lesson 2.5

UNIVERSITY OF PORTSMOUTH - METTL

Innate Response to Infection - Inflammation

Learning Objectives

  • Upon completion of this session, students should be able to:

    1. Understand inflammation as a critical component of the innate immune response to infection.

    2. Identify the classical signs of inflammation.

Key Concepts of Inflammation

  1. Sentinel Cells

    • Types: Macrophages and Dendritic Cells (DCs)

    • Function: First to detect infectious agents such as bacteria and fungi.

  2. Recognition Mechanisms

    • Pattern Recognition Receptors (PRRs):

      • **Toll-Like Receptors (TLRs)

      • NOD-Like Receptors (NLRs)

    • Action: These receptors induce the synthesis and release of inflammatory mediators.

  3. Key Inflammatory Mediators

    • Cytokines:

      • Interleukin 1 (IL-1)

      • Interleukin 6 (IL-6)

      • Tumor Necrosis Factor alpha (TNF-α)

      • Interleukin 12 (IL-12)

    • Chemokines

    • Lipid Mediators:

      • Prostaglandins

      • Platelet-Activating Factor (PAF)

      • Leukotrienes

  4. Initiation of Inflammation

    • Inflammatory mediators lead to the following effects:

    1. Increase vascular permeability.

    2. Activate endothelium (change adhesive properties).

    3. Activate incoming phagocytes (neutrophils, monocytes/macrophages).

    4. Activate Natural Killer (NK) cells.

    • Endothelial Activation: Triggers activation of both the kinin cascade and coagulation cascade.

Symptoms of Inflammation

  • Classic symptoms (cardinal signs of inflammation):

    • Heat (calor)

    • Swelling (tumor)

    • Redness (rubor)

    • Pain (dolor)

    • Loss of function may also occur

Timeline and Overview of Inflammatory Response

  1. Within minutes of infection, an influx of proteins and cells occurs to control and contain the infection.

  2. Cellular Response: Acute Inflammation

    • First responders: Neutrophils are attracted to the site of infection, followed by monocytes (innate response).

    • Later stages involve lymphocytes (adaptive response).

  3. Leukocyte Migration

    • In the absence of infection, immune cells (except macrophages) remain in circulation.

    • During infection, cells migrate to tissues, specifically occurring in venules.

Mechanism of Leukocyte Migration

  1. Vascular endothelium is activated to express specific cell surface molecules:

    • Selectins (E-selectin, P-selectin)

    • Cell Adhesion Molecules (CAMs) (ICAM-1, VCAM-1)

    • Chemokines (e.g., IL-8)

  2. Rolling of Leukocytes

    • Leukocytes in blood recognize selectins leading to weak binding and rolling effect along the endothelium.

  3. Activation and Attachment

    • Rolling stimulates by IL-8 causing leukocytes to flatten, activating integrins from low to high affinity state, which bind to ICAM-1 and VCAM on endothelium.

  4. Diapedesis

    • Leukocytes are anchored on the endothelial surface, utilizing proteolytic enzymes to exit the blood stream between endothelial cells.

  5. Chemotaxis

    • They migrate towards the site of infection along a chemokine concentration gradient and are activated by locally produced inflammatory mediators (e.g., C5a).

Antiviral Response and Type I Interferons

  1. Primary Mechanism: Induce expression of Type I interferons to inhibit viral replication.

  2. Types of Type I Interferons:

    • IFNα

    • IFNβ

  3. Genetic Encoding: Encoded by genes on chromosome 9.

  4. Major Source: IFNα is important, produced by plasmacytoid DC and mononuclear phagocytes.

  5. Stimuli: Most potent stimuli includes viral nucleic acid (DNA, RNA).

  6. Receptors: Type I interferon receptors are IFNAR1 and IFNAR2, present on all nucleated cells.

Regulatory Functions of Type I Interferons

  • Enhances various innate immune responses:

    • Monocytes: Increased recruitment & differentiation.

    • Dendritic Cells: Enhanced costimulation, antigen presentation, and migration to lymph nodes.

    • Macrophages: Increased regulatory functions.

    • NK Cells: Increased recruitment, activation, cytotoxicity, and IFNγ production.

  • Facilitates adaptive immune responses:

    • Helper CD4+ T Cells: Enhanced Th1 differentiation and B cell activating capacity.

    • B Cells: Increased activation, class switching, and plasmablast differentiation.

    • Cytotoxic CD8+ T Cells: Increased clonal expansion and survival.

Critical Summary of Inflammation

  • Inflammation plays a key role in the innate immune response by facilitating pathogen clearance and tissue repair.

  • Recognizing the classical signs of inflammation (redness, heat, swelling, pain, and loss of function) is essential in diagnosing and understanding inflammatory responses.