MM Exam 4 Notes PDF

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Exam 4 Study Guide for Dr. HErtz ...

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Vaccination ●

Unique feature of Adaptive Immunity to protect ind from disease ○ Immunological Immunity ■ 2nd encounter w/ pathogen results in faster, more finely timed response ■ Antibodies produced w/ T cell hep have higher affinity & be of more functional isotype ■ Take advantage when we vaccinate ● Immune system ‘remember’ encounter & respond quickly ■ Vaccination & immunological memory requires active immunity ○ Passive Immunity ■ Antibodies passed naturally (thr/ mother) or artificially to another person (injections)

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Passive Immunity ○ Rely on immune effectors (antibodies) made in another person, animal or cell creature ■ Decreases over time, no memory

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Active Immunity ○ Person’s own immune system generates effectors to protect from diseases ■ Increase over time

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Passive Immunity ○ Transfer antibodies to another person ■ Natural - maternal antibodies passed to fetus thr/ placenta & breastfeeding ■ Artificial - antibodies in human serum (gamma globulin) or from animal ● Given to someone who … ○ Immunodeficient ○ Suffering from infection ○ Bitten by poisonous snake ● Why we collect plasma from those who recovered from Coronavirus

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Monoclonal Antibodies for use in Artificial Passive Immunotherapies can be made in cell culture ○ MUCH better than antibodies raised in vaccinated animals ■ ex) horse or snake venom ○ SAFER then using gamma globulin that is made from sera collected from many donors (risk of disease transmission) ○ mAbs are used ar antivenoms/anti-toxins, therapeutically as pharmaceuticals, as key components of diagnostic test and for MANY differ research lab applications ○ Cell line (hybridoma) produces antibodies of chosen specificity & isotype is created ■ B cell fused w/ T cell ○ Hybridoma immortalized & can be grown indefinitely, in limitless quantities, & can be easily shared w/ other labs ■ -as - mab = monoclonal cancer drug

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Active Immunity ○ Person’s own immune system generated effectors to protect them from disease

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Vaccination (or acquisition of infection induces active immunity) - the person’s own immune system makes effectors that provide protection against disease & usually confere long-term immunity ○ Vaccines stimulate immune system w/ SOMETHING that at min resembles real infectious agent or inactivated form of pathogen ■ In order to stimulate response & have memory

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How Do Vaccines Work ? ○ Inflammation - stimulate dendritic cells to activate … ■ CD4+ Helper T cell so they can activate … ● B cells to produce neutralizing antibodies, which can … ○ Attach to surface of bacteria & prevent them from attaching to tissue ○ Attach to viruses to prevent them from attaching to host cells ○ Bind to toxins so they cannot attach to & affect host cells

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Basis of Jenner’s Smallpox Vaccine ○ Cowpox generates neutralizing antibodies that ‘neutralize’ virus & prevent it from entering cells & replicating ○ All vaccines in use work cause they stimulate production of neutralizing antibodies that block attachment of viruses, bacteria and/or toxins

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Types of Vaccines ○ Attenuated/Modified Live Vaccines ■ Contain LIVE microbes that are active but have been weakened so they don’t cause disease ■ If viral vaccine, virus can actually infect cells, replicate & sometimes be passed to those around them ■ May cause in those who are immunosuppressed, OR if vaccine strain reverts or mutates to disease causing form ● ex) Sabin Oral Polio vaccine ○ Ex live vaccines) - measles, mumps, yellow fever, nasal influenza ○ Inactivated/Killed Vaccines ■ Whole agent vaccines produced w/ whole organisms that have been treated w/ formaldehyde, heat or radiation to inactive them so they can’t replicate ■ Subunit vaccines are produced w/ just the antigenic fragments ■ Often given w/ adjuvant that helps boost immune response ● Adjuvants - stimulate inflammation/activation of innate immunity ○ Subunit Vaccines ■ Use antigenic components of virus ● Parts which you need to raise neutralizing antibodies ■ Antigens can be produced by recombinant DNA tech ● ex) Hepatitis B ○ Toxoid Vaccines ■ Toxins are purified & inactivated w/ Formalin ● Toxoids that are still antigenic ■ Generates antibodies that block binding component ● ex) D tap, Tetanus ○ Conjugate Vaccines (bacteria), capsular polysaccharides ■ Antibodies are generated to polysaccharides in bacterial capsules ● ex) S. pneumonia, N. meningitidis

