Shared Flashcard Set


I and I Test 1 Week 2
self explanatory
Undergraduate 3

Additional Biochemistry Flashcards










  • aerobic gram negative bacilli (aranged as pairs)
  • cytochrome oxidase positive
  • capable of producing polysacc capsule (mucoid strains)
  • ubiquitous: water, soil, plants, animals
  • pili, alginate, flagella
  • elastases: Las A, B involved in lung injury
  • proteases: complement activity
  • exoenzymes through type III secretion
  • endotoxin (LPS)
  • enterotoxin A Type III secretion and important 
  • risk patients: cystic fibrosis, mech ventilated, burn patients, immuno compomised and vascular cathetars





Exotoxin A



  • disrupts protein synthesis by blocking peptide chain elongation
  • catalyzes NAD-Dependent ADP ribosylation of EF-2
  • same mechanism of action as diptheria toxin
  • causes tissue destruction
  • type III sec?






Pseudomonas Infection

  • pulmonary infection most common
  • mild to severe bilat bronchopneumonia
  • respiratory colonization is common in hospitalized (diagnostic dilemma cause might be benign)
  • high mortality cause of frequent treatment resistance
  • burn wound infection, folliculitis (hot tub folliculitis), osteochondritis (foot or ear from puncture), ear (otitis externa, malignant or not), and eye (corneal inf, and vision loss may occur)  
  • non malignant otitis externa is swimmers ear
  • loves moist environments





Pseudomonas Bacteremia

  • most common in immunocompromised hosts: neutropenic patients, diabetes mellitus, burn patients and hematologic malignancies
  • common sources: pulmonary, urinary tract, soft tissue sources, indwelling catheters
  • endocarditis: IV drug users





Pseudomonas Laboratory Diagnosis

  • grows on typical blood and MacConkey agar
  • oxidase postive
  • non-fermenter
  • fruity odor
  • colony morphology can vary depending on mucoid production





Pseudomonas antimicrobial resistance

  • accumulatse resistance
  • common resistance mech: mutation of porin proteins, beta lactamases, cephalosporinases
  • includes plasmid and chromosomal encoded resistance
  • resistance may develop while on therapy
  • multiple drug resistance is common






  • similar to psuedomonas, opportunistic colonizer
  • B. cepacia complex most common: cystic fibrosis pts, chronic granulomatous disease, and involves lung lymph skin soft tissue and blood stream
  • B. pseudomallei: immunosuppressed, renal insufficiency, diabetes, melioidosis
  • treatment: sensitive to trimethoprim-sulfamethroxazole
  • the treatment is distinct from pseudomonas, which is resistant to that





Stenotrophomonas maltophilia*

  • similar to pseudomonas, passed thru multiple classif
  • opportunistic pathogen: impaired immunity most often
  • bacteremia and pulmonary infections predominate
  • multiple drug resistance is typical: susceptible to trimethoprim-sulfamethoxazole (pseudomonas resistant to it)
  • stenotrophomonas is resistant to carbapenems
  • he skipped this slide*






  • opportunistic pathogen, similar to pseudomonas
  • gram neg coccobacilli, oxidase negative, strict aerobe
  • A. baumannii most common species
  • respiratory, wound, UTI infections most common
  • risk factor is tx with broad spectrum antimicrobials
  • multi drug resistance is a major problem
  • therapy guided by susceptibilities






  • similar to pseudomonas
  • M. catarrhalis is the most important member
  • gram negative diplococci
  • oxidase positive
  • common illnesses: otitis media, sinusitis, pneumonia
  • beta lactamase producer (90% of isolates)








  • non pathogen (n. subflava) and pathogen (gonorrhoeae and meningitidis)
  • aerobic, nonmotile, gram negative diplococcus
  • oxidase and catalase positive





N. gonorrhoeae

  • fastidious, sensitive to drying; no true capsule
  • sensitive to temps less than 35C
  • CO2 promotes growth
  • Human pathogen
  • major world prob and reservoir in asymptomatic people (more common in females)
  • transmission through various forms of sex
  • decline since 1980, peak incidence 15=24 (15-19 women at highest risk)
  • males reported more than females





N. meningitidis

  • moderately fastidious (not as much as gonorrhoeae) , polysacch capsules (12 serotypes)
  • Type A. B, C, W-135, Y are important cause found in diseases
  • Type B - poor immunogen
  • human pathogen, colonize nasopharynx
  • respiratory droplet transmission and close contact and lack of Ab promote disease
  • peak occurence 6-24 months of age, adolescents, young adults
  • 8% fatality rate 
  • outbreaks at military, colleges and child-care
  • carrier rate 18% (9.6 months) and adult men 19-39% in nasopharynx
  • incubation: 3-7 days







Virulence Mechanisms

  • pili (to enter cell), porin proteins (cell entry and resistance to serum bactericidal effects) and opa membrane protein (involved in adherence) (makes it opaque)
  • Rmp (reduction modifiable protein): block serum bactericidal activity
  • iron acquiring proteins
  • IgA1 protease that degrads LAMP1 on lysosomes
  • Lipooligosaccharide (LOS), rather than lipopolysach (LPS)







  • found in neisseria (menigitidis and gonorrhoeae)
  • potent endotoxin, much like LPS)
  • LOS is similar to LPS: same lipid A moiety but contains oligosacch rather than polysacch O-antigen
  • LOS is associated with invasiveness
  • LOS provides useful vaccine epitopes





N. gonorrhoeae


Clinical Disease

  • uncomplicated urogentical infection
  • females: vaginal discharge, dysuria, often asypmtomatic
  • males: acute urethritis; often symptomatic
  • rectal GC: 40% w/ genital or urogentical infectin
  • pharyngeal GC: 10-20% w/ urogenital disease
  • disseminated gonococcal infectin: 0.5%, arthritis and dermatitis (rash and joint pain)
  • pelvic inflammatory disease (PID): 10-20% of women with GC
  • perinatal transmission: opthalmia neonatorum (lots of pus)





N. gonorrhoeae diagnosis


treatment and prevention

  • gram stain, culture (organism fragile), Nucleic acid amplification tests (urine/self-collected swabs)
  • gram stain of urethral discharge
  • third gen cephalosporins, treat suspected co-infections
  • management of sexual contact
  • neonatal eye prohylaxis
  • no protective immunity
  • also treat for chlamydia co-infection





N. meningitidis



  • transient bacteremia: fever, malaise (lasts 24-48 hours)
  • meningococcemia (no meningitis): rash, sepsis, shock and skin necrosis (in blood)
  • meningitis (+/- meningococcemia): meningeal signs/symptoms
  • chronic meningoccemia (rare): 2-10 days of rash-may last months





N. meningitidis


Fulminant Meningococcemia

  • Neisseria bacteria
  • where meningitidis gets into the blood stream and goes all over
  • vascular collapse
  • multiorgan system failure
  • adrenal hemorrhage -waterhouse-friderischen syndrome
  • high mortality despite therapy





N. meningitidis Diagnosis


Treatment and Prevention

  • cultures: blood, CSF and petechial lesions
  • thayer martin media or chocalate
  • CSF - gram stain, latex agglutination
  • antimicribial therapy (penicillin/treat home) and supportive care 
  • meningococcal vaccine: groups A, C, Y and W-135, conjugate vaccine (MenACWY)
  • MenCY for infants with high risk (comb Hib-MenCY)
  • No vaccine for Group B








