Micro Block III Raw

What are the different routes of infection to the CNS
Blood stream, nerves, direct spread from adjacent focus of infection
What is the most common cause of bacterial infection of the nervous system in newborns?
Group B Strep (S. agalactiae)
Also E. coli, Listeria, Klebsiella, and others
Which E. coli serotype causes neonatal meningitis?
K-1 E. coli
How do newborns most commonly contract bacterial infections of the meningitis?
At birth due to colonization of th ebirth canal
What is the most common cause of bacterial infection of the nervous system in infants and children?
Strep pneumoniae
Neisseria meningitidis
Haemophilus influenza
What is the most common cause of acute purulent mingitis?
Strep pneumoniae
Neisseria meningitidis
Haemophilus influenza
Meningitis associated with trauma, neurosurgery, or foreign intracranial bodies is most often caused by what pathogens?
Staph aureus
Staph epidermidis
Strep pneumoniae
Pseudomonas
Intracranial abscesses not associated with trauma or surgery is usually due to what?
Microaerophilic or anaerobic streptococci, anaerobic Gram-negative bacteria (often mixed aerobic and anaerobic flora of upper respiratory tract origin)
What is the rule of thumb when determining whether a pathogen is intracellular or extracellular?
Intracellular causes granulous lesions
Extracellular causes pyogenic and pus formation
What is purulent meningitis?
An infection of the meninges associated with marked acute inflammatory exudates, usually due to bacterial infection
What are the symptoms of purulent meningitis?
Acute onset and rapid progression of fever, stiff neck, irritability, neurologic dysfunction, and PMNs
What are the characteristics of chronic meningitis? What causes it?
Insidious onset, progresses over weeks
Most often caused by mycobacteria but can also be due to fungi (granulomatous inflammations) and protozoa (rare)
What is asceptic meningitis?
A syndrome of meningeal inflammation associated with an increase of cells, primarily lymphocytes and mononuclear cells of the CSF
Usually due to viral infection
What usually precedes asceptic meningitis?
Viral infections
CSF shows an absence of readily cultivable bacteria or fungi
What is encephalitis?
CNS dysfunction due to infection: seizures, paralysis, disordered mentation
CSF findings may or may not be comparable with asceptic meningitis
What causes encephalitis?
Most often viral infection but can also be due to acute or chronic demyelinating diseases such as postinfectious or allergic encephalomyelitis syndrome
What is Poliomyelitis?
Selective destruction of anterior motor horn cells in the spinal cord and/or brainstem
What causes poliomyelitis?
Most commonly due to polio virus
Can also be due to Coxsackie virus type A7 or other enteroviruses
What is acute polyneuritis?
An inflammatory disease of the peripheral nerves with characteristic symmetric flaccid paralysis of muscles
What causes acute polyneuritis and how is it prevented?
Rabies, influenza, polio, Hep A
These diseases are uniquely prevented using killed viruses (RIP Always)
Also can be associated with C. diptheriae, enteric bacterial pathogens, CMV, EBV, and others
What is Reye’s syndrome?
Encephalopathy with fatty infiltration of viscera
Seen in childhood, associated with the flu, chicken pox, and the measles
What causes Reye’s syndrome?
Cerebral edema, hepatic dysfunction, or hyperammonemia is followed by treatment with aspirin which can precipitate the syndrome
How is Reye’s syndrome diagnosed?
Lumbar puncture is first step in a suspected CNS infection, results determine the next step
CT and MRI
Biopsy of the brain (last resort)
What are lumbar punctures contraindicated?
When intracranial pressure is severely increased
What PMN levels would you expect to find in the CSF during a CNS infection?
Much higher PMNs in bacterial, lower in viral
Normal is 0
Viral <50
Pyogenic bacterial >60
Tuberculosis and mycosis <50
What glucose levels would you expect to find in the CSF during a CNS infection?
Unchanged if viral, lowered if bacterial or fungal
What protein levels would you expect to find in the CSF during a CNS infection?
Slightly increased if viral (30-80), much higher if bacterial or fungal (>60)
How is bacterial meningitis confirmed?
Culture – isolation from CSF or blood
Latex agglutination test for Crypto, Strep pneumo, Neisseria, and H. influenza
Gram stain
What are the clinical findings/symptoms in bacterial meningitis?
Acute onset of fever and headache
Either neck stiffness or altered consciousness or both
What types of meningitis cannot be differentiated on clinical grounds alone?
Hib, meningococcal meningitis and pneumococcal meningitis
What lab findings increase the probability of a patient having bacterial meningitis?
Turbid appearance
Leukocytosis (> 100 cells/mm3)or
Leukocytosis (10-100 cells/ mm3) AND either an elevated protein (> 100 mg/dl) or decreased glucose (< 40 mg/dl)
How is meningitis treated
Antimicrobials (unless it’s viral), course varies from days if uncomplicated bacterial to a year for tuberculous meningitis and several years in some cases of fungal meningitis
Correct metabolic defects if any
Monitor and control intracranial pressure
Supportive treatment if viral (except HSV which responds to early antiviral treatment)
What are the general characteristics of Neisseria meningitidis?
Gram neg cocci, appears in pairs
Kidney bean appearance
Transmitted via inhaled respiratory droplets
Humans are only host
Neisseria meningitidis can be cultured on what mediums?
Blood agar and Chocolate agar
What are the important serotypes of Neisseria meningitidis?
A, B, C, W-135, and Y
50% of cases are caused by B which is the serotype absent in the vaccine
Which Neisseria meningitidis serotype is historically associated with epidemic outbreaks?
A
What are the virulence factors of Neisseria meningitidis?
Meningococcal polysaccharide capsule
IgA protease
LPS/LOS
What inhibits opsonin-mediated phagocytosis in Neisseria meningitidis?
Meningococcal polysaccharide capsule
How does Neisseria meningitidis avoid ciliary activity in order to escape host mucosal defenses?
Secretes IgA protease
How does Neisseria meningitidis cause endotoxemia?
Cytokines are released by leukocytes in rsponse to LPS (LOS), causing damage to blood vessels and vascular collapse, hemorrhaging, and petechiae on the trunk and appendages
Similar to toxic shock syndrome
How does Neisseria meningitidis cause intense subarachnoid inflammation?
Is in response to cytokines secreted due to virulent factors
N. meningitidis is the only gram neg bacteria that does not need to die to release LPS and can do so while replicating
How does Neisseria meningitis manifest?
Acute purulent meningitis is the most frequent
Meningococcemia without meningitis can progress to fulminant DIC and shcok as well as destruction of the adrenals glands (Waterhouse-Frederichson syndrome)
How is Neisseria meningitis diagnosed?
Culture of CSF, blood, or skin lesions of Neisseria meningitidis on chocolate or blood agar for 12-18hrs
What age group is most susceptible to Neisseria meningitidis?
Children between 6-24mo due to the disappearance of the maternal antibody
How is Neisseria meningitis prevented?
Vaccine against serogroup A, C, and W135 are available
Not long lasting, not effective under 2yo
Prophylaxis with rifampin for exposed individuals
How is Neiserria meningitis treated?
Penicillin due to good CSF penetration
If resistant, use 3rd gen cephalosporin
What are the general characteristics of Streptococcus agalactiae (aka group B strep)?
