unit 4 , lesson 5, Cytokines

• Lesson 5 focuses on Cytokines

Cytokines Overview

• Cytokines are involved in both cellular and humoral immunity
• Cytokines are associated with both innate and adaptive immunity, influencing neutrophils, monocytes, macrophages, natural killer cells, mast cells, B cells, T cells, complement, and antibodies

Effective Immune Response

• Communication is required for an effective immune response.
• Lymphocytes, inflammatory cells, and hematopoietic cells communicate through cytokines.
• Cytokines are a diverse family of small proteins or glycoproteins (<30 kDa) with immunomodulatory capabilities
• Cytokines act as signalling molecules.
• Cytokines initiate signalling by binding to cytokine receptors.
• Cytokines are released by cells to act as intercellular mediators.
• Cytokines influence both innate and adaptive immune responses.
• The main cytokine producers are helper T cells (CD4+, Th cells) and macrophages.
• Cytokines are produced by immune cells in response to pathogenic or other antigens.
• Cytokines act via cell-surface receptors expressed on immune cells.
• Cytokines regulate immune-inflammatory response amplitude and duration.
• Cytokines activates macrophages, control growth and differentiation of T cells and B cells

Terminology

• Monokines are produced by mononuclear phagocytes (monocytes).
• Lymphokines are produced by activated T cells, primarily T helper (CD4+) cells.
• Interleukins are cytokines made by one leukocyte and acting on another leukocyte.
• Chemokines are cytokines with chemotactic activities

Cytokine Action

• Cytokine action requires that have a high-affinity binding to its cytokine receptor expressed on the surface of a target cell
• Cytokine action includes autocrine (acting on the same cell) and paracrine (acting on a nearby cell)
• Cytokine receptor engagement triggers intracellular signalling cascades.
• these signalling cascades then alter gene expression in the target cell.
• The final result of cytokine action is a biological effect, such as differentiation, proliferation, and activation of the target cell.

Cytokine Functions

• Cytokine receptors are cell-surface glycoproteins.
• These receptors bind specifically to cytokines and transduce their signals.
• Cytokine receptors enable cells to communicate with the extracellular environment.
• Receptors respond to signals in the vicinity or other parts of the organism.
• Different cytokines bind to specific receptor families, such as the II-6 binding to II-6R.
• Cytokines interact in complex ways to modulate immune responses

Ways that Cytokines can Intereact

• Cytokines can be pleiotropic: exhibit different effects on different types of target cells.
• Cytokines can be redundant: multiple cytokines have the same effect.
• Cytokines can be synergic: multiple cytokines have a cooperative effect.
• Cytokines can be antagonistic: one cytokine inhibits the effects of another.
• Cytokines can cause cascade induction: a multiple-step feed-forward mechanism amplifies the production of a particular cytokine.
• Cytokines orchestrate the coordinated recruitment and activation of immune cells.
• Relatively few cytokines produced by a single cell type, such as macrophages or Th cells, can activate entire networks of immune cells.

Examples of Cytokine Function

• Pleiotropy example: IL-4 has different effects on different target cells.
• Redundancy example: IL-2, IL-4, and IL-5 can all stimulate proliferation.
• Synergic example: II-4 & IL-5 inducing B cell class switch to IgE
• Antagonistic example: INFg blocks II-4 inducing B cell class switch to IgE
• Additive example: Cascade induction

Functional Categories

• Mediators and regulators of innate immunity are produced by activated macrophages and NK cells during microbial infection
• Affecting mainly endothelial cells and leukocytes.
• Stimulate early inflammatory response to microbes
• Mediators and regulators of adaptive immunity are mainly produced by T lymphocytes recognizing foreign antigens.
• Includes IL-2, IL-4, IL-5, IL-13, INF, TNF-α, and TNF-β
• Stimulators of haematopoiesis are produced by bone marrow cells and leukocytes.
• Stimulate leukocytes' growth and differentiation (IL-3, IL-7, GM-CSF).

Biological Effects of Cytokine Stimulation

• Biological effects on cells include differentiation, proliferation, and activation.
• Interferon family cytokines have antiviral actions.
• Chemokine family direct cell migration, adhesion and activation.
• Tumour necrosis factor family regulates inflammatory and immune responses.
• Interleukin family has a variety of actions dependent upon the specific interleukin and cell type.
• Haematopoietins promote cell proliferation and differentiation.
• Transforming growth factor beta family regulates immune cells

Examples of Interleukins & Interferons

• Interleukins IL-2, IL-4, and IL-7 stimulate T cell proliferation through autocrine and paracrine signalling.
• Interferons (IFNs) are proteins released by host cells in response to pathogens like viruses, bacteria, parasites, or tumor cells.
• They interfere with viral replication within host cells.
• IFNs activate immune cells like natural killer cells and macrophages (e.g., INFy).
• IFNs Symptoms like aching muscles and fever relate to the production of IFNs during infection.
• IFNs increase infection/tumor cell recognition by up-regulating antigen presentation to T lymphocytes (MHC complex).

IL-8 Chemotaxis

• IL-8 is a neutrophil chemotactic factor with two primary functions: inducing chemotaxis in target cells and stimulating phagocytosis once cells arrive.
• IL-8 induces chemotaxis in target cells, causing them to migrate toward the site of infection
• IL-8 is primarily neutrophil chemotaxis
• The case study revolves around IL-8 and inflammation
• Interleukin-8 (IL-8) is a potent chemotactic cytokine implicated in inflammatory diseases.
• Blocking agents of IL-8 binding to its receptor block inflammation in animal models of diseases.
• This suggests drugs specifically targeting IL-8 may treat multiple human diseases.
• Blocking IL-8 has been found to block IL-8-dependent cellular roles:
• neutrophil activation,
• up-regulation; and
• neutrophil chemotaxis.
• Fully human anti-IL-8 mAb (Monoclonal antibody) supports clinical trials to treat inflammatory diseases.
• Fulminant neutrophilia (a specific form of neutrophilia) is most significant finding in patients who require ICU management.
• COVID-19 patients admitted to the ICU had greatly increased blood neutrophil counts compared to SARS-CoV2-positive patients with less severe symptoms (Huang et al., 2020).