Immunology: Hypersensitivity & Autoimmunity Quiz

Immunological Tolerance

• Tolerance is acquired, not hardwired.
• The immune system is trained to recognise and respond to infectious non-self.
• Adjuvants cue the immune system that an infection is occurring, converting soluble proteins into particulate material ingested by antigen-presenting cells (e.g., macrophages).
• Complete Freund's Adjuvant (CFA) contains ground-up mycobacteria.
• Tolerance is generally Central, occurring during lymphocyte development, or Peripheral, occurring after lymphocytes leave the primary organs.

Central Tolerance - T Cells

• Clonal selection generates a diverse T cell repertoire, initially independent of specificity.
• Positive selection selects clones with some affinity for MHC and self, and negative selection deletes clones binding strongly to self MHC plus peptide in the thymus.

Tolerance and Factors Affecting it

• Tolerance is influenced by antigen timing, dose, costimulation, and location.
• A celebrated experiment: Mice of strain A injected at birth with bone marrow from strain B, six weeks later grafted with skin from mouse B. The skin graft from mouse B was accepted, whereas a graft from mouse C was rejected.

Central Tolerance - B Cells

• Theoretically, B cells require T cell help and shouldn't need tolerance.
• B cells that react to abundant self-antigens are eliminated during their development.
• Receptor editing allows self-reactive B cells to avoid apoptosis.

Five Mechanisms of T Cell Tolerance

• Ignorance: Potential self-reactive T cells remain unactivated if antigens are hidden from the immune system.
• Anergy: Occurs when TCR engagement occurs without the second signal, leading to non-responsiveness
• Treg suppression(Regulatory T Cells): Suppress certain autoreactive T cells through mechanisms such as suppression of proliferation of naive T cells.
• T cell exhaustion: A possible pathological phenomenon occurs when T cells fail to clear a chronic infection or tumour.

Immunologically Privileged Sites

• The brain, eye, and testes have limited or no lymphatic drainage.
• Tolerance can be broken If an organ is damaged or exposed to immune system.
• Pregnancy has an immunologically-privileged site, the placenta. Tolerance mechanisms involve a physical barrier to maternal T cells, the lack of MHC class I on trophoblast cells, and the production of immunosuppressive factors such as alpha-fetoprotein and IDO.

Split Tolerance

• Immune system components including T cells and B cells may not need to be tolerised as frequently as in other instances.
• T cell tolerance may have been established but some autoreactive B cells remain.
• It suggests that the immune response depends on different aspects (T cells versus B cells) that may be regulated to some degree independently.

Anergy

• Anergy is a state of nonresponsiveness that can be induced in T cells and B cells.
• It is triggered when the receptor is engaged with MHC molecules in the absence of the secondary signal, without cell death but with biochemical changes.

Dendritic Cells and Immune Activation

• Dendritic cells are important antigen-presenting cells.
• PAMPs or other stimulation induce the expression of high levels of the CD80 and CD86 costimulatory molecules.
• Cells without this stimulation induce tolerance instead of activation.

Regulatory T Cells - Treg Suppression

• Tregs are a special type of regulatory CD4 T cells.
• Tregs express high levels of IL2-receptor CD25 and the FOXP3 transcription factor.
• Development of Tregs is influenced by cytokine profile, chronic low-dose exposure to antigen, and antigen presentation by immature dendritic cells.

T Cell Exhaustion

• T cell exhaustion is a possible pathological phenomenon of prolonged T cell responses to chronic infection or tumors.
• It is characterized by expression of co-receptor PD1.
• These cells are usually less responsive to stimulation with antigen. 

Experimental Tolerance

• A procedure that established tolerance to foreign antigens that normally result in an immune response.
• Two examples of promising approaches are costimulatory receptor blockade (Abetacept) and cancer treatments that exploit and enhance immune responses to tumors (e.g., antibodies against CTLA4 or PD1)

Autoimmunity

• Autoimmunity is an adverse immune response against self-antigens, where the immune system attacks host components resulting in a pathological change.
• Many times the attack is short-lived and self-resolving following an infection. More serious cases (2-3% of people) can be chronic/life-threatening with major immunopathology.
• Several factors contribute, possibly including early exposure to less frequent infections and a microbiome that is not as diverse in individuals whose immune systems do not encounter frequent infections.

Mechanisms of Autoimmune Pathology

• Direct antibody-mediated effects: Antibodies binding to cells or tissues, leading to destruction or dysfunction.
• Immune complex-mediated effects: IgG complexes deposited in tissues activate complement, resulting in inflammation.
• T cell-mediated effects: CD8 T cells causing cytotoxicity or CD4 T cells activating macrophages damaging tissues.

Hypersensitivity

• Hypersensitivity is a damaging immune response rather than beneficial response to a foreign or innocuous antigen.
• Four main types of hypersensitivity: I, II, III, and IV. Type I: Immediate hypersensitivity (e.g., allergies) Type II: Antibody-mediated (e.g., blood transfusion reactions) Type III: Immune complex-mediated (e.g., serum sickness) Type IV: Cell-mediated (e.g., contact dermatitis)
• Characteristics of each type in terms of mechanisms/targets/response time.

Transplantation

• Allogeneic: most common type, the recipient's immune system is primed by the first encounter with donor antigen, and results in rejection when encountering the antigen again (second-set reaction).
• Hyperacute rejection: rapid rejection due to pre-existing antibodies (e.g., ABO mismatch).
• Acute rejection: T cell response rejection occurs within weeks due to antibodies and immune cells recognizing the graft cells as non-self.
• Chronic rejection: occurs gradually over years, characterized by a loss of organ function.