? Gram positive cocci arranged in short chains and diplococcal pairs
? Facultative anaerobes
B-hemolytic (less distinct than GAS) or non-hemolytic
Classified by group specific carbohydrate (B antigen) on cell wall, type-specific polysaccharide antigens in capsule, and surface protein (C protein)
How does Strep agalactiae infect newborns?
Gains access tot he amniotic fluid or colonizes newborns passing the brith canal
What serotypes of Strep agalacitae are most commonly associated with neonatal disease?
Ia
III (only unique one from adults)
V
What serotypes of Strep agalacitae are most commonly associated with adult disease?
Ia
V
What is the primary virulence factor of Strep agalactiae?
GB capsule, prevents opsono-phagocytosis
What defines early onset Strep agalactiae infections?
Disease in infants younger than 7 days
What defines late onset Strep agalactiae infections?
Disease appearing between 1 week and 3 months of age
When are meningitis and focal infections in the bones and joints in cases of GBS infections in infants more likely?
When they are late onset (between 1 week and 3 months of age)
When are high fever, headache and neck stiffness in cases of GBS infections in infants more likely?
When they are older than 2yo
How does a GBS infection in adults generally present?
2 groups:
The first are peripartum chorioamnionitis and bacteremia
Other infections include pneumonia and a variety of skin and soft tissue infections
May be serious but usually not fatal unless immunocompromised
Not associated with rheumatic fever or acute glomerulonephritis
How is GBS diagnosed?
Culture in blood agar produces small beta-hemolytic colonies
Confirmed via bacitracin sensitivity and CAMP test
Can also do determination of the Lancefield group (definitive identification)
How does GBS present on a CAMP test?
Produces a characteristic arrowhead area of hemolysis at the junction of S. aureus and S. agalectiae streaks on blood agar
How are GBS infections treated?
Although penicillin is the treatment of choice, GBS are slightly less susceptible to b-lactams than other streptococci
Neonatal infections are usually treated with treated with combinations of penicillin (or ampicillin) and an aminoglycoside
How is neonatal GBS infection prevented?
Screen birth canal for colonization in 3rd trimester
Assign risk on clinical grounds (eg, prematurity, prolonged membrane rupture, fever)
What is the only gram positive diplococcus?
Strep pneumoniae
What is the distinguishing structural feature of Strep pneumoniae?
Its capsule
How is Strep pneumoniae cultured?
On blood agar, produces round, glistening colonies surrounded by a zone of a-hemolysis
Why do S. pneumoniae colonies have a tendency to undergo autolysis?
Due to their susceptibility to peroxides produced during growth and the action of autolysins, a family of pneumococcal enzymes that degrade peptidoglycan
Autolysis of S. pneumoniae is accelerated with what?
Bile salts
How is S. pneumoniae differentiated from from S. viridans (another a-hemolytic streptococcus)?
Optochin sensitivity or by bile solubility tests
How is S. pneumoniae infection prevented?
Vaccine recommended for elderly due to their susceptibility
Conjugate vaccine is available to children (not as comprehensive)
How are S. pneumoniae infections treated?
? Penicillin and its derivatives
Macrolides (penicillin resistant strains)
Sulphamethoxazole-trimethoprim (in macrolide resistant strains)
Ketolides (when resistant to all other antibiotics)
How does S. pneumoniae avoid immunity?
Too many serotypes
What are the characteristics of Listeria monocytogen?
Gram-positive bacterium; morphology ranges from coccobacilli to long filaments in palisades formation
Produces catalase, flagella gives tumbling motility
What is unique about Listeria monocytogen growth?
Can grow at 4 C, unique to non-spore forming bacteria
Why is Listeria monocytogen a concern for pregnant women?
Can cross the placenta, produces widespread abscess in tissues of the fetus
Avoid deli meats and cheese
How is Listeria monocytogen most commonly contracted?
Ingestion of contaminated dairy products, poultry and meat (cold growth enhances infectivity)
What are the virulence factors of Listeria monocytogen?
Internalin
Listerolysin O (LLO)
Listeria monocytogen has what kind of characteristic movement?
“Like a comet through the evening sky”
What is the function of internalin secreted by Listeria monocytogen?
Bacterial surface protein, induce reorganization of host cell cytoskeleton with formation of a vacuole, within which Listeria enters the cell
What is the function of Listerolysin (LLO)?
Aids escape of Listeria to the cytosol
How does Listeria gain a tail?
In the cytosol using cellular actin filaments
Listeria has a tropism for what?
CNS; seeding of bacteria into the brain and its meninges cause encephalitis and/or meningitis
How does Listeria monocytogen infection manifest in adults?
Fever, headache, stiff neck, vomiting, impaired consciousness, convulsions
Abd pain, diarrhea, fever, nausea
In immunocompetent: fever, malaise, septicemia and meningitis (most common clinical presentation)
How does Listeria monocytogen infection manifest in early-onset neonates?
Granulomatosis infantisepticum in utero transmission; sepsis with high mortality; disseminated granulomas with central necrosis
How does Listeria monocytogen infection manifest in late-onset neonates?
2–3 weeks after birth from fecal exposure; meningitis with septicemia
Listeria meningitis is most common among what type of patients?
Most common cause of meningitis in renal transplant patients and adults with cancer
What mediates immunity to Listeria?
Both CD4+ and CD8+ T cell subsets are required for resolution and long-lived protection
How is Listeria meningitis diagnosed?
Gram staining of CSF sample reveal Gram-positive rods
Culture of CSF or blood specimens produce b-hemolytic colony on blood agar, isolates are gram positive rods (rather than cocci)
How are Listeria infections treated?
Sensitive to penicillin, ampicillin and TSX
Fulminant cases are treated with the combination of gentamicin and ampicillin
What is the general appearance of Hemophilus influenza?
Small gram-negative coccobacilli
Hemophilus influenza virulence is dependent on what?
The presence of a capsule (strains type A to F)
Capsule inhibits opsonization and phagocytosis
Type B is most virulent
Pili and other adhesins bind to epithelial cells
Hemophilus influenza grows on what type of media? What does it require for growth?
Chocolate agar
Requires hematin (X factor) and NAD for growth
Can create satellite colonies when grown with Staphylococcus which lyses RBCs
How does H. influenza tend to manifest differently depending on age?
Children under 2 years of age suffer mostly from meningitis
Children of 2-5 years of age suffer from epiglottitis and pneumonia
How is H. influenza diagnosed?
Combination of clinical findings and a typical Gram smear
Confirmed by isolation from CSF or from blood
Coccobacillus grow on chocolate agar but not blood agar
How is H. influenza infection prevented?
Conjugated vaccine exists, very effective
How are H. influenza infections treated?
Start with a third generation cephalosporin (e.g. ceftriaxone or cefotaxime)
May change to ampicillin if susceptibility tests indicate that the infecting strain is susceptible
How is H. influenza immunity mediated?
Anticapsular antibody is generated, which are bactericidal in the presence of complement
Infants are protected by maternal antibody up to 6 months of age
Antibody response to Hib PRP is poor in children less than 18 months of age
What causes Hansen’s disease (Leprosy)?
Mycobacterium leprae
What are the physical characteristics of Mycobacterium leprae?