  • commensal: humans, animals, and environment
  • pathogenic adaptations: enteric pathogens (diarrheal disease) and extra intestinal (pneumonia, sepsis, meningitis, and UTI)
  • O antigen: outer portion of LPS w/ large variety, useful in identification and assoc btw serotype and clinical disease
  • K antigen: capsular: composed of polysacc (ecoli K1, kebsiella and salmonella)
  • H antigen (flagella): typically motile (proteus), used in classification and may function in virulence (salmonella)








  • typically lactose fermenters but salmonella, shigella and proteus are not
  • structure: antiphagocytic, phase variation
  • toxins, adherence and invasion factors, and siderophores






  • an enterobacteriaceae
  • C. diversus and C. freundii
  • opportunist, especially for newborns
  • UTI, sepsis and meningitis
  • neonatal meningitis: C diversus- 75% develop brain abscess





Proteus mirabilis

  • enterobacteriaceae
  • flagellated swarmers (will cover plate)
  • urease production
  • UTI: struvite stones








  • endotoxin - LPS: TNF, IL-1, fever, DIC, hypotenstion and death
  • exotoxins: cytotoxins (nonspec cell injury) and enterotoxins (cell specific, receptor






Escherichia Coli


Urinary Tract Infection (UTI)

  • E coli most common cause of UTI: cystitis, pyelonephritis and urosepsis
  • uropathogenic strains of E. Coli: associated O serotypes, k antigen may play role and fimbriae(P fimbria) attachment-uroepithelium
  • Pap (pilus associated w/ pyelonephritis
  • Rod like projection: present in 60% of UTI strains and 50-90% pyelonephritis strains
  • adhesion subunit PapG (3 forms - I-III)









  • enterobacteriaceae
  • diarrhea: freq, consis, volume, watery, inflamm.
  • fecal-oral transmission
  • inoculum: bacterial load req for infection (101-108)
  • worldwide: 5 million deaths per year (dehydration)
  • e coli most common bacterial infection
  • sanitatin most common reason
  • diarrheagenic e coli  strains: EPEC, ETEC, STEC, EIEC, EAEC





Entopathogenic E. coli



  • enterobacteriaceae that caused diarrhea
  • first described, most common world wide
  • infantile diarrhea
  • protracted secretory (watery) diarrhea
  • specific O serotypes (O127)
  • complex pathogenic mechanisms
  • decreased incidence in developed countries
  • attachment: bundle forming pilus (bfp)
  • effacement: Type III secretion system, tir (intimin receptor, intimin(eae gene) cytoskeletal chages: actin polymerization





Enterotoxigenic E. Coli



  • diarrheal causing enterobacteriaceae
  • colonization fimbriae: mucosal adherence: CFA I-III
  • enterotoxins: plasmid encoded: heat labile toxin (L T-1, LT-2) LT-1 in humans; heat stabile toxin (Sta, STb) Sta in humans
  • Heat Labile Toxin (LT): related closely to vibrio toxin, one A and five B su, doughnut complex binds GM! ganglioside,
  • LT toxin complex endocytosed, A subunit actiavtes adenyl cyclase and increased secretion of Cl-





Enteroinvasive E. Coli



  • low incidence in developed countries
  • non lactose fermenters which is weird for ecoli
  • similar to shigella: biochemically and pathogenically (invasion of colon epithelium and enterotoxin production)
  • lesss severe than shigella: often watery diarrhea






Shigatoxin producing E coli



  • bloody diarrhea causing jenterobacteriaceae
  • associated w/ hemolytic uremic syndrome
  • 3rd or 4th most common foodborne infection in US
  • hemorrhagic colitis: little fever, bloody stools, abdominal pain and may be non blood
  • hemolytic uremic syndrome (HUS): anemia, renal failure, thrombocytopenia (5% of children less than 10 with 5% mortality)
  • serotype O157:H7 most frequent and fails to ferment sorbitol (convenient screen)
  • virulence mech adherence and cytotoxins





STEC pathogenesis

  • Shigatoxin producing E. coli
  • bloody diarrheae causing enterbacteriaceae
  • adherence ande effacement (A/E lesion): same as EPEC, uses tir and intimin
  • shiga toxin (Stx) I and II: Stx almost equal to toxin of S. dysenteriae type I
  • Stx has A, B subunit structure inhibts protein synthesis






Enteroaggregative E. Coli


  • diarrhea causing enterobacteriaceae
  • increasing cause of diarrhea worldwide
  • adhesins
  • toxins being described
  • stacked brick appearance on intestinal epithelial cells
  • dont know much about it







  • enterobacteriaceae
  • most common cause of infectious diarrhea in USA
  • 4 serogroups (dysenteriae, sonnei, flexnerii, boydii
  • fecal-oral transmission: low inoculum, human reservoir
  • major cause of dysentery: blood, mucus, tenesmus, s. dysenteriae type 1 in developing countries along w/ s. sonnei
  • sepsis is rare
  • complications (esp s dysenteriae): seizures, hepato urogenital syndrome (HUS), intestial perforation








  • invasiveness - M cells
  • invasion plasmid antigen (Ipa A-D) type III
  • enter lamina propria
  • induce production of IL-1, inflammatory response, loss of tight junctions
  • re-entry at basal surface (phagosomes)
  • escape phagosomal vesicle and spread to adjacent cells (IcsA, ATPase, polymerization (host cell actin) and propulsion, cell death and focal ulceration (exudation inflammatory cells)
  • Shiga toxin (Stx) I, II: identical to Stx I of STEC: cleavs adenine residue from 28S rRNA blocking binding of elongation factor (arrests protein synth)








  • over 2,500 serologic variants
  • serogrouping: A- I based on O antigen
  • s tyhpi (D1) and paratyphi A are important (typhoid fever)
  • animal reservoir: poultry, beef, pork, eggs, lizards, snakes and turtles
  • vehicles: food, pets, infected humans
  • inoculum: 106-108
  • nontyphoidal and typhoidal
  • not considered normal flora
  • diseases: typhoid (enteric) fever, gastroenteritis, bacteremia (w/ or w/o localized extraintestinal manifistations and asymptomatic
  • unlike shigalla, salmonella can get into the blood stream 








  • invade M cells in pyers patches
  • salmonella pathogenicity island 1 (SPI-1)
  • type III secretion system-encodes: proteins-insert into cytplams, 
  • promote actin polymerization, 
  • cellular ruffling and endocytosis
  • PhoP/PhoQ regulatory system





Typoid Fever

  • s. typhi of salmonella (enterobacteriaceae
  • lamnia propria
  • uptake by mononuclear cells (regional lymph nodes)
  • primary bacteremia: spread to liver, spleen, mesenteric nodes, marrow
  • septicemia
  • persistent fever, multiple organ involvment (spread to gall bladder may result in carrier state and persistent excretion in stool
  • treat blood stream infection 
  • found with people that were traveling
  • vaccines for typhoid







  • enterobacteriaceae
  • Y. enterocolitica: animal reservoir, cold enrichment (likes it cold), mesenteric lymphadenitis, gastroenteritis, bacteremia, meningitis
  • y. enterocolitica outbreak big in winter times (especially new years day from pork)
  • yersinia pestis: bubonic (buboes lymph nodes in groin and axilla), septicemic (buboes w/ bloodstream invasion), pnemonic (septicemic form reaching the lungs 





anaerobic bacteria

  • low oxidation-reduction potential is required
  • energy by fermentation
  • colonization of oxygen deficient microenvironments around the body (mouth and lower GI)
  • opportunistic (clostridium most aggressive)






