Innate Immunity: Induced Response

Introduction to Innate Immunity

  • Immediate Innate Immune Response (0-4 hours):

    • Pathogen invades tissue and proliferates.

    • The pathogen is recognized by preformed soluble effector molecules and resident effector cells in the infected tissue.

    • Result: Pathogen is eliminated, very minor tissue damage is repaired.

    • If the pathogen is not eliminated, transition to the induced innate immune response occurs.

  • Induced Innate Immune Response (4 hours to 4 days):

    • Pathogen continues to invade and proliferate.

    • Activation of resident cells and recruitment of effector cells to the tissue.

      • Induced response (mostly macrophages)

      • Macrophages found in almost all tissues, remain dormant until infection or change within the cell, at which point they become activated to phagocytose pathogens, produce pro-inflammatory cytokines, and orchestrate the immune response.

    • Characterized by inflammation, fever, and the acute-phase response.

    • Soluble effector molecules and recruited effector cells recognize and attack the pathogen.

    • Result: Pathogen is eliminated, minor tissue damage is repaired.

    • If pathogen persists, transition to adaptive immune response occurs.

  • Adaptive Immune Response (4 days until pathogen defeat or host death):

    • The pathogen invades tissue, leading to the possibility of host defeat.

    • Secondary lymphoid tissue is made aware of the infection.

    • Identification and proliferation of pathogen-reactive B and T cells in secondary lymphoid tissue.

    • B and T cells mature and become effector cells; antibodies and effector T cells travel to the site of infection.

    • Result: Pathogen is eventually eliminated, significant tissue damage is gradually repaired.

    • If elimination fails, the host may die from acute infection or suffer from chronic disease.

TLR4 recognition of LPS effecting gene expression in macrophages

Family of signal receptors, can recognize different pathogens

  • Induces inflammatory response upon activation explain, like activating other cells to or itself?

  • Eventually, releases cytokines that will be secreted, and induce an inflammatory response activating other immune cells. Toll like receptors come together by engulfing LPS and initiating a cascade that will lead to cytokine production.

Related conditions

  • X-Linked ectodermal dysplasia

    • lack of IKK leads to impaired activation of phagocytosis, leading to more bacterial infections as NFKB cant induce cytokine production to activate othet immune cells

Cytokines

  • TNF-a: Increases vasopermeability, enabling cells to, fluid and effector molecules to come to the site of infection

  • IL-6: Trigger heat production, disabling the pathogen

  • CCL2: recruits monocytes for macrophage differentiation

  • IL-12: Recruits NK cells enahnce macrophage activation by producing a cytokine.

  • CXCL8: Recruits neutrophils from the blood and directs them to the infection site

Nod-Like Receptors

Recognize bacterial degredationin cytoplasm

  • Complement TLRs but int he cytoplasm

  • activated when bound to degraded products of pathogens

  • result: release cytokines

Difference between TLR and NOD: NOD is found intracellularly, TLR found on cell membrane

*Go over Interferon production and function.



Inflammatory Response

  • Inflammatory Cytokines:

    • Raise body temperature and activate the liver for acute-phase response.

    • Key Cytokines include IL-1, IL-6, TNF-α.

    • Macrophage: extracellular- non self

    • NK cells: intracellular- self

  • Effects on Various Organs and Tissues:

    • Macrophages: Produce cytokines and induce inflammatory response.

      • Scavenger receptors: can signal and are helpful in phagocytosis, enhancing macrophage function and inducing a further innate response. (ask if thats correct)

      • Other receptors: Complement receptors, LPS and TLR

      • PAMP vs DAMP

      • Receptors of innate immunity can recognize patterns, not individuals

    • Liver: Produces acute-phase proteins (e.g., C-reactive protein, mannose-binding lectin).

    • Bone Marrow: Mobilizes neutrophils.

    • Hypothalamus: Increases body temperature.

Acute-Phase Proteins

  • Functions of Acute-Phase Proteins:

    • C-reactive protein (CRP):

    • Diagnostic marker for inflammation.

    • Opsonizes bacteria, triggering classical complement pathway.

    • Mannose-binding lectin (MBL):

    • Recognizes pathogens, serving as an opsonin.

    • Lipopolysaccharide-binding protein:

    • Facilitates pathogen recognition.

    • Complement Components (C3, C4, C9, Factor B):

    • Help in pathogen elimination.

    • Fibrinogen, Plasminogen:

    • Involved in coagulation processes.

  • Patterns of Plasma Concentrations:

    • A chart showing changes in plasma concentrations of various acute-phase proteins (CRP, Serum amyloid A) after inflammatory stimulus, visualizing recovery.

Lectin Pathway of Complement Activation

  • Activation Mechanism:

    • Initiated by Mannose-binding lectin (MBL) which interacts with sugars on pathogen surfaces.

    • Mannose-binding lectin-associated serine proteases (MASP-1 and MASP-2):

    • Trigger pathways leading to immune response.

    • MBL Deficiency:

    • Increases susceptibility to infections like Neisseria meningitidis.

  • Role of Cytokines:

    • Bacterial invasion prompts macrophages to produce IL-6, stimulating liver synthesis of acute-phase proteins (CRP, MBL, fibrinogen).

  • Step-by-Step Lectin Pathway Activation:

    • MBL binds to pathogens, activating MASP-2 which cleaves C4 into C4a and C4b.

    • C4b covalently binds to microbial surface.

    • C2 is also cleaved by MASP-2, creating C3 convertase (C4bC2a).

    • C3b binds to pathogen surface, important for opsonization and initiation of the membrane attack complex (MAC).

C-Reactive Protein and Complement Activation

  • Classical Pathway Trigger:

    • CRP binds to pathogens, allowing C1 (complement component) to bind and activate classical complement pathway.

    • Process of cleaving C4 and C2 to generate C3 convertase (C4b2a) begins once CRP is bound to bacteria.

Innate Lymphoid Cells (ILCs)

  • Characteristics of ILCs:

    • Five types of ILCs cooperate with myeloid cells, acting similarly to T cells but lacking TCRs (T-cell receptors).

  • Development Pathway:

    • ILCs develop from a common progenitor cell leading to various subtypes like NK cells, ILC1, ILC2, and ILC3.

  • Functions:

    • NK Cells:

    • Primary contributors to innate immune response.

    • Similar functionality to cytotoxic T cells with unique activation dynamics.

Natural Killer Cells

  • Role and Characteristics:

    • Main circulating lymphocyte types in innate immune response.

    • Functionally similar to cytotoxic T cells; necessary for combating persistent viral infections.

  • Subpopulations:

    • Two NK cell subpopulations exist, distributed across blood and tissues, differentially regulating immune responses.

NK Cell Activation and Cytotoxicity

  • Activation Mechanism:

    • Requires close proximity to target cells and multiple receptor interactions.

  • Effector Functions:

    • Releases granzymes, perforins, FasL, and granulysin to destroy infected target cells, affecting viral propagation.

Interactions with Dendritic Cells

  • Influence on Immune Response:

    • NK cells interact with dendritic cells, directing their maturation depending on their abundance relative to dendritic cells.

  • Outcomes:

    • If NK cells are abundant, they kill dendritic cells.

    • If scarce, they promote the maturation of dendritic cells necessary for initiating adaptive immunity.

  • Summary of Immune Dynamics:

    • Successful natural immune response successfully terminates infections; failure prompts adaptive immune mechanisms to engage.