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Use of Recombinant DNA Technology for production of Vaccines ○ If gene responsible for virulence of virus can be deleted & virus remains viruble, it will be avirulent ○ Avirulent viruses are excellent as vaccines because they cause infection but not disease ○ Can close antigenic proteins to form pathogen & use those in production of vaccine

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Vaccine Schedule ○ 37 shots in first 6 years

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Vaccine Side Effects & Safety ○ Benefits must outweigh risks ○ Typical side effects ■ Mild but annoying ● Inflammation @ site of injection, crankiness, fever ■ Less common, more serious ● High fever, seizures, hives ○ Guillain-Barre Syndrome - autoimmune disease causing temporary paralysis & sometimes permanent nerve damage ■ Also caused by Campylobacter  food poisoning ■ Reports of GBS after 1976 Swine Flu vaccine campaign ○ Autism ? Nope! ■ Many studies have failed to find connection bet/ autism & vaccines ■ Autism rates are also on rise in populations that don’t vaccinate

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Vaccine Refusal ○ Reasons ■ Fear of autism ■ Overwhelm immune system ■ Presence of toxic compounds ● Mercury was removed ● Formalin ● Alum used as adjuvant ■ Unnecessary ■ Personal belief exemptions ■ Previous adverse/allergic reactions ■ Immunosuppressed (live vaccines) ■ Pregnancy ○ Risk ■ Unvaccinated ind may contract preventable disease ● Especially if live in clustered w/ others who aren’t vaccinated ■ Unvaccinated ind pose risk to others who ● Too young ● Cannot be vaccinated for medical reasons ● Did not develop immunity ● Have been vaccinated but have lost immunity over time

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Herd Immunity ○ When enough people are vaccinated, pop is said to have herd immunity ○ Those who are NOT vaccinated are protected by those who are cause they are not around susceptible ind who can get the sick ○ Levels of vaccination required for Herd Immunity for particular disease depends on how contagious disease ■ Measles - very contagious → 95% vaccination rate

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Vaccine Success Stories ○ TWO disease been eradicated cause of successful Vaccination campaigns ○ Smallpox ■ Eradicated in 1980 ● Last case in Somalia in 1977 ○ Rinderpest ■ Eradicated in 2010 ● Viral disease of livestock & wild hooved animals ● Related to measles ● Spread via contaminated water & air ● Killed 90% cattle ○ Will save Africa $1 billion every year

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Vaccine Success ○ Why is smallpox successful ? ■ Effective vaccine ■ No animal reservoir ■ Could easily identify those who are affected ○ Current goal - polio - using oral polio vaccine ■ Vaccination campaigns being met w/ resistance in some areas ■ Must vaccinate EVERYONE cause there can be many asymptomatic carriers of disease ■ Total Polio cases per year ● 94 cased of Wild Polio in Afghanistan & Pakistan ● 104 cases of vaccine derived polio virus (VDPV) in Africa ■ Toal in 2018 ● 33 WPV, 104 vDPV ○ India declared Polio free on March 27, 2014

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Current Goal: Polio Eradication ○ World Polio Day - OCt 24, 2019 ■ WPV2 & WPV3 now eradicated ● Only WPV 1 remains

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COVID-19 is impacting efforts to eradicate Polio & disease threatens to return to areas that have been free of disease

