Week 5 Flashcards
Which layer of the epidermis prevents water loss and chemical entry?
Stratum corneum
____ is a critical component in diagnosis of skin diseases
Histology
Of the cutaneous infections we need to know. Name the four bacterial infections
Impetigo
Cellulitis
Folliculitis
Infectious fasciitis
Name the three viral cutaneous infections we need to know
Herpes virus
Molluscum contagiosum
Verruca vulgaris
Name the three fungal cutaneous infections we need to know
Tinea versicolor
Tinea corporis
Deep fungal infection
Name the two cutaneous infestations we need to know of
Scabies
Myiasis
Describe the normal skin flora
Aerobic cocci
Aerobic and anaerobic coryneform bacteria
Gram negative bacteria
Yeast
How does the skin flora prevent bacterial infections?
Skin flora provides ecological competition for pathogenic microbes
Hydrolyzes lipids of sebum to produce free fatty acids, which are toxic to many other types of bacteria
Note that ~20% of dermatology visits are due to bacterial infections
Where in the integumentary system do the following conditions occur? Impetigo Cellulitis Folliculitis Infectious fasciitis
Impetigo - epidermis
Cellulitis - dermis
Folliculitis - appendages (hair follicles)
Infectious fasciitis - hypodermis/fascia
Most cutaneous infections are caused by ____
Staphylococcus aureus
Scales and crusts (specifically honey-yellow crusts) will often result in neutrophils beneath the ____ in the epidermis. This condition is most likely ___
Stratum corneum
Impetigo
50-70% of impetigo cases are due to ____. They may also be due to ___ and ___
Staphylococcal
Streptococcal
Mixed infections
Describe the symptoms of impetigo, where they are likely to be found, and what the treatment is
Discrete, thin-walled vesicles that become pustular and rupture.
Thin, straw colored discharge noted which dries to form golden-yellow crusts
Most likely to be found on exposed areas of the face, hands, neck, and extremities.
Treatment: antibiotic ointment, sometimes with systemic antibiotic
Describe folliculitis, what causes it, and how to treat it
Inflammation of the hair follicle. Dome-shaped pustules around hair follicles
Bacterial infections Most often due to staph aureus
Treatment: decrease bacterial load with antibacterial soap, use topical or systemic antibiotics
Which of the following viruses are DNA and RNA viruses? Herpes virus Pox virus Retroviruses (HIV) Papovavirus
DNA: herpes virus, poxvirus, papovavirus (infect keratinocytes)
RNA: retrovirus (HIV, HTLV) (infect CD4 T cells)
Describe where each virus infects.. Molluscum contagiosum Herpes virus Verruca Folliculitis - herpes virus
Epidermis: molluscum contagiosum, herpes virus, verruca
Appendages: folliculitis - herpes virus
Name some features of a cutaneous herpes virus infection
Grouped papulovesicles on an erythematous base (typically doesn’t cross the midline)
Pain with no rash, then rash develops a few days later
Typically restrained to a single dermatome, unilaterally
Keratinocytes lose their connections (desmosomes) with other keratinocytes (acampolysis)
What does a positive Tznack smear indicate?
This is a herpes/chicken pox skin test
multinucleate giant keratinocytes
Peripheral marginization of chromatin (ground-glass appearance)
A negative interpretation is problematic in clinical situations in which a herpes virus infection is likely - you must go back and scrape another lesion.
Tzanck smear has high sensitivity and specificity
Why is it that herpes zoster (AKA varicella, AKA, shingles, AKA reactivated chicken pox) affects dermatomes?
The virus resides in dorsal root ganglia
What are adnexa?
Skin organelles such as hair follicles, sweat glands, etc.
What do you use to stain a tzanck smear?
HemaQuick (Dif Quik)
What is herpetic whitlow?
Herpes on the digits
True or false.. eczema herpeticum is a rare and sometimes life threatening disease
True
Oral hairy leukoplakia is most often seen in patients with ___. True or false.. this is life threatening and must be treated
HIV or epstein-barr or other immunocompromising conditions.
One of the most common viral induced oral diseases in HIV
False, it has low morbidity
True or false.. marginization of chromatin occurs in both herpesvirus - EBV, and herpesvirus varicella zoster
True
Red umbillicated papules located on the trunk that are scattered and grouped is a characteristic of…
Molluscum contagiosum
What causes molluscum contagiosum? Who does it primarily affect? How is it transmitted? What is significant about its histology? Describe its treatment.
Caused by poxvirus
Primarily affects young children, sexually active adults, those with systemic T-cell immunosuppresion.