Identical to M. tuberosis in morphology, structure, and staining
Aerobic, acid-fast, rod stains in beads
How is Mycobacterium leprae cultured?
Does not grow in culture but in living cells
Very slow growth (12-14day generations)
Mycobacterium leprae grows within what type of cells?
Within macrophages and Schwann cells
Humans are the only reservoir
What are the virulent factors of mycobacterium leprae?
Mycoside
Phenolic Glycolipid (PGL-1)
Lipoarabinomannan (LAM)
What are the manifestations of tuberculoid leprosy?
Areas of macule or large flattened plaques on the face, trunk, and limbs
Edges are raised and erythematous, dry, pale, hairless
Gradually becomes anesthetic when bacterium invades peripheral nerves
Peripheral nerve involvement is characteristic, will often become thickened and visible, leads to numbness
Biopsies of peripheral nerves infected with tuberculoid leprosy usually show what?
Non-caseating epithelioid granuloma with lymphocytic reactions
What causes lepromatous leprosy?
Uncontrolled Mycobacterium leprae growth due to a lack of or suppressed CMI and DTH
Histology/biopsy shows bacteria and lymphoyctes with little macrophage activation
What are the manifestations of lepromatous leprosy?
Skin lesions are extensive, symmetric, and diffuse, most obvious on the face: lips, ear, and forehead thickening is classic appearance
Loss of finger or toe digits, nasal bone, and nasal septum can occur if severe
Spreads systemically via the reticuloendothelial system
NO granulomas
How is lepromin used to distinguish tuberculoid and elpromatous leprosy?
Is analogous to tuberculin
Tuberculoid: positive lepromin test – minimal disease
Lepromatous: negative lepromin test – progressive and severe form of disease
Tuberculoid leprosy induces what type of immune response?
TH1-biased response – causes activation of infected macrophages and control of bacterial growth. Patients usually survive though may suffer from chronic disease
Lepromatous leprosy induces what type of immune response?
TH2-biased response – causes uncontrolled bacterial growth within MQ due to lack of MQ activation, pathogens are inaccessible to Abs
Bacilli disseminate and is often fatal
TH1 activates what cytokines?
IL-1
IFN-gamma
TNF-beta
TH1 response occurs in tuberculoid leprosy
TH2 activates what cytokines?
IL-4
IL-5
IL-10
TH2 response occurs in lepromatous leprosy
How is tuberculoid leprosy treated?
Sulfones block PABA metabolism, combine with rifampin for 6mo(?)
How is lepromatous leprosy treated?
Sulfones, rifampin, and clofazimine for at least 2yrs
Tuberculous meningitis is most common among what demographics?
Children and HIV patients
How does tuberculous meningitis present?
May be subtle as headache and mental changes but can also cause acute confusion, lethargy, altered sensorium, and neck rigidity
Course is 1-2wks, longer than bacterial meningitis
Often seen with paresis of cranial nerves, most often ocular nerves
Focal ischemia if it involves cerebral arteries is a risk, hydrocephalus is common
What is the general appearance of Mycobacterium tuberculosis?
Slender acid-fast, rod shaped bacterium, no spore
What is unique about the cell wall of Mycobacterium tuberculosis?
Unlike other Gram-positive bacteria, it contains N-glycolyl muramic acid rather than N-acetylmuramic acid
Highly resistant to drying, disinfectants, and strong acids/alkalis due to its hydrophobic lipid surface
What are the virulent factors for Mycobacterium tuberculosis?
Mycolic acid
Mycosides
Sulfolipids
Lipoarabinomannan (LAM) – analogous to LPS in gram neg bacteria
How is Mycobacterium tuberculosis diagnosed?
Colonized on Lowenstein-Jensen medium, shows granular waxy growth, very long generation time (>12hrs)
Fluorescent staining shows yellow-green fluorescent thin rods
Ziehl-Neelson stain shows red rods
What is a Tuberculoma?
An uncommon manifestation of tuberculosis
One or more space-occupying CNS lesions, usually causes seizures & focal signs
Biopsy is necessary for diagnosis
How does tuberculosis meningitis present?
Typical caseation is visible on stains
Presents with: seizures, fever, listlessness, loss of appetite, severe headache, nausea and vomiting, stiff neck, photophobia, loss of consciousness
MRI shows presence
How is tuberculosis meningitis diagnosed?
Lumbar puncture is cornerstone. CSF reveals:
High leukocyte count
High protein count of 1-8g/L (100-800mg/dL)
Low glucose
However, any of these can be within normal range
Culture of CSF is diagnostic in up to 80%
How do you evaluate a PDD skin test?
>5mm in HIV+ or anyone with recent TB exposure
>10mm in high risk population, IV drug abusers, etc.
>15mm in low risk populations
What is first line in the treatment of tuberculosis?
Isoniazid (INH)
Ethambutol
Rifampin
Treated with adjunctive glucocorticoids (such as dexamethasone) for faster resolution of CSF abnormalities and elevated CSF pressure
Pyrazinamide
Streptomycin
How is tuberculosis meningitis treated?
INH, rifampin, ethambutol and pyrazinamide – 2 mo (bactericidal phase)
INH and rifampin – 4 mo (sterilization phase)
What is the primary concern when treated tuberculosis?
Compliance
Irregular intake gives rise to resistant strains of TB bacillus
What is the general physical appearance of Nocardia?
Strict aerobic Gram-positive rods that form branched hyphae in tissue and culture
Which species of Nocardia are the most commonly involved in human infections?
N. asteroides and N. brasiliensis
N. asteroides and N. brasiliensis grow on what culture medium?
On blood and chocolate agar with white or orange dry, wrinkled colonies
Branching pattern of hyphae growth is indicative
N. asteroides and N. brasiliensis tend to have what differing patterns of infection?
Majority of Nocardia pulmonary and brain infections are due to N. asteroides
N. brasiliensis is involved with the cutaneous form
How does Nocardia avoid death by phagocytosis?
Most likely by disrupting acidification of phagosomes or by resisting the oxidative burst
How do Nocardia infections present clinically?
Recent history of pneumonia with focal CNS signs
Headache, fever, focal neurologic deficit, seizures, nausea, vomiting
Primary lesions in the lung show acute inflammation with suppuration and destruction of parenchyma
How is Nocardia infection treated?
Sulfonamide antibiotics
Amikacin, imipenem and broad-spectrum cephalosporins are also effective
Therapy should be continued for a longer period of time (about 6 weeks) in order to prevent diseminated infection
What causes botulism?
Clostridium botulinum – a gram pos spore forming anaerobe
Endospores are highly resistant to heat, can be killed by autoclaving
Which strains of Clostridium botulinum are responsible for human botulism?
A, B, E, and F strains
Botulism is associated with what practice?
Improperly canned foods
What type of toxin is secreted by Clostridium botulinum?
Heat labile C. botulinum exotoxin (neurotoxin + AB toxin) are absorbed into the blood from the intestine
What is the MoA of botulinum toxin?
Prevents the attachment of neurotransmitter vesicle to the cytoplasmic membrane of the nerve cells
What are the different types of botulism?
Intestinal – due to ingestion
Wound – dirty wounds or dead tissue can be colonized. Bacteria does not invade tissues but toxins diffuse into the blood
How is botulism treated?
