Immunological Tolerance and Autoimmunity

Immunological Tolerance and Autoimmunity

• Immunological tolerance is the unresponsiveness to self-antigens. It's a lack of response to antigens induced by lymphocyte exposure to those antigens.
• Immunogenic lymphocytes are activated, proliferating and differentiating into effector and memory cells (productive immune response) – usually for microbes.
• Tolerogenic lymphocytes are inactivated or killed resulting in tolerance – normally for self-antigens. Failure of self-tolerance causes autoimmune disease.
• Immunological ignorance refers to antigen-specific lymphocytes that do not react, ignoring the presence of an antigen.
• Central tolerance occurs in generative lymphoid organs (bone marrow and thymus) where immature lymphocytes specific to self-antigens are deleted.
• Peripheral (secondary) tolerance involves mature lymphocytes encountering self-antigens in peripheral lymphoid organs/tissues.
• CD4+ T cells mediate responses to protein antigens. They can induce tolerance, preventing both cell-mediated and humoral immune responses against self-proteins.
• Autoimmunity is when the immune system attacks the individual's own cells and tissues.
• Central T cell tolerance involves the removal of immature T cells that react with self-antigens.
• Negative selection occurs when immature T-lymphocytes interact with a self-antigen triggering apoptosis, preventing the T-cell becoming functionally competent.
• Self-proteins are crucial in thymic expression.
• Peripheral T cell tolerance involves mature T cells recognizing self-antigens, leading to functional inactivation (anergy) or death, or suppression by regulatory cells.
• Antigen recognition without costimulation leads to T-cell anergy or death, enhancing sensitivity to suppression by regulatory T cells.
• Anergy is a long-lived functional unresponsiveness in T cells due to abnormal TCR complex signaling or inhibitory signals from other receptors like CTLA-4, CD152, or PD-1.
• CTLA-4 and PD-1 are inhibitory receptors that regulate T-cell responses. CTLA-4 reduces costimulation and suppresses regulatory T-cell activity, while PD-1 terminates T-cell responses to self-antigens and chronic infections via ITIM.
• Checkpoint blockade is a cancer treatment that involves blocking inhibitory receptors such as CTLA-4 or PD-1, potentially causing autoimmune responses against one's own tissues.
• Regulatory T cells (Tregs), CD4+ cells expressing CD25 and FoxP3, suppress harmful lymphocytes specific to self-antigens.
• FoxP3 is a transcription factor essential for Treg development and function.

Mutations and Survival

• Mutations can cause multiorgan autoimmune disease (IPEX).
• Survival and function of regulatory T cells are dependent on the cytokine IL-2.
• TGF-beta stimulates FoxP3, a regulatory T cell-stimulating cytokine.
• Regulatory T cells suppress immune responses by producing cytokines (IL-10 and TGF-beta), blocking B7 on APCs using CTLA-4, and consuming T-cell growth factors.

Deletion and Antigen Recognition

• Deletion of mature lymphocytes occurs when they recognise self-antigens.
• Two mechanisms involve pro-apoptotic protein activation and co-expression of death receptors and their ligands which activate downstream caspases and apoptosis of the lymphocytes

B Cell Tolerance

• B lymphocytes prevent autoantibody production by self-polysaccharides, lipids, and nucleic acids (T-independent).
• Central B cell tolerance occurs when immature B lymphocytes interact with self-antigens leading to receptor editing or deletion.
• Receptor editing is the process where B cells modify Ig light chain genes to produce new receptors not specific for self-antigens.
• Anergy can affect B-cells, similarly to T cells.

Tolerance to Commensal Microbes and Fetal Antigens

• Commensal microbes and fetal antigens require tolerance to co-exist.
• Microbes in the intestines, skin, or respiratory tract are tolerated by mature cells.
• Paternal antigens in the placenta are typically tolerated by the mother.

Autoimmunity: Pathogenesis and Genetic Factors

• Genetic factors, mainly MHC genes, influence autoimmune disease susceptibility.
• HLA alleles can increase the risk of autoimmune diseases by influencing self-tolerance/immune response.
• Polymorphisms (variations in genes) can contribute to autoimmune diseases.
• Infections may trigger or influence autoimmunity as molecules might mimic self-antigens (molecular mimicry).