Transmitted by direct skin-to-skin contact especially if skin is wet.
Molluscum bodies (henderson paterson bodies) present in histologic samples
Spontaneous resolution of disease is certain in children within two years
Verrucous epidermal hyperplasia often is associated with a thick granular cell layer with ____. It is often caused by ____
Koilocytes
HPV (human papillomavirus)
Define each of the following.. verruca vulgaris, verruca plantaris, verruca plana, verruca condyloma
Verruca vulgaris - common wart
Verruca plantaris - wart on foot
Verruca plana - wart on arm?
Verruca condyloma - genital wart
Name the two fungal infections that infect the epidermis?
Tinea versicolor
Dermatophytosis
What should you do if the rash is scaly?
Do a KOH preparation looking for fungal elements
What does a KOH preparation look like for tinea versicolor?
Spaghetti (hyphae) and meatballs (yeast)
What causes tinea versicolor? Describe what this condition looks like
Caused by pityrosporum orbiculare. (Part of normal skin flora, normally non pathogenic)
Presents as multiple minimally scaly circular white, tan, or orangish macules or papules that coalesce into patches or plaques
What conditions predisposes you to tinea versicolor? Where is the most likely common site of infection?
Excess heat and humidity
Most commonly seen in upper trunk
What layer of the skin does pityrosporum orbiculare usually infect?
The stratum corneum
What is the technical name for scaling?
Parakeratosis
Why can’t dermatophyte infections survive in the mouth or vagina?
This is nonkeratinized tissue so the stratum corneum doesn’t form. Dermatophytes can only survive on dead keratin
What are the three genera that cause dermatophyte infections?
Microsporum
Trichophyton
Epidermophyton
What is the most important diagnostic test for dermatophyte infections?
KOH preparation
Note that hyphae are present in largest numbers at the advancing annular edge
A fungal infection with an ulcerated, firm plaque with satellite papules, has round cells within multinucleated giant cells, and the fungus cells look like a mariner’s wheel (round cell with multiple buds)… what is this?
Paracoccidiodomycosis
True or false… most deep fungal infections are a manifestation of systemic infections. Primary infections are introduced directly into the skin via puncture, abrasion, trauma, etc.
Both statements are true
Name 5 types of infections that can be deep fungal infections
Coccidioidomycosis (SW US)
Paracoccidiodomycosis (south america)
Histoplasmosis (mississippi river)
North american blastomycosis
Others (sporotrichosis, mycetoma)
Most opportunistic fungal disease is seen in patients with ___ or ___
Leukemia
Hematologist neoplasia
____ is the key risk factor for invasive deep fungal infections
Neutropenia
Female Scabies mites burrow into what layer of the skin?
Stratum corneum
What does a scabies infestation look like?
Intense itching
Pruritic papular lesions, excoriations, burrows
Sites of predilection include finger webs, wrists and hands, groins - the circle of Hebra
How is scabies transmitted? How is it treated?
Contracted by close personal contact, contaminated lenins.
Treatment with permethrin 5% cream, oral ivermectin
What is myiasis?
Infestation of human tissue by fly larvae
Human botfly, dermatobia hominis is a common cause
How is myiasis contracted?
Female botfly glues its eggs to the body of a mosquito, stablefly, or tick
When the vector punctures the skin, the egg enters the wound
Painful furuncle develops
How are maggots of myiasis removed?
Injection of local anesthetic or occlusion of breathing pre with petrolatum
Name two bacterial DNA replication enzymes that are targeted by antimicrobials
Topoisomerase 2 (DNA gyrase)
Topoisomerase 4
There are structural differences between bacterial topoisomerase and human topoisomerases that make this possible
What is the role of DNA polymerase 1?
Removes RNA primers from DNA and puts in DNA nucleotides
What is the difference between the roles of topoisomerase 2 (DNA gyrase) and topoisomerase 4?
DNA Gyrase - reduces supercoiling of DNA
Topoisomerase 4 - facilitates bacterial cell division by unblinking DNA following DNA replication
What is the only CNS penetrant fluoroquinolone?
Oxyfloxacin
Quinolone/fluoroquinolones bactericidal or bacterostatic? Narrow spectrum or broad spectrum?
Bactericidal
Broad spectrum
How does quinolones work? What is the difference between targeting gram - and gram + positive microbes?
Block DNA gyrase (topoisomerase 2) and topoisomerase 4
DNA gyrase for gram -
Topoisomerase 4 for Gram +
What is the trend as you go down quinolone generations?
First generations inhibit DNA gyrase only (gram -)
Subsequent generations broaden gram - coverage and/or add topoisomerase 4 inhibitions to also give them gram + coverage
What are the names of the second, third, and fourth generation quinolones?
2nd: ciprofloxacin
3rd: levofloxacin AND oxflaxacin
4th: moxifloxacin
Which is the best quinolone for treating pseudomonas?
Ciprofloxacin
Which quinolone isn’t the first choice for any infection but is a good alternative for gonorrhea, anthrax, strep. Pneumonia, or H. Influenzae infections when resistant to B-lactams?
Levofloxacin (3rd generation)
Which quinolone is effective in treating systemic gram - infections such as traveller’s diarrhea?
Ciprofloxacin
-acts synergistically if given with B-lactams
Which quinolone is conserved the best respiratory fluoroquinolone?
Moxifloxacin
What is the drug of choice for prophylaxis or treatment of Anthrax?
Ciprofloxacin
Which quinolone is good at treating chronic bone infections (osteomyelitis) due to enterobaceriacaie?
Ciprofloxacin
True or false… Moxifloxacin is good at treating pseudomonas Aeruginosa.
False.. ciprofloxacin is the best at treating pseudomonas aeruginosa
Which quinolone has excellen anaerobic activity and enhanced gram + S. Pneumoniae activity
Moxifloxacin
True or false ciprofloxacin is good at treating pneumonia or sinusitis
False… because ciprofloxacin has weak activity against streptococcus pneumoniae
True or false… fluoroquinolones is readily absorbed orally, and should be taken with food
The first part of this statement is true… however, fluoroquinolones should not be taken with food because Al and Mg antacids or Fe or An will interfere with oral adsorption
Although quinolones are distributed through all tissues and body fluid, which organ has quinolone levels that actually exceed those levels detected in the serum?
Lung
What is the only fluoroquinolone that can reach the CSF in clinically-active levels?
Oxfloxacin
How are quinolones eliminated from the body?
Excreted by kidneys
Why is it that the respiratory quinolones like levofloxacin and moxifloxacin only need to be taken once daily?
They have long half-lives and accumulate in the lung
What drug is the most common cause of a C. Difficile super infection?
Ciprofloxacin
What are some adverse effects of quinolones?
GI upset
CNS problems (headache, dizziness)
Photosensitivity
Prolongation of QT interval
Connective tissue problems
True or false… quinolones should be used with caution with patients with epilepsy. Why?
True because it may provoke seizures
How is it that ciprofloxacin should be used with caution with asthma patients?
It interferes with the metabolism of theophylline inhalers, and can produce toxic doses that may provoke seizures
Fluoroquinolones taken with ____ can increase the risks of CNS stimulation and convulsions
NSAIDs
Which quinolone is known to prolong the QT interval?
Moxifloxacin
The use of quinolones is contraindicated in what kind of patients to prevent connective tissue problems?
Pregnant, nursing mothers, children
Patients with myasthenia gravis
Patients with tendinitis (can lead to ruptured tendons)
Quinolones have what known drug interaction?
Antacids - decreases food absorption
Inhibits drug metabolism of theophylline*** warfine, caffeine and cyclosporine
Name three non-quinolone drugs that disrupt nucleic acid synthesis
Metronidazole
Rifampin
Nitrofurantoin
Which non-quinolone drug is the drug of choic for diarrhea due to superinfection of pseudomembranous colitis?
Metronidazole
Which non-quinolone is the drug of choice for tetanus?
Metronidazole
What is the mechanism and spectrum of metronidazole?
Mechanism - inhibits DNA replication
Spectrum - anaerobes, trichomonas vaginalis, entamoeba histolytica, C. Difficile
What are the adverse effects of metronidazole? What is a contraindication?
Metallic taste, GI disturbance
CNS (dizziness, vertigo, headache, depression)
Dark urine
Contraindications - do not take with alcohol… disulfuram like reaction
If drugs that cause a disulfuram-like reaction are taken within ___ hours of drinking alcohol, an “instant hangover” is produced due to a build-up of ___
72
Acetaldehyde
Name 8 drugs that have disulfuram-like reactions
Beta-lactams Cephalosporins Chloramphenicol Isoniazid Ketoconazole Metronidazole Nitrofurantion Sulfonamides
What is the mechanism and spectrum of rifampin?
Mechanism: inhibits DNA-dependent bacterial RNA polymerase
Broad spectrum (gram +, - and mycobacteria)
What are the clinical uses of rifampin?
