3C_When Tolerance Fails

Understanding autoimmune disorders is crucial for developing therapies in immunoengineering.

Central Tolerance: Mechanisms in the thymus that prevent self-reactive T cells from maturing.
Antigen Segregation: Physical separation of self-antigens to prevent immune response.
Peripheral Tolerance: Mechanisms that prevent immune responses to self-antigens outside of the thymus.
Regulatory T cells: Promote tolerance and prevent autoimmunity by suppressing self-reactive T cells.
Functional Deviation: Changes in immune cell functionality that prevent responses to self-antigens.
Activation-induced Cell Death: A process where T cells that respond to self-antigens are induced to die.

Discussed in:
- Akirav, Eitan M., Ruddle, Nancy H., and Herold, Kevan C. (2011). "The role of AIRE in human autoimmune disease." Nature Reviews Endocrinology.

Mechanism Breakdown:
- Trauma can trigger B cells to bind self-antigens from dying cells.
- Activated B cells differentiate into plasma cells, producing antibodies against self-antigens.
- This leads to an inflammatory response, creating a vicious cycle of further tissue damage and activation of more B cells.

Reference: Green, Douglas R., et al. (2009). "Immunogenic and tolerogenic cell death." Nature Reviews Immunology.

Reference: Theofilopoulos, Argyrios N., et al. (2017). "The multiple pathways to autoimmunity." Nature Immunology.
Activation of autoreactive T cells can result from nucleic acid sensing mechanisms.

Example 1: Trauma to one eye results in exposure of sequestered intraocular antigens, activating T cells, causing a systemic immune response impacting both eyes.
Example 2: In multiple sclerosis (MS), an unknown trigger causes inflammation in the brain and breaches the blood-brain barrier, allowing autoreactive T cells to cause further inflammation and demyelination.

Unknown initial triggers cause inflammation in the synovial membrane that attracts leukocytes.
Autoreactive CD4 T cells activate macrophages; these produce pro-inflammatory cytokines which sustain inflammation leading to joint destruction.

Single-Gene Traits Associations:
- AIRE: Associated with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED).
- CTLA4: Associated with Graves' Disease and Type 1 Diabetes.
- FOXP3: Linked to Immune dysregulation in IPEX syndrome.
- FAS: Related to Autoimmune Lymphoproliferative Syndrome (ALPS).
- C1q: Associated with Systemic Lupus Erythematosus (SLE).

Key genes involved:
- CTLA4, IL2R, PTPN22, Insulin - Can influence the tolerance mechanisms.
- Studies by Katsarou et al. highlight the importance of genetic predispositions.

Linked to Systemic Lupus Erythematosus (SLE):
- Defects in IgM antibodies and complement proteins contribute to the pathogenesis of autoimmunity.
- Reference: Schmidt et al. discussing autoimmunity and primary immunodeficiency.

Factors leading to psoriasis include:
- Initial Insult: Trauma, infections, medications.
- Genetic Risk Factors: Involvement of specific alleles like HLA and CARD14.

Understanding these factors can provide insight into disease development and potential therapies.

Multiple factors can lead to Crohn's disease:
- Failure of central tolerance, inability to sequester bacteria, changes in Treg function, and mutations linked to immunological responses.

Uneven antigen presentation due to polymorphic self-proteins can lead to transplant rejection.

Immunoengineering involves understanding the complex interactions between tolerance, genetics, and environmental factors in autoimmunity.