Administration of antitoxin (iv) ASAP
Stomach wash and enema to remove any unabsorbed toxin
Cleaning and surgical debridement of the wound
Supportive treatment including artificial respirations
What are the symptoms of viral meningitis?
Fever, headache, nuchal rigidity
Photophobia
Myalgias
Vomiting
Rash
What are the symptoms of bacterial meningitis?
Fever, headache, neck stiffness, nuchal rigidity, meningismus
Vomiting, nausea, photophobia, seizures
Coma, lethargy, stupor, myalgia
Unilateral cranial nerve abnormality
Dilated, non-reactive pupil(s)
Posturing: decorticate/decerebrate
What does a Meningoencephalitis panel screen for?
Herpes Simplex Virus 1/2
Lymphocytic Choriomeningitis Virus
California Serogroup Viruses
West Nile Virus
Eastern and Western Equine Encephalitis Virus
St. Louis Encephalitis Virus
What are the the expected CSF findings in a viral meningitis infection?
Pleocytosis with lymphocyte predominance (neutrophils may predominate early)
Pressure: 200-250 mmHg (higher)
WBC: 100-1000/mL (<5)
Increased protein
Decreased or normal glucose
Negative gram stain or culture
What type of cells are most dominantly present in cases of viral meningitis?
Lymphocytes (neutrophils may predominate early)
What are the the expected CSF findings in a bacterial meningitis infection?
Pressure: 100-200 mmHg (80-180)
WBC: >1000/mL
Neutrophil predominance (80%)
Gram stain positive 60-90%
Protein: <200mg/dL (15-60)
Glucose: <40 mg/dL (45-80)
What type of cells are most dominantly present in cases of bacterial meningitis?
High WBCs, predominately Neutrophils
What is the most common cause of viral meningitis?
Enterovirus (includes Coxsackievirus, echovirus, etc)
What are the California serogroup viruses?
Belongs to the Bunyaviridae family
La Crosse virus
California encephalitis virus
Jamestown canyon virus
Snowshoe hare virus
What is distinct about the detection of California serogroup viruses?
Not recoverable in CSF during acute phase
What are the characteristics of encephalitis due to a measles (Paramyxoviridae family) infection?
Insidious onset of personality change
Poor school performance
Progressive intellectual deterioration
Development of myoclonic jerks (periodic muscle spasms)
Motor dysfunctions
What are the unique characteristics of chronic encephalitis due the measles?
Subacute sclerosing panencephalitis (SSPE)
Occurs about 7 years after infection with measles, mainly in those infected before 2yo
Meningitis most commonly occurs in mumps infections (Paramyxoviridae family) when what other symptoms are present?
Occurs in 1-10% of cases that also present with parotitis (which is 30-40% of all mumps infections)
Cases without parotitis are indistinguishable from other viral meningitis cases
What are the characteristics of meningitis due to Lymphocytic choriomeningitis virus (LCMV)?
Uncommon infection
Lasts 1-3 weeks, but 15% have biphasic symptoms with meningeal signs and more prominent headache in second phase
How does meningitis due to HIV infection usually present?
Initial infection is symptomatic in 40-90% of cases, but often overlooked
Usually a mono-like syndrome
May present as aseptic meningitis, or less commonly as an encephalitis or cranial nerve palsies
How is viral encephalitis best detected?
MRI (shows better than meningitis infections)
What is the most common cause of viral encephalitis?
HSV
What are the symptoms of HSV induced viral encephalitis?
Altered consciousness >fever >headache >disorientation >behavior or personality changes >seizures
What distinguishes the strains of HSV that cause viral encephalitis?
HSV-1 more likely in sporadic encephalitis
HSV-2 more common in recurrent benign lymphocytic meningitis
What are the unique characteristics of viral encephalitis caused by West Nile Virus?
50% of cases show neutrophil predominance in CSF instead of lymphocytes
Unique symptoms (20-40% of cases) include: tremors, parkinsonism, and myoclonus
Can cause poliomyelitis like paralysis
St. Louis encephalitis virus is most likely to cause encephalitis among what demographic?
Predominant in those over 60yo
In younger, meningitis is almost just as common
What is a common complication of St. Louis encephalitis virus?
Seizures occur in 47% of patients
What are the characteristics of encephalitis caused by Eastern/Western encephalitis virus
Prodrome (malaise, fever, chills, myalgias) is followed by recovery or encephalitis symptoms
Mortality is 33% (EEEV) except in those over 60 (50%)
Western disease is more mild than Eastern
How does Rabies virus infect humans?
Animal bites introduce virions in saliva which invade motor & sensory nerves
How long does Rabies virus lay dormant?
Can incubate anywhere from 7 days to greater than 6 years (median is 1-2 months)
What are the characteristics of “furious” rabies?
80% of cases
Hyperactivity with hydrophobia and aerophobia due to spasms of pharyngeal and nuchal muscles
Spasms increase followed by hallucinations, agitation, autonomic hyperactivity, and seizures
Body temp may be as high as 107
What are the characteristics of “dumb” rabies?
20% of cases
Paresthesias, weakness, and flaccid paralysis in the bitten limb
What is abortive poliomyelitis?
Nonspecific febrile illness caused by poliovirus for 2-3 days without CNS involvement
What are the symptoms of asceptic meningitis due to poliovirus (nonparalytic poliomyelitis)?
Signs of meningeal irritation (stiff neck, pain and stiffness in the back) in addition to the signs of abortive poliomyelitis
Rapid and complete recovery within a few days
How does paralytic poliomyelitis progress (usually less than 2% of the infections)?
Starts as a minor illness followed by signs of meningeal irritation along with asymmetric flaccid paralysis with no significant sensory loss
In severe cases, all four limbs may be paralyzed, involvement of respiratory muscles is life threatening
Recovery of affected neurons may take as long as 6mo
Severity increases with age at infection
What are the basic problems with transplantation therapy?
Transplants must be introduced to allow them to perform normal function, health of recipient and transplant must be maintained during surgery, recipient immune system must be prevented from developing adaptive immune responses to antigens on grafted tissue
What are the hallmark of successful transplantation?
Matching the tissue type between donor and recipient
Successful suppression of the recipient’s immune system to inhibit response to the grafted organ or tissue
What is an autograft?
A graft from one part of the body to another location on the same individual
What is an isograft?
A graft between genetically identical individuals (identical twins)
What is an allograft?
A graft from a genetically dissimilar donor to a recipient of the same species
What is a xenograft?
A graft from a donor of another species
What is an allorection?
Refers to the immune reactions provoked by the alloantigen
What is an alloantigen?
Refers to an antigen that differs between members of the same species (e.g. HLA molecules and blood group antigens)
What are minor histocompatibility antigens?
Allelic forms of normal cellular proteins that happen to be different between donor and recipients; these non-MHC antigens can also induce graft rejection
What is most commonly responsible for allograft rejection?
HLA (MHC) mismatching is generally most important
However, multiple minor histocompatibility mismatching can be as severe as HLA mismatching
Which MHC mismatching causes the most severe rejection in transplants?
Mismatching of MHC II (HLA-DQ, DP, DR) often causes more rapid and severe rejection than mismatching MHCI (HLA-A, B, C)
Which major HLA are considered for matching?
