Autoimmune Disorders Notes

Autoimmune Responses

An autoimmune response is an adaptive immune response to self-antigens.
Autoantigens are self-antigens that trigger an immune response.
Several mechanisms ensure tolerance to self-antigens, but none are perfect.
Collectively, these mechanisms are usually effective at preventing autoimmunity.
Autoimmune responses occur when self-tolerance breaks down.
A major task of the immune system is to differentiate self from non-self.
There is no single ‘self-antigen’.

Mechanisms Producing Self-Tolerance: Negative Selection

Negative selection selects against lymphocytes that are strongly/moderately ‘self-reactive’.
Many lymphocytes weakly reactive to ‘self-antigens’ will escape negative selection. These weakly self-reactive lymphocytes can also recognize foreign antigens.
If all weakly self-reactive lymphocytes were eliminated, the immune response would be impaired.
However, weakly self-reactive lymphocytes can potentially produce autoimmune disease.
T-cells are activated when their receptor binds antigen in the presence of a co-stimulatory signal from the dendritic cell.
B-cell activation requires signals delivered from a conjugate TFH cell, which must recognize a linked antigen.
Lymphocytes that bind antigen in the absence of co-stimulation are signaled to undergo apoptosis or become anergic.

Mechanisms Producing Self-Tolerance: Lymphocyte Requirement for Co-stimulation

Some T-cells that are negatively selected during development in the thymus become Tregs (natural Tregs).
Naïve T-cells that bind antigen in the presence of anti-inflammatory cytokines become Tregs (induced Tregs).
Tregs can inhibit the activation of other T cells that recognize autoantigen being presented by the same cell; they do not have to recognize the same antigens.

Mechanisms Producing Self-Tolerance: Tregs

Mechanisms that result in the breaking of self-tolerance are not completely known, but a likely possibility includes:
- Dendritic cells could pick up self-antigen in the presence of an infection and become activated (mature) by microbial PAMPs taken up at the same time. The dendritic cell could then activate self-reactive T-cells.
- Inflammatory cytokines produced during an infection may also down-regulate Treg responses.

The Breaking of Self-Tolerance

Responses resemble those that target microbes, but autoantigens often cannot be eliminated.
Therefore, autoimmune disorders are chronic.
Even if the autoantigen is eliminated, the resulting symptoms are chronic.
Autoimmune disorders usually arise spontaneously (i.e., with a couple of exceptions, an individual is not born with the disorder).
Autoantigens are well characterized, but what triggers the initial immune response against them is not (most likely some type of inflammation in the body).
Immune mechanisms are analogous to type II, III, and IV hypersensitivity reactions.

Autoimmune Disorders

An IgG antibody response is directed at a cell surface antigen. Examples of type II response.

Examples of Type II Response

An antibody response is directed at a cell surface antigen.
- E.g., Autoimmune hemolytic anemia
  - IgG antibodies are directed at an antigen on RBCs.
  - Results in opsonization, activation of complement system, and ADCC. Compare to type II hypersensitivity reaction.
- Grave’s disease
  - Antibodies directed at thyroid receptor stimulate excessive production of thyroid hormone, resulting in hyperthyroidism.
- Myasthenia gravis
  - Antibodies directed at acetylcholine receptor at the neuromuscular junction block nerve transmission, resulting in weakness and rapid fatigue.

Examples of Type III Response

An excess of small soluble antigen forms small antigen:antibody immune complexes that deposit in vessels and activate the classical complement pathway and act as opsonins.
- Systemic lupus erythematosus
  - Autoantigens are ubiquitous cellular antigens released at high concentration from apoptotic cells or damaged tissue (e.g., DNA, histone proteins, spliceosome proteins, etc.).
  - Form small autoantigen:antibody immune complexes that deposit in glomeruli of kidney, joints, and blood vessels of the skin and other organs, causing inflammation and damage via activation of the classical complement pathway.

Examples of Type IV Response

Immune response is due to the actions of effector T-cells.
- Multiple sclerosis
  - A T-cell response against antigens in the myelin sheath surrounding CNS neurons causes destruction of myelin.
  - Results in progressive muscle weakness, blindness, and paralysis.
- Type I diabetes
  - T-cell response against β cells in the pancreas causes destruction of the cells and insulin deficiency.
  - Results in high blood sugar.
- Rheumatoid arthritis
  - T-cells initiate an immune response against autoantigens in the synovial membrane of joints (antibody response also develops later).
  - Inflammation spreads to bone and cartilage.
  - Results in pain, reduced function, and disability.
Autoimmune disease results from genetic susceptibility and breakdown in tolerance mechanisms, which can be influenced by environmental factors.

Genetic Susceptibility

Susceptibility to autoimmune disease is consistently associated with MHC genotype.
- A relative risk >1 indicates increased susceptibility.
- A relative risk <1 indicates increased protection.
These results are from studies of MHC genotypes in sibling pairs with type I diabetes and sibling pairs with no type I diabetes.
Affected siblings inherit the same sets of MHC genes (i.e., the same set from the mother and father) much more often than would be expected if MHC genotype did not influence susceptibility.

Other Genes Predisposing to Autoimmunity

Mutations in other categories of genes may also predispose to autoimmunity:
- Genes that affect autoantigen availability and clearance:
  - e.g., mutations in early complement system proteins cause increased risk of developing SLE, as the complement system is involved in clearing cellular debris.
- Genes that affect apoptosis:
  - Deficiencies with apoptosis result in a longer duration immune response.
    - Excessive tissue damage may mean self-antigens are available for longer.
    - Inflammation is present for a longer duration.
- Genes involved in signals that control lymphocyte activation:
  - Reduced function of negative regulators (that wind-down an immune response) may lead to longer-lasting responses (with the same outcome as above).
  - Dampened signaling from T-cell/B-cell receptor means fewer cells negatively selected.
- Genes involved in the development and function of Tregs.
There are sex differences in susceptibility to autoimmune diseases:
- Pink – higher incidence in females.
- Purple – equal incidence.
- Blue – higher incidence in males.

Environmental Factors Contributing to Autoimmunity

The hygiene hypothesis:
- Improvements in hygiene and sanitation practices in developed countries are correlated with an increased incidence of allergies and autoimmune disorders.
Vitamin D deficiency.
Molecular mimicry in the case of rheumatic fever: antibodies produced against a group A strep infection that goes untreated can cross-react with self-proteins in the heart, skin, joints, and brain.
Chance factors may also be involved:
- An unfortunately timed infection may trigger autoimmune disease by providing PAMPs that could cause maturation of a dendritic cell that picked up self-antigen.
- Unfortunate timing could see the chance meeting of a B-cell and T-cell that both escaped negative selection and recognize linked autoantigens.
From: The Lancet: https://doi.org/10.1016/S0140-6736(13)60591-7
Prevalence of type I diabetes between 1950 - 2006.

Environmental Factors Enhancing Genetic Susceptibility to Rheumatoid Arthritis

Four of the DRB1*04 alleles listed confer increased susceptibility to developing rheumatoid arthritis.
One DRB1*04 allele confers protection.
In individuals with the DRB1*04 susceptibility alleles, smoking substantially increases susceptibility.