Autoimmunity

Question 0

What is autoimmune disease? Give example.

Answer 0

A specific and sustained adaptive immune response directed against self which causes damage to host. Example: In SLE, antibodies are formed against self DNA, histones and other nuclear components.

Question 1

Example of physiologic or regulatory autoimmunity

Answer 1

Body removes aged RBCs by rxn of IgG autoantibodies with senescent cell antigen

Question 2

What is tolerance?

Answer 2

It is the acquired and specific lack of immunological activity to a particular antigen.

Question 3

What is autoimmunity?

Answer 3

The immune system responds against self causing destruction of normal cells and tissues d/t a failure of mechanisms of tolerance to self antigens. Can be caused by inheritance of susceptibility genes, hormonal milieu and/or environmental factors (heavy metals or infection)

Question 4

Diseases with MHC associated genetic predispositions

Answer 4

RA, myasthenia gravis, Type I diabetes, Goodpasture’s syndrome, SLE, ankylosing spondylitis, Grave’s disease, Multiple sclerosis

Question 5

What is molecular mimicry?

Answer 5

Infectious pathogen bears peptides that mimic AA sequence of self antigens. An APC presents pathogen peptide to CD4+ Th cell => activates macrophages and B-cells that mount immune response against self tissues.

Question 6

How do protein changes in self cells and cryptic antigens cause a immune response?

Answer 6

Tissue injury, cell death or reparative changes can make self proteins unrecognizable to immune system and induce autoimmune response. Cryptic antigens are proteins normally sequestered or shielded from immune recognition that can become immunogenic when exposed to the immune system

Question 7

What are superantigens and how do they mount an immune response?

Answer 7

Superantigens are proteins produced by bacteria or mycoplasmae or virus that bind TCR irrespective of its antigenic specificity causing activation of a large number of T lymphocytes of different antigenic specificity.

Question 8

How is tolerance normally effected?

Answer 8

Self reactive, immature B-cells are deleted in the bone marrow; self reactive DP T-cells are deleted at the CM junction in the thymus

Question 9

Are all self-reactive lymphocytes deleted? Why or why not?

Answer 9

Only strongly self reactive B and T cells are deleted during positive and negative selection. Not all self antigens are expressed in the thymus and bone marrow so some self-reactive lymphocytes do escape to the periphery.

Question 10

What are central tolerance mechanisms?

Answer 10

Immature lymphocytes specific for self antigens are deleted. B lymphocytes change their specificity by receptor editing. Some T lymphocytes develop into regulatory T cells.

Question 11

What are peripheral tolerance mechanisms?

Answer 11

Some mature self reactive lymphocytes in peripheral tissues may be inactivated or deleted by encounter with self antigens or suppressed by regulatory T cells.

Question 12

What are examples of autoimmune diseases with mendelian inheritance?

Answer 12

Multiple sclerosis, rheumatoid arthritis, lupus

Question 13

What is the mechanism of genetic susceptibility resulting in autoimmune disease?

Answer 13

Susceptible genes result in failure of self tolerance. Self reactive lymphocytes interact with APCs during an infection. Influx of self reactive lymphocytes into tissues causes tissue injury.

Question 14

What is the mechanism bystander activation?

Answer 14

During an infection or tissue damage, activated APC presents epitope spread from microbial to self peptides to self-reactive T cells that cause self-tissue destruction.

Question 15

What is the microbial mechanism of induction of costimulators?

Answer 15

Microbes activate APCs to express co-stimulators (B7-1, B&-2) so that when self antigens are presented to self-reactive T cells they become activated instead of being rendered tolerant (become anergic or apoptose).

Question 16

What is the mechanism of cross-reactivity in autoimmune disease?

Answer 16

An infectious agent causes disease. Recovery from disease d/t T cell and Ab response. A portion of antigenic protein mimics self protein. D/t the MHC composition, T-cells specific for antigenic protein also cross-reacts with self protein. T-cell responds to self protein and recruits immune cells causing tissue destruction.

Question 17

Which autoimmune diseases do Th17 cells appear to be intimately involved?

Answer 17

Crohn’s, psoriasis, inflammatory bowel disease and rheumatoid arthritis. Deficiencies in Th17 or its receptor result in chronic mucocutaneous candidiasis syndrome.

Question 18

What are some factors contributing to autoimmune disease?

