Immunity B - Study Guide on the Adaptive Immune System and Immunopathology

Basic Antibody Structure

• Antibodies, or immunoglobulins, typically present as a T-shaped or Y-shaped monomer structure constructed from four looping polypeptide chains.
• These chains are interconnected by disulfide bonds.
• The architecture includes two identical heavy (H) chains, which feature a hinge region at their center and are also referred to as Mu chains.
• The structure also contains two identical light (L) chains, known as Kappa chains.
• Variable (V) regions are situated at one end of each arm; these come together to create two identical sites designed for antigen binding.
• The stem of the antibody is formed by constant (C) regions of the heavy chains.
• Constant regions perform several essential tasks, such as determining the specific antibody class and dictating which cells or chemicals the antibody interacts with to eliminate antigens.

Functional Classes of Immunoglobulins

• IgM exists as a large pentameric molecule, consisting of $10$ heavy chains and $10$ light chains. It is the primary antibody released during the initial immune response and the first produced by an infant's immune system. It serves as a potent agent for agglutination and is highly effective at fixing and activating the complement system.
• IgA, often called secretory IgA, appears as a monomer or a dimer. It is prevalent in body secretions such as saliva, sweat, milk, and gastrointestinal juices. Its main role is to protect mucosal barriers and prevent pathogens from attaching to epithelial surfaces.
• IgD is a monomer found on the surface of B cells, where it functions as an antigen receptor.
• IgG is the most abundant class, representing approximately $75-85\%$ of all circulating antibodies in the plasma. It is the main antibody for secondary and late primary responses, can cross the placental barrier to provide passive immunity to newborns, and readily fixes complement.
• IgE is a monomer that remains in trace amounts in the plasma but increases significantly during parasitic infections or severe allergic reactions (Type I hypersensitivity). Its stem binds to mast cells and basophils, triggering the release of histamine when an antigen binds to its receptor end.

Mechanisms of Antibody Action

• Antibodies do not destroy antigens directly; instead, they inactivate them and tag them for destruction by forming antigen-antibody (immune) complexes.
• Neutralization: This is the simplest mechanism where antibodies block specific sites on viruses or bacterial toxins, preventing them from binding to receptors on tissue cells. These complexes are then removed via phagocytosis.
• Agglutination: Because antibodies have multiple binding sites, they can cross-link lattice-like complexes of cell-bound antigens, such as mismatched red blood cells, causing them to clump.
• Precipitation: Soluble molecules are cross-linked into large complexes that settle out of solution, making them easier for phagocytes to capture.
• Complement Fixation and Activation: This is a primary defense against cellular antigens. Multiple antibodies bind close together on a cell, aligning complement-binding sites on their stems. This triggers cell lysis and amplifies the inflammatory response through opsonization and a positive feedback cycle.

Cellular Immune Response and T Cell Populations

• Cellular immunity is mediated by T cells, which target intracellular antigens. Some T cells kill targets directly, while others coordinate the immune response through chemical signals.
• CD4 cells are naive cells that typically differentiate into helper T ($T_H$) cells, regulatory T cells ($T_{Reg}$), or memory T cells. Helper T cells are essential for activating B cells, other T cells, and macrophages.
• CD8 cells are naive cells that differentiate into cytotoxic T ($T_C$) cells or memory T cells. Activation is triggered by cytokines like interleukin $1$ and interleukin $2$.
• MHC Restriction: T cells only recognize antigens presented on Major Histocompatibility Complex (MHC) proteins. CD4 cells bind to Class II MHC proteins (found on APCs like dendritic cells and macrophages), while CD8 cells bind to Class I MHC proteins (found on all nucleated body cells).
• T Cell Activation: This is a two-step process requiring both antigen binding and co-stimulation, both of which must occur on the surface of an antigen-presenting cell (APC).

Specialized T Cell Functions and Cytokines

• Helper T ($T_H$) Cells: These are central to both humoral and cellular immunity. They mobilize B cells and CD8 cells, and without them, there is effectively no adaptive immune response. They also amplify innate defenses by making macrophages more potent killers.
• Cytotoxic T ($T_C$) Cells: These cells directly attack virus-infected, cancerous, or foreign cells. They deliver a "lethal hit" using perforins, which create membrane pores, and granzymes, which enter the pores to trigger programmed cell death (apoptosis).
• Natural Killer (NK) Cells: These provide immune surveillance by identifying abnormal cells that lack Class I MHC proteins or are coated in antibodies.
• Regulatory T ($T_{Reg}$) Cells: These cells dampen the immune response to prevent autoimmune reactions. They function by direct contact or by releasing inhibitory cytokines like $IL-10$ and $TGF-b$.
• Cytokines: Chemical messengers like Interleukin $1$ ($IL-1$) and Interleukin $2$ ($IL-2$) act as growth factors and inflammatory mediators. Interleukins encourage T cell division and leukocyte recruitment.

Organ Transplants and Rejection

• Transplants are classified into four varieties based on the donor-recipient relationship:
  • Autografts: Tissue moved from one site to another on the same person.
  • Isografts: Tissue transferred between identical twins.
  • Allografts: Tissue transferred between non-identical individuals of the same species (the most common type).
  • Xenografts: Tissue taken from a different animal species.
• Prevention of rejection involves matching ABO and MHC antigens as closely as possible and using immunosuppressive therapy, including corticosteroids and antiproliferative drugs.
• Long-term success is difficult; rejection occurs in $50\%$ of patients within $10$ years. Immunosuppression also leaves patients vulnerable to fatal bacterial and viral infections.

Immunodeficiencies and Autoimmune Diseases

• Severe Combined Immunodeficiency (SCID) Syndrome: A genetic defect resulting in a marked deficit of B and T cells. One cause is a deficiency in the adenosine deaminase ($ADA$) enzyme, leading to toxic metabolite accumulation in T cells.
• Hodgkin’s Disease: A cancer of B cells that depresses the function of lymph nodes. Symptoms include painless swelling of the lymph nodes (often in the neck), night sweats, and weight loss.
• AIDS (Acquired Immune Deficiency Syndrome): Caused by the Human Immunodeficiency Virus (HIV), which targets and destroys CD4 ($T_H$) cells. HIV uses reverse transcriptase to integrate its genetic material into the host cell's DNA. This often leads to opportunistic infections like Kaposi's sarcoma or pneumonia, and eventually death from immune collapse.
• Autoimmune Diseases: These occur when the system fails to distinguish self from foreign, resulting in tissue destruction. Examples include Multiple Sclerosis, Graves' disease, Type $1$ diabetes mellitus, and Rheumatoid Arthritis. Treatments involve suppressing the immune system or blocking specific inflammatory cytokines.

Hypersensitivities

• Immediate Hypersensitivity (Type I): Common allergies that occur within seconds of contact with an allergen. IgE antibodies bind to mast cells, and subsequent exposure triggers a massive release of histamine. Systemic reactions can lead to anaphylactic shock, treated with epinephrine.
• Subacute Hypersensitivities: Caused by IgM and IgG, with an onset of $1-3$ hours and a duration of $10-15$ hours.
  • Type II (Cytotoxic) entails antibodies binding to specific cell antigens (e.g., mismatched blood transfusions).
  • Type III (Immune Complex) occurs when insoluble complexes cannot be cleared, causing intense local inflammation (e.g., systemic lupus erythematosus).
• Delayed Hypersensitivity (Type IV): Involves T cells rather than antibodies, with an onset of $1-3$ days. This mechanism is responsible for allergic contact dermatitis (such as poison ivy) and is the basis for the tuberculin (TB) skin test.