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L01 I&I Introduction to Defensive Pathways of Immunity

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tagsinfection-and-immunity, lecture
aliasesL01 I&I Introduction to Defensive Pathways of Immunity

17 min read

Overview

This lecture introduces the two arms of the immune system, innate and adaptive immunity, and how they work together to control infection. It covers the exterior barriers to infection, the soluble (humoral) and cellular components of innate immunity, how phagocytes detect pathogens and tissue damage via pattern recognition receptors, the local (acute inflammation) and systemic (acute phase response) consequences of innate activation, how dendritic cells carry antigen to lymph nodes to activate T and B cells, the structure and diversity of antigen receptors (antibodies and T cell receptors), MHC and MHC restriction, central tolerance (thymic and bone marrow selection), the three-signal model of T cell activation, immunological memory, and the effector mechanisms (cytotoxic, antibody-mediated) by which the adaptive response clears infection.

Innate versus adaptive immunity

  • Innate immunity is the early response (acting within hours, 0-12h after infection). It uses pattern recognition receptors that specifically recognise conserved pathogen-associated molecules. It has no memory.
  • Adaptive immunity is the later response (developing over days, 1-5 days after infection). It uses antigen-specific receptors that recognise variable pathogen molecules (antigens). It generates memory.
  • Both arms have humoral (soluble molecule) and cellular components.
  • Innate immunity broadly comprises epithelial barriers, phagocytes, complement, and natural killer cells. Adaptive immunity comprises B lymphocytes, which proliferate and differentiate into antibody-secreting cells (humoral), and T lymphocytes, which proliferate and differentiate into effector T cells (cellular).

Physical and chemical (exterior) barriers

  • Biochemical defences: lysozyme (in most tears, nasal secretions, and saliva), sebaceous gland secretions, commensal organisms (in gut and vagina), spermine (in semen).
  • Chemical and physical defences: mucus, cilia lining the trachea, acid in the stomach, skin.

Humoral innate and adaptive immunity

Soluble molecules found in blood and tissue fluid.

  • Collectins (innate), e.g. mannose-binding lectin (MBL): binds with high avidity to mannose and fucose residues, associated with MASP-1 and MASP-2. Feeds into complement activation and opsonisation/phagocytosis.
  • Pentraxins (innate), e.g. C-reactive protein and serum amyloid protein. Feed into opsonisation/phagocytosis and complement activation.
  • Antibodies (adaptive): five isotypes, IgM, IgD, IgG, IgE, IgA. Feed into opsonisation/phagocytosis and complement activation.
  • So both collectins/pentraxins (innate) and antibodies (adaptive) converge on the same two downstream effects: activating complement and driving opsonisation/phagocytosis.

Cellular immunity: cell types and locations

Based on Janeway’s Immunobiology Fig 1.3.

  • Blood: B cell, T cell, NK cell, immature dendritic cell, granulocytes (neutrophil, eosinophil, basophil), an unknown precursor of the mast cell, monocyte, platelets, erythrocyte. Adaptive lineage = B and T cells; the rest are innate lineage.
  • Lymph nodes: B cell, T cell, NK cell.
  • Tissue: B cell, T cell, NK cell, dendritic cell, mast cell, macrophage.
  • Neutrophils are the main effector cells in blood.
  • Dendritic cells (in tissue) initiate the adaptive immune response.
  • Mast cells and macrophages are the main effector cells in tissue.