HIV ●

Emergence of HIV ○ Chimpanzees (infected w/ SIV) aer source of HIV ○ Molecular clocks suggest that HIV-1 emerged around 1921 ■ “Cut/Hunter” Theory - hunter cut himself & contracted virus - rare event ● Likely not sexually transmitted @ this time ○ Up thr/ 1960s - colonialism & gender imbalances in cities led to normalization of ‘low - volume’ prositution ■ One woman takes care of couple of men (cooking, cleaning, laundry) ○ Colonia Medicine ■ Massive campaigns to treat people for tropical disease (Sleeping Sickness & Yaws) ● Reuse of needles, poor sterilization ● Stuy of OTHER viruses & archived blood samples suggest HIV-1 from just couple of people could spread at low level thr/ iatrogenic transmission ○ Virus evolves to be sexually transmitted ○ Fall of Colonialism ■ Recruitment of teachers from other places ● including Haiti ■ Poor economic conditions → “high volume” prostitution ○ New economic conditions facilitate spread of HIV-1 ○ HIV believed to have been introduced to Haiti by teacher returning from Africa ■ Americans visiting Haiti for ‘sex tourism” especailly MSM → HIV in MSM (men sex w/ men) in US ○ Spread of HIV in Haiti thr/ Plasma Centers/Apheresis ■ Plasma being sold to rish, developed countries (US & Europe) for production of blood products (gamma globulin, clotting factors) ● → Hemophiliacs in US contract HIV ○ Populations in US w/ high rates of HIV 1. Homosexuals 2. Hemophiliacs 3. Haitians

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Why is there still no HIV Vaccine ○ No one knows what a protective immune response is like or if possible ■ For other viruses causing acute infections: contract virus, generate immune response ■ h

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New Hope: Broadly-Neutralizing Antibodies to HIV ○ Most HIV vaccines have been thr/ clinical trials have failed ■ Attempt to stimulate neutralizing antibodies ■ Mutation rate of HIV is too great ○ Some people infected are elite neutralizers ■ Produce Broadly-Neutralizing Antibodies ● Made during ongoing immune response ● Recognize highly conserved regions of gp120 ● Immunoglobulin variable regions contain ● h

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Resistance to HIV ○ Ind homozygous for a mutant form of CCR5 (delta 32) are resistant to HIV infection ■ About 10% of Caucasians are heterozygous carriers, 1% are homozygous for delta 32 mutation ■ Macrophages/dendritic cells can’t get infected in ind lacking the receptor, so they are resistant to infections ○ CCR5 mutations probably common cause of wild type allele serves as docking point for smallpox virus ■ In time of smallpox epidemics, CCR5 mutations would have conferred some protections & lessened severity of disease ● Why in Europeans ? Cause they were living in cities were smallpox & plague would have been a problem

Tuberculosis (TB) ●

TB ○

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Typically, respiratory disease that causes chronic & often bloody cough, fever, nights sweats, weight loss ■ Can also infect the bones Historically was called “consumption” cause it seemed to consume its victims as the wasted away Believed to have originated in cattle ■ Evidence of Pott’s Disease (TB in vertebrae) in Egyptian Mummies ■ Transmission thr/ contaminated milk used to be common

Mycobacterium tuberculosis ○ Acid-fast bacillus w/ waxy cell wall ■ Not Gram + or Gram ○ Confers resistance to drying, acid, alkali, osmotic lysis & complement deposition ○ Slow growing: 15-20 hours/generation ○ Obligate aerobe, facultative intracellular parasite ■ Can easily live inside of macrophages ○ Spread by aerosols ■ Droplet nuclei expelled during coughing spasms of those w/ active cases can remain suspended for several hours in air ● M. bavis - related organisms, infects cattle & can be can be transmitted thr/ consumption of contaminated milk ● Can also infect other organs & bone marrow ○ Only Active cases are contagious - bacilli are no longer contained in granulomas & are expelled by coughing ■ Transmit organism, on average, to about 20 other people ■ Can be diagnosed by detection of acid-fast bacilli in sputum smears ■ Latent TB is when you are infected but immune system controls organisms & have no symptoms of illness ○ Atbc Resistance ■ Non genetic - bacteria live inside cells & walled off in granulomas ■ Genetic - acquiring resistance to atbt for variety of reasons

