Learn & Review: Immunology 1 – Diversity, Specificity, & B cells

Summary of Immunity and the Immune System

This summary outlines the fundamental concepts of immunity, its historical development, and the two main branches of the immune system: innate and adaptive immunity. It further details the components and mechanisms of adaptive immunity, including humoral and cell-mediated immunity, the structure and function of antigen receptors (antibodies and T cell receptors), and the generation of diversity and immunological memory.

I. Introduction to Immunity

• Definition: Immunity is the body's resistance to disease, developed through prior exposure.
• Historical Context:
  • The principle of immunity has been utilized for centuries.
  • Edward Jenner (18th Century): Observed that milkmaids exposed to cowpox (a milder variant of smallpox) became immune to smallpox. He demonstrated this by inoculating an 8-year-old boy with cowpox material and then exposing him to smallpox, showing immunity.
  • Origin of "Vaccine": The word "vaccine" originates from the Latin word "vaca," meaning cow, due to Jenner's work with cowpox.

II. Levels of Immunity

The body has several levels of defense against disease, with two primary levels discussed:

A. Innate Immunity

• Definition: This is the immunity we are born with; it is inborn.
• Characteristics:
  • Immediate Activation: It provides a first line of defense with an immediate response, without delay.
  • Non-Specific: It recognizes general features of pathogens but cannot distinguish between different types of the same pathogen.
  • No Change with Prior Exposure: The response does not change or improve upon repeated exposure to the same infectious agent.
• Example:
  • Neutrophils: These are cells of the innate immune system that actively hunt and kill bacteria.

B. Adaptive Immunity (Acquired Immunity)

• Definition: This type of immunity is acquired through exposure to foreign agents.
• Characteristics:
  • Adapts and Changes: It adapts its response based on prior exposure.
  • Delayed Response: It takes time to activate, meaning there is a delay before the full response is mounted.
  • Highly Specific: It is highly specific to the particular foreign agent (antigen) encountered.
• Example:
  • Annual Flu Shot: The need for an annual flu shot illustrates the specificity of adaptive immunity. The flu virus constantly changes, requiring new vaccinations for the body to recognize and fight the altered strains.

III. Branches of Adaptive Immunity

Adaptive immunity is divided into two main branches:

A. Humoral Immunity

• Mediated by: Proteins called antibodies.
• Antibodies: These proteins can be secreted into the body's fluids (humors), such as blood.

B. Cell-Mediated Immunity

• Mediated by: Different types of cells, primarily T cells.

IV. Cells of Adaptive Immunity

• B Cells:
  • Produce antibodies.
  • Mature in the bone marrow (hence "B" for bone marrow).
• T Cells:
  • Involved in cell-mediated immunity.
  • Mature in the thymus (hence "T" for thymus).
• Origin: Both T and B lymphocytes originate from a multipotent hematopoietic stem cell, which gives rise to a common lymphoid progenitor.

V. Antigen Receptors

Both branches of adaptive immunity utilize antigen receptors that recognize specific antigens (substances that activate the immune system).

A. B Cell Antigen Receptor (Antibody/Immunoglobulin)

• Synonyms: Antibody, Immunoglobulin (IG).
• Structure:
  • Composed of two identical heavy chains and two identical shorter light chains.
  • Each chain contains immunoglobulin (IG) domains, which are modular protein folds.
  • The variable domains (VH and VL) at the tips of the receptor are responsible for antigen binding.
• Forms:
  • Membrane-bound form: Anchored in the plasma membrane of the B cell.
  • Secreted form: Lacks a transmembrane domain and is released into the blood, especially during infection.

B. T Cell Receptor (TCR)

• Structure:
  • Structurally different from antibodies.
  • Consists of two chains: alpha (α) and beta (β).
  • Has fewer immunoglobulin repeats.
  • The tip of the TCR interacts with the antigen.
• Form: Exists only as a membrane-bound form.

VI. Antigen Recognition

• Antibodies: Can recognize a wide range of molecules, including small molecules, proteins, DNA, and carbohydrates. They are described as "promiscuous" in the range of molecules they can recognize, though a specific antibody recognizes a very specific structure.
• T Cell Receptors: More restricted; they recognize peptides (short amino acid sequences) presented by MHC (Major Histocompatibility Complex) molecules.

