Pathology 3: Neutrophils, eosinophils and immune complex-mediated disease

What are some causes of neutrophil-rich inflammation?

Trauma, foreign material, thrombosis, burns, necrosis, immune complexes

Words for neutrophil dominated lesion

Purulent, suppurative, neutrophilic

How long does it take neutrophils to enter the tissue?

Within hours

How long does pus take to form?

Days, almost always from bacterial infection

Morphologic diagnosis

mesenteric abscess, severe chronic focal neutrophilic/suppurative mesenteric lymphadenitis (began in mesenteric lymph node)

Morphologic diagnosis

localized subcutaneous creamy abscess

Morphologic diagnosis

Inter-ventricular septum and into the R ventricle of the heart is multifocal suppurative and necrotizing myocarditis

How does a neutrophil get to the site of infection?

neutrophil migration from the blood into issues is a carefully controlled process, that includes selectin mediated rolling adhesion to endothelium, integrin mediated firm adhesion to endothelium, trans-endothelial migration, and directed migration or chemotaxis toward the inflammatory stimulus.

How long does an abscess take for form?

At least a Week

What are some terms we can use to describe inflammation dominated by neutrophils ± mucus?

suppurative, purulent, mucopurulent, catarrhal

Tarsus from a dairy cow

1. Pathologic process

2. Acute or chronic

3. Benefits of the reaction

4. Harm of the reaction

1. Suppurative inflammation & fibrosis

2. Chronic (thick white fibrous tissue)

3. contain and wall off the bacterial infection

4. reduced mobility, pain

What are some outcomes of neutrophilic/suppurative inflammation?

• resolution

• Chronic suppurative inflammation

• Stimulation of fibrosis

• Containment abscess formation

What is this an example of?

Neutrophilic/suppurative inflammation

What’s the mechanism for neutrophil response to inflammation?

• bacteria come in

• Recognized by phagocytes, complement, antibody

• Inflammatory mediators stimulate endothelial cells and leukocytes

• Rolling adhesion: selections

• Firm adhesion: interns on leukocytes. ICAM-1 on endothelium

• Diapedesis

• Chemotaxis: IL-8, C5a, LTB4

What is neutrophil chemotaxis?

Directed migration toward a stimulus.

Neutrophils move toward higher concentrations of inflammatory mediators by extension of lamellipodia that adhere to tissue matrix

Steps for phagocytosis

Opsonins enhance the recognition of bacteria by leukocytes

IgG → FcγR (acquired), C3b → CR3 (Innate & acquired), SP-A MBL(innate)

What do Toll-like receptors recognize?

the conserved structures on pathogen surfaces leading to cellular activation such as production of inflammatory mediators

What specificity does TLR 7, 8 trigger for?

single stranded RNA (RNA viruses)

What are some processes of killing bacteria?

• Oxidative killing (peroxide H2O2)

• Antimicrobial protein in neutrophil granules (lysozyme)

• Proteolytic enzymes (collagenase)

How do leukocytes recognize bacterial infections?

1. Opsonization (antibody)

2. PAMPs (TLR)

3. Cytokines from other cells

How do leukocytes kill bacteria?

1. Oxidative killing

2. Proteolytic enzymes

3. Bactericidal proteins

4. NETs

What are the roles of neutrophils?

contain or eliminate infection

• from impaired organ function

• injury to host tissue

• stimulation of fibrosis

What does malondialdehyde indicate?

Oxidative stress (brown immunohistochemical staining)

Where do we find neutrophils in healthy animals in the absence of inflammation?

blood and lymph nodes

What calls neutrophils to site of infection?

TNF, Type 1 and 2 interferons

How do neutrophils recognize that infection is present?

IgG and complement

What are 2-4 ways neutrophils kill bacteria?

NETs, cytotoxic granules

What happens to neutrophils when the infection is resolved?

they die, phagocytosed by macrophages

What role do eosinophils play in inflammation?

Stimulated by parasites and allergies. Play similar roles of neutrophils but they are not phagocytic cells, involved in oxidative injury, the proteins in granules injure cell membranes

What is Type 3 hypersensitivity?

Immune complexes: antibody + antigen

Systemic reactions. Circulating immune complexes deposit in vessel walls, synovium, glomeruli, skin

Antigen localized in vessel walls may react with circulating antibody

Type 3 hypersensitivity: Sequelae to immune complex deposition

1. activation of complement (classical) and activation of macrophages and neutrophils (FcRs)

2. neutrophil recruitment and activation from injury to vessel wall

   1. leakage of fluid and proteins which causes edema, fibrin, hemorrhage

3. platelet activation, thrombosis

   1. ischemia infarction

4. vascular injury

Where in the body do type 3 hypersensitivity reactions occur?

Disease manifestation depends on the site of immune complex deposition

Joints, glomeruli, skin, uveitis, many tissues at once

What would happen if an animal did not have any of β-integrin / CD18?

genetic defect in the gene encoding CD18 and causes impaired neutrophil migration to site of infection

What ways do antibodies protect against bacterial infection?

• bind to bacteria and activate complement mediated lysis

• opsonizes the bacteria to promote killing by neutrophils and macrophages

• binds bacterial cell adhesion proteins to block colonization of surfaces

• binds and neutralizes bacterial toxins

Vasculitis

Inflammation that specifically targets blood vessel walls

What main cells are recruited during allergy and parasitism stimuli?

Eosinophils

When do neutrophils phagocytose bacteria?

when opsonized by immunoglobulin , C3b, or other opsonins

How are ingested bacteria killed?

Proteolytic enzymes, bactericides proteins in neutrophil granules, and oxygen radicals like hypothalamus acid

What can kill extracellular bacteria?

Neutrophil traps

How can neutrophil accumulation cause harm?

Space occupying lesion, inducing proteolytic or oxidative injury to host tissues, trigger thrombosis, scarring of tissues

What triggers formation of immune complexes?

Persistent antigenic stimuli, neoplasia, virus, immune mediated drug reaction, autoimmune reaction

What incite a neutrophil inflammatory response?

Aggregates of antigen and antibody deposited in the wall of blood vessels

Where are immune complex diseases most apparent

In well vascularized tissues such as synovium, renal glomeruli, skin

Causes vasculitis

How do eosinophils kill parasites?

Synthesis of oxygen radicals and secretion of basic proteins from their granules (can also damage tissue)