Tolerance and Autoimmune Disease

 Tolerance

Tolerance in the immune system refers to a state where the immune system does not respond to specific antigens (or epitopes) even though it functions normally otherwise. This means that the immune system ignores certain substances as if they were not harmful. Typically, antigens that are present during embryonic development are identified as "self" and do not trigger an immune response. This is because self-reactive T-cell precursors are eliminated in the thymus during fetal development. Antigens encountered later, after the immune system has matured, are considered "NonSelf" and usually provoke an immune response. Although both T cells and B cells are involved in tolerance, T-cell tolerance is more crucial.

 T Cell Tolerance

Tell tolerance mainly occurs in the thymus during fetal development. This process, known as clonal deletion, involves the destruction of T cells that react against self-antigens (mainly self-major histocompatibility complex [MHC] proteins). This is called negative selection. These self-reactive T cells undergo apoptosis, a programmed cell death. Tolerance developed within the thymus is called central tolerance. Outside the thymus, it is known as peripheral tolerance.

A transcriptional regulator called autoimmune regulator (AIRE) helps thymic cells present a wide range of self-proteins, ensuring efficient negative selection. Mutations in the AIRE gene can cause autoimmune diseases like autoimmune polyendocrinopathy.

Peripheral tolerance is needed because not all self-antigens are present in the thymus. Mechanisms in peripheral tolerance include killing self-reactive T cells, making them inactive, or suppressing them with regulatory T cells that produce inhibitory cytokines. Clonal anergy refers to self-reactive T cells that are not activated due to a lack of proper stimulation, while clonal ignorance means these cells ignore self-antigens either due to physical separation or because the antigens are in very low amounts.

Self-reactive T cells in a state of clonal anergy can become active and cause autoimmune disease if conditions change later. Anergy occurs due to a failure in costimulatory signals, such as inadequate production of interleukin2 (IL2) or improper interaction of cell surface proteins like CD28 and B7.

 B cell Tolerance

B cell tolerance involves two main mechanisms: clonal deletion in the bone marrow and clonal anergy in the periphery. However, Bcell tolerance is less complete than Tell tolerance, which explains why many autoimmune diseases are mediated by antibodies. B cells can escape clonal deletion through a process called receptor editing, where a new light chain is produced, changing the receptor's specificity to avoid self-recognition. This process does not occur in T cells.

 Induction of Tolerance

Whether an antigen induces tolerance rather than an immune response depends on several factors:

1. Immunologic Maturity: Neonates, or newborn animals, are immunologically immature and do not respond strongly to foreign antigens. For example, neonates will accept transplanted tissues (allografts) that mature animals would reject.

2. Structure and Dose of Antigen: Simple molecules induce tolerance more easily than complex ones. Very high or very low doses of an antigen may lead to tolerance instead of an immune response. Large doses of purified polysaccharides or amino acid copolymers can cause "immune paralysis," where there is no immune response.

Additional factors influencing tolerance include:

·         T cells become and remain tolerant more readily and for longer periods than B cells.

·         Introducing a cross-reacting antigen can terminate tolerance.

·         Immunosuppressive drugs can enhance tolerance, useful in patients with organ transplants.

·         Continuous presence of the antigen helps maintain tolerance.

Autoimmune diseases arise when the immune system mistakenly targets and attacks the body's own tissues. This loss of self-tolerance can lead to a wide variety of conditions, many of which involve complex interactions between genetic, hormonal, and environmental factors. Here, we will delve into the mechanisms behind autoimmune diseases and explore some key examples.

 Mechanisms of Autoimmunity

1. Genetic Factors:

Autoimmune diseases often show a familial pattern, indicating a genetic predisposition. Specific human leukocyte antigen (HLA) genes, particularly class II genes, are frequently associated with these diseases. For instance, rheumatoid arthritis is linked to HLADR4, while ankylosing spondylitis is strongly associated with HLAB27. These genes may encode MHC proteins that more effectively present autoantigens, leading to an autoimmune response.

2. Hormonal Factors:

Women are disproportionately affected by autoimmune diseases, accounting for about 90% of cases. Estrogen is believed to influence the immune system by altering Bcell activity and enhancing antibody production. For example, systemic lupus erythematosus (SLE) often flares up during pregnancy, suggesting hormonal involvement.

3. Environmental Factors:

Infections with certain bacteria and viruses can trigger autoimmune diseases. For example, Streptococcus pyogenes infections are linked to rheumatic fever, and Campylobacter jejuni infections can lead to Guillain-Barre syndrome. Other triggers include drugs and environmental toxins that can modify self-antigens, making them immunogenic.

4. Molecular Mimicry:

Some pathogens have antigens that closely resemble human proteins. This can lead to an immune response that targets both the pathogen and the host tissue. A classic example is the similarity between the M protein of S. pyogenes and cardiac myosin, which can lead to rheumatic fever.

5. Release of Sequestered Antigens:

Certain antigens are typically hidden from the immune system (e.g., in the brain or eyes). Injury or infection can release these antigens, provoking an immune response. For instance, trauma to the eye can lead to sympathetic ophthalmia, where the immune system attacks both the injured and the healthy eye.

6. Failure of Regulatory T Cells:

Regulatory T cells (Tr) help maintain tolerance to self-antigens. A deficiency or dysfunction in these cells can lead to uncontrolled immune responses. Mutations in the FoxP3 gene, which is crucial for Tr cell function, are associated with increased autoimmune diseases.

 Examples of Autoimmune Diseases

1. Antibody Mediated Diseases:

 Myasthenia Gravis: Autoantibodies target acetylcholine receptors at the neuromuscular junction, leading to muscle weakness.

 Graves’ Disease: Autoantibodies stimulate the TSH receptor, causing hyperthyroidism.

 Systemic Lupus Erythematosus (SLE): Autoantibodies against DNA and other nuclear components lead to widespread tissue damage.

 Rheumatoid Arthritis: Autoantibodies against IgG (rheumatoid factor) and citrullinated peptides cause joint inflammation.

 Pemphigus: Autoantibodies against Desmoulins in the skin cause blistering.

2. Cell Mediated Diseases:

 Multiple Sclerosis: Autoreactive T cells attack myelin in the central nervous system, leading to demyelination and neurological symptoms.

 Type 1 Diabetes Mellitus: T cells destroy pancreatic islet cells, leading to insulin deficiency.

 Celiac Disease: T cells react to gliadin in gluten, damaging the intestinal lining.

3. Mixed Antibody and Cell Mediated Diseases:

 Hashimoto’s Thyroiditis: Both antibodies and T cells target thyroid tissue, causing hypothyroidism.

 Goodpasture’s Syndrome: Autoantibodies against collagen in the basement membranes of kidneys and lungs lead to organ damage.

 Summary

Autoimmune diseases are complex and multifactorial, often involving a combination of genetic susceptibility, hormonal influences, environmental triggers, and immune system dysregulation. Understanding these mechanisms helps in diagnosing, managing, and potentially developing targeted therapies for these chronic and often debilitating conditions.