Autoimmune diseases

what is the central ability for the normal functioning of the immune system?

The ability to distinguish between ‘self’ and ‘non-self’ antigens

what is central tolerance?

Tolerance to self antigens that can be induced during immune cell development in the primary/central lymphoid organs

what is peripheral tolerance?

Tolerance induced after immune cells leave the primary/central lymphoid organs

what is negative selection?

Process by which developing thymocytes that recognize self antigens with high affinity in the thymus undergo apoptosis

How are many issue-specific antigens are expressed and presented in the thymus?

they are expressed by thymic epithelial cells and DCs, and are presented to the developing thymocytes to facilitate negative selection of self-reactive thymocytes

what does the transcription factor, AIRE (autoimmune regulator) do?

responsible for turning on many peripheral genes in the thymus. Defects in AIRE function impair negative selection and allow self-reactive T cells to develop and move to the periphery, leading to an autoimmune disease known as autoimmune polyglandular syndrome type 1 (APS-1).

what are immunologically privileged sites?

sites in the body are off-limits for naïve lymphocytes. antigens in these sites do not induce immune attack.

what are some characteristics of immunologically privelged sites?

• Extracellular fluids do not pass through conventional lymphatics.

• Privileged sites are surrounding by a barrier that exclude naïve lymphocytes; e.g. the blood-brain barrier.

• Soluble factors, such as the anti-inflammatory TGF-β, are produced in the immunologically privileged sites to induce suppressive Treg cells instead of the inflammatory TH17 cells.

• Expression of FasL in the immunologically privileged sites induce apoptotic cell death in Fas-expressing lymphocytes that enter these sites.

what can happen to antigens sequestered in immunologically privileged sites? (bad)

can become targets of autoimmune attacks; for e.g. myelin basic protein of the brain and spinal cord is targeted in the autoimmune disease multiple sclerosis.

what are the 2 subsets of regulatory T cells?

1. Those committed to a regulatory fate during development in the thymus are called natural Treg (nTreg) cells

2. Those which differentiate from naïve CD4 T cells under the influence of particular environmental conditions are called induced Treg (iTreg) cells.

What induces differentiation into iTreg cells?

Antigen recognition by auto-reactive CD4 T cells in the presence of TGF-β

what happens when iTreg cells recognize their antigen?

they produce inhibitory cytokines, TGF-β and IL-10, to supress other auto-reactive T cells.

what does transcription factor FoxP3 do? what happens if you dont have it?

essential for the development of both nTreg and iTreg cells. Humans and mice carrying mutation in the gene for FoxP3 develop severe autoimmune disease, demonstrating the importance of regulatory T cells in preventing autoimmune responses.

Induction of autoimmune diseases:

1. Genetic predisposition – mutations that break down immune tolerance.

2. Accidental exposure of the immune system to autoantigens that are normally sequestered from immune cells (e.g., lens protein and myelin basic protein).

3. Inflammation-promoting environmental factors such as lifestyle (smoking), malnutrition, altered gut microflora, etc.

4. Infection – Certain pathogens express molecules that closely resemble self-antigens and may therefore induce autoimmunity; e.g., T cells reactive with mycobacterial heat shock antigens (hsp65) cross react with human heat shock antigen (hsp60) that is expressed on stressed cells, leading to autoimmune disease.

These mechanisms are not mutually exclusive and that one or more of these mechanisms may contribute to the induction of a particular autoimmune disease

what is molecular mimicry?

a phenomenon where pathogens express antigens that resemble host molecules. Antibodies produced against a pathogen epitope may cross-react with a self molecule causing autoimmune tissue injury

are autoimmune diseases caused solely by a single effector pathway?

mostly no.

what are autoimmune diseases caused by in general?

autoimmune diseases are caused by an integrated immune system involving both the adaptive (T and B cells) and the innate arms of the immune system.

Both T and B cells, as well as effector cells of innate immune system, in particular the phagocytic myeloid cells, contribute to tissue damage in autoimmune diseases, even in cases where a particular type of response predominates.

what are the three classes of autoimmune diseases?

1. Diseases caused by autoantibodies

2. Immune complex disease

3. T cell-mediated disease

what is autoimmune hemolytic anemia?

autoantibodies against blood cells promote cell lysis

Autoimmune hemolytic anemia: the details

• Autoantibodies against antigens on the surface of red blood cells trigger their destruction of cells, leading to anemia.

