Week 2 Innate immunology.pdf, Summaries of Law

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Innate Immunity

Peter M. Morganelli, Ph.D

Week 2 2024

Topics for Week 3

§ Importance of innate immunity to health.

§ How microbes are sensed by innate cells.

§ Effector functions of innate cells.

§ Role of innate immunity in inflammation.

§ Mechanism of neutrophil transmigration.

§ Complement system.

Innate antimicrobial activity exists for all types of microbial infections.

§ Extracellular bacteria, fungal pathogens, parasites- destroyed by phagocytes

(phagocytosis, production of reactive oxygen intermediates, (ROI), complement

proteins, and antimicrobial peptides (defensins) produced by many cell types.

§ Intracellular pathogens that infect macrophages- destroyed after

macrophage activation by interferon- g (gamma interferon or Type II interferon)

produced by NK cells or T helper cells.

§ Viruses- viral replication in healthy cells is inhibited by interferon- a or - b

produced by infected cells (Type I interferon antiviral response) ; virus-

infected cells are destroyed by NK cells.

Antimicrobial effector cells and molecules in innate

and adaptive responses

PAMPs and DAMPs are recognized by pattern

recognition receptors (PRRs).

§ PRRs are present on the surface of, or within cells, meaning that they can

be activated by extra- as well as intracellular pathogens.

§ Activation of PRRs has multiple effects- stimulation of antimicrobial activity

(phagocytosis) , production of antimicrobial molecules ( reactive oxygen species,

ROS, nitric oxide) , production of proinflammatory cytokines , and changes in

cell surface phenotype.

§ Major proinflammatory cytokines- tumor necrosis factor (TNF- a ),

interleukin- 1 b (IL- 1 b ), and interleukin-6 (IL-6) , that have numerous

overlapping effects:

• Development of fever (endogenous pyrogens)
• Cell death and cachexia (esp TNF-a)
• Stimulation of production of acute phase proteins by hepatocytes (esp IL-6)
• Regulation of adhesion molecule expression (important for neutrophil

transmigration)

Activation of PRRs by PAMPs or DAMPs is a potent stimulus of innate cells.

§ Binding or recognition of PAMPs or DAMPs by pattern recognition receptors

activates transcription factors such as nuclear factor kappa B (NFkB),

interferon regulatory factors (IFRs), and others, resulting in a stereotypical

pattern of cytokine production plus activation of numerous other effector

functions.

Interleukin-1 (IL- 1 b )

Interleukin- 6

Tumor necrosis factor alpha (TNF- a )

IFRs

Toll-like receptors (TLRs) § TLRs are pattern recognition receptors that activate innate and other cells, stimulating microbial killing mechanisms, cytokine production, and cell maturation. § TLR4 is activated by bacterial LPS and is the best studied TLR; in macrophages, LPS activates transcription factor NF-kB, resulting in production of TNF- a , IL- 1 b , IL-6 and other cytokines.

Macrophages, neutrophils, and dendritic cells are myeloid cells that

destroy microbes by phagocytosis and other mechanisms.

§ Phagocytosis- engulfment of large particles stimulated by the binding of

PAMPs or DAMPs to PRRs.

§ Phagocytosis usually results in destruction of the microbe by exposure to

antimicrobial molecules (ROS, degradative enzymes).

§ Intracellular pathogens such as Mycobacterium and Listeria intermediates

have evolved virulence factors that prevent destruction after phagocytosis.

Endocytic mechanisms by myeloid cells Receptor-mediated endocytosis- soluble molecules Non-opsonic or opsonic phagocytosis

Interferon antiviral response § The antiviral interferon response is important for limiting viral infection of cells during the early phase of infection for many types of viruses. § Viral nucleic acids activate intracellular PRRs including several types of TLRs stimulating secretion of IFN- a and IFN- b (type I interferons); there are also type II (IFN-g) and type III interferons (IFN-l) that also activate the anti viral response. § IFNs bind to receptors on neighboring uninfected cells (bystander effect), leading to production of enzymes and other proteins that inhibit viral replication and assembly. § Corona viruses have been shown to limit the type I interferon antiviral response by blocking IFN synthesis and IFN signaling pathways.

§ Vascular phase- dilation of blood vessels, which increases delivery of leukocytes and blood to the site of infection or damage; histamine, nitric oxide (NO) and other molecules produced by endothelial and/or other cell types are important vasodilators. § Cellular phase- transendothelial migration of neutrophils in great numbers from blood to the site of infection; tissue macrophages activated by PAMPs at the site of infection produce cytokines and chemokines that stimulate movement of neutrophils to the site of infection or damage. § If inflammation persists, blood monocytes will eventually follow neutrophils; each contributes to microbe destruction; monocytes (immature macrophages) eliminate dead cells and tissue debris, forming pus. § Activation of the complement system - an important contributor to killing of microbes and enhances neutrophil migration to the site of infection (more later). § Resolution or persistence- elimination of microbes leads to healing; without resolution, cytokines may act systemically- initially fever, pain, etc, acute phase response, then sepsis. Events of acute inflammation- two phases.

A skin abscess demonstrates elements of acute

inflammation in response to a bacterial infection.

§ Accumulation of leukocytes is a hallmark of inflammation and may lead to the formation of pus, which contains mostly dead neutrophils, dead microbes, macrophages, and cell debris. § Redness- results from vasodilation caused by histamine, proinflammatory cytokines, and other factors produced by mast cells and macrophages. § Swelling- fluid and plasma proteins accumulate due to vascular leakiness caused by damage from ROI and enzymes produced by macrophages and neutrophils.

Beta 2 ( b 2) integrins are cell adhesion molecules

possessing two different subunits.

§ b 2 integrins consist of a unique alpha chain non-covalently linked to the same beta chain (CD18). § Examples: LFA- 1 consists of CD11a linked to CD18 ; complement receptor 3 (CR3) consists of CD11b linked to CD18. § During acute inflammation, LFA-1 on neutrophils becomes a high-affinity receptor for ICAM-1 on endothelial cells , resulting in tight binding that triggers diapedesis or movement across the endothelium and into tissue spaces.

CD18 CD11a

http://bangordailynews.com/2013/11/28/health/presque-isle-family-thankful-for-babys-bone-marrow-donor/ (August 9, 2016). https://www.emjreviews.com/allergy-immunology/article/leukocyte-adhesion-deficiency-type- 1 - a-case-series-and-review-of-the-literature/ § In LADS syndromes, neutrophils are unable to transmigrate to the site of infection; a hallmark of LADS is increased production of neutrophils (neutrophilia) and the absence of pus. § LADS are due to mutations in adhesion molecules; cases may be relatively mild or quite severe; symptoms of bacterial and fungal infections on the skin and in mucosal environments (oral, nasal, respiratory, urogenital) can occur shortly after birth. § In LAD-1, a mutation in CD18 prevents formation of LFA-1. Leukocyte adhesion deficiency syndromes (LADS)