Tolerance and Autoimmunity

what is immunological tolerance?

lack of response to an antigen

Immunological tolerance is specific to what?

antigen-specific

the immune response is tolerant to…/

self-antigens (autoantigens)

Tolerance to self-antigens is a central feature of

Clonal Selection

Autoimmunity results from a failure of

immunological tolerance

what are the 2 major types of tolerance?

central and peripheral

what is central tolerance?

tolerance due to the elimination of self-reactive developing lymphocytes (i.e. negative selection)

t/f: CENTRAL TOLERANCE is a perfect system.

false. some autoreactive B cells/autoreactive T cells ESCAPE from bone marrow/thymus

what is peripheral tolerance?

tolerance due to the elimination, inactivation, or inhibition of self-reactive mature lymphocytes (T and B cells) in the peripheral tissues (not BM or thymus)

what specific processes are involved in central tolerance?

• Immature B cells deleted in bone marrow

• Immature T cells deleted in thymus

what specific processes are involved in peripheral tolerance?

• Deletion due to lack of co-stimulation

• Anergy due to lack of co-stimulation

  • Anergic lymphocytes are inactivated and eventually die

• T-regulatory cells suppress specific responses

In which situations might it be valuable to induce tolerance in adults?

– Allergy
– Transplantation
– Autoimmune disease

normal immune response to ‘dangerous’ antigen

Peripheral tolerance: Deletion or anergy of lymphocytes that recognize self or innocuous antigen

(aka Self reactive lymphocytes are removed (apoptosis) or inactivated (anergy))

Antigen recognition in the absence of co-stimulation leads to

B-cell anergy (or T cell anergy)

Antigen recognition in the absence of co-stimulation leads to

T-cell anergy (or B-cell anergy)

how do T regulatory cells affect the immune response?

downregulate by:

• turning off response

• prevent autoimmunity

how does TLA4 and PD-1 affect T cell responses?

inhibit

T regulatory cells suppress via:

1) Cytokines
2) Contact-dependent mechanisms

The oral route of antigen exposure tends to induce/suppress tolerance

induce

autoimmune diseases are generally complex. what factors play a role?

multigenic and environmental

autoimmunity tend to follow which pattern of genetic inheritance?

familial (not Mendelian)

t/f: Autoimmune diseases are generally multigenic and not due to a single gene

true (with exceptions!)

what are 2 examples of autoimmune diseases caused by a single gene defect? (exceptions to the multigenic rule)

1. APS-1 (Autoimmune polyglandular syndrome type 1))

2. IPEX (Immunodysregulation, polyendocrinopathy, enteropathy, X-linked)

autoimmune disease are more common in what groups of people?

• family members (especially twins)

• females (due to hormonal factors)

Most autoimmune disease are associated with particular ___ alleles

MHC (HLA)

what are some immunological and microbial factors that could give rise to autoimmunity?

• exposure of hidden antigens

• nonspecific lymphocyte activation

• molecular mimicry

• hormonal factors

exposure of hidden antigens can occur due to…?

damage (physical or microbial) to cell

Example: Uveitis that occurs after trauma to the eye - Sympathetic ophthalmia

what is nonspecific lymphocyte activation?

• Stimulation of B-cells nonspecifically

• Superantigens stimulate T-cells

• Example: EBV

what is molecular mimicry?

Foreign antigen closely resembles self antigen
• Example: rheumatic fever

Damage to the tissue may be mediated primarily by:

• antibodies

• T-cells

• both

Rheumatic fever is an example of

molecular mimicry (Microbes may function as adjuvants and stimulate immune responses)

what are some examples of antibody mediated autoimmune diseases?

• Autoimmune hemolytic anemia

• Myasthenia gravis

what are some examples of T cell mediated autoimmune diseases?

– Crohn’s disease
– Insulin-dependent diabetes mellitus (IDDM)
– Psoriasis
– Multiple sclerosis
– Celiac Disease

what are some examples of both antibody AND T cell mediated autoimmune diseases?

Rheumatoid arthritis

lupus (SLE) is 9x more common in males/females

females (estrogen may play a role in onset)

SLE patients have autoantibodies to..? This results in immune complex formation (antigen-antibody complexes) that cause tissue damage, especially nephritis.

DNA and other nuclear self-antigens

Graves disease is caused by stimulating/blocking autoantibodies

stimulating

Myasthenia gravis is caused by stimulating/blocking autoantibodies

blocking

what is Myasthenia gravis?

Progressive weakness and loss of muscle control caused by autoantibodies against acetylcholine receptors

type I diabetes is _______ mediated?

T cell

what are treatment options for autoimmune disease?

• anti-inflammatory drugs (NSAIDs, etc.)

• immunosuprressant drugs

• biologics

Helen is a 6-year old who was brought to her pediatrician with fever and a swollen knee. Her mother reported that 2 weeks prior to this, Helen and her brother had “strep throats” which had been treated with amoxicillin. An X-ray of the knees showed no abnormalities, but the pediatrician detected a heart murmur.

Because of the previous strep infection, blood samples were sent for evaluation of antibodies to Streptococcal proteins. The level of antibody was markedly elevated confirming a diagnosis of…?

rheumatic fever

An 8-year-old reports that they have been thirsty and tired and often leave the classroom to use the bathroom. Physical examination is normal. A urine sample and a simple reagent strip indicates the
presence of glucose. To confirm the diagnosis, a blood sample is sent to the laboratory and glucose levels are 395mg/dl (normal is less than 139 mg/dl).

Diagnosis?

Type 1 Diabetes mellitus (T1DM).> 90 % of T1DM cases carry HLA type DR4, DQB*0302, and/or DR3, DQB*0201
• If a T1DM person with both HLA regions, has a sibling with both HLA regions, then
the sibling has a higher risk of developing T1DM - 80%.

% of T1DM cases carry HLA type DR4, DQB*0302, and/or DR3, DQB*0201

> 90

If a T1DM person with both HLA regions, has a sibling with both HLA regions, then the sibling has a % risk of developing T1DM

80%