Clinically Common Infections



  • intra-cranial, oral/dental abscess
  • skin and soft tissue infections
  • aspiration pneumonia
  • Pleuro-pulmonary infections
  • intra-abdominal infections
  • pelvic infections
  • bacteremia
  • endocarditis





Clinical Presentations

  • foul smell/discharge
  • location, location, location
  • festering of trauma
  • necrotic tissue
  • abscess formation
  • gas in tissue/crepitus






  • gram positive anaerobe found in colon
  • normal flora of GI, respiratory tract, vagina and skin
  • 20-40% of the anaerobic infections: bacteremia, pleuro-pulmonary infections, female genital infections, skin and soft tissue infections







  • gram negative anaerobic bacteria
  • normal flora of mouth, upper airways, GI tract, and vagina
  • predomnantly mixed infectinos (likes friends)
  • veillonella parvula: osteomyelitis, meningitis, can cause infection as a solo pathogen
  • veillonella dispar and alcalescens: bacteremia nad endocarditis





Non-spore forming


anaerobic bacilli

  • actinomyces
  • lactobacillus: normal flora for the GI tract and vagina, ferments glucose to lactic acid to make vagina pH less than five
  • mobiluncus
  • bifidobacterium
  • eubacterium
  • propionibacterium: normal flora for skin





Bacteroides SPP.

  • small coccobacillus, obligate anaerobe, non spore forming
  • mouth, upper resp tract, GI tract, urogenital (aprox 30% of stool isolates)
  • major conversion of glucose to butyric acid
  • mixed endogenous infections 






Bacteroides Fragilis

  • pleomorphic rods w/ rounded ends in pairs enclosed in a capsule
  • very resilient, aerotolerant
  • ferments glucose to lactate, fumarate and malate
  • virulence factors: capsular polysaccharides, pilli, neuraminidase, proteases, enterotoxin, hemagglutinin, and adhesis





Fusobacterium SPP.

  • fusiform: elongated bacilli w/ swollen center and pointed ends
  • gram negative bacilla
  • normal flora of the oral cavity, large intestine, and genitourinary tract
  • virulence factors: LPS, leukotoxin, hemolysin, phospholipase, proteases, adhesins






Prevotella spp

  • gram negative anaerobic bacillus
  • extremely small, bile sensitive, saccharolytic bacilli
  • normal flora of the mouth, upper resp tract and vagina
  • virulence factors: lipopolysaccharides, proteases






anaerobe culture


and identification

  • aspirated pus or fluid
  • tissue specimen
  • require specialized transport media
  • pre-reduced blood agar (general growth media)
  • thioglycolate broth: generalized borth enrichment media
  • bacteroides bile esculin (BBE) agar
  • phenylethyl alcohol (PEA) agar
  • for identification: gram stain, colony, and biochemical tests (fermentation, detection of metabolic products by gas-lipid chromatography)





Non-pharmacologic intervention


for anaerobic infection

  • necrosis=scalpel
  • abscess need to be drained
  • debridement
  • remove obstructions
  • hyper-baric oxygen therapy





Antimicrobials and Antitoxins


Anaerobic infections

  • beta lactams: penicillins (gram positive only), lactam and lactamase combos, cefoxitin, cefotetan, and carbapenems
  • moxifloxacin
  • tetracyclins, glycylcycline, metronidazole and nitazoanide (used if anaerobe not major pathogen)
  • anittoxins specific for each organisms: clstridium tetani antitoxin and clostridium botulinum anti toxin





What Is an antimicrobial?

  • enzyme inhibitor or structure
  • disruptor
  • bacterial not human targets
  • antimicrobial targets unique to bacteria: peptidoglycan, membrane, DNA topoisomerases, ribosome and metabolism
  • inhibits essential enzyme
  • kills rather than inhibits growth
  • broad spectrum w/ limited resistance
  • cheap and plentiful





Types of Antibacterials

  • bacteriocidal (antilife): slower acting (inhibits an essential enzyme, or important pathway); or 
  • faster acting: dirsupts an essential structure (ribosome or membrane
  • Bacteriostatic: inhibits gorwth only when present, lets immune system kill bug






Mechanism Antibiotic Resistance

  •  drug activation: bacterial encoded enzyme
  • decreased permeability: outer membrane (gram negatives and only alow entry to small hydrophilic molc), wax layer (MYCOBACTERIA), and biofilm
  • decreased retention (spit it out) (tetracycline)
  • altered target
  • overproduction of target enzyme or structure
  • bypass of metabolic pathway





Inhibitors of Peptidoglycan Synthesis

  • beta lactams: penicillins, cephalosporins, etc
  • vancomycin
  • bacitracin 






Beta Lactams

  • penicillin, cephalosporins
  • four member (unstable) ring that can get cleaved attached to thiazolidine ring
  • target: crosslinking of peptidoglycan (PG): backbone of drug looks like DAla DAla
  • Penicillin binding proteins (PBP): dAla transpeptidase and carboxypeptidases, importnat for cell growth
  • Mechanism of killing: inh of peptidoglycan syn, autolysis due to degradation of PG w/o synthesis
  • requires growing cell to work!!
  • outer membrane block, poor binding and lactamases and non growing or cell wall lacking cells are resistance to it (mycoplasm)





Beta Lactamase


Derivatives and analogues

  • Penicillins: benzyl penicillin (G), ampicillin (also gram negs), and methicillin (beta lactamase resistant)
  • cephalosporins
  • monobactams, imipenems, carbapenems
  • beta lactamase inhibitors: sulbactam, clavulanic acid
  • made ampicillin- hydrophillic to get into gram negs (benzyl is hydrophobic) 
  • made methicillin bulky so that it is resistant to beta lactamase
  • all of them have four member ring 





Methicillin Resistant S. auerus



  • beta lactamase does not work on methicillin
  • alternative mechanisms of resistance:
  • altered transpeptidase (PBP2A) does not bind penicillin
  • PBP2A is both a transglycosylase and transpeptidase
  • Chromosomal (natural) and plasmid carried gene
  • MRSA plasmid encode additional virulence factors






Vancomycin (Teicoplanin)

  • inhibitor of petidoglycan synthesis
  • big complex structure
  • binds to d ALA -D Ala of peptide (clamps)
  • blocks extension and crosslinking
  • only for gram positives (MRSA ect)
  • resistance (VRSA or VRE): thicker cell wall, use of D ala-d-lactate or other ones instead of d-ala-d-ala






  • peptide antibiotic
  • binds bactoprenol-PPi: prevents recycling of bactoprenol (stops conveyor belt) 
  • gram positives
  • topical ointment w/ neomycina nd polymyxin






Disruptions of membrane structure

  • polymxin, colistin, and daptomycin: cationic peptide w/ FA tail (staph or gram negs, topical ointments w/ neomycin/bacitracin
  • Bacitracin: peptide, topical ointments, and distinguishes Group A from other strep
  • isoniazid ethionamide: antimetabolites, inhibits mycobacterial mycolic acid (wax)








