Lecture 4 - Innate Immunity 3 - Mircoimm 2500

Learning Objectives

• Understand self-nonself discrimination and immunological tolerance.

• Explore natural killer (NK) cells' recognition of "missing self".

• Study the alternative pathway of complement activation.

• Understand the process and significance of inflammation.

Self-Nonself Discrimination

• The immune system's response encompasses:

  • Invading organisms (bacteria, viruses, fungi, parasites).

  • Transplanted blood cells or organs (unless properly matched).

• The immune system identifies and reacts to nonself antigens, demonstrating a lack of response to self antigens (immunological tolerance).

Mechanisms of Self-Nonself Discrimination

• Innate and Adaptive Immune Mechanisms:

  • Self-nonself discrimination involves both types of immune responses.

  • Key innate immune pathways include:

    1. Natural Killer Cell recognition of "missing self".

    2. The alternative pathway of complement activation.

Missing Self Concept

• is there a cell-surface molecule that defines a cell as “self”, and allows the immune system to distinguish between self and nonself?

  • yes and the proteins responsible are called Major Histocompatibility Complex (MHC) proteins

• MHC (Major Histocompatibility Complex) proteins are vital for distinguishing self from nonself.

• MHC Class I proteins are found on all nucleated cells, inhibiting NK cell activity when present.

Natural Killer Cells

• Type of Innate Lymphoid Cell (ILC).

• Inhibitory receptors on NK cells interact with MHC molecules to recognize self signals, preventing activation.

• How do Natural Killer cells and healthy cells interact

  • NK uses inhibitor receptors to bind to MHC class I molecules on healthy cells, ensuring that they do not attack and kill these cells, thereby maintaining self-tolerance and preventing autoimmune responses.

  • Activating receptors interact with the activating ligands on infected or stressed cells, allowing NK cells to identify and eliminate these potentially harmful targets.

Natural Killer Cell Function

• Missing Self Activation:

  • NK cells respond to cells with lost MHC expression (e.g., infected or tumor cells).

  • Cytokines and cytotoxic mediators trigger NK cell activation, leading to destruction of altered self cells.

  • cytokines and cytotoxic mediators go from the activated NK cell to the altered self-cell

  • Loss of MHC Molecule Expression promotes killing of altered self-cell by NK cells, as they recognize these changes as signals for potential danger, thus enhancing the immune response against pathogens and tumors.

• Balanced Signals

  • up-regulation of stress-induced ligans promotes killing of altered self-cell

  • even though the inhibitor receptors are binding to MHC class 1 molecules, there are more activating receptors binding to activating ligands thus showing the NK cell that the altered self-cell is under stress and requires elimination to maintain homeostasis within the immune system.

The Complement System

• Composed of ~50 plasma proteins enhancing antibody action to eliminate target cells.

• Functions of the complement system include:

  • Direct cell killing via alternative pathway.

  • Antibody interaction for cell lysis (Classical pathway).

  • Lectin pathway interaction.

  • Opsonization of pathogens for phagocytosis.

  • Recruitment of leukocytes, fostering inflammation.

Alternative Pathway of Complement Activation

• An innate immune pathway of self-nonself discrimination that promotes killing of nonself cells unless they have inhibitory molecules

• Dependent on spontaneous cleavage of C3, transitioning it to C3b.

• Process Breakdown:

  • Fluid-phase convertase (C3) cleaves to C3b, leading to the formation of membrane-bound C3 convertase.

  • Factor D and Properdin are necessary for formation of C5 convertase (C3bBbC3b), facilitating pathway activation.

Inflammation Overview

• First described by Celsus in the 1st century A.D.

• Key symptoms include: redness (rubor), swelling (tumor), heat (calor), pain (dolor), and loss of function (functio laesa).

• Critical for coordinating immune responses, promoting wound healing, and regulating metabolism.

Purpose of Inflammation

• Coordinates blood component delivery (plasma and leukocytes) to affected areas.

• Regulates metabolism, body temperature, and behavior (fever reduces pathogen replication).

• Contains infections via action of neutrophils and macrophages.

• Facilitates tissue repair and homeostasis direction.

Inflammatory Stimuli

• Exogenous Inducers:

  • Pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide, dsRNA, flagellin.

  • Chemicals (e.g., alum) and toxins inducing cellular responses.

  • Toxins and venom components

  • complement proteins C3a, C5a acting through C3aR, C5aR

• Endogenous Inducers:

  • Damage-associated molecular patterns (DAMPs) from cell injury or stress, such as ATP and histones.

    • signals include ATP, uric acid, mitochondrial DNA, histones, Heat Shock Proteins, S100, HMGB1 and various cytokines that can activate innate immune responses, contributing to the overall inflammatory process.

Inflammatory Signals

• Key cytokines mediating inflammation include:

  • Interleukin-1 beta (IL-1 beta).

    • interleukin-1 beta plays a crucial role in the activation of immune cells and the promotion of inflammatory responses, thereby contributing to the body's defense against pathogens.

  • Tumor Necrosis Factor alpha (TNF alpha).

    • TNF alpha is another key cytokine involved in systemic inflammation, and it is primarily produced by macrophages. It plays an essential role in the regulation of immune cells, inducing fever, apoptotic cell death, and inhibiting tumorigenesis.

  • Interleukin-6 (IL-6).

    • IL-6 is a multifunctional cytokine that is secreted by various cells, including macrophages and T cells, and is crucial for the immune response, promoting B cell differentiation, and stimulating the acute phase response during inflammation.

Summary

• The immune system distinctly identifies self from nonself, remaining tolerant to self while responding to nonself.

• Natural killer cells and the alternative complement activation pathway exemplify innate responses facilitating this discrimination.

• Inflammation is crucial for cellular response delivery and recovery from injuries.