7.1 Theme 2 - introduction to immunology

What are the three primary levels of immune defence?

The immune system defends through external barriers, innate immunity, & adaptive immunity.

How do innate & adaptive immunity differ?

Innate immunity provides a broad, rapid, non-specific defence with no memory, found in all invertebrates & vertebrates.
Adaptive immunity offers a highly specific, slower response focused on antigen recognition, develops immune memory, & occurs in vertebrates only.

What are the key features of the immune system?

• It recognises pathogens & differentiates self from non-self

• It has mechanisms to kill or eliminate pathogens

• It uses cytokines to coordinate immune activity, including interleukins, interferons, TNFs & CSFs, & chemokines that induce cell movement (chemotaxis)

How do innate immune cells recognise non-self?

• Innate immune cells, e.g. phagocytes, have pattern recognition receptors (PRRs) that detect pathogen antigens

• PRRs can be on the cell surface or inside the cytoplasm depending on pathogen location

• Pathogen components recognised by PRRs are called Pathogen-Associated Molecular Patterns (PAMPs)

How does adaptive immunity recognise previously unencountered pathogens?

• Lymphocytes (T & B cells) express T cell receptors (TCRs) & B cell receptors (BCRs) with randomly generated specificities

• Targets are peptides from pathogens (antigens) presented via MHC molecules to the receptors

• This allows the immune system to specifically recognise and respond to non-self pathogens

What are the primary & secondary lymphoid organs?

• Primary organs: lymphocyte formation & maturation – bone marrow & thymus

• Secondary organs: recognise & respond to foreign material – lymph nodes & spleen

How does the lymphatic system contribute to immune responses?

Antigens from the site of infection enter the lymphatic system
They travel to regional lymph nodes = stimulation of immune response

How does lymphocyte recirculation work?

• Recirculation is essential for lymphocytes to encounter antigens anywhere in the body

• Lymphocytes flow from blood → tissues → lymph nodes → lymph → back to blood

• At infection sites, they are attracted by adhesion molecules & chemokines

• Neutrophils only circulate in the blood and do not return

What are the key features of phagocytic cells in innate immunity?

• Macrophages & PMNs are main phagocytes

• Macrophages need IFNγ activation for digestion

• Macrophages present antigens to T cells

What are the main characteristics of neutrophils?

• Produced in bone marrow from stem cells in ~2 weeks

• Polymorphonuclear (PMN) leukocytes (segmented nuclei)

• Granulated, with granules containing antimicrobial substances that kill bacteria, fungi & protozoa

What is neutrophil margination?

• In healthy individuals, neutrophils mostly stay in blood, but during inflammation they move to vessel margins (margination) and are attracted to tissue damage or infection by chemical mediators.

• The vessel margins is the lining of the endothelium

How do neutrophils move from blood into tissues (diapedesis)?

In response to tissue distress signals (cytokines, e.g. TNF-α), endothelial cells express adhesion molecules (ICAMs) that make neutrophils bind tightly. Chemotaxins then guide neutrophils to cross endothelial junctions (diapedesis) and enter tissues toward the site of infection or injury.

How do neutrophils locate pathogens in tissues (chemotaxis)?

• Neutrophils follow chemotactic gradients to find bacteria or fungi
• E.g. of chemotactic factor: Complement component C5a
• Chemotactic factors bind receptors on one edge of the neutrophil
• This causes pseudopodium formation to move forward and engulf the pathogen

How do neutrophils perform opsonization and phagocytosis?

• Neutrophils are inefficient at engulfing bacteria without opsonins e.g. complement C3b

• Opsonins bind bacterial surface and interact with neutrophil receptors

• This triggers pseudopodia formation to engulf the bacterium into a phagosome

• The bacterium is then killed via oxygen-dependent & oxygen-independent mechanisms

How do neutrophils kill pathogens via oxygen-dependent mechanisms?

• Respiratory burst and H₂O₂–myeloperoxidase–halide system generate reactive oxygen species

• Respiratory burst: NADPH oxidase converts O₂ → superoxide (O₂^-) → H₂O₂

• Myeloperoxidase converts H₂O₂ + Cl⁻ into toxic hypochlorous ions

• Neutrophils protect themselves with antioxidants like vitamins C and E

How do neutrophils kill pathogens via oxygen-independent mechanisms?

• Examples include lysozyme (breaks bacterial cell walls), lactoferrin (binds iron), and cationic proteins like defensins or phospholipase A2

• Important in anaerobic conditions, such as deep abscesses

What are the roles of mast cells and basophils in inflammation?

• Mast cells (skin, around blood vessels, gut) and basophils (blood) mediate the acute inflammatory response

• They have granules with histamine and leukotrienes to ↑ vascular permeability

• IgE (Immunoglobulin E), damage, or complement (C3a, C5a) trigger degranulation

• Causes reactions from wheal and flare to anaphylactic shock

Outline the stages of the immune response following initial infection.

• Initial infection: Pathogen enters the body, triggering tissue inflammation.

• Antigen capture: Dendritic cells in the tissue capture and process antigens.

• Migration: Dendritic cells migrate to lymph nodes to present antigens to lymphocytes.

• Activation: Lymphocytes (T and B cells) become activated and proliferate.

• Response: Antibodies and activated lymphocytes migrate to inflamed peripheral tissue to destroy the pathogen.

Where are dendritic cells found and what do they do?

• Found mainly in tissues (low levels in blood) & Langerhans cells (specific type of dendritic cell) in skin. They migrate to lymphoid organs to present antigens and activate lymphocytes.

How do dendritic cells migrate to lymph nodes and activate T cells?

• PRRs on dendritic cells recognise pathogens

• They internalise and degrade antigens, presenting peptides (from the antigne) on MHC

• PRR activation stimulates the DC to migrate to secondary lymphoid tissue

• In the lymph node, DCs activate antigen-specific T cells

• Dendritic cells can also migrate to the spleen or MALT to activate T cells

What are natural killer (NK) cells and their function?

• Large granular lymphocytes with cytotoxic activity

• Make up 5–20% of mononuclear cells in blood and spleen

• Kill tumour cells and virus-infected cells before virus maturation

• Resemble cytotoxic T cells but lack classical T-cell receptors and don’t need prior sensitisation

How do NK cells detect infected or abnormal cells?

• NK cells use a missing- or altered-self strategy to identify virus-infected or tumour cells

• Activator receptors (AR) recognise glycoproteins on many host cells

• Inhibitory receptors (IR) detect MHC class I molecules

• If MHC I is present, the cell is spared

• If MHC I is absent or altered, the NK cell kills the infected or abnormal host cell, preventing pathogen spread

note: MHC I is normally on host cells to display self-peptides. Virus-infected cells may lose, ↓, or alter MHC I. NK cells detect this and kill the infected cell, stopping the pathogen from replicating and spreading.

How do NK cells kill target cells?

• High extracellular Ca²⁺ causes perforin to form pores in the target cell membrane = ↑ in permeability = granzymes enter through the pores

• Granzymes activate caspases = triggers apoptosis (programmed cell death) of the target cell

What is the role of NK cells in IFNγ production and pathogen control?

• NK cells rapidly produce IFNγ

• Production and cytotoxic activity are stimulated by cytokines (e.g., IL-12)

• IFNγ activates macrophages to kill internalised bacteria (Listeria, Salmonella, Mycobacterium), some viruses (CMV), and protozoa (Leishmania, Toxoplasma)

• IFNγ inhibits viral growth in infected cells