Properties and Overview of Immune Responses

1. The Two Arms of Immunity

Innate Immunity (Natural / Native Immunity)

• Physical/chemical barriers: skin, mucosal epithelia, antimicrobial molecules
• Phagocytic cells: neutrophils, macrophages
• Dendritic cells (DCs) - act as tissue sentinels
• Natural killer (NK) cells and other innate lymphoid cells (ILCs)
• Mast cells
• Blood proteins: complement system, lectins

1. Inflammation - recruiting phagocytes to destroy microbes
2. Blocking viral replication or killing virus-infected cells (non-inflammatory mechanisms)

• Cellular and Molecular Immunology, p. 30-31

Adaptive Immunity (Specific / Acquired Immunity)

• Cellular and Molecular Immunology, p. 31

2. Cardinal Properties of Adaptive Immune Responses

A. Specificity and Diversity

• Immune responses are specific for distinct antigens, and even for different portions (epitopes/determinants) of a single complex molecule.
• Individual lymphocytes express membrane receptors that distinguish subtle structural differences between distinct epitopes.
• Clones of lymphocytes with different specificities exist before antigen exposure - this is clonal selection (Macfarlane Burnet, 1957).
• When an antigen enters the body, it binds to and activates preexisting antigen-specific clones.
• The total diversity of an individual's lymphocyte repertoire allows discrimination of 10^7 to 10^9 distinct antigenic determinants.

B. Memory

• Each exposure to antigen generates long-lived memory cells specific for that antigen.
• Secondary immune responses are:
  • More rapid
  • Greater in magnitude
  • Often qualitatively different from the primary response
• Why secondary responses are stronger: memory cells are more numerous than the naive lymphocytes that existed at initial exposure, and they react more rapidly and vigorously.
• Memory allows the immune system to combat microbes encountered repeatedly in the environment.

C. Clonal Expansion

• Antigen recognition activates lymphocytes, causing them to proliferate - increasing the size of the antigen-specific clone.
• Activated lymphocytes then differentiate into:
  • Effector cells - perform the immediate defensive functions
  • Memory cells - survive long-term and respond vigorously on re-exposure

D. Contraction (Homeostasis)

• After the infection is eradicated, stimuli for lymphocyte activation dissipate.
• Most effector cells die by apoptosis.
• The response contracts, restoring homeostasis.
• Memory cells persist, ready to respond if the infection recurs.

E. Non-reactivity to Self (Self-tolerance)

• Both innate and adaptive immunity do not react against self tissues under normal conditions.
• Breakdown of self-tolerance leads to autoimmune disease.
• Cellular and Molecular Immunology, pp. 33-35

3. Two Types of Adaptive Immunity

Humoral Immunity (B-cell Immunity)

• Mediated by B lymphocytes and their secreted products, antibodies (immunoglobulins).
• B cells recognize antigens, proliferate, and differentiate into plasma cells that secrete antibodies.
• Protein antigens require CD4+ helper T cell activation (T-dependent); many nonprotein antigens (polysaccharides, lipids) can activate B cells without T cell help (T-independent).
• Different immunoglobulin classes have distinct roles:
  • IgM: produced first (within ~6 days of infection); activated by polysaccharides/lipids
  • IgG: coats microbes for phagocytosis (opsonization); activates complement; crosses the placenta to protect the newborn; half-life ~3 weeks
  • IgA: secreted at mucosal epithelia; neutralizes microbes in respiratory and GI tracts
  • IgE: involved in allergy and antiparasitic defense
• Key protective mechanisms of antibodies:
  • Neutralization (blocking microbial entry into cells) - the only adaptive mechanism that stops infection before it is established, which is why vaccines target neutralizing antibodies
  • Opsonization - coating microbes for phagocytosis by neutrophils/macrophages
  • Complement activation (IgG and IgM)
  • Mucosal protection (IgA)
  • Maternal passive immunity (IgG across placenta)
• Some long-lived plasma cells reside in bone marrow or mucosal tissues for years, continuously secreting low levels of antibodies.
• Affinity maturation: helper T cells stimulate production of antibodies with increasing affinity - this improves the quality of the humoral immune response over time.
• Cellular and Molecular Immunology, pp. 48-49; Guyton and Hall Textbook of Medical Physiology, p. 461

Cell-Mediated Immunity (T-cell Immunity)

• Mediated by T lymphocytes - they do not produce antibody.
• T cells recognize peptide fragments of foreign proteins bound to MHC (major histocompatibility complex) molecules on cell surfaces - so they respond to cell-associated, not soluble, antigens.
• Major T cell populations:
  • CD4+ Helper T cells: secrete cytokines and express membrane molecules that activate other cells (macrophages, B cells) to kill microbes; also drive humoral responses
  • CD8+ Cytotoxic T lymphocytes (CTLs): directly kill infected host cells; major drivers of long-term immunity (e.g., after viral infections)
  • Regulatory T cells: inhibit immune responses, maintaining tolerance and limiting immunopathology
• After activation, naive T lymphocytes differentiate into effector cells that migrate to sites of infection.
• Cellular and Molecular Immunology, pp. 49-50

4. Antigen-Presenting Cells (APCs) and Initiation of Adaptive Responses

• Adaptive responses are initiated when antigens are captured, processed, and displayed to specific lymphocytes.
• The most specialized APCs are dendritic cells (DCs), which:
  • Capture microbial antigens entering from the external environment
  • Transport them to lymphoid organs
  • Present them to naive T lymphocytes to initiate immune responses
• Other APCs operate at different stages of the response.

5. Cytokines - The Communication Network

• Cells of the immune system interact via secreted proteins called cytokines.
• Cytokines regulate and coordinate activities of both innate and adaptive immunity.
• Functions of cytokines include:
  • Promoting growth and differentiation of immune cells
  • Activating effector functions of lymphocytes and phagocytes
  • Stimulating directed migration of immune cells (chemokines - a structurally related subfamily)
• Cytokines are involved in immunological diseases and are key drug targets (e.g., TNF-α inhibitors in rheumatoid arthritis and inflammatory disease).
• Cellular and Molecular Immunology, pp. 47-48

6. Connections Between Innate and Adaptive Immunity

• Innate and adaptive responses are not isolated - they reinforce each other:
  • Innate → Adaptive: Innate immune responses provide early "danger signals" that stimulate and shape adaptive responses (e.g., DCs activated by innate receptors present antigen to T cells)
  • Adaptive → Innate: Adaptive responses enhance innate protective mechanisms - e.g., antibodies opsonize microbes for phagocytes; T cell-derived cytokines activate macrophages
• Many pathogens have evolved to resist innate immunity, but the stronger, more specialized adaptive response can eradicate these infections.
• Cellular and Molecular Immunology, p. 31

Summary Table: Innate vs. Adaptive Immunity

• Cellular and Molecular Immunology (Abbas, Lichtman, Pillai), pp. 30-50 - primary reference for this overview
• Guyton and Hall Textbook of Medical Physiology, p. 461