• Both IgG and IgM antibodies are involved.

• RBCs with bound IgG and IgM are cleared from the circulation by interaction with the Fc or complement receptors on phagocytic cells.

• RBCs with bound antoantibodies can also be lysed by formation of the membrane attack complex of complement.

what is the therapeutic approach to autoimmune hemolytic anemia?

• Removal of spleen, the organ in which clearance of RBCs, platelets and leukocytes occur.

• Intravenous administration of large quantities of nonspecific IgG (IVIG; intravenous immunoglobulin) to block Fc receptor-mediated phagocytosis of antibody-coated cells.

what is Graves’ disease?

Autoantibodies against receptors cause disease by stimulating receptor function

theres a diagram for this one

what is Myasthenia gravis?

autoantibodies against receptors cause disease by blocking receptor function

what causes Myasthenia gravis?

results from the production of auto-antibodies directed against acetyl choline receptors (AChR) on the motor end plates of muscles.

AChR blockade leads to progressive weakening of structural muscles and eventual death of AChR-bearing cells

what are the symptoms of Myasthenia gravis? how do you treat it?

potentially fatal progressive muscle weakness.

Removal of auto-antibodies by plasmapheresis, suppression of B cell activation with corticosteroids, and/or using cholinestease
inhibitors to increase acetyl choline levels are used to treat the condition.

what is goodpastures syndrome?

autoantibodies against extracellular antigens cause inflammatory injury

how does goodpastures syndrome work?

Autoantibodies are formed against the α3 chain of basement membrane collagen.

Autoantibodies cause glomerular damage in the kidney by binding to
collagen in the basement membrane of the glomerular capillaries, causing activation of complement and recruitment of innate effector cells, such as monocytes and neutrophils. Influx of monocytes and neutrophil and their activation, as well as complement activation in the glomerulus cause tissue injury.

what is Systemic lupus erythematosus (SLE)?

autoantibodies against soluble antigens

what causes Systemic lupus erythematosus (SLE)?

Immune complexes are formed when there are antibodies against soluble antigens. Failure to clear immune complexes can cause tissue injuries.
SLE is caused by either overproduction or defective clearance of immune complexes, or both. The main antigens are three types of intracellular nucleoprotein particles:

(i) the chromatin, (ii) spliceosome, and (iii) small cytoplasmic ribonucleoprotein complex.

what causes the release of SLE autoantigens?

extensive cell death coupled with inadequate clearance of apoptotic fragments. In such a scenario, B cells specific for chromatic components can internalize unmethylated CpG sequences, which are recognized by TLR-9, providing the co-stimulator signal for B cell activation and production of anti-chromatin autoantibodies.

what causes activation of phagocytic cells and tissue injury? (SLE)

Deposition of large amounts of immune complexes in the walls of small blood vessels in the renal glomerular basement membrane, joints, and other organs

What is type 1 diabetes?

T cells-mediated destruction of pancreatic β cells

theres a diagram to look at in the slides

what is multiple sclerosis (MS)? what is is caused by?

T cell-mediated neurologic disease. Caused by demyelination of central nervous system tissue, leading to progressive neurologic dysfunction, such as muscle weakness, blindness, paralysis, etc.

what happens if the blood brain barrier breaks down?

autoreactive T cells can enter the brain where they encounter myelin antigens presented on MHC class II by
infiltrating macrophages or microglial cells.

what do autoreactive TH17 cells specific for myelin basic protein do?

produce cytokines that attract and activate macrophages that damage the myelin sheath of nerve fibers. Autoreactive CTL, autoantibodies, complements and cytokines are also involved in the pathology of MS.

what is rheumatoid arthritis (RA)?

chronic inflammation of the joints due to granulocyte/monocyte infiltration, cartilage/collagen destruction by hydrolytic enzymes, fibrin deposition and joint fusion.

what causes rheumatoid arthritis?

immune mechanisms involving T cell, B cells, and effectors of the innate immune system.

B cells produce autoantibodies of the IgM class (rheumatoid factor) that react with the Fc portion of self IgG. The resulting IgM-IgG immune complexes deposit in the synovia of the joints where complement is activated.

how to treat rheumatoid arthritis?

Therapeutic antibodies against TNF-α, B cells, and T cell activation have all been used to treat symptoms of the disease.