HLA A
HLA B
HLA DR
Which blood group only has the core structure and therefore are considered universal donors?
O blood group
Which blood group has both antigens and therefore can only be given the same blood group or the O blood group?
AB blood group
How are gut bacteria involved in the production of blood group antibodies?
Gut bacteria bear antigens that are similar or identical to the blood group antigens which stimulates the production of Ab against these Ag
What is a cross-matching test?
Refers to a method of direct assessment of reactivity between recipients serum and donors blood cells
How is tissue typing done via serology?
Microcytotoxicity test or lymphocyte cross-matching: patient’s serum is cross-matched with potential donors lymphocytes
Tests all HLA loci
How is tissue typing done via DNA or molecular techniques?
Via PCR
Tests all HLA loci
How is tissue typing done via mixed lymphocyte reaction/response?
Done with in vitro culture containing blood leukocytes from both donor and recipient
For DR (DQ, DP) molecules
Hyperacute rejection of transplantation is comparable to what type of hypersensitivity?
Type III
Immune complex deposition cause complement activation in blood vessel wall
What can causes hyperacute rejection of transplantation?
Preexisting antibodies against A, B, O or HLA antigens in the recipient’s serum
How might someone gain pre-formed anti-HLA Abs?
Generation from pregnancy, blood transfusions, or previous tranplantation
Acute rejection of transplantation is comparable to what type of hypersensitivity?
Type IV hypersensitivity
Mediates acute rejection via generation of alloreactive effector cells dependent on whether they are presented by MHCI or MHCII
What is allorecognition?
Recognition of the alloantigen by the recipient’s T cells in a direct or indirect fashion. Seen in acute rejection of transplantation
What is direct allorecognition?
HLA Ags presented on the donor APC interacts w/ CD4 and CD8 T cells
What is indirect allorecognition?
Membrane fragments of dead donor APCs are endocytosed by the recipient’s APC, presents peptides to CD4 T cells only by the recipient’s MHC-II APC
How do CD4 alloreactive cells cause transplant rejection?
They migrate in blood to the graft and activate macrophages to exacerbate the inflammation
How do CD8 alloreactive cells cause transplant rejection?
They migrate in blood to the graft and attack the cells in the transplanted tissue directly
How is acute rejection development significant when it comes to treatment?
Develops over a period of days and therefore, unlike hyperacute rejection can be reduced or even prevented
What causes chronic rejection of transplantation?
Likely due to the indirect pathway of allorecognition
Recipient dendritic cells process the internalized allogenic HLA and present them to CD4 T cells
Helper T cells get activated which then activate B cells
Results in anti-HLA 1 and 2 Ab production
How does chronic rejection of transplantation manifest?
Develops over a period of months to years
Thickening of vessel walls and narrowing of their lumina
Develops into ischemia and loss of function followed by death
What corticosteroid is most commonly used for transplant patients?
Prednisone
Needs to be converted to prednisolone to be active
Must be combined with others to prevent graft rejection
What is the MoA of prednisone?
Binds to hsp90 in the cytoplasm
Receptor binding induces release of hsp90
Receptor/steroid complex enters nucleus and binds to selective genes to induce transcription
What are the effects of prednisone?
Inhibits inflammatory mediators
Inhibits inflammatory cell migration
Promotes apoptotic death of leukocytes, including lymphocytes
What is the MoA of Azathioprine?
A cytotoxic pro-drug, must be converted to 6-thioinosinic acid which inhibits inosinic acid, an intermediate in the biosynthesis of adenine and guanine
Ultimately inhibits DNA replication
What are the effects of Azathioprine?
Damages all the tissue of the body normally active in cell division, especially bone marrow, intestinal epithelium, and hair follicles
What is the main concern in using Azathioprine as a cytotoxic immunosuppressant?
Hepatotoxicity
What is the MoA of Cyclophosphamide?
A cytotoxic pro-drug with a metabolite that alkylates and cross-links DNA molecules
Affects normal cell division and transcription
Very toxic to the urinary bladder
What is Cyclophosphamide used for?
Both pre- and post-transplant patient therapy
Used as an alternative to methotrexate
Cyclophosphamide has what significant side effect?
Very toxic to the urinary bladder
What is the drug of choice for inhibiting GVHD in bone marrow transplant patients?
Methotrexate
What is the MoA of Methotrexate?
Prevents DNA replication by inhibiting dihydrofolate reductase essential for thymidine synthesis
What is Cyclosporin?
Derived from a soil fungus, inhibits T cell activation by antigens by disrupting transduction of signals from TCR resulting in inhibition of IL-2 production and subsequent shut down of the activation, proliferation, and differentiation of T cells
What is Tacrolimus?
Derived from soil actinomycetes, suppresses T cell activation by a similar mechanism as that of cyclosporine (inhibiting IL-2 production to prevent T cell activation)
What is Rapamycin?
Isolated from a soil bacterium, inhibits T cell activation by preventing signal transduction from IL-2 receptors
What are the antibodies specific for T cells?
Antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) are prepared from animals’ blood
Abs can also be prepared from hybridoma cell line which produce mouse monoclonal Abs specific for proteins present only on T cell surfaces such as CD3
Bone marrow transplantation is most commonly prescribed for what?
SCID
What hematopoietic diseases are treatable with bone marrow transplant?
SCID, Fanconi’s anemia, thalassemia major, sickle-cell anemia
How is the preparative phase for bone marrow transplant different from solid organ transplants?
The entire immune system will be affected by transplant and therefore, the whole hematopoietic system, including immune system is ablated by combined radiation and immunosuppressive drugs
Referred to as myeloablative therapy
What is the purpose of myeloablative therapy?
Prevents rejection of graft cells by recipient T cells
Provides room for the transplanted stem cells to interact with bone marrow stromal cells in BMT
What is required for a successful bone marrow transplant?
The donor and recipient should have at least one HLA class I and one HLA class II allotype in common (more is better)
What causes Graft-versus-Host Disease?
Mature T lymphocytes in donor bone marrow recognize tissues of the new host as foreign and cause a severe inflammatory disease in the recipient
What are the symptoms of acute GVHD?
A rash
Diarrhea
Pneumonitis
Liver damage
What is characterized by chronic GVHD?
Fibrosis and atrophy of one or more of the same organs without evidence of cell death
If severe, can lead to complete dysfunction of the affected organ, may be fatal
How does the skin rash seen in bone marrow transplant BMT present?
Often starts at the face and neck and then spreads to involve the trunk and limbs
A bright red rash that characteristically involve the palm and sole
The rashes may cause severe pruritis
May be accompanied with fever
What is histologically distinct in skin rashes in BMT?
In early GVHD, lymphocytes emerging from blood vessels adhere to the basal layer of epidermis
The basal cells of the epidermis begin to swell and vacuolate; their nuclei become condensed as these cells die
What is characteristics about GI disturbance in GVHD?
Appears after skin manifestation
Causes watery diarrhea
How is the liver affected in GVHD?
Infiltrated with inflammatory cells, causes liver enzymes to rise
What are the different grades of skin rashes in GVHD?
I: maculopapular rash on <25% of body
II: maculopapular rash on <25-50% of body
III: generalized erythroderma
IV: generalized erythroderma with bullous formation and desquamation
What are the different grades of liver damage in GVHD?
