Failure of tolerance leads to autoimmunity.

a) What mediates damages?

b) How invasive is autoimmunity?

c) What gender is it more prevalent in?

d) Is autoimmunity heriditary and is it possible to have more than one?

a) antibody-mediated or T-cell mediated

b) systemic or organ-specific

c) females

d) Can be passed down and if a person has one their probability is likely that they will have more than one autoimmune disease.

Establishment and maintenance of Tolerance

What is Tolerance? Is it specific or non-specific?

To establish tolerance,

what does it help to have?

• high doses of antigen
• soluble forms of the antigen
• persistence of the antigen in host
• intravenous or oral administration of the antigen
• absense of adjuvants
• low levels of costimulators

Tolerance

What are some mechanisms that will help prevent self reativity?

Tolerance

a) What is central tolerance?

b) When and where does it occur?

c) What is the mechanism?

a) serves to delete self-reactive T or B lymphocytes

b) During maturation in the bone marrow or thymus

c) The Lymphoid precursor begin to clone immature lymphocytes, which then self antigen is present in generative lyphoid organ and begin to delete lymphoctes that are specific to self antigens. Maturation occurs for the lymphocutes that are not specific for self antigens.

Tolerance

a)What is peripheral tolerance?

b) Where does it occur?

c) What other cells may be involved and what does it inhibit?

d) Explain the mechanism of peripheral tolerance.

a) inactivates self-reactive lymphoctes that survive the initial selection process

b) secondary lymphoid tissue

c) regulatory T cells (Treg)- (CD4CD25 T cells). Treg cells can inhibit autoimmunity and the proliferation of other t cells.

d) an antigen will bind to a mature lymphocyte, and it will undergo deletion or anergy of lymphocytes that recognize self antigens in peripheral tissues.

Establishment of Tolerance

a) What are tolerogens?

b) What can become a tolerogen, but how?

c) What happens when antigens present to t cells that don't have the proper costimulation?

a) antigens that induce tolerance

b) immunogens, when it is presented differently to the immune system.

c) can lead to anergy

An antigen can be either immunogenic or tolerogenic.

a) What is this dependent on? What is found experimentally?

b) What response occurs when a mature lymphocyte encounters an immunogenic and a tolerogenic antigen?

a) Dependent on the variety of factors of dose and the avenue of exposure. Experimentally that the same antigen will response immunogenically if exposed intravenously, but will response tolerogenically via oral exposure.

b) Immunogenic response: Proliferation of lymphocytes
    Tolerogenic response: apotosis or anergy.

a)What is Antigen Sequestration?

b) Do these antigens have tolerance?

a) Compartamentalization of antigens, so that they do not react with immune cells.

b) No, it will be prone to attack if the barriers fail.

• blood brain barrier protecting various proteins
• sperm
• eye lens
• heart muscle

• It is directed primarily against a single organ or gland.
• The antigen is unique to that organ.
• it may be humoral or cell mediated

• directed against a broad spectrum of tissues
• general defect in immune regulation
• hyperactive t and b cells 

Risk Factors for Autoimmune Diseases

What are genetic (HLA) risk factors?

• HLADR2 with SLE and MS
• HLADR3 with djorre syndrome, MG, SLE and DM-1
• HLADR4 with RA and DM-1

Risk Factors for autoimmune disease

What is a risk factor for females?

Risk Factors for Autoimmune Disease

What drugs are risk factors?

• procainamide
• minocycline
• qunadine w/ DILE

• Hashimoto's diases: thyroiditis
• Goodpasture
• Vitiligio

Organ Specific Disease

a) What is Hashimoto's thyroiditis?

b) What cells are involved?

c) what is the treatment?

a) chronic inflammation and enlargement of the thyroid

b) autoantibodies and TH1 cells specific to thyroid antigens. Infiltration of lymphocytes, macrophages, and plasma cells that will cause hypothyroidism (decrease in production of thyroid hormones).

c) Treatment by thyroidectomy.

Organ Specific Diseases

a) What is Good Pasture's syndrome?

b) What becomes activated and what is the result of activation?

c) What tissues are affected?

d) How is it detected?

a) auto-antibodies specific for basement membrane antigens binding to the kidney glomeruli and alveoli of the lungs that leads to kidney damage and pulmonary hemorrhage

b) Complement which results in cellular damage and side products of the complement leading to inflammation.

c) death of kidney tissues and lung tissues which may lead to death

d) Fluorescent-labeled anti-IgG and anti-c3b staining during biopsies.

Organ Specfic Disease

a) What is Insulin-Dependent Diabetes Mellitus (Type I)?

b) How does direct cellular damage occur?

c) What other complications may arise?

d) What increases with the decrease of insulin production?

e) What therapy could a patient with type I diabetes undergo?

a) Autoimmune attack on insulin producing cells (beta cells) of the pancrease

b) CTLs bind to cell membrane antigens causing lysis, followed by the development of auto-antibodies.

c) Glycoma, obesity, deafness, blindness, metabolic problems, and vascular lesion leading to gangrene in the extremeties.

d) increased in blood glucose levels

e) Daily insulin injection; some may not need to monitor as closely

Autoantibodies are antagonist

a) What is Grave's Disease?