  • inhibition of DNA synthesis (ciprofloxacin/nalidixic acid)
  • targets topoisomerase II or topo IV: prevents maintenance of DNA, gyrase from connecting cleaved strands and replication, recombination and repair
  • broad spectrum: not anaerobic bacteria, fluoroquinolones used (improv on nalidixic acid
  • Resistance: mutation in target enzyme, proins in gram neg outer membrane determine perm, and pumps promote eflux





Inhibitors of RNA synthesis

  • rifamycins (rifampin or rifabutin)
  • large drug structure
  • target is bacterial RNA polymerase: mycobacterium (TB), staphylococci and N. meningitidis
  • resistance: mutated polymerase, most gram negs because of poor perm and used in combinations due to rapid development of re sistance





Inhibitors of Protein Synthesis

  • inhibits ribosome
  • only -cidal one is aminoglycosides
  • rest are all static
  • tetracycline
  • chloramphenicol
  • macrolides (erythromycin)
  • lincosamides(clindamycin)
  • linezolid






  • bstatic protein synthesis inhibitor
  • inhibits binding of tRNA to mRNA/ribosome complex
  • binds calcium (chelator)
  • actively transported into/out of cell
  • gram pos and neg
  • resistance: pumped out of cell






  • bcidal protein synthesis inhibitor
  • prototype is streptomycin: irreversible binding to 30S causing misreading and prevents initiation of translation
  • gram neg and positive but toxic side effects
  • resistance: change in ribosomal binding site, decreased uptake/perm, modification by plasmid encoded enzyme, anaerobes cannot power the transport of drug





Metabolic Inhibitors: Folic Acid Pathway

  • sulfonamides (bstatic): comp inibitor of aminobenzoic acid and external source of end products makes resistance
  • trimethoprim: folate analogue that blocks dihydofolate reductase
  • dapsone and p aminosalicyclic acid:m tuberculosis
  • do not give to pregnant women





Variable heavy and Light domain

  • Variabe heavy (Vh) domain is comprised to 3 gene segments: Variable (V), Diversity (D), Junctional (J)
  • variable gene codes for 90 AA and the others 10ish
  • Variable Light (Vl) domain is comprised of 2 gene segments V and J
  • first rearangement is DJ than VDJ for heavy chain
  • light chain DNA is next  and VJ of kapp is first than DNA of lambda 
  • 2.7 million different variable ends (antigen binding sites)





Minimum bactericidal concentration


  • minimal concentration to kill greater than 99.9% of viable bacterial in an 18-24 hr period





Bactericidal Agents

  • beta lactams: penicillins, cephalosporins, carbapenims, monobactam
  • aminoglycosides
  • fluroquinolones
  • preferential use: endocarditis, meningitis, ozteomyelitis, and immunocompromised host






Inducible Beta-Lactamases

  • Found in SPACE organisms
  • Serratia
  • Pseudomonas
  • Acinetobacter
  • Citrobacter
  • Enterobacter
  • avoid treating w/ beata lactams    if possibe






Time Dependent Killing

  • characterized by T>MIC and AUC/MIC
  • want conc 2-4X MIC throughout the interval
  • concentration doesnt influence faster killing
  • minimal to no post antibiotic effect
  • goal of therapy: maximize duration of exposure above MIC
  • associated w/ cell wall agents: beta lactams and vancomycin






Concentration Dependent Killing

  • characterized by Cmax/MIC and AUC/MIC
  • want concentration 10X MIC throughout the interval
  • associated post antibiotic effect
  • goal: maximize concentrations
  • drugs: aminoglycosides, daptomycin, fluoroquinolones, metronidazole, amphotericin B and azithromycin






Drugs w/ post antibiotic effect

  • time during which bacterial growth is inhibited after antibiotic concentrations have fallen below MIC
  • influenced by types of organism, class of antibiotic, conc of antibiotic and duration of exposure
  • aminoglycosides, fuoroquinolones, tetracyclines and clindamycin
  • typically a once a day or every other day very large dose






Complement Overview

  • key role in defense against bacteria, fungi and some parasites
  • most important functions are:
  • opsonization
  • mediators of inflammation (a fragments): attraction and opens vasculature (anaphylaxis)
  • direct killing of organisms
  • facilitates antigen-activation of B cell






Pathways of Complement Activation

  • Alternate (innate): microbial and other surfaces (unless inactivated); LPS's
  • Lectin (innate): mannose-binding lectin (MBL) that binds to pathogen surface
  • Classical (humoral): Ag-Ab complexes or C-reactive protein






Complement Consequences

  • three pathways of proteases which coalesce at C3
  • cleavage products have activity
  • produce chemotaxins: C5a
  • produce anaphylataxins: C3a, C4a, C5a: induce small muscle contr, vascular permeability, 
  • C3a and C5a induce sticky molecules (act of integrins)
  • C3a and C5a activate mast cells to release histamine and TNFa
  • opsonizes microbe: C3b
  • activates B cell: C3d
  • produce membrane attack complex: C5-9: especially gram neg bacteria and niesseria






Classical Pathway

  • antigen-antibody complexes are main activators of this pathway (change in Fc conformation enables C binding): soluble Ag-Ab complexes (IgM or IgG) or Ag-Ab on a target cell (same Ig)
  • C1q binds to the CH3 domain of IgM or CH2 domain of IgG and both require at least two adjacent Fc regions
  • IgM is more effective at activating complement than IgG
  • C-reactive protein binds to the surface of many bacteria and is also an activator
  • cleavage of thiol ester bond of C4 causes covalent attachment to antigen
  • C4b and C2a combnine to form C3 convertase






Lectin Pathway

  • antibody independent pathway" components are dsignated by abbreviations and numbers (MASP-1 resembles C1)
  • mannose-binding lectin binds to mannose and similar sugar residues on foregin surface
  • binding activates MASP-1 and MASP-2 that cleave and activate C4 and C2
  • cleavage of thiol-ester bond in C4 causes covalent attachment to antigen
  • cleaved C4b and C2a generate C3 convertase
  • converges w/ the classical pathway at activation of C3






Alternatve Pathway

  • Antibody independent: designated by letters
  • initiated by spontaneous C3 cleavage and sticking to cell surface proteins
  • produces active C3 and C5 convertase
  • host cell's membrane proteins inactivate C3 and Stop progression
  • DAF, MCP, H, and I prevent spontaneous attachment of C3a






Activities of C3 Fragments

  • C3a promotes inflammation
  • C3b fixation to surfaces leads to opsonization
  • C3b fixation leads to immune complex clearance: C3b biunds to complement receptor 1 ( CR1) on phagocytic cells
  • C3b bound membrane anchors C5 convertase activity and later steps of cascade'
  • C3d bindsd to antigen and CR2 (C3d receptor/EBV receptor) to facilitate actiavtion






C5 Convertases





  • C4b2b3b forms C5 convertase
  • alternative pathway: C3bBbC3b forms C5 convertase
  • cleaves C5 to C5a and C5b
  • C5a relased into fluid phase: potent anaphylatoxin, potent chemoattractant and INFLAMMATION
  • C5b binds to the cell surface: anchor for binding the terminal complement components
  • C5b, C6-9 are terminal and common to all pathways
  • terminal components form MAC and result in cell lysis