Based on serum bilirubin
I: 2-3 mg/dl
II: 3-6 mg/dl
III: 6-15 mg/dl
IV: 15 mg/dl
What are the different grades of GI disturbance in GVHD?
>500 ml diarrhea/day
>1000 ml diarrhea/day
>1500 ml diarrhea/day
Severe abdominal pain with or without ileus
Who are the best possible donors for BMT?
HLA identical siblings
Why do some HLA identical siblings still develop GVHD?
Occurs particularly in males who receive from sisters. If the specific HLA molecule is on a male-specific Y chromosome, the sister T cells cannot be toleran
What are minor histocompatibility antigens?
Alloantigens in which the allogenic difference is due to the bound peptide and not due to MHC molecule are called minor histocompatibility antigens
Encoded by minor histocompatibility loci
How can minor histocompatibility antigens precipitate GVHD?
Self-proteins are routinely digested by proteosomes within the cells cytosol. These proteins are presented on the surface in the context of MHC molecules
If a polymorphic protein differs between the graft donor and the recipient, it can give rise to an antigenic peptide that can be recognized by recipient’s T cells as non-self and elicit an immune response
How does GVHD impart a beneficial effect on leukemia patients?
Removal of T cells from the bone marrow graft in the treatment of GVHD leads to increased rates of graft failure and particularly, with cancer, a high incidence of recurring of disease
Called graft-versus-tumor or graft-versus-leukemia effect
What is the purpose of autologous bone marrow transplants?
Designed to help patients clinically eligible for BMT unable to find a suitable HLA-matched donor
What are autologous bone marrow transplants?
Samples of patients own bone marrow are taken before the remainder is destroyed by irradiation and immunosuppressive therapy
The stem cells are separated from the tumor and other cells and are reinfused to the patient
What are the limitations of autologous bone marrow transplants?
Frequent relapse of cancer compared to allogenic transplant
What is a hematopoietic stem cell transplant?
Donor is treated with G-CSF and GM-CSF to mobilize hematopoietic stem cells to the peripheral blood from the bone marrow
Leukocytes are selectively removed from the blood by a process called leukapheresis where the CD34 positive stem cells are isolated and used as transplant
The other source of hematopoietic stem cells is umbilical cord cells obtained from placenta after birth
How many cells are required to perform a hematopoietic stem cell transplant?
0.25 to 0.5 billion cells are required for prompt engraftment after transplantation
What are the Transmissable Spongiform Encephalopathies (TSE)?
Creutzfeld-Jakobs Disease (CJD)
Bovine Spongiform Encephalopathy (BSE)
Kuru (humans), scrapie (sheep)
Chronic wasting disease (CWD)
What are normal, healthy prions (PrPc)?
Product of PRNP gene on chromosome 20
Glycoprotein anchored to cell membrane
Well-conserved in most mammalian species
Predominantly expressed in neuronal cells
What is the function of normal healthy prions (PrPc)?
Maintenance of neuronal integrity in the brain
Possible role in Cu metabolism & cellular response to oxidative stress
What are the characteristics of aberrant PrPsc?
Resistant to proteolysis
Insoluble in nondenaturing detergents
What how are aberrant prions (PrPsc) formed?
Conformation change from a predominantly ?-helical structure to predominantly ?-sheets
Endogenous PrPc interacts with PrPsc, converts PrPc to PrPsc, can begin spontaneous generation
What are the symptoms of prion disorders (Transmissable Spongiform Encephalopathies)?
Personality changes, depression
Lack of coordination – jerky movements
Insomnia, confusion, memory problems
Severe mental impairment and inability to move or speak in later advanced stages
Vacuolization of neuronal cytoplasm results in sponge-like appearance of brain parenchyma
What is Kuru?
Restricted to the highlands of New Guinea
Ritualistic cannibalism lead to spreading of spongiform encephalopathies (prion diseases) due to brain tissue being highly infectious
What is the most common parasitic infection of the CNS?
Toxoplasma gondii
How is Toxoplasma gondii most commonly contracted?
Ingestion of tissue cysts in undercooked meat
Primary hosts are cats
What are the 3 infectious stages of Toxoplasma gondii?
Tachyzoites (rapidly multiply in any cell, see in acute infection, released when organism is ingested)
Bradyzoites (found in tissue cysts, multiply slowly in chronic stages)
Sporozoites (found in oocysts, shed in feces)
What type of people are more susceptible to Toxoplasma gondii infection?
Immune response normally neutralizes and removes tachyzoites
Immunocompromised at heightened risk, can cause necrotizing encephalitis
What are the symptoms of Toxoplasmosis?
Fever, malaise, night sweats, sore throat
Retroperitoneal & mesenteric lymphadenopathy
Chorioretinitis
CNS disease in 50% of infected immunocompromised patients
What are the complications of congenital toxoplasmosis?
Severe if maternal infection occurs early in pregnancy
May cause CSF pleocytosis & elevated protein levels
Microcephaly
Affected survivors may have mental retardation, visual defects, seizures
What is the deadliest complication of Plasmodium falciparum (malaria)?
Cerebral malaria
The major cause of death from malaria
What are the symptoms of cerebral malaria?
Encephalitic syndrome
Ataxia, seizures, hemiplegia, coma, death
Parasitized RBCs are sequestered in the cerebrum, cerebellum, and medulla oblongata, causes compensatory vasodilation, increased brain volume
Cerebral malaria patients who have undergone successful parasitic treatment can still retain what negative effects?
Can still retain residual neurological damage
Memory, learning, and language impairments
Visuospatial and motor deficits
Psychiatric disorders
Describe the life cycle of Plasmodium falciparum
Travel to the liver, replicate into merozoites
Merozoites leave the liver and invade RBCs
Continue to replicate, lyse RBCs, and invade other RBCs
Cycle continues when mosquitos bite an infected human
What causes RBC Rosettes? What are they?
RBC rosette-forming P. falciparum
Parasitized RBC surrounded by 3 or more uninfected RBCs
Interaction appears to be mediated by knobs seen on the parasitized RBC
What is Naegleria fowleri?
Thermophilic, free-living amoeba seen in waterways contaminated by thermal discharge of powerplants, heated swimming pools, hot springs (up to 45degC)
Inhabits fresh water ponds, lakes, rivers
How does Naegleria fowleri cause primary amebic meningoencephalitis (PAM)?
Amebic-contaminated water enters the nose during activities such as swimming
Migrates to the brain through the olfactory nerve from the olfactory mucosa
Rare, but nearly always fatal infection
Symptoms arise around 2-3 to up to 7-15 days after infection
What are the symptoms of amebic meningoencephalitis (N. fowleri)?
Early symptoms: Upper respiratory distress, headache, lethargy, olfactory problems
Sore throat, stuffy, blocked, or discharging nose, severe headaches
Pyrexia, vomiting, stiffness of neck are also possible
Mental confusion, coma occur about 3-5 days before death
Symptoms indistinguishable from bacterial meningitis
What is the most common cause of death due to amebic meningoencephalitis (N. fowleri)?
