Autoimmunity: T Cells and Molecular Mimicry

• Autoimmunity arises from multiple factors, not a single event.
• Self-reactive immune cells can evade normal control mechanisms and attack the body.
• T cell exposure to self-antigens is crucial for self-tolerance.
• Sequestered antigens, hidden from T cells, can later trigger auto-reactivity.

T Cell Exposure to Sequestered Antigens

• T cells exposed to sequestered antigens can induce self-reactivity.
• This process leads to proliferation and inflammation.
• Tissue damage occurs as these cells target tissue epithelium.
• This leads to the proliferation of cytotoxic T lymphocytes (CTLs).
• B cells are activated, resulting in auto-reactive antibodies produced by plasma cells.

Overcoming Anergy

• Anergy normally inhibits auto-reactive cells.
• In highly inflammatory sites with high cytokine levels, self-recognizing T cells can be activated.
• Cytokine signals from neighboring cells, often associated with infections, facilitate this activation.

Molecular Mimicry

• Some pathogens use molecular mimicry as a survival strategy.
• They express epitopes similar or identical to those on host molecules.
• Host cells responding to the pathogen can also target host cells, leading to autoimmune injury.

Self-Tolerance Mechanisms

• The body has a complex system for weeding out self-reactive cells through self-tolerance.
• Negative and positive selection processes promote self-tolerance.
• Central tolerance is limited because not all self-antigens are present in primary lymphoid organs.
• Some antigens develop later, such as during puberty.
• Autoimmune diseases vary in pathology.
• Pathology depends on the Th1/Th2 balance in response to specific self-antigens.
• The Th1/Th2 balance against a self-antigen determines the manifestation of autoimmune disease.

Anergy and Regulatory Cell Inhibition

• Anergy happens when T cells bind to non-antigen-presenting cells (APCs).
• Engagement of T cell receptors (TCRs) on naive CD8+ T cells with protein MHC class I molecules on non-APCs provides the first signal.
• A second signal is not provided, leading to T cell unresponsiveness.
• Regulatory T cells (Tregs) inhibit auto-reactivity.
• Tregs can inhibit the activation of autoreactive cells, even those already activated.

Immune Tolerance: A Safeguard Mechanism

• Immune tolerance prevents the production of autoreactive cells.
• Central tolerance and peripheral tolerance are two levels of immune tolerance.
• These mechanisms are employed on both T cells and B cells.

B Cell Development and Central Tolerance

• Lymphoid progenitor cells give rise to immature B cells.
• Immature B cells have B cell receptors (BCRs) that recognize antigens.
• If BCRs recognize self-antigens with high affinity, preventive measures are taken.
• Self-reactive B cells can be eliminated via apoptosis (programmed cell death).
• They can be suppressed.
• They can enter hibernation (anergy) by down-regulating BCRs.
• Immature B cells can re-edit their BCRs to reduce affinity.
• Central tolerance prevents auto-reactive B cell production in the bone marrow.

Peripheral Tolerance

• Peripheral tolerance occurs in the lymph nodes.
• Naive B cells populate, divide, and undergo clonal expansion.
• They undergo affinity maturation and class switching.
• They differentiate into plasma cells.
• Sometimes auto-reactive plasma cells are created which secrete auto-reactive antibodies.
• Peripheral tolerance ensures these auto-reactive B cells or plasma cells die by apoptosis.
• Clonal anergy occurs instead of proliferation, where cells hibernate and don't react with other antigens.

Mechanisms of Autoimmunity and Protective Measures

• Loss of tolerance occurs in central lymphoid organs.
• Negative selection eliminates cells with strong reactivity against self-antigens in the thymus (T cells) and bone marrow (B cells).
• Receptor editing modifies B cell receptor specificity in the bone marrow to avoid self-reactivity.
• Peripheral tolerance mechanisms are used.
• Anergy functionally inactivates self-reactive lymphocytes that escape negative selection.
• Regulatory T cells (Tregs) suppress auto-reactive T cells.
• Clonal deletion eliminates self-reactive lymphocytes during development.
• Immunological anergy occurs when self-reactive lymphocytes don't receive co-stimulatory signals.
• Suppressive cytokines, such as transforming growth factor-beta (TGF-β), suppress immune responses.
• Tissue-specific mechanisms, like restricted self-antigen expression or immunosuppressive microenvironments, prevent autoimmune responses.