Answer 18

• Estrogen - induces IFN-gamma production => ^ HLA expression on APCs; may also push Th2 autoimmune response toward Th1
• Infections - superantigenic effect of Staph or Mycoplasma may activate T-cells causing them to secrete cytokines and/or expand autopathogenic T-cell pop. d/t prolonged inflammatory response
• Stress - stimulation of hypothalamus and pituitary may lead to ^ cytokine secretion => inflammation

Question 19

What are important cytokines in autoimmunity?

Answer 19

TNF-a, IL-1, IL-6 => begin acute phase response
IL-2 => induces T-cell, NK and B-cell proliferation (minor)
IL-4, IL-5 => induces IgG1, IgE and IgA, eosinophil production (IL-5)
IL-7, GM-CSF => hematopoiesis
IL-10 => suppresses Th1 response
IFN-gamma => upregulates MHC class I and II expression

Question 20

What is systemic autoimmunity?

Answer 20

Autoimmune pathology is evident in a number of organ systems. Examples include SLE, Sjogren’s and scleroderma

Question 21

What is organ-specific autoimmunity?

Answer 21

Autoimmunity is exhibited in specific tissues in which the target antigen is found. Examples are thyroiditis (thyroid), diabetes (islets), Addison’s (steroid producing cells of adrenals and ovary)

Question 22

What are treatments for autoimmune disease?

Answer 22

1) corticosteroids - prednisone
2) NSAIDs - ASA, ibuprofen, tylenol
3) cyclosporin A, Tacrolimus, Rapamycin
4) monoclonal antibodies (anti-CTLA-4)
5) TCR peptide immunization
6) anti-TNF-a biologicals - infliximab, etanercept, adalimumab

Question 23

How does the hygiene hypothesis cause autoimmune disease?

Answer 23

The hygiene hypothesis suggests that exposure to microbes early in life is associated with the prevention of asthma and certain autoimmune diseases. This observation may be d/t the levels of T-regs and iNKT cells stimulated by the presence or absence of microbes.

Question 24

What is IVIG?

Answer 24

IVIG, intravenous immunoglobulin, is administered to patients to suppress inflammation. The presence of N-linked glycans on the IgG Fc receptor bind lectin expressed on myeloid regulatory cells resulting in reduced antigen presentation and inhibition of antigen specific T cells responses.

Question 25

What is the proposed mechanism of disease in RA?

Answer 25

The inciting event is unknown, perhaps d/t superantigen. Rheumatoid factor bind w/Fc portion of IgG resulting in the formation of ICs that precipitate and deposit on the synovial lining of joints. Synovial membranes are infiltrated by PMNs, macrophages, lymphocytes and plasma cells. Pannus (vascular granulation tissue) forms and erodes the cartilage of the joint. Considered to be Type IV hypersensitivity (destructive process involves T-cells), HLA association w/DR4.

Question 26

What is the difference b/t autoimmunity and autoimmune disease?

Answer 26

Autoimmunity is normal while autoimmune disease results in tissue damage and disease.

Question 27

What is the mechanism of disease in multiple sclerosis?

Answer 27

Disease mediated by Th1 and possibly Th17 cells specific for myelin based protein (MBP) causing demyelination of nervous tissue. HLA association w/DR2. Th1, CTL and macrophage infiltrates are found upon examination of the brain in MS patients.

Question 28

What is the mechanism of disease in Hashimoto’s disease?

Answer 28

CD4+ and CD8+ T-cells and B-cells produce autoAbs to thyroid antigens (thyroglobulin, peroxidase). Lymphocytes cause significant tissue destruction resulting in hypothyroidism and goiter. Considered to be type IV hypersensitivity.

Question 29

How do cyclosporin, tacrolimus and rapamycin work?

Answer 29

Inhibit production of IL-2 resulting in the suppression of naive T-cell proliferation and differentiation and any immune response that require activated T cells. Side effects: renal tox

Question 30

How do corticosteroids work?

Answer 30

1) decrease inflammation caused by IL-1,3,4,5,8, TNF-a, GM-CSF, NO, prostaglandins, leukotrienes, adhesion molecules, chemotaxis
2) increase apoptosis of lymphocytes
Side effects: fluid retention, wt. gain, ^ blood glucose, osteopenia, hyperactivity

Question 31

What is the relationship b/t age and autoimmunity?

Answer 31

Aged immune system prone to autoimmune responses and ^ in autoimmune disease. ^ autoAb titers observed after 60y/o. RA only develops in females after menopause; polymylagia rheumatica and giant cells arteritis occur after 50y/o. Other factors - decreased T-regs, unstable peripheral tolerance, lymphopenia, changes in intracellular signaling mechanisms