Lecture 3 Notes: Adaptive Immune Response

Adaptive Immune Response

  • Adaptive immunity is also known as acquired immunity.
  • Acquired immunity refers to the vast, unique set of antibodies and T cell receptors that develop over time to recognize the antigenic universe.
  • Vaccination utilizes acquired immunity to generate antibody molecules and T cells designed to recognize pathogens.

Antibodies

  • Antibodies are a critical component of the acquired immune response.
  • Next lecture will cover the cellular arm which is T-Cells.

Evolution of Adaptive Immunity

  • Adaptive immunity is unique to higher vertebrates.
  • It was acquired around 500,000,000 years ago.
  • Agnathans (jawless invertebrates like lamprey eels and hagfish) have variable lymphocyte receptors, representing an early form of repertoire generation.
  • Transposition, or jumping genes, is a mechanism used by bacteria and lower organisms to share and reposition genes.
Transposition Mechanism
  • Transposase/Recombinase Enzymes: Enzymes that cut DNA at specific sequences.
  • Recognition Sequences: Unique DNA sequences recognized by recombinase enzymes.

Adaptive Immunity and Memory

  • Adaptive immunity leads to immune memory, providing lifelong protection after an initial challenge.
  • Measles vaccination provides lifelong protection.
  • Measles is highly contagious, with an R0 (infection ratio) of 18.
Immune Response to Pathogens
  • The immune system generates a vast repertoire of B cells and T cells with slightly different antibody molecules before birth.
  • Upon pathogen recognition, B cells undergo affinity maturation, improving their ability to recognize the pathogen.
  • Memory B cells respond rapidly to subsequent exposures, providing protection.
Genetic Recombination
  • Diversity in the immune system is achieved through genetic recombination or gene rearrangement at immunoglobulin (IG) and T cell receptor loci.
  • Recombinase genes are only expressed in B cells and T cells which allow them to rearrange unique regions in the genome.

Antibody Structure

  • Immunoglobulins are made up of multiple Ig domains.
  • Ig domains are approximately 12.5 kilodaltons in size (about 110 amino acids).
  • The Ig domain has a beta barrel structure and is stable and soluble.
  • The ends of the sheets that form the beta barrel structure are called loops, and these loops determine the diversity within the antibody.
  • Disulfide bonds hold together each of this barrel shape.
Key Features of Ig Domains
  • Ig fold is about 110 amino acids long.
  • Formed from two antiparallel beta-pleated sheets.
  • Stabilized by a disulfide loop.
  • Loops at the ends of strands can accept millions of different amino acid combinations.
Antibody Composition
  • An antibody molecule is made up of heavy chains and light chains.
  • Two heavy chains are joined by disulfide bonds, and light chains are joined to each of the heavy chains by disulfide bonds.
Functional Regions
  • FAB Region (Fragment Antibody Binding): The arms of the antibody responsible for antigen binding.
  • Fc Region (Fragment Crystalline): The back end of the antibody, recognized by Fc receptors on immune cells.
Classes of Antibodies: GAINED
  • IgM: Default antibody made by all B cells. Uses the Mu gene.
  • IgG: Most common form in blood. Uses the gamma gene. Generated after class switching.
  • IgD: Uses the delta gene.
  • IgE: Important in allergy and inflammation. Uses the epsilon gene.
  • IgA: Found in mucosa, breast milk, and colostrum. Uses the alpha gene. Transports across epithelial barriers.
IgM Properties
  • IgM is a pentamer in the blood, with ten antigen-binding sites.
  • It exhibits high avidity binding, enhancing its ability to stick to microbes.

Affinity vs. Avidity

  • Affinity: Strength of attractive molecular forces between two surfaces (e.g., antigen and antibody).
  • Avidity: Overall strength of binding, considering multiple interactions (e.g., Velcro).
  • IgG is bivalent, exhibiting avidity binding.
  • IgM is multivalent, with up to 10 binding sites.
  • Multivalent interactions trigger the immune system.

Immune Repertoire and Gene Rearrangement

  • The immune system can produce approximately 101110^{11} different antibody molecules from only 30,000 genes.
  • Variations occur in the variable domain at the tip of the antibody.
Complementarity Determining Regions (CDRs)
  • CDRs are three discrete regions in the variable domain formed by loops.
  • CDR1, CDR2, and CDR3 are hypervariable regions.
Genetic Loci
  • The heavy chain gene locus and light chain gene locus contain segmented genes.
  • These segments are classified into variable (V), diversity (D), and joining (J) clusters.
Gene Rearrangement Process
  • Recombinase enzymes randomly join segments from the V, D, and J clusters.
  • A diversity segment joins to a joining segment to form a DJ.
  • A variable region segment joins to the DJ segment to form a VDJ join.
  • Everything in between the new join gets discarded.
Junctional Diversity
  • Generated when segments come together imprecisely.
  • Enzymes add and chew back base pairs, resulting in unique junctions.
  • This process results in approximately 101110^{11} possible combinations.

Clonal Selection and Affinity Maturation

  • The immune system generates many possible combinations of B cells in the hope that one will recognize a pathogen.
  • Antigen selects and expands the right clone through clonal selection and affinity maturation.
Process
  1. Naive B cells are triggered by an antigen and expand within a germinal center.
  2. The B cell switches from making an IgM molecule to an IgG molecule.
  3. Somatic hypermutation occurs in the gene, improving the affinity of some antibodies.
  4. B cells with higher affinity are selected.
  5. After successive rounds, a B cell becomes a plasma cell, producing long-lived, highly specific immunoglobulin.
  6. Some mature B cells take on a memory phenotype and reside in lymph nodes and tissues.
Lymph Nodes
  • Lymph nodes are clustered around regions that confront the environment.
  • When a B cell is activated, it sticks in the lymph node and forms a germinal center.
  • T cells drive B cells to make antibodies and undergo affinity maturation.

Vaccination

  • Vaccination, sanitation, and antibiotics have saved more lives than any other combinations of medical developments.
Herd Immunity
  • If you vaccinate enough people, the pathogen has nowhere to go (approximately 90% of the population).
  • Examples include smallpox and polio eradication.
Common Concerns
  • Measles and whooping cough are on the rise because people are deciding not to get vaccinated.
  • The MMR vaccine does not cause autism.
  • Whooping cough is caused by Bordetella pertussis and is life-threatening in infants.