Phagocytosis and pattern recognition receptors

  • Tissue-resident phagocytes: macrophages, mast cells, dendritic cells.
  • These release chemical mediators (cytokines, chemokines, lipid mediators, histamine) that recruit neutrophils from blood into tissue.
  • Phagocytes detect infection or tissue damage via pattern recognition receptors (PRRs), e.g. Toll-like receptors, which recognise:
    • Pathogen-associated molecular patterns (PAMPs): common microbial molecular patterns, e.g. lipopolysaccharide (LPS).
    • Danger-associated molecular patterns (DAMPs): markers of tissue damage, e.g. DNA, ATP, uric acid.
  • PRR engagement (via an endocytic PRR binding pathogen, or a Toll-like receptor binding PAMP/pathogen) activates macrophages, causing phagocytosis and killing, and release of inflammatory cytokines: IL-1, IL-6, IL-18, TNF-alpha, IL-8, and other chemokines.
  • Macrophages, neutrophils, and dendritic cells phagocytose and kill microbes: PRR engagement drives phagocytosis, and the microbe is transported to the phagolysosome for killing and antigen presentation. The phagolysosome is a hostile environment: low pH, reactive oxygen and nitrogen intermediates, and enzymes. Bound material is internalised in phagosomes, which fuse with lysosomes to form phagolysosomes where microbes are broken down.

Acute inflammation

Sequence (Janeway Fig 3.6):

  1. Macrophages detect PAMP/DAMP and release cytokines, chemokines, and lipid mediators, causing dilation of local small blood vessels (vasodilation). Complement (C5a), and allergen cross-linked to mast-cell-bound IgE, also trigger histamine release, contributing to the same vasodilation/permeability pathway.
  2. Endothelial activation: increased expression of adhesion molecules causes leukocytes to move to the periphery of the blood vessel (margination); vascular permeability also increases.
  3. Leukocytes (e.g. neutrophils) extravasate at the site of infection, recruited by the endothelial changes.

Clinical correlates (cardinal signs of acute inflammation):

  • Vasodilation causes erythema (redness) and heat.
  • Increased vascular permeability causes oedema (swelling).
  • Extravasation of neutrophils causes accumulation of pus.
  • Pain is also a cardinal sign.

Systemic acute phase response

Driven by IL-1β, IL-6, TNF-α, and lipid mediators acting on multiple organs (Janeway Fig 3.27):

  • Liver: produces acute-phase proteins (C-reactive protein, mannose-binding lectin), activating complement and opsonisation (raised CRP).
  • Bone marrow endothelium: mobilises neutrophils, increasing phagocytosis (raised neutrophil count).
  • Hypothalamus: raises body temperature (fever), which decreases viral and bacterial replication and increases antigen processing and the specific (adaptive) immune response.
  • Fat and muscle: mobilise protein and energy to support the increased body temperature.
  • Dendritic cells: TNF-α stimulates their migration to lymph nodes and maturation, initiating the adaptive immune response.

Bridging innate to adaptive immunity: antigen presentation

  • Dendritic cells capture antigen in tissue and migrate via lymphatic vessels to the lymph node to present it to lymphocytes. Free (particulate) antigen can also drain directly through the lymphatic system to the lymph node.
  • Activation of T cells and B cells in the lymph node proceeds in four steps:
    1. Dendritic cells present peptides on MHC to the T cell receptor (TCR) on T cells, activating them.
    2. B cells recognise antigen directly via the B cell receptor (BCR).
    3. B cells phagocytose the antigen and present it to T cells via MHC.
    4. T cells then enhance B cell activation.

