Immunology: Leukocyte Migration, Mediators & Cytokines

What is the role of leukocytes in inflammation?

Leukocytes migrate to the site of injury to combat pathogens and facilitate healing.

What are the two main types of leukocytes discussed?

Neutrophils and monocytes.

How do neutrophils and monocytes differ in their response time during inflammation?

Neutrophils respond earliest (6-24 hours), while monocytes appear in exudate around 24-48 hours.

What is chemotaxis?

Cellular locomotion directed by a gradient of extracellular signals.

What is the significance of integrins in leukocyte migration?

Integrins on leukocytes facilitate adhesion and migration through endothelial cells and extracellular matrix.

What are some examples of chemoattractants for leukocytes?

Bacterial peptides, chemokines, leukotrienes, and complement proteins like C5a.

What is the complement system?

A system of ~20 plasma proteins that, when activated, enhance inflammation and immune responses.

What are the three major neutrophil responses to pathogens?

Phagocytosis, respiratory burst, and degranulation.

What is phagocytosis?

The engulfment of pathogens by leukocytes, often enhanced by opsonization.

What is the respiratory burst?

A rapid release of reactive oxygen species (ROS) by neutrophils to kill engulfed pathogens.

What role does myeloperoxidase (MPO) play in neutrophil function?

MPO catalyzes the production of hypochlorite from hydrogen peroxide, a potent antimicrobial agent.

What are azurophilic granules?

Granules in neutrophils that contain enzymes and proteins involved in microbial killing.

What is the role of cytokines in inflammation?

Cytokines regulate immune responses and inflammation, often produced in response to injury or infection.

What are N-formyl peptides?

Exogenous mediators from bacteria that induce neutrophil chemotaxis and activation.

How do leukocytes discriminate between different chemoattractants?

They prioritize signals based on concentration, timing, and the identity of the attractant.

What is the function of leukotrienes in inflammation?

Leukotrienes are lipid mediators that contribute to inflammation and attract leukocytes.

What is the role of bradykinin in inflammation?

Bradykinin is a plasma protein that increases vascular permeability and promotes pain.

What happens during degranulation in neutrophils?

Neutrophils release granule contents that aid in the destruction of pathogens.

What is the importance of opsonization in phagocytosis?

Opsonization enhances the recognition and engulfment of pathogens by leukocytes.

What is the time course of neutrophil migration in response to injury?

Neutrophils migrate within 6-24 hours, while monocytes follow after 24-48 hours.

What is the effect of increased vascular permeability during inflammation?

It leads to fluid edema and facilitates the migration of leukocytes to the site of injury.

What are the potential negative effects of inflammatory mediators?

They can harm host tissues while fighting infections.

What is the function of defensins in neutrophils?

Defensins disrupt the membranes of pathogens, leading to their destruction.

How do leukocytes respond to bacterial infections?

By migrating to the site of infection, undergoing phagocytosis, and releasing reactive substances.

What is the role of signaling proteins in leukocyte activation?

They mediate responses such as chemotaxis and superoxide production in neutrophils.

What is the significance of the NADPH oxidase complex?

It produces reactive oxygen species essential for the respiratory burst in neutrophils.

What is the primary mechanism of bacterial killing by neutrophils?

The NADPH oxidase/myeloperoxidase/halide system.

What are the main cells that release histamine?

Mast cells, basophils, and platelets

What stimulates the release of histamine?

Physical injury, antibody binding to mast cells, C5a, and cytokines

What is the primary physiological effect of histamine on blood vessels?

Vasodilation and increased endothelial permeability

Which receptor does histamine activate to cause endothelium-dependent relaxation?

H1 histamine receptor

What are the effects of H1 histamine receptor activation?

Vasodilation, increased endothelial permeability, bronchoconstriction, and stimulation of sensory nerve terminals

What is the role of H2 histamine receptors?

Gastric acid secretion

Name two second-generation H1 antagonists.

Fexofenadine (Allegra®) and Cetirizine (Zyrtec®)

What is bradykinin?

A 9 amino acid peptide that causes vasodilation and increased vascular permeability

What receptor is responsible for the vasodilatory effects of bradykinin?

B2 bradykinin receptor

What is the function of the B1 bradykinin receptor?

Induced by inflammatory mediators, its function is still unknown but may relate to chronic pain

What is thrombin's role in the immune response?

Activates GPCRs on endothelial cells and produces pro-inflammatory effects

What are the two isoforms of cyclooxygenase (COX)?

COX-1 and COX-2

What is the primary function of COX-1?

Produces prostaglandins that regulate vascular homeostasis and protect the GI mucosa

What triggers COX-2 expression?

Inflammatory stimuli such as TNF-a and interleukin-1

What are the effects of prostaglandins?