Immune Surveillance and Responses Against Tumors

• Immune surveillance is the immune system's role in controlling and eliminating malignant cells.
• Evidence for this includes lymphocyte infiltrates around tumors, rapid rejection of transplants if exposed previously to the tumor, and immunodeficiencies associated with increased tumor incidence.
• Tumor antigens include products of mutated genes, oncogenes, or mutated tumor suppressor genes, and overexpressed or aberrantly expressed proteins.
• Cytotoxic T lymphocytes (CTLs) act to kill tumor cells specific for tumor antigens.

Evasion of Immune Responses by Tumors

• Tumors may evade detection or resistance to immune response by losing antigens, neglecting MHC molecules, inhibiting T cell activation, or producing immunosuppressive cytokines.

Cancer Immunotherapy

• Cancer immunotherapy focuses on activating anti-tumor effectors, actively immunizing against tumors, or activating the patient's antitumor immune response.
• Passive immunotherapy uses immune effectors (antibodies) specific for tumor antigens to activate host effector mechanisms.
• Adoptive cellular therapy involves isolating tumor-specific T lymphocytes and returning them to a patient.

Immune Responses Against Transplants

• Direct allorecognition refers to recipient T cells directly recognizing donor MHC molecules on graft dendritic cells and attacking them.
• Indirect allorecognition involves graft allo-antigens being processed and presented by recipient dendritic cells and recognized by alloreactive CD4+ T cells.
• Transplants can be rejected based on MHC antigens, leading to inflammatory reactions, damaging the transplanted tissue.

Prevention and Treatment of Graft Rejection

• Immunosuppression inhibits T-cell activation and effector functions to prevent graft rejection.
• FK506 and Rapamycin are immunosuppressive drugs that block immune responses.

Hypersensitivity Reactions

• Hypersensitivity reactions describe when immune responses to an antigen result in sensitivity to challenge with that antigen.
• Immediate hypersensitivity (Type 1) involves mast cells releasing mediators such as histamine against environmental antigens following IgE binding.
• Antibody-mediated (Type 2) involves antibodies (other than IgE)(IgM or IgG) attacking cell or tissue antigens.
• Immune complex-mediated (Type 3) involves soluble antigen and antibody complexes depositing in blood vessels and tissues leading to inflammation and tissue injury.
• T-cell mediated (Type 4) reactions occur via macrophage activation, cytokine-mediated inflammation, direct cytotoxicity, and damage.

Mechanisms of Tissue Injury and Disease

• Mediators such as proteases, arachidonic acid metabolites, and cytokines damage tissues.

Immunodeficiency Diseases

• Immunodeficiency diseases are disorders due to defective immunity.
• Congenital (primary) immunodeficiencies arise from genetic abnormalities affecting immune system components.
• Acquired (secondary) immunodeficiencies develop due to factors like infections, nutritional issues, or medical treatments altering functionality of immune components.
• Severe combined immunodeficiency (SCID) involves defects in both B and T lymphocytes.
• Chediak-Higashi syndrome or Ataxia-telangiectasia are diseases exhibiting impaired phagocyte and/or lymphocyte function.
• Therapy for deficiencies often involves hematopoietic stem cell transplantation or intravenous immunoglobulin (IVIG) injections.

Acquired Immune Deficiency Syndrome (AIDS)

• The Human immunodeficiency virus (HIV) largely affects CD4+ T lymphocytes, causing progressive destruction of immune cells and leading to opportunistic infections.
• HIV lifecycle includes infecting cells (using gp120), producing viral DNA copies, integration into host genome, and expression/production of viral particles.
• Clinical features of HIV show signs like acute HIV syndrome followed by latency- a period of viral suppression where HIV might cause mild symptoms or remain asymptomatic but continues to destroy the immune system. Symptoms of AIDS develop progressively as CD4+ T cells decline (below 200 cells/mm^3).
• Advanced AIDS is marked by characteristic opportunistic infections and cancerous tumors (Kaposi's sarcoma and B-cell lymphomas from Epstein Barr Virus).

Explore the complex concepts of immunological tolerance and autoimmunity in this quiz. Understand how the immune system distinguishes between self and non-self antigens, and learn about mechanisms like central and peripheral tolerance. Test your knowledge on the activation of lymphocytes and the implications of failure in self-tolerance.