cyclophosphamide, mycophenolate - inhibit proliferation of lymphocyte by interfering with DNA syntheiss

Rapamycin - inhibits proliferation of effector T cells by blocking Rictor-dependent mTOR (important for growth) activation

Cyclosporin A, tacrolimus - inhibit activation of NFAT, which blocks IL-2 production and proliferation by T cells.

Question 37

Corticosteroids: can down-regulate adhesion molecules. It can also kill many active ___ with corticosteroids.

Question 38

Explain how cyclosporin A works:

Answer 38

Normally, calcium binds to calmodulin, the activated calmodulin activates calcineurin. Calcineurin then dephosphorylates NFAT, and NFAT goes to the nucleus and started trascribing IL-2 and CD25, which are essential for T cell develpment.

Cyclosporin basically inhibits calcineurin activation by calmodulin, thus preventing dehosphorylation of NFAT –> no transcription

Question 39

What does Rapamycin do?

Answer 39

It inhibits mTOR, which is essential for T cell growth.

Question 40

The small molecule immunosupressives are:

What do they do?

Answer 40

The small immunosuppressive molecules are:

Azathiprine, Cyclophosphamide, Mycophenolic, Methotrexate.

They all inhibit DNA syntheiss

“A Zany Cycler, stole my Meth at the DiNA”

Question 41

Rituximab is a biologic which eliminates what? What is this used for?

Answer 41

B cell

It is an Anti-CD20

Non-hodgkins lymphoma

Question 42

Omalizumab is an anti-___, and removes ___ antibodies. It is used to treat chronic ___

Answer 42

Omalizumab - removes IgE antibodies and is treated for chronic asthma.

Question 43

Ipilimumab increases ____ cell responses because it is an anti___. It is used to treat what?

Answer 43

Ipilimumab increases CD4 T cell responses because it is an anti-CTLA-4. It is used to treat what? Metastatic melanoma

Question 44

____ is an anti-alpha integrin. It is used to treat MS.

Answer 44

Natalizumab

Question 45

What are three monoclonal antibodies developed for immunotherapy? What do they do?

Answer 45

At Zumba class in Monaco, alpha Natalie with MS and general educator Omar ate an Ipple from the City of LA.

Natalizumab, Omalzumab, Ipilimumab

Natalizumab - anti-alpha integrin - MS

Omalzumab - removes IgE antibody - Chromic Asthma

Ipilimumab - anti CTLA-4 - metastatic melonoma

Question 46

Biologics can also be used for immunotherapy. These are ___. For example IFN can be used for patients with ___. They are not small molecules but they are not cells. They are inbetween –> biologics.

Answer 46

Biologics can also be used for immunotherapy. These are cytokines. For example IFN can be used for patients with MS. They are not small molecules but they are not cells. They are inbetween –> biologics.

Question 47

What are the three cellular based therapies?

Answer 47

• HSCT - hematopoetic stem cell transplant
• Regulatory T Cell Transfer - injecting them back into a person
• CAR Therapy - take out a patients T cell, and reprogram them –> create a franken receptor that recognizes a specifc antigen on a tumor cell. Chimeric T cell recognized this, and causes the T cell to kill the tumor cell.

Question 48

T/F: CAR therapy is great because you can target more than just a peptide (like T cells)

Answer 48

T