May produce both pro- and anti-inflammatory effects, including vasodilation and pain enhancement

What is the mechanism of action of aspirin?

Irreversibly inhibits COX-1 and COX-2 by acetylating a serine residue

What are leukotrienes and their primary source?

Eicosanoids synthesized on demand, primarily from leukocytes

What is the role of 5-lipoxygenase in leukotriene synthesis?

Acts on arachidonic acid to produce leukotrienes

What are cysteinyl leukotrienes?

Leukotrienes LTC4, LTD4, and LTE4, primarily produced by mast cells and eosinophils

What is the primary effect of LTB4?

Promotes inflammation by attracting neutrophils and stimulating their responses

What is the role of phospholipase A2 (PLA2) in eicosanoid synthesis?

Enzyme required for the generation of free arachidonic acid from membrane phospholipids

What is the significance of autocoids?

Rapidly released mediators that act locally in response to stimuli

What are the main categories of regulators of immune response?

Exogenous products, vasoactive amines, plasma protein regulators, lipid mediators, and cytokines

What is the function of tumor necrosis factor-alpha (TNF-a)?

A cytokine involved in systemic inflammation and the acute phase response

What is the effect of glucocorticoids on inflammation?

Inhibit COX-2 induction and PLA2 activity, reducing inflammation

What is the relationship between histamine and allergic reactions?

Histamine is released during IgE-mediated hypersensitivity, causing symptoms of allergies

What are LTC4, LTD4, and LTE4 known for?

They are recognized for their role in asthma by causing bronchoconstriction and mucous production.

What role do leukotrienes play in inflammation?

They increase vascular permeability and may attract and activate eosinophils and monocytes.

What is Zileutin (Zylflo®)?

A competitive inhibitor of 5-Lipoxygenase used in leukotriene-targeted therapy.

What are Zafirlukast (Accolate®) and Montelukast (Singulair®)?

Selective high-affinity competitive antagonists of the CysLT1 receptor.

What is the primary function of TNF-a in inflammation?

It is a key cytokine that drives inflammatory responses and is implicated in chronic inflammatory diseases.

What happens to NF-kB when TNF-a binds to its receptor?

NF-kB is released from its inhibitor IkB and translocates to the nucleus to drive gene transcription.

What is the role of IL-1 in the immune response?

IL-1 promotes prostaglandin release, leukocyte invasion, and stimulates the release of other cytokines.

What is the function of IL-1Ra?

It is an endogenous antagonist that binds to IL-1 receptors but does not induce a signaling response.

What is the significance of IL-6 in inflammation?

IL-6 is produced during inflammation and plays a role in fever and the acute phase response of the liver.

How does IL-6 signal through JAK-STAT pathway?

IL-6 binds its receptor, activating JAK, which phosphorylates STAT proteins that then translocate to the nucleus.

What are some therapeutic agents targeting TNF-a?

Simponi®, Cimzia®, Humira®, and Remicade®.

What is the role of E-selectin, VCAM, and ICAM in inflammation?

They are increased in endothelial cells by TNF-a, enhancing leukocyte adhesion and migration.

What triggers the production of IL-6?

TNF-a, other cytokines, bacterial and viral products, and substances released by necrotic cells.

What is the active form of TNF-a?

A 17 kDa protein that is released from various cells after cleavage by TNF-a Converting Enzyme (TACE).

What physiological responses are associated with IL-6?

Fever, transition of leukocyte types, and acute phase response of the liver.

What is the function of bradykinin in the immune response?

It acts as a plasma protein regulator involved in inflammation.

What is the role of prostaglandins in inflammation?

They are lipid mediators that contribute to the inflammatory response.

What is the mechanism of action of Anakinra?

It is an IL-1Ra that acts as an antagonist to inhibit IL-1 signaling.

What is the role of cytokines in cell signaling?

Cytokines are small proteins important in autocrine, paracrine, and endocrine signaling as immunomodulators.

How do therapeutic antibodies function in inflammation?

They disrupt or block protein-protein interactions to modulate immune responses.

What is the significance of the N-formyl-methionine (fMet-Leu-Phe) peptide?

It is a prototypical example of exogenous regulators of immune response, usually from bacteria.

What is the role of macrophages in TNF-a production?

Macrophages are major sources of TNF-a during the inflammatory response.

What is the effect of TNF-a on endothelial cells?

It increases vascular permeability and enhances the expression of adhesion molecules.

What does the term 'trans-signaling' refer to in IL-6 signaling?

It refers to the signaling pathway where IL-6 binds to its receptor and activates downstream signaling through gp130.

What is the primary role of thrombin in inflammation?

Thrombin acts as a plasma protein regulator involved in the inflammatory response.