Central & Peripheral Tolerance

• Tolerance is the body's mechanism to prevent the immune system from attacking self.
• Tolerance creates a state of unresponsiveness to self-antigens.
• Central and peripheral tolerance are the main mechanisms used.
• B and T cells are removed before maturing if they recognize self-antigens with a high affinity.

Central Tolerance

• Occurs in primary lymphoid organs like bone marrow and thymus.
• B or T cells possessing receptors with high affinity for self-antigens are deleted.
• Some self-reacting lymphocytes are altered or edited to reduce affinity for self-antigens.

Peripheral Tolerance

• Renders self-reactive lymphocytes inactive or anergic in secondary lymphoid tissues.
• Some self-reactive lymphocytes evade tolerance checkpoints, leading to autoimmunity.

Mechanisms of Tolerance

• Apoptosis and anergy are used during central and peripheral tolerance.
• Inactivation of lymphocytes during development reduces self-reactive B and T cells that reach circulation.
• Clonal deletion and anergy induce central or peripheral tolerance.
• Autoimmune diseases are caused by failure of the tolerance process.

Central vs Peripheral Tolerance

• Central tolerance occurs in the thymus for T cells and bone marrow for B cells.
• Peripheral tolerance occurs in secondary lymphoid organs and peripheral tissues.
• Central tolerance ensures lymphocytes entering the bloodstream can distinguish between self and non-self antigens.
• Peripheral tolerance ensures lymphocytes don’t attack self-tissues, even after leaving primary lymphoid organs.

Central Tolerance Mechanisms

• Developing T cells undergo positive and negative selection in the thymus.
• Positive selection ensures T cells recognize self-MHC molecules.
• Negative selection eliminates T cells that bind too strongly to self-antigens.
• Immature B cells are tested for reactivity to self-antigens in the bone marrow.
• B cells that bind too strongly to self-antigens undergo clonal deletion or receptor editing.

Peripheral Tolerance Mechanisms

• Anergy occurs if self-reactive T or B cells encounter their antigen but don’t receive a second activation signal, becoming functionally unresponsive.
• T Regulatory (Treg) cells suppress the activation of self-reactive T cells through anti-inflammatory cytokines.
• Ignorance occurs when self-reactive cells do not encounter their specific self-antigens in peripheral tissues.

Importance of Both Tolerance Types

• Central tolerance prevents autoimmune reactions from the beginning by ensuring the immune system does not start with dangerous self-reactive T and B cells.
• Peripheral tolerance acts as a backup mechanism for self-reactive cells that evade central tolerance.
• Together, they create a dual-layer defense against autoimmunity.

Anergy vs Apoptosis in Peripheral Tolerance

• Anergy allows the immune system to maintain potential responses to infections without allowing self-reactive cells to cause harm.
• Apoptosis (cell death) is a more definitive and permanent solution.
• Anergy avoids the risks of eliminating potentially useful immune cells needed for future infections or altered self-antigens.
• Peripheral tolerance operates in secondary lymphoid organs and tissues.
• Anergy offers a way to "turn off" self-reactive cells rather than removing them, re-engaging them if necessary.
• Apoptosis of autoreactive cells can trigger inflammation and tissue damage if it releases self-antigens.
• Anergic cells are kept in a state of non-responsiveness without triggering immune activation.
• For T or B cells to become fully activated, it needs not only to recognize its antigen but also to receive a co-stimulatory signal
• Self-reactive lymphocytes that recognize low-affinity self-antigens may be anergized rather than deleted.

Clonal Behavior

• "Clonal" refers to a group of identical cells originating from a single progenitor cell.
• These cells share the same receptor or antibody that recognizes a particular antigen.

T Regulatory Cells

• Inhibit other immune cells by soaking up IL-2 and adenosine.
• Secrete anti-inflammatory cytokines.
• Cause dendritic cells to express inhibitory ligands.
• Clonal anergy occurs due to a lack of co-stimulation.
• Clonal exhaustion occurs to chronic stimulation of T cells.
• Clonal deletion is when cells are induced to die due to a fast-ligand interaction.
• Anergy can inhibit B cell proliferation and differentiation.
• IgG antibodies can bind the FC gamma receptor on B cells, inhibiting their differentiation and proliferation

Central vs Peripheral Tolerance

• Central tolerance occurs in primary lymphoid organs, such as the thymus for T cells, and is essential during T cell development.
• Peripheral tolerance occurs in secondary lymphoid organs and peripheral tissues, where mature T cells interact with antigens.
• In the thymus, developing T cells go through positive and negative selection processes.
• Positive selection ensures that T cells recognize self-major histocompatibility complex (MHC) molecules.
• Negative selection eliminates T cells that strongly react with self-antigens presented by MHC molecules.

Anerty in T cell Cancer

• Anergy is a state of functional unresponsiveness in T cells, where they do not mount an immune response, even when exposed to an antigen.
• In the context of T cell lymphoma, malignant T cells may develop anergy as a mechanism to escape immune recognition and destruction
• Challenges in Treatment: Anergy in malignant T cells can pose challenges in the treatment of T cell lymphoma
• Anergic T cells do not respond to conventional immunotherapies, such as immune checkpoint inhibitors

Ignorance via Tregs (Regulatory T cells)

• Refers to a mechanism by which self-reactive lymphocytes (usually T cells) do not mount an immune response against self-antigens, not because they are actively suppressed or rendered unresponsive, but because they never encounter their self-antigens in the first place or their recognition of these antigens is tolerated by Tregs.
• Tregs suppress the activation and proliferation of self-reactive T cells, thus preventing them from attacking the body's own tissues
• Tregs express the FoxP3 transcription factor, which is crucial for their development and function.
• Tregs suppress inflammation and immune responses, which helps to prevent damage in tissues such as the CNS, even if self-reactive T cells are present.

Central and peripheral tolerance are mechanisms to prevent the immune system from attacking self. Central tolerance happens in the bone marrow and thymus, where self-reacting B and T cells are removed if they recognize self-antigens. Peripheral tolerance renders self-reactive lymphocytes inactive in secondary lymphoid tissues.