Complement-Mediated Cytolysis

  • only works if complement can build upon a membrane (MAC)
  • works especialy well on Neisseria, easy to get to plasma membrane
  • Gram positive bacteria resistant because of Cell wall
  • works well on gram negs though
  • lysozyme can cleave peptidoglycan so complement can get close to gram positive cell walls





Regulation of Complement Activity

  • A suicide substrate mechanism, in which an inhibitor forms a covalent bond with the active site of the enzyme (C1 inhibitor binds to C1r and C1s and prevents it from becoming proteolytically active)
  • proteolytic digestion of the active fragments into smaller inactive fragments
  • inhibition of association of complement components





Factor 1 


Regulation of Complement Activity

  • proteolytic digestion of the active fragments into smaller inactive fragments
  • digestion of C4b and C3b 
  • MCP acts as cofactor for factor 1 mediated proteoltyic cleavage of C3b
  • especially in alternate pathway where DAF displaces Bb from C3bBb





Complement Deficiency and

Clinical Syndromes

  • C1q, C1r, C1s C4 or C2: results in suboptimal C3b and increased risk of pyogenic bacteria (lupis like immune complex disease)
  • C3:  results in no C3b and recurrent infections w/ pyogenic bacteria and NEisseria (immune complex disease)
  • C5, C6, C7 or C8: results in no MAC and Neisseria infections and no immune complex disease






Normal Flora Glossary of Terms

  • pathobiont: refers to a member of the microbiota that under specific conditions can cause pathology
  • dysbiosis: state of microbial imbalance, may produce a disruption in the homeostasis btw host and the microbial community
  • prebiotic: food ingrediate that supports the growth of beneficial properties of one or more resident gut symbionts
  • probiotic: a live microbe that when ingested provides benefit to the host either directly through interactions w/ host cells or indirectly through effects on members of the microbiota





NOD-like Receptors (NLRs) and



  • recognize microbial molecules w/i cytopasm
  • deficiency of a specific NOD reduced IL-18 levels which may alter the microbiota and lead to colitis





Acute Inflammation


Characteristic Tissue Changes

  • expansion of capillary bed: hyperemia, due to change in permeability and slowing of flow
  • increase i interstitial tissue: edema, d ue to an increase in vascular permeability and escape of protein containing fluid into the interstitium
  • migration of inflammatory cells into the tissue: involves mediator modification of endothelium resulting in attachment and transmigration of neutrophils and macrophages into the tissue





Integrins and 


Inflammatory response

  • interaction of mediators w/ slowed rolling induces activation of integrins, most notably LFA-1 or CD11/18, on neutrophil surface
  • these integrins interact w/ endothelial surface ICAM-1 to hold neutrophils tightly in place so that migration of neutrophils into tissue can occur
  • this tight binding is also called margination
  • once bound, integrins expressed on surface interact w/ molecules at the junctions btw endothelial cells, most notably PECAM-1 or CD31
  • neutrophils elongate and pass btw the cells, a process called diapedesis or transmigration 





Acute Phase Proteins



  • role in promotion of or protection during acute inflammatory rx
  • pentraxins: increase markedly (100fold) in concetration ripdly, non-specific bacterial opsonins, and C-reactive protein (CRP) and amyloid protein
  • complement proteins: 10 fold increases
  • Proteinase inhibitors: alpha-1 antitrypsin and alpha 1 antichymotrypsin
  • metal binding proteins: espicially iron, copper and zinc (removes from serum so bacteria cant use it)
  • negative reactants: stops synthesizing albumin and transferrin





Acute inflamation in Meningitis

  • organisms are present in cerebral spinal fluid (CSF) and that is where the acute inflammatory reaction occurs
  • changes in chemical constituents reflect the changes in vascular permeability
  • cells move into the CSF which normally does not contain significant numbers of cells
  • because one is dealing with an enclosed fluid space the number of ogranisms can become quite large




Active Acute Inflammation


Termination Mechanisms

  • witch from proinflammatory leukotrienes to anti inflammatory lipoxins
  • cytokine scavengering by non-functional or soluble receptors
  • release of anti-inlflammatory cytokines, including transforming growth factor beta (TGF) and IL-10 from macrophages
  • production of antiinflammtory lipid mediators, called resolvins and protectins, derived from polyunsaturated fatty acid
  • there are circulating cytokine antagonists that help to limit the extent and severity of the acute phase reaction





Community Acquired Staphylococcus


Protein A and Fc Cloaking

  • virulent staphylococcus ahs a gene spa which produces protein A which is excreted 
  •  protein A has high affinity for human IgG fc region and acts to cloak bacteria and prevent binding to phagocytes
  • staph infecting hcikens lack this protein but chick Ig Fc differers greatly
  • genetically engineered protein A is useful in human immunoglobulin capture and purification





Community Acquired Staphylococcus


Panton-Valentine Leukocidin

  • Panton=Valentine leukocidin (PVL) is a polymer consisting of two peptides secreted by staph which can bind to and lyse white cells
  • CA- MRSA which causes necrotizing pneumonia in otherwise healthy individuals is always associated with PVL production
  • PVL may be why CA-MRSA is so virulent (evidence exists to both support and refute)






Sweet Syndrome

  • sweet syndrome (acute febrile dematosis) w/ extensive necrotizing extracutaneous involvement (soft tissue, skeletal muscle, uterus anad placenta)
  • sweet syndrome consists of abrupt onset of erythematous skin lesions on biopsy shows dense dermal neutrophil infiltrate, there is fever and neutrophilia. cultures are negative. responds to steroids
  • underlying mechanism is incompletely understood-thought to be dysregulation of cytokinese especially GM-CSF. Levels are consistently very high in patients. sweet syndrome has been associated with neoplasms which secrete GM-CSF and occurs in marrow donors stimulated with GM-CSF
  • studies of nucleotide polymorphisms suggest an underlying genetic predisposition related to a locus on chromosome 3





Inflammation Initiators

  • tissue damage: release of interleukin 1, uncovering of alternative complement activation structures, release of proteases, phospholipases and other proteins and release of DAMPs(damage associated molecular pattern molecules
  • infection
  • immune responses (hypersensitivity): example poison ivy





M Cell

  • internalizes antigens for priming immune response
  • found in colon
  • grabs stuff and brings it to a peyers patch






Recruited T Cells

  • Th17 Cells: activated by DC (IL1 and TGFβ) or IL23; reinforce peithelial cella nd neutrophil function w/ cytokines
  • Th1 cells: activated by DC and IL12p70; reinforce macrophage, DC, LC inflammatory responses, promote antibody class switch
  • Treg Ce lls: always active, regulate other responses and produce TGF beta and IL10
  • helper t cells and said dont need to know well





Variable Heavy (Vh)


Gene segments

  • 3 gene segments
  • V: variable gene segments code for about 90 amino acids
  • D: diversity gene segments code for 10 amino acids
  • J: junctional gene segments code for 15 amino acids
  • 38 V gene segments, 27 D segments and 6 J segments





Recombination Active Genes

  • Rag 1 and Rag 2 enzymes
  • active only in cells that undergo rearangement of their DNA (developing B and T cells)
  • both bind recognition signal sequences
  • orientate the DNA allowing the V and J coding sequences to align
  • unwanted DNA is looped out and excised
  • coding sequences connect (junctional diversity)
  • if you dont have Rag you cannot make B cells and T cells causing SCID or Omenn Syndrome





