MECHANISM OF AUTOIMMUNITY

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Autoimmunity occurs when the immune system mistakenly targets and attacks the body’s own cells, tissues, and organs. This can result in various autoimmune diseases, where the immune response is directed against self-antigens. The development of autoimmunity involves a breakdown in the normal mechanisms of immune tolerance, which are designed to prevent immune cells from attacking the body’s own tissues.

1. Genetic Predisposition:

Certain individuals are genetically predisposed to developing autoimmune diseases. Several genetic factors can contribute to the breakdown of tolerance mechanisms, including:

• Human Leukocyte Antigen (HLA) genes: HLA genes encode proteins involved in antigen presentation to T cells. Variants in specific HLA alleles, particularly HLA class II molecules, are associated with increased susceptibility to autoimmune diseases. For example, HLA-DR3 and HLA-DR4 are linked to diseases like Type 1 diabetes and rheumatoid arthritis.
• Non-HLA genes: Other genes involved in immune regulation, such as those encoding cytokines (e.g., IL-2, IL-10), costimulatory molecules (e.g., CTLA-4), and toll-like receptors (TLRs), can also influence the risk of autoimmunity.

2. Loss of Immune Tolerance:

Under normal conditions, the immune system distinguishes between self and non-self through central tolerance and peripheral tolerance mechanisms. Autoimmunity arises when these tolerance mechanisms fail.

• Central Tolerance:
  • Occurs in the thymus (for T cells) and the bone marrow (for B cells).
  • During development, autoreactive T and B cells that recognize self-antigens with high affinity are eliminated through a process called negative selection (apoptosis).
  • Some autoreactive cells escape this process, which makes peripheral tolerance crucial.
• Peripheral Tolerance:
  • Anergy: Autoreactive T and B cells that escape central tolerance may become anergic (non-responsive) if they encounter their specific antigen without the appropriate costimulatory signals.
  • Regulatory T cells (Tregs): These cells play a major role in maintaining immune tolerance by suppressing autoreactive immune cells.
  • Apoptosis: Autoreactive cells can be eliminated through activation-induced cell death if they recognize self-antigens.
  • In autoimmunity, failure of peripheral tolerance allows these autoreactive cells to proliferate and cause tissue damage.

3. Molecular Mimicry:

This mechanism involves the immune system mistaking self-antigens for foreign antigens due to structural similarities between the two. This cross-reactivity can lead to an autoimmune response.

• Pathogen-induced autoimmunity: Certain infections, such as those caused by viruses or bacteria, may share epitopes (antigenic determinants) with self-proteins, leading to an immune response that targets both the pathogen and host tissues. For example, rheumatic fever follows a streptococcal infection due to cross-reactivity between streptococcal antigens and heart tissue.

4. Epitope Spreading:

Epitope spreading occurs when the immune response initially targets a specific epitope (part of an antigen) but over time, it expands to target other epitopes on the same or different proteins.

• Example: In multiple sclerosis (MS), the immune system may initially target a specific myelin protein, but as the disease progresses, other myelin proteins become targets as well, resulting in wider tissue damage.

5. Release of Sequestered Antigens:

Some self-antigens are normally hidden or “sequestered” from the immune system in immunologically privileged sites, such as the eye, brain, or testes. These areas are protected from immune surveillance under normal conditions.

• If these antigens are released due to injury, infection, or trauma, they may be recognized as foreign by the immune system, leading to an autoimmune response. An example is sympathetic ophthalmia, where trauma to one eye releases sequestered antigens, leading to an immune attack on both eyes.

6. Aberrant Expression of Major Histocompatibility Complex (MHC) Molecules:

• MHC molecules (especially MHC class II molecules) are involved in presenting antigens to T cells. Normally, MHC class II molecules are expressed only on antigen-presenting cells (APCs), but in certain conditions, other cells (like epithelial or endothelial cells) may inappropriately express MHC class II molecules and present self-antigens to T cells.
• This inappropriate presentation can lead to the activation of autoreactive T cells and subsequent tissue damage.

7. Polyclonal Lymphocyte Activation:

• In some cases, B cells and T cells can be activated in a non-specific, polyclonal manner, bypassing normal regulatory checkpoints. This can be triggered by certain infections (e.g., Epstein-Barr Virus) or substances like superantigens.
• Once activated, these lymphocytes may produce autoantibodies or lead to cytotoxic activity against self-tissues.

8. Cytokine Imbalance:

The balance between pro-inflammatory and anti-inflammatory cytokines is crucial in maintaining immune homeostasis. In autoimmunity, there is often an imbalance in cytokine production, leading to excessive inflammation.

• Pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, and IFN-γ promote inflammation and activation of autoreactive immune cells.
• Anti-inflammatory cytokines (e.g., IL-10, TGF-β) are often deficient or less effective in autoimmune conditions.

9. Dysfunction of Regulatory T Cells (Tregs):

• Regulatory T cells (Tregs) play a critical role in suppressing autoreactive T cells and maintaining peripheral tolerance.
• In many autoimmune diseases, there is a decrease in the number or function of Tregs, leading to uncontrolled activation of autoreactive lymphocytes.

10. Autoantibodies and Autoimmune Diseases:

In many autoimmune diseases, the production of autoantibodies is a key feature. These antibodies target self-antigens and form immune complexes that can deposit in tissues, leading to inflammation and tissue damage.

• Examples:
  • Anti-nuclear antibodies (ANA) in systemic lupus erythematosus (SLE).
  • Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis.
  • Anti-thyroid antibodies in Hashimoto’s thyroiditis and Graves’ disease.

Summary of Mechanisms of Autoimmunity: