Baselski 1

Baselski handed out slides in class. WARNING. DO NOT STUDY WHILE EATING.
Host Response to Infection
Next 2 lectures –she is a clinical microbiologist. She runs clinical microbiology lab to diagnose infectious disease. Objectives:
She will show you how host responses influence response, or how specific immune responses play into creating pathology/tissue damage in specific infectious disease. Focus on damage- not the virulence mechanisms of the organisms. Point is to show how interactions create tissue damage.
Tomorrow- show novel disease associations. Concept that interactions may be responsible for chronic diseases.
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Key concepts
None of things we talking about today are easy to understand. We don’t understand all the mechanisms of any of these diseases.
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non-immune inflammation (non-specific or innate immunity. What she calls non-specific or non-immune inflammation, Marion called innate immunity. )
phagocytosis- enzymes contribute to tissue damage
cytokines increase inflammatory response and tissue damage
endotoxins and superantigens activate immune response.
These can mediate tissue destruction.
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Pneumococcal pneumonia is one of major causes of pneumonia and meningitis. Obstructive inflammation- organism has capsule to evade phagocytosis until development of opsonizing antibody. C peptide on surface is potent inflammatory promoter with massive accumulation of neutrophils. Alveolar spaces fill with inflammatory cells and protein components. Person becomes hypoxic (not enough oxygen) and hypoxemic(lack oxygen in blood).
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Lung – massive accumulation of neutrophils and pus. Tissue damage is promoted.
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Consolidation- you see the “white out “of area under X-ray. Initial disease- massive immune response.
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Contrast with anthrax organism, which likes to enter through lymph nodes and travel to brain. Right- spinal fluid from 1st case anthrax in terror attack in 2001- Massive number organisms with capsule. Has virulence component that promotes hemorrhage. Due to non-specific inflammatory response to organism.
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2 diseases in news: SARS and avian influenza have massive initial response that causes respiratory failure. SARS and the flu are viruses, so you get lymphocytic as well as neutrophilic infiltration.
Cytokines can create cascades of events leading to exaggerated response due to superantigens and endotoxins. LPS is endotoxin. Superantigen causes nonconventional binding betweenT cell and B cell receptors for abnormal and coninuous activation. Here the inflammatory damage is intense cytokine response resulting in tissue wide destruction.
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meningitis
organism is gram negative. Cell wall promotes systemic inflammatory response that destroys tissue. Pili allow it to attach to cells.
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Organism tightly adheres to upper respiratory cells through receptors. Internalized and transcytosed into deeper tissues. Can mask inside macrophages. Has capsule, but not protected from phagocytosis.
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Human host- 30% people harbor organism. There is some host susceptibility component to disease. Following viral upper respiratory infection, tissue damage allows organism to enter. It can spread to meninges. Fulminant meningococcemia kills. Involves variable expression of bacterial genes in variable presentation of disease. There have to be host susceptibility factors as well.
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Short version sepsis cascade. Vascular effect is vascular leakage, which leads to hemorrhage and necrosis.
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Terminology. What you will see in sepsis. Purpura- overwhelming areas of necrosis.
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Rash- necrosis is from inside out.
Necrosis can result in gangrene.This is only organism in her lab she is afraid to handle.
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Evidence of necrosis internally. Adrenals hemorrhage.
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Diagnosis- look in spinal fluid and blood. Vaccine is recommended by CDC.
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Specific immune response can also cause tissue damage through mechanisms already discussed.
Potential is there for destruction in addition to protection. Anaphylactic response is primarily allergic.
Most damage from specific immune responses is from T cell cytotoxicity or formation of granulomas.
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infectious diseases mechanisms and major defenses listed.
Helminths are worms. They promote hypersensitivity reactions.
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Neutralization protection through vaccines, destruction through atypical measles.
Vasculitis- immune complexes can lodge in vessels.
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Cellular effects primarily responsible for destructive components.
ADEM acute demyelinating encephalomyelitis
Granuloma walls off organism, but displaces and destroys normal tissue.
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Group A Streptococcal disease. Colonizes epithelium. Virulence factors promote tissue damage. Organism’s M protein is superantigen. Gets into blood, causes severe toxic strep or necrotizing fascitis. Lot like endotoxin effects of sepsis cascade. Non suppurative- cross reactions in cardiac tissue (rheumatic fever) from molecular mimicry. Organism can provoke tissue damage from immune reaction.
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Strep pyogenes- no endotoxin. Electron micrograph shows that it has capsule, pili, components so it can invade host.
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Many things help it be a successful pathogen.
Adjuvant promotes immune reaction.
M protein binds fibrinogen to act sepsis cascade.
Host factors determine whether you are susceptible to immunopathologic outccomes.
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Inflammatory response. Suppurative in throat.These are from non-specific inflammatory response.
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Virulence factors have cross-reactive components in body. Cross reactivity results in response to components of bacteria attacking normal tissue.
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What one sees in tissue in myocarditis- accumulation of lymphocytes called Aschoff bodies. “Myocytes” are components of granuloma formation.
Valvular disease- no organism there-immunopathologic destruction. Organism demonstrates how it provokes immune response. Fast treatment rids organism before immune response leads to rheumatic fever. Want to clear antigen fast.
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Glomerulonephritis follows impetigo.
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Superantigens cause massive activation of immune system by interaction with class II MHCs. Mechanisms have been worked out.
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Increased vascular permeability – less than 24 hrs from a nick(minor cut in skin) to massive necrosis to need for debridement.
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in blood- peripheral gangrene- host response to organism.
31 TB forms granuloma
Acid fast- has waxy coat to resist phagocytosis. Enters machrophage and resists killing. Promotes predictable immune response.
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Granuloma becomes tissue displacement process.
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EM shows organism entering macrophage. Survives in cell. You cannot underestimate genetic susceptibility.
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Granulomas become large. Macrophages try to wall of the mass.
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Early- lymphocytes accumulate.
Giant cells form- acid fast organism inside. Upper right- can see remnants of organisms. Just a few promote cellular immune response.
Later- caseous necrosis- interior looks like cottage cheese.
Lower right- lung withlesion.
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Spleen granulomas, top.
Lower right large granuloma. Organized T cell response displaces normal tissue.
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Individual who is T cell deficient (HIV or alcoholic)- Disease disseminates. Cannot wall off organism. Disease process extensive. Immune compromising causes more extensive dsease process.
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MAI less virulent, but infects HIV+ people.
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Granuloma from helminthic infection. Coat with host proteins and live in mesenteric veins. Mate and ova move into adjacent tissue.
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Granuloma forms around ova. Moves through bowel into stool.
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Measles virus is comparable to GAS.
Vaccinations are not 100%. Virus travels all throughout bdy. Oral mucosa-Koplik spots.
Rash is from destruction virus in vascular bed.
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What can go haywire.
CTL results in clasical rash.
Immunocompromised host- virus not contained. Person gets hemorrhagic measles. Killed vaccine did not neutralize protein involved in cell-to –cell spread. Person responds like immunocompromised host.
Virus has autoimmune effect. Virus in neurons cannot complete replication cycle, but in small number of indivuals causes subacute sclerosing panencephalitis.
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Typical measles
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Disease not contained- as in immunocompromised and pregnant women. Virus infected cells fuse together.
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Young children before immunity- less speckled- individual cannot respond effectively.
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ADEM- response to myelin in 1/1000 cases.
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SSPE- accumulation of viral particles. Rash in brain. No one knows what makes virus go into neurons in some individuals and not others.
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What happens in immunodeficient individual. There is host susceptibility component. Keep equation in mind if you study infectious disease.
Lower host resistance- change equation. Infection more severe.
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Empiric therapy is based on defect and temporal considerations.
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Immunodeficient conditions
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Selective immunodeficiency
56 Leishmania- granulomas on surface. Organisms grow at surface temperature. Do not see organism because of immune response.
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Mucocutaneous- lesion widespread. Organism not walled off. Large number organisms and inflammatory cells.
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A TLR in dark-skinned individuals makes them more susceptible to TB. For many diseases papers are beginning to explain host susceptibility components.
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We do things to patients to take away immune system.
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Normal- get patches of yeast after you take an antibiotic and disrupt normal flora. Neutropenic- see slide 65. Fatal esophago gastritis.
No ability to control invasion
How do you treat immunospressed person- treat the agent of infection.

If you tilt balance of immune system, can create problems.
Lectures will go up on blackboard by tomorrow morning.