Mechanism of Junctional Diversity

  • Rag allows for unwanted DNA to be excised leaving two blunt ends on exons
  • phosphodiesterase hair pin bond forms between the two
  • Rag genes will nip DNA to create a 3' overhang
  • enzymes come in and new nucleotides are added that arent coded for by germline
  • called the P region (palindrome)
  • terminal deoxynucletidyl transferase addes these nucleotides that werent coded for (up to 20) (N region diversity)
  • Ligase will connect everything
  • w/ junctional diversity the total diversity for variable end of the antibody aproaches 1011 






Somatic Hypermutation

  • following Ag Contact
  • primary response it makes IgM
  • B cells go into follicles of lymph node to germ center
  • undergoes somatic mutation at or near variable end (meant to help you increase affinity)
  • makes a bunch of mutations and the one with the highest would bind to the limited antigen brought there
  • occurs in secondary follicles
  • requires follicular T helper cells in the form of CD40 ligand








  • short, curved, gram neg rods that are highly motile
  • grow in alkaline conditions (selective media)
  • oxidase positive
  • V. cholerae, V pharahaemolyticus, V. vulnificus
  • V. cholerae has O1 serogroup (and O139) and non O1 serogroups
  • O1 serogroups have serotypes ogawa, inaba and hikojima and biotypes classical and El Tor






Vibrio Clinical manifistations

  • V. cholerae serogroup O1: epidemic, pandemic cholera
  • V. cholerae serogroup O139: cholera and milder diarrhea
  • V. parahaemolyticus: gastroenteritis (seafood)
  • V. vulnificus: wound infection







Virulence and treatment

  • orally ingested
  • gastric acid inactivates the organism (requires high inoculum)
  • colonizes small intestine
  • requires attachment ot cause diarrhea: toxin coregulated pilus (tcp A)
  • elaborates enterotoxin - cholera toxin 
  • treated with IV fluids, monitoring of output, oral rehydration and tetracyclin (TMP/SMX)







Cholera Toxin

  • 1 a subunit, 5 b subunits
  • A subunit 2 components: A1 is catalytically active and A2 binds to B
  • B subunit binds to GM1 ganglioside
  • activation of adenyl cyclase
  • causes water to pour out into the lumen
  • same as LT toxin of ETEC






Vibrio Infections

  • Vibrio parahaemolyticus: gastroenteritis, shellfish associated
  • virbio vulnificus: wound infections, severe cellulitis, water associated injuries and shellfish associated






  • gram negative comma shaped rods
  • 5-10% O2, 10% CO2 (grows best in campy jar)
  • selective media: campy- BAP
  • campylobacter jejuni grows best at 42 degrees C
  • survives at 4C for up to several days
  • C. jejuni, coli, fetus, laridis and others
  • Campylobacter reservoirs: cattle, swine, goats, sheep, poultry, pets (young), food and water
  • transmitted by fecal-oral transmission
  • usually surface bacteria on food 






Clinical Manifistations and


post infections complications

  • C. Jejuni: gastroenteritis: secretory or inflamm diarrhea, pseudoappendicitis and bacteremia (rare)
  • C. Fetus-septicemia: opportunistic infection, meningitis and other organ systems
  • post infection compl: arthritis, reiter syndrome, seizures (conjunctivitis), seizures, guillain barre syndrome (antibodies mimic host ganglioside structure and cause rising paralysis)








  • following for c. jejuni
  • Lipooligosaccharide (immune avoidance, molecular mimicry)
  • surface adhesins
  • flagella: chemotaxis (AA of chick GI tract and components of mucus)
  • toxin production: cytolethal distending toxin (arrest of cell cycle)
  • C. fetus uses surface (s) protein: disrupts C3b binding, renders resistant to  phagocytosis and sustains bacteremia





Heliocobacter pylori

  • microaerophilic curved gram negative rods
  • multiple flagella
  • produces large amounts of urease
  • grows optimally at pH 6-7
  • utilizes the mucus layer overlying mucosa (and adheres to mucosa)
  • inhibits local acid production
  • neutralizes pH with urease production (urea into NH4 and CO2)





H. pylori


Virulence factors

  • induce inflammatory responses: various virulence factors involved
  • CagA protein: CagA strains more virulent (inducer of IL-8); encoded by cag pathogen. idland and type IV secretory system that is highly complex
  • vacuolating cytotoxin: secreted vacA gene product induces pore formation in the cell membrame, vaculation in tissue cultures and promotes apoptosis (peptidic ulcer disease)
  • BabA/B - blood group antigen binding: adhesin enhances binding to gastric mucosa





Helicobacter pylori


clinical features

  • acute infection: may persist 1 year (nausea, vomiting, abdominal pain)
  • chronic infection: years lifelong: chronic superficial gastritis, gastric and duodenal ulcers, chronic arophic gastritis (gastric adenocarcinoma and lymphoproliferative disease)





H. pylori diagnosis and treatment

  • invasive (endoscopy): culture (5% O2), PCR, and histology
  • noninvasive: serology (ELISA), urea breath test and stool antigen detection
  • relapse is common (in vitro not in vivo effectiveness)
  • acquired resistance is a concern
  • single antimicrobial regimens not effective
  • standard aproaches: triple therapy (typically 2 antibiotics w/ acid supressing regimens
  • quadruple therapy (2 antibiotics, PPI and bismuth salt therapy
  • sequential therapy (PPI, antibiotic, PPI than two antibiotics





Cytokine Storm Inducers

  • pathogen associated molecular patterns: cell wall components and double stranded RNA or DNA (virus)
  • toxic Shock syndrome toxins (superantigens)
  • sytemic viral infections (later in course)





Gram-negative vs. gram-postive inducers

  • gram positives: cell wall structure: TLR2, inflammasome etc; and superantigen exotoxins
  • Gram negative: LPS that sets off TLR 4 and is highly immunoreactive 






Toll Like Receptors (TLRs)

  • innate immunity recognizes uniqure repetitiveness of microbial structures (PAMPs)
  • ligand binding triggers intracellular transduction
  • Ten TLRs identified in humans
  • recognize similar structures - lipids nucleic acids
  • interact direct interaction or via intermediate PAMP binding molecule
  • ability tor ecognize structurally and biochemically unrelated ligands (LPS by TLR4)







Primary mediators of storm

  • cytokines that activate macrophages: innate TNF alpha, IL1 and interferons alpha and beta
  • immune cytokines: IL17 and IFNgamma





Responses to TNF-alpha

  • induces production of IL-1, IL6 and acute phase proteins
  • facilitates diapedesis of neutrophils
  • loss of muscle, body fat, and appetite (cachexia)
  • neutrophil activation
  • kills cells
  • NO production from macrophage
  • decreased vascular tone and cardiac output






  • clinical condition resulting from complex interactions btw pathogens and host immunity which results in systemic inflammatory and ocagulation responses
  • sepsis and spetic shock highly complex
  • Death secondary to a vigorous and exaggerated immune resposne due to: cytokines, chemokines, prostaglandins, lipid mediators and ROS
  • vasodilation, upregulation of adhesion molecules, activation of WBCs and endothelial cells, myocardial suprression and coagulation system activation





s. pneumoniae



  • cell wall, polysaccharide capsules, exotoxins all responsible for inflammatory response
  • activate the alternative pathway of complement cascade
  • bind the acute phase reactant C reactive protein
  • activate procoagulant activity on the surface of endothelial cells
  • induce production of cytokines, NO and platelet activating factor (PAF) upon binding to eptihelial and endothelial cells
  • initiate the influx of neutrophils