Antigen receptor structure and diversity

  • Antibodies and T cell receptors both have variable regions (the antigen-binding site) and constant regions (effector function for antibodies).
    • Antibody: Y-shaped, two heavy and two light chains; variable region at the tips binds antigen, constant region provides effector function. Expressed on the B cell surface as the B cell receptor, or secreted. Antibodies bind epitopes on unprocessed (native) antigen.
    • T cell receptor: made of α and β chains, with a variable region (antigen-binding site) and constant region, anchored on the T cell membrane. The TCR recognises a peptide epitope only when it is bound to MHC (it cannot bind free/unprocessed antigen): antigen is broken into peptide fragments, an epitope peptide binds a self MHC molecule, and the TCR binds the MHC-peptide complex, with a CD4 or CD8 co-receptor also engaging the MHC. CD4 T cells recognise MHC class II; CD8 T cells recognise MHC class I.
  • Diversity is generated by somatic (V(D)J) recombination of antigen receptor gene segments:
    • Antibody heavy chain germline DNA has 39 Variable (V), 27 Diversity (D), 6 Joining (J), and 6 Constant (C) gene segments. Somatic recombination joins D to J, then V to DJ, followed by transcription and splicing.
    • Antibody light chain germline DNA has 36 V, 5 J, and constant segments (1 kappa, 4 lambda). Somatic recombination joins V to J, then transcription and splicing.
    • [Slide flags detail on the numeric comparison table (variable/diversity/joining segment counts, junctional diversity, total diversity for immunoglobulins vs αβ TCRs) as not important, but notes overall diversity is enormous: approximately 5x10^13 for immunoglobulins and approximately 10^18 for αβ TCRs.]
  • Antibody isotypes: IgM, IgD, IgG, IgE, IgA (with constant regions Cμ, Cδ, Cγ, Cε, Cα respectively). All isotypes share the same variable-region arms (so recognise the same antigen) but differ in their constant region, giving different structures and functions. IgA is assembled as a dimer joined by a J chain; IgM is assembled as a pentamer joined by a J chain.

MHC and MHC restriction

  • The human MHC (HLA) has three regions: class II (includes DP, DQ, DR genes), class III, and class I (HLA-A, HLA-B, HLA-C).
  • Each individual has up to 2 unique alleles at each locus, and there are significant inter-individual differences in MHC (extensive polymorphism), especially at DRB and HLA-B/-A. [Slide flags this level of detail as not important.]
  • MHC restriction: the TCR recognises a specific MHC allele (class I or II) together with a specific bound peptide. The same TCR against a different MHC allele presenting the same peptide gives no recognition, and the same TCR against the correct MHC allele presenting a different peptide also gives no recognition. Both the correct MHC allele and the correct peptide are required for recognition.

Lymphocyte selection (central tolerance)

  • T cells are selected in the thymus; B cells are selected in the bone marrow.
  • Positive selection of αβ T cells occurs via cortical epithelial cells in the thymus: it selects for the ability to recognise self-MHC (T cells only). A thymocyte with weak or no TCR-MHC binding dies; one with moderate or strong binding survives.
  • Negative selection of αβ T cells occurs via dendritic cells, macrophages, and other cells in the thymus (and, for B cells, in the bone marrow): it eliminates cells that recognise self antigen too strongly (applies to both T cells and B cells). A thymocyte with moderate MHC binding survives; one with tight binding (recognising self-antigen too strongly) dies.

The three-signal model and T helper differentiation

The innate immune response drives the adaptive immune response. Three signals are required to activate a naive T cell:

  1. TCR engagement with peptide-MHC on the dendritic cell -> activation.
  2. Co-stimulation (e.g. CD80/86 on the dendritic cell binding CD28 on the T cell) -> survival.
  3. Cytokines (e.g. IL-12) -> differentiation and function.
    Depending on the cytokine signal received, the naive T cell differentiates into either a Th1 cell (secreting IFN-γ) or a Th2 cell (secreting IL-4, IL-5, IL-10); IL-12 drives Th1 differentiation.

Immune memory

Activation of naive T and B cells results in immune memory, producing a more rapid and larger response on re-challenge. Four phases:

  • A. Priming: an antigen-presenting cell (APC) engages a naive T cell.
  • B. Expansion: the T cell proliferates into a large population of effector cells (with some regulatory T cell suppression), followed by contraction of that effector population (largely via apoptosis).
  • C. Homeostasis: most effector cells die by apoptosis, leaving a smaller, stable population of memory cells.
  • D. Challenge: on re-exposure to antigen, memory cells expand more rapidly and to a larger degree than in the primary response, giving a faster, larger secondary effector response.