Autoantibodies are antagonist

a) What is myasthenia gravis?

b) What is the result of untreated patients?

c) Is this disease treatable?

a) autoantibody blocks acetylcholine receptors that inhibit muscle activation.

b) patients can stop breathing, heart stops pumping, and muscles become weakened

c) yes, this disease is treatable.

Systemic Auto Immune Diseases

a) What is Systemic Lupus Erythemastosus (SLE)?

b) What tissue antigens do the autoantibodies attack?

c) What gender is affected at what ratio and age group?

d) What symptoms are found?

e) What type of hypsersentivity reaction develops?

f) Is there treatment?

a) A systemic auto immune disease usign auto-antibodies against a vast array of tissues.

b) DNA, histones, leukocyes, platelets, clotting factors, and anti-nuclear antibodies are diagnostic

c) Females 10:1 in the age groups of 20-40

d) fever, weakness, arthritis, skin rashes, inflammation around the lungs (pleurisy) and kidney disfunction

e) Type II and III and inflammatory damage from elevated C3a and C5a which leads to vasculitis.

f) Corticosteroids, NSAIDS, immunosuppressants, pain medication and life style changes.

Systemic Autoimmune Diseases

a) What is multiple sclerosis?

b) what age groups are affected?

c) what are symptoms?

a) produce autoreactive T cells that participate in the formation of inflammatory lesions along the myelin sheath of nerve fibers.

b) Age groups 20-40

c) may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision.

Systemic Autoimmune Diseases

a) What is Rhematoid arthritis?

b) what age group and gender is affected?

c) What types of auto-antibodies are produced and what do they react with?

d) What complex is deposited in joints to cause what type of reaction?

a) chronic inflammation of the joints

b) age 40-60 in women

c) Rhematoid factors react w/ Fc of IgG

d) IgM-IgG cause type III inflammatory reaction

Antibody-caused autoimmune diseases

Can auto-antibody be transferred from patient to recipient?

Antibody-caused autoimmune disease

Can Grave's Disease be transffered from humans to rats?

Antibody-caused autoimmune Disease

Can a fetus contract grave's disease from the mother? Is there a treatment?

One mechanism

• Release of sequestered antigen onto Th Cell,
• inappropriate MHC expression on non-APCs eg. epithelial tissue TH cell release of IFN-gamma
• release IL-2 onto a Tc cell activates CTl to the epithleal tissue causing tissue damage.

a) How does autoimmunity occur?

b) What are three types of proposed mechanisms?

a) Transferred by T cells (CD4+ specificically)

    - TH1 cells cause disease and TH2 cells protect against it

b)

• Release of sequestered antigens,
• molecular mimicry (microbial viral antigens)
• inappropriate class II MHC expression

Proposed Mechanisms

How can autoimmune disease be avoided by releasing "sequestered antigens"?

• sequestered antigens are seen so lymphocytes are not deleted in t cell development
• animals can avoid autoimmune diseases by injection of sequestered antigens with adjuvants into thymus to induce tolerance to avoid autoimmune disease.

a) What is molecular mimicry?

b) What is the percentage of anti-ciral mAbs that react w/ normal tissue antigens

c) What are two diseases that are found in molecular mimicry?

a) Viruses and bacteria having ID that is similar Ag to self Ag's

b) 3%

c) post rabies encephalitis when virus grown in rabbit T cells, post-streptococcal theymatic heart disease

Proposed Mechanisms

a) What is innapropriate expression of Class II MHC?

b) What are some additional signals?

a) non-APCs induce to express class II MHC antigen, Diseases such as IDDM and hashimotos

b) IFN gamma release to produce IL1 and TNF

a) What types of pathogens can activate polyclonal b cells?

b) is it dependent of T cells?

c) What is produced?

a) Cytomegalovirus (CMV), Epstein-Barr Virus (EBV) and some gram negative bacteria.

b) No

c) large amounts of IgM

Rhuematic Fever is a classic molecular mimicry.

Explain how it occurs.

• Group A strep is found in throat infections; which express large amounts of M protein.
• large amounts of IgG produced against M protein on Strep
• ab against M protein can bind to molecules on cardiac cells that are similar to M protein of strep
• ab-induced injury to heart valves and sarcolemma

a) What can occur with hormones during pregnancy?

b) what are two factors that are believed to be autoimmune in nature?

c) What is the hypothesis?

a) Increase level associated w/ pregnancy may lead to abortion of the fetus (RSA)

b) endometriosis and preclapsia

c) estrogen response elements in several genes

• reduce symptoms via immunosuppression via corticosteroids, azathioprine, cyclophosamide.
• removal of thymus
• plasmapheresis is a short term relief for MG, Grave's disease, RA and SLE

• TNF-alpha blockers (RA, chron's disease) psoriasis) eg enbrel, remicade, humira 
• IL-1 receptor antagonist (RA)
• Ab's against IL-6R and IL-15 R
• Statins, shown to lower CRP (RA, MS)

A monoclonal antibody against CD-20. It eliminates B cells in non-Hodgkins lymphoma.

• maybe also RA and other AB-mediated autoimmune diseases

• t cell vaccines
• interfere w/ antigen presentation
• monoclonal ab against a variety of target antigens
• oral induction of tolerance (MS)