Cardiorespiratory arrest and pulmonary edema
Describe the pathophysiology and virulence of Naegleria fowleri
High oxygen content of CSF and brain tissue enhances growth due to containing mitochondria
Ingests RBCs and brain tissues to cause severe hemorrhagic necrosis, produces an amebostome (food cup) and secretes lysosomal hydrolases and phospholipases
Produces and secretes heat stabile hemolytic proteins, heat-labile cytolysin, phospholipase A, cysteine protease
Presence of protein and glucose in CSF supports N. fowleri
How is Naegleria fowleri diagnosed?
Spinal tap ASAP shows:
Elevated protein
Normal or slightly reduced glucose levels
WBC high (400-26000/?L)
RBC high
Wet mount positive for motile trophozoites
Smears can be stained using Wright’s/Giemsa stain
How is Naegleria fowleri treated?
Early diagnosis is essential due to rapid course of infection
Near immediate chemotherapy is essential for survival
What is the characteristic feature of Acanthamoeba?
The presence of spine-like pseudopods called acathapodia
How are Acanthamoeba infections contracted?
Primary entry sites are the skin and lungs
Usually repelled using humoral immunity and complement activation
Patients tend to have no history associated with exposure to recreational freshwater
What are the consequences of unsuppressed Acanthamoeba infections?
Causes granulomatous amebic encephalitis (GAE)
Primarily in immunosuppressed or chronically ill patients
Route of invasion is believed to be hematogenous
Causes CNS lesions with trophozoites and cysts
What are the risk factors for granulomatous amebic encephalitis (GAE) due to Acanthamoeba infection?
Chronically ill, immunologically impaired,
Malignancies, SLE, HIV, Hodgkin’s, DM
Infections are associated with trauma and underlying disease
What is Trypanosoma brucei gambiense?
West African trypanosomiasis
Exclusively human reservoir
Slow-progressing that can be self-limiting or develop into a chronic disease involving the CNS and lymphatic system
What is Trypanosoma brucei rhodesiense?
East African (or Rhodesian) trypanosomiasis
Zoonotic disease (animal reservoir)
Rapidly progressing disease
What are kinetoplastids?
Potentially infectious mitochondrial DNA (?)
Describe the progression of African Sleeping Disease (Trypanosomiasis)
1-2 wk incubation period
Acute blood stage: fever, headaches
Invades lymphatics, causes lymphadenopathy, weight loss, weakness, rash, itching, intermittent febrile attackes
Relapses due to antigenic variation of trypanosomal surface
Nervous System Impairment: 6-12mo w/ gambiense, w/in weeks w/rhodesiense
What happens when Trypanosomes (African sleeping disease) crosses the blood brain barrier?
Meningoencephalitis
Apathy, fatigue, confusion, motor changes (tics, slurred speech)
Changed sleep patterns: Extreme fatigue during day, extreme agitation during night
If untreated, can progress to coma or death
Taenia solium is most commonly contracted through what means?
Eggs ingested from poorly cooked pork, hatch in the stomach
What are the symptoms of neurocystercercosis?
Larvae attach either to brain tissues or the cavities through which the brain fluid flows, develop into cyst-like structures
Seizures, altered mental states, headache, nausea, dizziness, can block flow of brain fluid
How does Taenia solium avoid the immune system?
Brain not easily accessible to immune cells due to the BBB
Cysts are able to degrade antibodies made to it
Produces protein signals that inhibit phagocytosis
What is Echinococcus granulosus? How is it contracted?
Zoonotic tapeworm infection
Dogs are the definitive hosts, humans are accidental, intermediate hosts
Eggs are ingested and hatch in small intestine
High risk: own/live with dogs used to herd sheep
Transmission enhanced by feeding dogs raw viscera of slaughtered livestock
How does Echinococcus granulosus progress?
Eggs hatch, penetrate gut wall, and enter circulation
Larvae can be distributed almost anywhere in the body. Most common site is the liver but brain can be infected as well
Develop into hydatid cysts over about 5 months
What are the characteristics of hydatid cysts (Echinococcus granulosus)?
An outer, friable, nonnucleated layer
And an inner, nucleated germinal layer
Daughter cysts bud off from the inner germinal layer
Later detach and float in the interior of the fluid filled cyst
Organized as unilocular cysts
How is Echinococcus granulosus treated?
Surgical removal if cysts are accessible
Cysts injected with anti-protoscolicidal agent to reduce chance of leakage of anaphylactogenic or infectious contents during surgery
Sensitive to Praziquantel
What is the most common cause of human eosinophilic meningitis?
Cerebral Angiostrongyliasis (Angiostrongylus cantonensis)
How are Angiostrongylus cantonensis infections contracted?
Human infection due to accidental ingestion of infective larvae
Slugs, snails, raw fish, amphibians, reptiles, crustaceans, seafood
Vegetables contaminated with larvae
Infected water
Oral contact with hands contaminated with mollusk larvae
Sometimes through the skin
What are the symptoms of Cerebral Angiostrongyliasis?
Due to presence of larvae in the brain and the host response
Severe headaches, convulsions, weakness of limbs, facial paralysis, neck stiffness, fever
Vomiting, constipation, anorexia, nausea
Pulmonary symptoms usually absent
Sometimes, ocular invasion
Incubation period approximately 20 days
How is Cerebral Angiostrongyliasis diagnosed?
CSF analysis shows
Elevated pressure
Elevated protein levels
Presence of leukocytes: 100-2000/mm3
Eosinophilia
Often peripheral eosinophilia with moderate leukocytosis
Larvae, or young adult worms can be recovered in the CSF
Elevated IgG, IgA, IgM, IgE
CT scan shows brain lesions
What is Cryptococcus neoformans?
Encapsulated yeast-like fungus
Under certain environmental conditions, is capable of forming mycelia
Usually grows as a yeast with a prominent capsule
Found in soil contaminated with pigeon droppings
Most common clinical form is meningoencephalitis
What are the virulence factors of Cryptococcus neoformans?
Polysaccharide capsule
Ability to grow at 37 degC
Phenol oxidase enzyme prevents formation of toxic hydroxyradicals and oxidative stress
What are the symptoms of meningoencephalitis due to Cryptococcus neoformans?
Antigen in the CSF can potentially change the osmolality affecting flow and absorption
Increases intracranial press
Headaches, vision loss, early death
What is Coccidioides immitis infection (coccidiodomycosis) and how is it contracted?
True, systemic mycosis Acquired by inhalation – dry arthroconidia carried by dust storms Related to activities involving tillage of soil (agriculture, archaeology, telephone post digging) Seen in the southwest US, thrives in warm, dry soils Initially presents as a pulmonary infection that can disseminate to other organs
What are the symptoms of CNS disseminated Coccidioides immitis (coccidiodomycosis)?
Chronic granulomatous meningitis in the basilar meninges, cerebral and cerebellar abscesses, headache, nausea, vomiting, altered mental status Intense immunologic rashes when disseminated
What is the most lethal form of coccidioidomycosis?
Dissemination to the CNS causes chronic granulomatous meningitis (basilar meninges), cerebral and cerebellar abscesses. Causes headache, nausea, vomiting, altered mental status
What are Tumor-Specific Transplantation Antigens (TSTA)?
Unique to tumor cells and not expressed on/in normal cells
Responsible for rejection of tumor
What are Tumor Associated Transplantation Antigens (TATA)?