Effector mechanisms of adaptive immunity

  • T cells act by making contact with other cells and inducing them to change:
    • CD8 T cells (restricted by MHC class I) are cytotoxic: they kill other cells, e.g. contacting a virus-infected cell resulting in its death.
    • CD4 T cells (restricted by MHC class II) are helper cells: they deliver cytokines on contact, e.g. activating a macrophage (which then releases cytokines), or helping a B cell differentiate into an antibody-secreting plasma cell.
  • Activated B cells (activated by antigen and helper T cells) secrete antibodies and differentiate into memory B cells and plasma cells. Antibodies secreted by plasma cells mediate four effector functions:
    • Antibody-dependent cellular cytotoxicity (ADCC): cross-linking of Fc receptors on an NK cell by antibody bound to a target cell signals the NK cell to kill that target cell.
    • Neutralization: antibody bound to a pathogen prevents bacterial adherence to epithelial cells.
    • Opsonization: antibody coating promotes phagocytosis of the pathogen.
    • Complement activation: antibody binding activates complement, which enhances opsonisation and lyses some bacteria.

Coordinated control of infection

At a site of infection, phagocytes act on pathogens together with antibodies and complement/other molecules, while the lymph node generates activated CD8+ T cells, CD4+ T cells, and B cells. Control of infection by adaptive immunity depends on this coordination between the effector response at the infection site and lymphocyte activation in the lymph node.

Self-test

  1. Distinguish innate immunity from adaptive immunity in terms of timing, receptor specificity, and memory.
  2. List the biochemical and the chemical/physical exterior barriers to infection given in the lecture.
  3. Name the two classes of soluble innate humoral molecules described, give an example of each, and state the two downstream effects they share with antibodies.
  4. Which cell type is the main effector cell in blood, and which two cell types are the main effector cells in tissue?
  5. Describe the steps by which phagocytes detect infection or tissue damage, distinguishing PAMPs from DAMPs, and give one example of each.
  6. Describe what happens to a phagocytosed microbe after it is internalised, including why the phagolysosome is hostile to microbes.
  7. Describe the sequence of events in acute inflammation, from initial detection of PAMP/DAMP to leukocyte extravasation.
  8. For each cardinal sign of acute inflammation (redness, heat, swelling, pus), state the underlying vascular or cellular event that causes it.
  9. Describe the systemic acute phase response: name the driving cytokines and, for each of the five listed organs/tissues, state the effect produced.
  10. Describe how antigen reaches the lymph node from a peripheral site of infection.
  11. Describe the four steps by which T cells and B cells are activated in the lymph node.
  12. Distinguish how antibodies recognise antigen from how T cell receptors recognise antigen.
  13. Describe the process of V(D)J recombination that generates antibody heavy chain diversity, including the segment types and numbers involved.
  14. Explain why the five antibody isotypes can all recognise the same antigen but have different effector functions.
  15. Distinguish MHC class I from MHC class II in terms of which T cell subset recognises each.
  16. Explain what is meant by MHC restriction, using the three-panel recognition/no recognition/no recognition experiment as your basis.
  17. Distinguish positive selection from negative selection of T cells in the thymus, including which cells mediate each and what determines whether a thymocyte lives or dies.
  18. Describe the three-signal model for T cell activation, naming what drives each signal and its consequence.
  19. What determines whether a naive T cell differentiates into a Th1 versus a Th2 cell, and what cytokines does each subset secrete?
  20. Describe the four phases of an adaptive immune response over time (priming, expansion, homeostasis, challenge) and what happens to the T cell population in each.
  21. Distinguish the effector function of a CD8 T cell from that of a CD4 T cell, with an example target cell for each.
  22. List the four effector functions of secreted antibody and briefly describe the mechanism of each.
  23. A patient develops a red, hot, swollen, painful lesion with pus five days after a skin injury, then mounts a much faster, stronger response when re-exposed to the same organism months later. Explain, in terms of innate and adaptive immunity, why the initial response looks as it does and why the second response is faster and larger.

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