Staphylococcus Toxic Shock

  • fever: temp > 102
  • rash
  • desquamation
  • hypotension
  • multi-system involvement
  • negative results: 
  • blood, throat, CSF (blood could be positive)
  • rise in RMSF, leptospirosis or measles titer







  • bacterial exotoxins cross-link MHC class II molecules on APC outside peptide groove to TCR on T cell
  • each superantigen is known to interact with a family of V (beta) elements of T cell receptor
  • uncontrolled release of pro-inflamm cytokines (TNF-a, IL-1, IFNy)
  • clinical sequelae: SIRS, Shock (toxic shock)
  • paradoxical effects: powerful proliferative effect on t cells, but also produce a profound state of Tcell unresponsiveness and even death
  • production of pores on cell membranes: endothelial contracile microfilaments and influx of ions and small molcs
  • inhibit myocardial and pulmonary function: elevated pulm artery pressure, pulm edema and elveated ventilation pressure





Hemophilus influenzae

  • colonize human respiratory tract
  • encapsulated (serotypes a-f, most important Hib): conjugated capsular polysaccharide vaccine
  • mucosal disease-pneumonia, brochitis, otitis and occasionally invasive disease
  • small gram neg pleomorphic rod, facultative anaerobe and non motile
  • fastidious, oxidase +, factor X and V
  • capsule and outer membrane does adherence
  • LPS elicits strong immunologic and inflamm resposne






Sepsis Therapeutics

  • sepsis induces procoagulant state
  • inflammatory cytokinesactivate the coagulation cascade and inhibit fibrinolysis-disseminated intravascular coagulation
  • Treatments: activated protein C-potent anticoagulant and profibrinolytic enzyme
  • inhibitors of SIRS, NO induced vascular dysfunction, apoptosis of lymphocytes and PMNs activation
  • drotrecognin alfa (activated) 





Immunoreceptor Tyrosine-based Activation Motifs



  • Igα and Igβ transmit signals via this
  • they are bumped by the Fc region of the heavy chain after activation whic causes them to transmit signal
  • C3d on antigen can bring together CR@ molecule to also signal through CR2:CD19:CD81 as well as ITAM 
  • no T cells are involved here






Clonal Selection 

  • each B cell advertises its product on the membrane
  • the B cells with the best Ig binds the antigen and gets stimulated
  • as more cells make higher affinity IgM: strength of antibody increases
  • the immune response matures






T-Cell Independent Antigens

  • antigen and B cell activator: LPS
  • antigen and receptor cross linking activation: bacterial polysach, polymerized flagellin, membrane glycolipids and Nucleic Acids
  • facilitated by C3d
  • facilitaed by TLR stimulation
  • may require cytokines from acute phase or other capsules
  • bacterial polysaccharides found in capsule or biofilm (Making IgM essential to elliminate these)





B Cell Class Switch

  • requires T cell help
  • B Cell-T cell interaction: T cell receptor inteaction w. B cell (CD40=CD40L
  • cytokine determines type of antibody
  • recombination of VDJ w/ new heavy chain gene regeion deletion out invervening sequence
  • does not change the antigen binding regions (VDJ)
  • want same specificity w/ a different functionality
  • depending on whats deleted you can get: IgD and IgM becoming IgG, IgE or IgA (from chainging heavy chain genes) 
  • binding of CD40 to B cell is by peptide so they only developed against a protein antigen





Afiinity maturation due to somatic hypermutation

  • T cell help (CD40L-CD40) induces production of a mutation promoting enzyme
  • T cell help promes B cell growth
  • VDJ in Ig gene undergoes mutations (1/1000 bps)
  • clonal selection (best BCR gets to grow!)
  • T cell resue of best IgG producing B cells





Development of Antibody Response in Serum

  • T independent antibody: IgM
  • clonal selection enhances antibody strength
  • T cells provide help to b cells: cytokines determine class switch and type of antibody
  • Affinity maturation and clonal selection: somatic mutation of VDJ portion regardless of heavy chain in growing B cells
  • lower affinity IgM producing cells cant compete with IgG, IgE or IgA producing B cells for clonal selection and dissapear: except for polysaccharide antigens!!!
  • B cells differentiate into memory B cells and plasma cells






Primary Antibody Responses

  • inducible by both T ind and T Dep Ag
  • Starting from naive B and T cells (no memory cells)
  • longer lag period (4-7d)
  • gradual rise in Ab titer
  • initally all IgM, later (6-8 days) class switching for IgG, IgE and IgA
  • lower Ab affinity (limited affinity maturation)






Secondary Antibody Responses

  • inducible by T dependent Ag only
  • memory B and T expansion
  • shorter lag period (1-3 days)
  • rapid rise in Ab titer
  • mostly IgG, IgA or IgE (due to class switching)
  • a more persistent response
  • higher Ab affinity with time (affinity maturation)





Primary B Cell Abnormaliites


(3 yo w/ history of bacterial infections)

  • X linked agammaglobulinemia: defect in brutons tyrosine kinase, no naive b cells nor IgM
  • X linked hyper-IgM syndrome: defect in CD40L in T cell and b cell can not mature (class switchm no memory); little IgG and high IgM
  • common variable hypogammaglobulinemia: herogenous group, low amount of IgG and IgA






Structure of MHC I and II    

  • structure: immunoglobulin-like strc; two different subunits
  • MHC I (HLA A, B, C): heavy chian and beta 2 microglobulin, cloded ended peptide binding pocket and forms trimers
  • MHC II (HLA DP, DQ, DR): Alpha and beta chains of similar size, open ended peptide binding pocket
  • peptides that bind to MHC II and be larger and floppier (not as defined in size)
  • get the sets from both mom and dad
  • additional binding sites inside pocket that make them more specific for specific peptides (pathogens)Can only bind a peptide!!!!!
  • size of binding peptide: MHC 1 (8-9 AA) and MHC II (11-12+)






Properties of MHC

  • co dominant expression (sets from both mom and dad) increases number of different MHC molc that can present peptides
  • polymorphic genes: many different alleles in population ensure that diff individiuals can respond to diff microbial peptides
  • Class II proffesional APCs, macrophages and bcells (cd4 helper t cells interact w/ dendritic cells, macrophages and b cells)
  • Class 1 (all nucleated cells): CD8 CTL can kill any virus infected cell
  • each MHC displays only one peptide at one time
  • low affinity but broad specificity (many dif peptides can bind to one MHC molc
  • verly slow off rate (displays for long time)






MHC I Properties

  • on all nucleated cells
  • binds to CD8 molcs on TCells
  • binds a single linear peptide of 8-9 amino acids
  • peptide reflects intracellular antigens





MHC II Properties

  • on antigen presenting cells: macrophages, DC, B cells
  • binds to CD4 molecules on T cells
  • binds a single linear peptide of 11-13+ amino acids
  • peptides from exogenous material (debris)






CD1 (a-e)

  • MHC I like structure: heavy chain and beta 2 microglobulin that binds glycolipids
  • gene on chromosome 1 (not MHC locus)
  • recognized by NKT and other t cells
  • important for innate response  (especially against tuberculosis)





 MHC Locus

  • major MHC locus: chromosome 6
  • genetic locus containing immune response genes: MHC I (HLA, A, B, C) and MHC II (DP, DQ, DR)
  • MHC molec are highly polymorphic (diff alleles in population)
  • co-dominant expression (3 from each parent)
  • other genes w/i MHC locus (associated w/ immune responses
  • disease associates (increased risk 4-100 fold): immune response mediated and epitope presenting?