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Epidemiology of TB ○ Historically ■ In late 1800s, in US would kill 1% of pop each year ■ Today that would be 200,000 people/yr in CA ● 100,000 in LA county ○ Became treatable in 1950s due to wider availability of atbt ■ Active public health programs greatly reduced # of cases, so programs eliminated ○ As many of 40% of world’s pop are infected ■ Infection does NOT mean you have active disease - when immune system is robust, organism is suppressed ■ 5-10% of those infected will go on to develop active cases ■ 50% of those co-infected w/ HIV will develop active cases → contributes to current epidemic ■ Worldwide: 9 million new cases, 1.5 million deaths in 2013 ● Africa, Asia, India, Russia, China have many cases ○ Those w/ social issues (poverty, prison, alcoholics) & living in communal settings (nursing homes, dorms, prisons) are @ greatest risk

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Host Immune Response in TB ○ Mycobacterium are taken up by alveolar macrophages that patrol airways ■ Macrophages destroy pathogens but … ○ Mycobacterium can survive & grow inside macrophages ■ MTB inhibits fusion of lysosomes containing antimicrobial substances & phagosomes in which they live, resisting killing ○ Macrophages become activated via TLRs ■ TLRs sense generic molecular patterns present in pathogens & lead to activation of trx factor, NF-kB ■ NF-kB turns on expressions of genes of encoding cytokines, leading to inflammation ○ Adaptive Immune response to TB gets initiated & Granulomas form ■ H ■ H ■ H ■ H Virulence Factors in TB ○ No true Virulence Factors ■ Intracellular growth allows MTB to avoid most immune response ■ h Transition from Latent TB infection to Active TB & Disease ○ “Reactivation” refers to conversion from latent infection to active infection ■ Granulomas break down & TB bacilli are released

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Occurs when immune response weakness, such as w/ HIV infection, aging, malnutrition Symptoms of Active Disease ■ Fever ■ Productive cough ■ Weight loss ■ Chest X-ray showing cavitation & shadowing ■ Lung tissue gets damaged resulting in decrease in lung fx & coughing up blood

Treatment of TB ○ Start w/ combination of 4 atbt ■ Isoniazid (INH) ■ Rifampin (RIF) ■ Ethambutol (EMB) ■ Pyrazinamide (PZA) ■ Streptomycin ○ Duration is 6 months - 2 years ○ Multi drug resistant TB (MDR-TB) is resistant to INH & RIF ■ Drugs needed to treat MDR-TB have greatest side effects ○ Extensively Drug Resistant TB (XDR-TB) is resistant to additional drugs ○ DOTs - Directly Observed Therapy TB in US ○ About 10,000 new cases/year ■ ⅔ are foreign born ind ○ About ⅓ of cases are MDR-TB ■ Strains are resistant to more than one first line atbt BCG Vaccine & PPD Skin Test ○ BCG - Bacillus Calmette & Guerin ■ Used very safe vaccine ■ Somewhat effective in preventing infections in kids, but ineffective in adults & in preventing reactivation ■ People vaccinated w/ BCG will test pos in Mantoux skin test with PPD ○ PPD - Purified Protein Derivative ■ Injected under skin of forearm ■ Determines in ind has been previously exposed to MTB ■ Minor reaction (10 mm or less) indicated vaccination w/ BCG or false pos ■ Larger reactions 10-15 mm indicated previous exposure or current infection ■ Those w/ suppressed immunity may gave false neg cause their immune system are impaired

Fungal Diseases ● ● ● ● ●

Rare in healthy ind ○ More those w/ compromised immune systems Often acquired from environment rather than another person Most are subacute (NOT rapid onset) or chronic infections Diagnosed by examining pus, fluids or tissues for presence of fungi Relatively few antifungal drugs available ○ Many are toxic to humans ■ Cell walls don’t have PGN

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Common Fungal Diseases in Humans ○ Superficial diseases ■ Ringworm ■ Candida albicans ○ Systemic Infections ■ Pneumocystis jiroveci ● Causes fungal pneumonia ○ Leading cause of death in people w/ HIV ■ Coccidioidomycosis (Valley Fever) ● H

