Baselski 2

Baselski 2

Beginning of each lecture-“concept” determines objectives. Be able to discuss in essay. She asks questions about examples of infections where immunopathology is important. She wants examples of how hypersensitivities cause tissue damage.

This the lecture she likes most. Least concrete information.All new. Where we are going identifying causes of disease. 1st lecture laid stage for how host can turn on itself. Defined how components of the immune system can cause damage. Today- chronic diseases caused by infection. Difficult to make association and difficult to interpret data used to make associations.
3
CDC focus heart disease, hypertension, etc in “chronic disease”.
4
She draws on these- look at them. “triggers” to emphasize that disease may not have strict cause and effect, but disease sets up condition.
There are data to support her assertions today.
5
ASM report-3 mechanisms listed. 1st most important.
2. less common example- polio causes muscle wasting secondary to neuronal damage which is not reparable.
3. Indirect- maternal-fetal diseases. Ex- cytomegalovirus. TORCH syndrome.
She will focus on 1st mechanism.
6
Mechanisms from yesterday reviewed.
Ongoing provokation can cause ongoing inflammation and damage. Can aslo cause oncogenesis thru ongoing inflammation.
Autoimmune mechanisms listed. Directed against cross-reacting/self antigens- molecular mimicry can result in chronic conditions and physical dysfunction with regulatory problems with protein. Adrenal necrosis causes hormone problems.
7
Chronic infectious diseases
Hepatitis B and C oncogenes from viral genome hepatitis B can result in oncogenesis.
CMV in fetus- neurologic sequelae from calcifications in brain.
For 2 sit- HPV and Hepatitis B we have vaccines against agents, which can be considered anticancer vaccines.
8
Bacterial diseases. Tertiary syphilis-no bacteria in sight, but molecular mimicry results in cross reacting immunopathology.
TB is chronic condition due to granuloma formation. Leprosy same.
Chlamydia- agent of infertility from scarring. Organism sets up scarring.
Reiter’s syndrome is complication of gram – bacteria. Triad conjunctivitis, arthritis, urethritis that can last years.
9
Fungal conditions
Ringworm- prolonged inflammatory reactions.
10
protozoans
Chagas disease-cardiac effects. Damages heart for life. Schistosoma- reaction to adults in portal veins- portal hypertension. Can lead to bladder cancer from inflammation.
Taenia solum- huge granulomas in brain.
Filariasis- response to adult forms- lymphatic obstruction and infections.
11
SWAT analogy- prolonged inflammation with organized immune response- something causes it. Common cause- infection. Look for infectious agent when lymphocytes are infiltrating tissue.
12
these conditions have active ongoing research going on.
13
Problems establishing causality. MS may be caused by Epstein Barr viral infection 30 yrs before. PCR may help. You don’t always know what stage of infection causes problems. If disease is latent, very difficult to diagnose. One pathogen may cause more than one chronic disease, or one disease may have more than one trigger. Etiology may be multifactorial (smoking, genetic, etc.)
14
Diagnostic testing is becoming molecular. Can use primers for large groups of organisms to find the organism (whippels)
Representational difference analysis- used to compare small differences to find new organisms.
Microbial and host protein profiles used to look at differences in diseased and healthy individualuals.
Antibodies (as in HCV) can be found in microarray.
15
New agents Identified by molecular techniques.
16
ASM quotes
17
Etiology
Koch’s postulates do not cut it mostly.
18
Postulates listed.
Straightforward cause and effect. Not always the case. Worked for heliobacter ylori.
Look for relative differences.
19
Hill’s criteria. Statistical associations.
20
Relman focuses on dose-response and detection issues for organisms not detected by traditional tecniques. This asumes you will fnd organism at site of effect. If present, mol techs can be useful.
22
Clues
20 listed in ASM report.
Seasonality- disease in cluster.
Some people believe strongly in their theories of causation and will give antimicrobial before they know what organism causes disorder.
If you find T cells at higher level or some specificity in affected individuals, infectious etiology
23
Complex situation. Conditions folllow.
24
Correct spelling to gastroduodenal. Gastrocarcinomas can result.
25
H pylori strains with CagA have potential to get into bloodstream and may affect other parts of body.
26
Chlamydia pneumonia associated with atherosclerosis- causes 15% community acquired pneumonia. Can lead to adult onset asthma and CAD, MI, CVD.Association is confirmed in rabbits and mice.
How association occurs is not clear
27
Organism may injure heart. Organism is obligate intracellular organism. Hitch hiker- other cells become hung up in plaque and exacerbate problem.
Echo- cytokines from injury at another location make atherosclerosis worse.
30
Antibiotic trials for CVD- antibiotics does not prevent first MI.Not introduced at right time. Trying to prevent sequelae. Where to interrupt infection is problem.
Organisms associated with periodontal disease also associated with CVD.
31
GI pathogen and GBS (demyelinating peripheral neuropathy) Certain serotypes are worse and more resistant- the ones that get into bloodstream are associated with GBS. Is a strong association. Not just camphylobacter. Swine flu vaccine caused GBS several years ago.
32
Molecular mimicry is mechanism for provokation of GBS. What to do? We do not know how to treat yet. May be better not to treat. GBS causes ascending paralysis.
33
foodborne diseae. Presence of organism in gut- gut is entry mechanism through lymphatics.
34
IDDM – genetic susceptibility of the individual exists and mouse model confirms.
35
inverse seasonality- Cocksackie virus infection happens in late summer (hand foot mouth disease)- IDDM happens in winter. Takes about 6 months for damage to occur.
PCR detects dose response effect.
36
More evidence. Specific component of the enterovirus induces the immune response through molecular mimicry.
37
SSRNA viruses (simple little things) cause complicated diseases.
Skin condition pityriasis rosea. Chronic fatigue syndrome is a disease in search of infectious etiology- enteroviruses may be one among many causes.
38
Bornavirus- some viruses may be associated with neurological diseases. New RNA virus. Associated with disease in horses. Infects cells non-lytically and lingers despite immune response. Inflammation and virus may cause the neurological disorder.
39
Disrupts dopamine circuits, influences hippocampus and coordination.
40
human evidence
CIC- circulating immune complexes found in bipolar disorder. Some benefits treating with agent for flu virus.
1.5 billion people in world are bipolar?.
41
Other links.
42
Not always successful in finding organism. No matter how hard you try, no mycobacterial conserved sequences are found in sarcoidosis, though the symptoms look the same.
44
Other associations are more successful. New Mycobacterium species are found in chronic obstructive lung disease.
45
Obesity
Associated with adenovirus (close to 50 types) 36 causes obesity in animal models.
46
Other pathogens established in animal models. Infection may change metabolism.
47
MS
Histological symptoms are symptoms of viral infection.
48
Increased antibodies noted 30 years prior to disease. Antibodies directed against EBV found. CSF is cerebrospinal fluid.
49
Most likely mechanism- molecular mimicry.
2 recent articles.
50
lessons to remember.