VII. Properties of the Immune System

A. Specificity

• Definition: The ability to discriminate between very closely related molecules.
• Importance: Crucial for distinguishing foreign agents from the body's own components, preventing autoimmune diseases.
• Mechanism of Specificity (Antibodies):
  • Variable Regions: The variable domains (VH and VL) of antibodies contain hypervariable regions, also known as complementarity-determining regions (CDRs).
  • CDRs: There are three CDRs per variable domain (total of six per antibody). These regions form loops that directly contact the antigen.
  • Sequence Variation: Small differences in the amino acid sequences within these CDRs lead to significant changes in an antibody's ability to bind to a specific antigen.
  • Unique Antibodies: Each B cell expresses a unique antibody with a unique CDR sequence, conferring specific antigen recognition.
  • Monoclonal Population: A clonal expansion of a single B cell results in a population of cells (monoclonal) all expressing the exact same antibody.

B. Generation of Diversity

• The Challenge: The human genome has approximately 30,000 genes, which is insufficient to encode the millions of unique antibodies required for a diverse immune response.
• Mechanism: VDJ Recombination:
  • Gene Segments: Antibody genes (heavy and light chains) are composed of multiple gene segments: Variable (V), Diversity (D - heavy chain only), and Joining (J).
  • Shuffling: During B cell development, these gene segments are shuffled and recombined through a process called VDJ recombination.
    • Heavy chain: One V segment combines with one D segment, which combines with one J segment.
    • Light chain: One V segment combines with one J segment.
  • Lymphocyte-Specific: This recombination is mediated by lymphocyte-specific enzymes called RAG1 and RAG2 (recombination-activating genes).
  • Intrachromosomal Recombination: It involves recombination within a single chromosome, deleting intervening sequences.
• Further Diversity Mechanisms:
  • Junctional Imprecision: The joining of gene segments is imprecise, leading to the insertion or deletion of nucleotides. If the number of inserted/deleted nucleotides is a multiple of three, a functional antibody is still produced, but with altered amino acid sequences.
  • Somatic Hypermutation (Affinity Maturation): After T cell activation, there is an elevated mutation rate specifically at the immunoglobulin (antibody) gene locus. This further increases the diversity of amino acid sequences in the variable regions, leading to antibodies with higher affinity for the antigen.
• Allelic Exclusion: A B cell expresses only one antibody. If recombination on one allele produces a functional antibody, recombination on the other allele is suppressed, ensuring that each B cell produces a single, unique antibody.
• CDR3 Variability: The junctions between V, D, and J segments fall within the CDR3 region, contributing significantly to its high variability.

C. Memory

• Definition: The immune system's ability to "recall" past encounters with infectious agents.
• Principle Behind Vaccination: Vaccines introduce attenuated or inactivated pathogens to induce immunological memory, allowing for a faster and stronger response upon subsequent exposure to the actual pathogen.
• Primary vs. Secondary Response:
  • Primary Response (First Exposure):
    • Lag phase: 5-10 days.
    • Magnitude: Smaller antibody production.
    • Antibody Affinity: Weaker (e.g., KD ~10⁻⁷ M).
  • Secondary Response (Subsequent Exposure):
    • Lag phase: 1-3 days (faster).
    • Magnitude: Larger antibody production.
    • Antibody Affinity: Stronger (e.g., KD < 10⁻¹¹ M).
• Mechanism of Memory:
  • Memory B Cells: These cells persist in the body after an infection. They express the specific antibody generated during the initial encounter.
  • Irreversible VDJ Recombination: The VDJ recombination process is irreversible, ensuring that the genetic information for the specific antibody is retained in memory B cells.
  • Persistence: Memory B cells remain in the body even in the absence of the antigen.

VIII. Effector Functions of Antibodies

Antibodies perform several functions to combat foreign substances:

• Neutralization: Binding to a foreign substance (e.g., bacteria, virus) and interfering with its normal function or ability to infect cells.
• Phagocytosis: Recruiting phagocytic cells (cells that engulf and destroy pathogens) to engulf antibody-bound bacteria.
• Killing: When antibodies bind to a foreign cell, they can recruit cytotoxic cells (like Natural Killer cells) to kill the target cell.

IX. Therapeutic Applications of Antibodies

• Herceptin: A humanized monoclonal antibody used to treat HER2-positive breast cancer. It targets the HER2 growth factor receptor overexpressed on cancer cells, potentially neutralizing its activity or recruiting immune cells to kill the cancer cells. Antibodies can be valuable therapeutic agents.