Antigens expressed by both tumor and normal cells
May have higher expression in tumor cells or may be cease expression by normal cells as adults and re-expressed in tumors
Which tumor antigen is considered a product of mutated genes or oncogenic virus genes?
Tumor-Specific Transplantation Antigens (TSTA)
Which tumor antigen is considered to be a product of abnormal expression of normal genes?
Tumor Associated Transplantation Antigens (TATA)
Tumor Associated Transplantation Antigens (TATA) are composed of what normally expressed antigens?
Oncofetal antigens
Altered glycolipid and glycoprotein antigens
Tissue-specific differentiation antigens
What is the consequence of gene mutations producing new antigens?
A change in the sequence changes what peptides can be presented. This can also be caused by oncogenic viral infection
Papilomavirus has been linked to the development of which associated tumors?
Benign warts
Carcinoma of the uterine cervix
HBV has been linked to the development of which associated tumors?
Liver cancer/hepatocellular carcinoma
EBV has been linked to the development of which associated tumors?
Burkitt’s lymphoma
Nasopharyngeal carcinoma
B-cell lymphoproliferative disease
HIV and HHV8 have been linked to the development of which associated tumors?
Kaposi’s sarcoma
What is the consequence of expression of fetal proteins in tumor cells?
Allows the presentation of peptides the majority of the immune system has never seen
How many MHC:peptide complexes are required on a target cell to activate a T cell?
10-100 identically loaded MHC;Peptide complexes
Without a costimulatory receptor (CD4 or CD8), it would take 10,000
What are tissue-specific differentiation antigens?
Cell surface markers or intracellular proteins/receptors that are found only on/in specific lineages of cells (ex. CD4 on T cells or CD10/CD20 on B cells)
What are the abnormal cell surface antigens continually secreted by most human tumors?
Gangliosides (GM2, GD2, GD3)
Blood group antigens
Mucins
What abnormal markers are recognized by NK cells?
Altered cell-surface glycoproteins
Loss of class I MHC
Bound antibodies
How do NK cells facilitate killing targeted cells?
Release of cytotoxic granules
Activation and killing by NK cells is dependent on what factor?
The extent of inhibitory and activating receptors being used. If there are more activating than inhibitory, the NK cell will be activated
What are the different protein families of NK cell receptors?
NKG2 family (6 members): A and B are inhibitory, C and D are activating
Ly49 family: A and G are inhibitor, D and H are activating
What abnormal markers are recognized by macrophages?
Bound antibodies
Receptor interactions such as NKG2D receptor expression
How do macrophages facilitate the killing of targeted cells?
Phagocytosis
Production of NO
How do actively replicating tumor cells continue to mutate while growing in number?
Each round of replication increases mutations
Mutations that increase growth or are silent propagate
Mutations that are incompatible with replication lead to apoptosis and engulfment by phagocytic cells
What is recognized by CD8+ T cells?
Tumor antigens presented in class I MHC
How do CD8+ T cells facilitate the killing of targeted cells?
Release of cytotoxic granules
Fas receptor ligation
What is the mechanism of recruitment by Regulatory T-cells (Treg)?
Tumor expressed chemokines (CCR4-9)
How do Regulatory T-cells cells suppress tumor cells?
Production of TGFb and IL-10
What is the mechanism of recognition by B-lymphocytes?
Cell surface tumor antigen, requires T cell help
How do B-lymphocytes facilitate the killing of targeting cells?
ADCC, antibody dependent cell mediated cytotoxicity
Compliment activation
What is the function of TLRs?
Can provide additional co-stimulation to T cells TLR-9 is downregulated by the tumor microenvironment and chronic viral infections
How do tumors employ tolerance?
Most tumor cells do not express co-stimulatory receptors needed to activate CTLs
Lack of signal 2 induces anergy or death by T cells
Most tumor antigens are self or subtly modified (mutated) self proteins, are negatively selected against
What is the role of CD4+ CD25+ autoreactive T cells?
Act to inhibit the activation of other autoreactive T cells, significantly involved in controlling tumors
How does the loss of Class I MHC help tumors evade the immune system?
Loss of Class I MHC is positively selected for by protecting the cell from CTL killing
Tumors often lose expression from non-vital genes due to rapid mutations and selection by the immune system
How does the immune system respond to the loss of MHC Class I on tumor cells?
Cytotoxic T-lymphocyte killing falls
NK-cell killing rises
However, this is not sufficient to control tumor growth, CTLs must be active
What mediates the loss of tumor antigens by tumor cells?
Loss of any protein is positively selected for if it is not essential for growth and is being responded to by the immune system
Tumors often lose expression from non-vital genes due to rapid mutations
What are the properties of an “optimal tumor antigen”?
Homogenous expression through the tumor Minimal or no expression on normal tissues High expression levels on tumors Activity in immune repertoire Surface expressed and not shed Plays a role in tumor progression****
How do tumor cells modulate their local microenvironment?
Some may secrete TGF-Beta or other immunosuppressive factors. Some may express the FasL to kill off tumor specific CTLs
What are exosomes?
Rather than being destroyed within lysosomes, membrane receptors fuse with the plasma membrane and releases exosomes
A very common signaling system in the body
What cells can release exosomes?
Mast, T, B, and Dendritic cells
Intestinal epithelial cells
Macrophages
Tumor cells*
What is the consequence of tumor cells releasing exosomes?
Causes systemic effects whereby the immune system becomes more tolerant of the tumors cells or initiating apoptosis by secreting FasL
How do macrophages participate in chronic inflammation
Releases factors that promote angiogenesis and tissue remodeling
Also promotes DNA damage (oxygen free radicals)
Both of these processes can encourage the growth of tumors or cancer inducing pathogens such as HBV or H. pylori
What is tumor vaccination?
Dendritic cells from patient are removed and “loaded” with tumor antigens, then returned
You can also use a plasmid that will express a tumor antigen. Dendritic cells from a patient are transfected with the same plasmid before return
How can tumor responses be augmented?
Tumor cells are removed and forced to express immune modulating genes or costimulatory receptors, then returned
How are inhibitory pathways blocked in order to combat tumor cells?
Normal pathways that are used to inhibit or down-regulate an immune response include CD152/CTLA-4
Antibodies are injected to block this receptor, allowing the immune system to respond to the tumor (self)
Essentially initiates auto-immunity
What is non-specific immune stimulation?
Antigen non-specific stimulators of the immune system are injected in the tumor
ex. Cytokines, BCG, Anti-CD3 antibodies
Causes severe side effects
What are the different types of passive immunotherapy?
Adoptive cell cultures
Graft-vs.-Leukemia reaction
Anti-tumor antibodies
What are adoptive cell cultures in passive immunotherapy?
Lymphocytes are removed, activated by non-specific tumor antigens, expanded in vitro, then returned to patient
Creates Lymphokine-activated killer cells
What is a Graft-vs.-Leukemia Reaction in passive immunotherapy?
Alloreactive T cells are administered along with stem cell transplants
Causes death of B cells in the process
What are anti-tumor antibodies in passive immunotherapy?
Antibodies to tumor cell markers are injected to induce humoral immunity
What is leukapheresis?
Blood is removed, partly separated, with the bulk of the blood returning to the patient. The collected blood containing immune cells will be manipulated to increase their cancer-killing ability before being returned to the patient

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