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Pneumocystis jiroveci pneumonia (PCP) ○ Organism cannot be cultured so little is known ○ Found around world in variety of environments ■ Most people have antibodies by age 4 ○ Considered only mildly virulent since hosts w/ normal T cell fx rarely have disease ○ Causes ne of hallmark infection of AIDS/Uncontrolled HIV but can also occur in immunosuppressed people, premature babies & malnourished ○ May bind to host cells using MSG - major surface glycoprotein ■ MSG can undergo antigenic variation - antigen changes escape immune system ○ Disease presents as diffuse pneumonia ■ 50% will develop non productive cough ○ Alveoli fill w/ fluid & monocytes ○ Patients have difficulty breathing (dyspnea) & have low levels of oxygen & blush color due to lack of oxygen in tissues ○ Treated w/ TMP/SMX (atbt) ■ Sulfa drugs -- attach metabolism over structure

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Coccidioidomycosis (Valley Fever) ○ Named for San Joaquin Valley ■ Found in SW US & Mexico ○ Contracted by inhaling spores that are present in air ■ Especially when windy or soil disturbed ● Outbreaks been associated w/ windstorms ○ Can be mild & resolve on its own (60% of patients) OR severe like pneumonia, TB ○ About 14,000 cases is CA in 2017 ■ Majority over 60

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Pathogenesis Coccidioidomycosis (Valley Fever) ○ Inhaled spores must get past innate barriers of upper respiratory tract ○ Spores germinate in alveoli from Spherule ■ Spores form inside spherule - enlargers until bursts & releases new spores ○ Allows spores to rapidly spread ○ Can spread systemically & produce skin lesions

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Distinguishing “the Flu” from other Respiratory Infections (colds, pneumonia) ○ Influenza - high sudden onset of fever, last 3-5 days, fatigue

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Influenza Virus ○ Enveloped virus ○ Infects humans, swine (pigs), birds & horses ○ Three serotypes ■ Type A - Humans & animals, Pandemic potential ■ Type B - Humans only ■ Type C - animals only ○ New strains (variants) emerge every year ■ 10% pop will get infected each year ■ Pandemics occur about every 30 years

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Transmission of Influenza ○ Primarily thr/ Aerosols ○ Fomites less important ○ Occurs more readily in colder temp (41F) & lower humidity found in Winter ○ Person is contagious about 1 day BEFORE they show symptoms

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Influenza Causes seasonal Outbreaks & Occasional Pandemics

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Influenza Virus Structure ○ Envelope studded w/ two viral proteins ■ Hemagglutinin ■ Neuraminidase ■ 16 differ H’s, 9 different N’s ● Different strains have different combinations ○ HSN1, H1N1 ○ Genome is segmented - 8 segments of ssRNA

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Replication of Influenza Virus 1. Attachment of virus attaches to respiratory cells 2. Entry of virus by endocytosis & release of all RNA that then migrate to nucleus 3. Synthesis - viral enzyme begins making viral proteins which are used to synthesize viral genome 4. Assembly of new viruses assemble @ cell membrane must pick up one of 8 segments of genome 5. Neuraminidase facilitates release of virus by cleaving sialic acid from cell membrane

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Reassortment of Influenza Virus Genome @ Assembly Step ○ Segmented genome of Influenza Virus allows radically differ viruses to be created ○ When new viruses are being made the virus picks up 8 differ virus genome segments ○ When two or more differ influenza viruses infect single cell, new viruses can contain unique combinations of genome segments from the two differ viruses ■ Hybrid of other two

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Antigenic Drift vs Antigenic Shift ○ Antigenic Shift (major mutations → pandemic) ■ Results in major changes to virus (assembly stop) ■ Occurs due to reassortment of segments of influenza virus genomes ● ex) 2009 H1N1 Swine Flu ■ Relatively true ■ Results in completely new strains of influenza that are a ‘hybrid’ of viruses from differ species ■ Emerge abo...