MHC II Antigen Presentation

  • MHC II acquires antigenic peptides from lysosome degraded material -- Exogenous trash (debris)
  • exogenous trash is only presented by antigen presenting cells (APC)
  • APCs: dendritic cells, macrophages, B cells and others on special occasions





MHC II Synthesis and Antigen Acquisition

  • proteins phagocytosed and endosome acts w/ lysosome
  • In ER MHC II molecules are being made and invariant chian binds to cleft of MHC II molc and blocks things from going in
  • complex moves from ER to golgi to Lysosome
  • Invarient chain gets clipped producing the CLIP protein in the lysosome 
  • HLA-DM helps put peptide into cleft and sends MHC II to cell surface
  • now a CD4 T cell can read the peptide






MHC I Presentation of Antigen

  • in all cells: MHC I acquires antigenic peptides from endogenous proteins which get transported into the ER
  • In some APC: MHC I acquires some exogenous trash delivered to the ER for cross presentation (dendritic cells are the best at cross presentation)
  • potentially any protein with in a cell
  • proteins identified for degradation, misfolded, viral proteins in cell, tumor antigens, MHC molecules (transplants) and signal peptides





Which Peptides will become T Cell Antigens

  • proteins in higher concentration in cell
  • ptoential for ubiquitination
  • potential for degradation by proteosome and traversal of TAP channel (into ER)
  • able to bind to MHC I molecules





Cross Presentation

  • phagocytosed proteins
  • exogenous material is sent to the ER
  • peptides are presented on MHC I
  • allows activation of CD8 T cells by viral and tumor antigens
  • occurs pirmarily in dendritic cells
  • differers from endogenous because molecule leakes out of endosome or lysosome rather than just being in cell initially 





Dendritic Cells

  • T cell interacting: myeloid, langerhans and plasmacytoid
  • B cell interacting is follicular: antigen skticky not APC
  • only matures when triggered by a danger signal
  • mature DC have a lot longer half life
  • regulate IL12, IL23, IL6, IL10, IL18






Myeloid (Interstitial) Dendritic Cells

  • location: tissue
  • precursors: monocytes or pre-DCs
  • Cell surface markers: MHC II, CD4, CD11b, CD11c, CD13 and CD33
  • receptors for microbial and cellular debris: iDC: TLRs, CD14 (LPS receptor), lectins, Fc receptors, complement receptors and apoptotic cells
  • cytokine production DC1: IL23, IL12, IL6
  • DC2: IL6 and other cytokines





Langerhans DCs

  • Langerhans DCs: myeloid-like DCs located in the epidermal layer of skin
  • contain Birbeck granules
  • mature langerhans cells also express MHC II, CD4, CD11b, CD 11c, CD13 and CD33






Plasmacytoid DCs

  • found in blood, spleen and lymph nodes
  • precursors: pre-DCs
  • MHC II and CD4 (CD123, and BDCA-2(blood dendritic cell antigen: C type lectin for sialic acid))
  • purpose: cytokine production and antigen presentation
  • cytokines: immature plasmacytoid DCs produce large amounts of interferon alpha in response to viruses, espeically envoloped viruses (Herpes simplex virus)
  • also produce beta, IL-12 and inflammatory cytokines
  • migrate to virus infection site






Follicular DCs

  • follicular DCs are sticky cells present in the follicles of the lymph node and spleen and get coated with antigen for display to B cells rather than T cells (like a bulletin board)
  • follicular DCs do not process antigen
  • folliclular Dcs are important fro B cell stimulation and antibody production





Antibody Effector Deficiencies

  • gets severe case of giardia diarrhea and is prone to respiratory infections: IgA deficiency
  • IgM present but no IgG, IgE or IgA: hyper IgM syndrome due to lack of T cell helper signaling
  • 3yr old prone to bacterial infectinos, esp staph and encapsidated bacteria: complement C3 def
  • NK cells cannot kill antibody coated cells: NK cells w/ leukocyte adhesion def weakly bind but not kill antibody coated cells






Overview of Antibody Functions

  • neutralization: blocking attachment to cellular receptors, hence function
  • Fc mediated activities: complement, opsonization for phagocytes, NK cells,and Fc receptor mediated activites
  • Immune Complexes: type III hypersensitivity (C')






Active Antibody Transport

  • mucosal secretion of IgA (pIgR mediated): secretory component (cleaved J chian) mediated (one way transeptihelial)
  • Bidirectional transport of IgG, IgE (FcRn mediated): across polarized epithelial cells and inflammatory cytokines promote FcRn expression (IgG transport)
  • IgE goes from mildly acidic to neutral environment in GI tract  and is important during worm infection





Secretory IgA

  • protection of respiratory and GI Mucosa: as first line of defense, can perform many IgG-like functions and regulates local flora
  • bactericidal activity: against gram neg organisms in presence of lysozyme
  • antiviral, antifungal, antiparasitic: neutralization of attachment
  • passive immunotherapy: breast milk
  • Synthesized by plasma cells as IgA dimer w/ J chain and is cleaved upon transepidermal passage to produce s component and cleavage of Fc binding site ensures one way transfer
  • sIgA producing Bcells migrate to mucosa ass tissues
  • Function: agglutination of bacteria and viruses and neutralization of toxins and adherence factors






  • highest conc in blood/longest half life
  • transported to EC spaces to protect tissues from infections
  • transplacental and endothelial cell transport: mammalian babies have IgG antibody protectino while suckling and can make IgM
  • neutralizes toxins and blocks binding of viruses and bacteria
  • clumping of particulate antigens and helps precipitation of multi-epitope antigens (agglutination and aggregation)
  • activation of complement via CH2 domain
  • opsinization: Fc rec and activation of C'
  • Antibody dep cell mediated cytotoxicity (ADCC): Fc receptor on NK cells (also eosinophils, neutrophils and macrophages)






  • first ig produced following immunization: primary response, T cell independent and produced against carbohydrates (capsule)
  • only calls of Ig syn by fetus and neonate (begins at 5 months gestation)
  • primarily a serum atnibody (too big to leave bloodstream)
  • most efficient I g for mediating complement fixation (CH3 Domain)
  • highest avidity: most efficient agglutinating antibody
  • blood group: naturally present antibody reactive w/ A/B blood groups







  • meiates type I hypersensitivity reactions: mast cells and basophils have receptors for IgE Fc portion
  • most serum IgE is cell associated
  • Ag crosslinking IgE on surface induces degranulation, secreiton of histamine, heparin and other pharmacological agents from granules
  • important in parasitic infections





Antibody Induced Pathology

  • Allergy (Type 1 Hypersensitivity): IgE mediated
  • Autoantibodies (Type 2 Hypersensitivity): complement mediated inflammation
  • Immune Complexes (type 3 Hypersens): occurs when antibody-antigen complexes are not adequately cleared (macrophages have difficulty clearing small complexes)
  • all lead to inflammation and tissue damage
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