Treatment of mycobacteria
Prevention of haemophilus influenzae type B and meningococcal disease
True or false… rifampin is absorbed well orally, penetrates the CNS and is excreted in saliva, tears, sweat, urine, and feces
True
What are some adverse effects of rifampin?
Turns urine, sweat, and tears to a reddish-orange color
Dose-dependent hepatotoxicity risk
CYP450 inducer (increases metabolism of other drugs)
What is the mechanism of nitrofurantoin? How is it selective for bacteria?
Forms highly-reactive intermediates that attack bacterial ribosomal proteins, DNA, and other macromolecules
Bacterial cells reduce the drug more rapidly than the host
What are the clinical uses for nitrofurantoin?
Treatment of uncomplicated UTIs and prophylaxis against UTIs in people prone to recurrent UTIs
Nitrofurantoin contraindications
Patients with decreased renal function
Patients in the last 4 weeks of pregnancy or in neonates up to one month (it can cause hemolytic anemia)
True or false.. nitrofurantoin is absorbed orally and tissue penetration outside the urinary tract is negligible
True
What is PABA (para-aminobenzoic acid)?
PABA is a key intermediate in the synthesis of dihydrofolic acid, which is then converted to folic acid (tetrahydrofolic acid)
What does the dihydropteroate synthetase enzyme do?
What does dihydrofolate reductase do?
Converts PABA to dihydropteroic acid
Converts dihydrofolic acid to folic acid
How does sulfamethoxazole work?
Structurally similar to PABA to compete for and inhibit dihydropterate synthetase
How does trimethoprim work?
Inhibits dihydrofolate reductase (second step for the production of folic acid)
Why are the sulfamethoxazole and trimethoprim so selective?
Humans lack the enzymes needed to convert PABA to folic acid
Humans get folate through dietary resources instead
Bacterial growth is selectively inhibited by folate deficiencies
Which sulfonamide antibiotic is used systemically, and is rapidly absorbed, and intermediate acting?
Sulfamethoxazole
What sulfonamide antibiotic is used topically only and used specifically for skin burns
Silver sulfadiaxine
How does sulfamethoxazole work? Is it bacetiocidal or bacteriostatic?
Competitive inhibitor of dihydropteroate synthetase
Bacteriostatic
No longer used clinically as a monotherapy
True or false… sulfadiazine is used as an oral monotherapy for UTIs and burns. Is it bacterostatic or bacterocidal
True
Bacterostatic
Is silver sulfadiazne use topically or orally? What is it used to treat?
Topically
It is used for prevention and treatment of infections relating to skin burns and superficial wounds
Name some adverse effects of sulfadiazine and silver sulfadiazine
Sulfa-hypersensitivity and photosensitivity. Allergic patients usually have cross sensitivity to all sulfa containing drugs
Accumulation in at risk patients can result in…
Hemolytic anemia
Nephrotoxicity
Kernicterus in infants (brain damage due to excessive billireubin in blood and brain)
Trimethoprim is bacterostatic and ___ as potent than sulfonamides alone
20-50x more
Describe the mechanism of trimethoprim
Binds to and inhibits dihydrofolate reductase, preventing the conversion of dihydrofolic acid to folic acid
Trimethoprim’ selectivity comes from its greater affinity from bacterial dihydrofolate reductase than the hosts
What are the adverse effects of trimethoprim?
Pseudomembranous colitis
Hematological disorders including bone marrow suppression (TMP-treats marrow poorly)
What is cotrimoxazole?
trimethoprim + sulfamethoxazole
Synergistic relationship
Describe the spectrum of cotrimoxazole
Broad spectrum. Gram + and - aerobic bacteria
No anaerobic coverage!
Is cotrimoxazole bactericidal or bacterostatic?
Time-dependent bactericidal
Combination provides 2 step blockade of folate synthesis, inhibiting bacterial DNA synthesis
What are the clinical uses for cotrimoxazole?
Drug of choice for treatment of pneumocystis jiroveci pneumonia
Gram + aerobes (recurrent UTIs)
Haemophilus influenzae (respiratory tract infections and otitis)
What was the 1937 elixir sulfanilamide tragedy?
Sulfanilamide was solublized in diethylene glycol to give it a sweeter taste, but resulted in the most consequential mass poisoning in the US in the 20th century
What are the components of the immediate innate immune system?
Barriers and soluble effectors
Barriers include mechanical, chemical, and microbiological
Soluble effectors include complement and antimicrobial peptides
What does the induced innate immune system consist of?
Cells (neutrophils, macrophages, etc.)
Cytokines (interleukins, chemokines, growth factors)
About how long does the immediate innate immune response last before the early induced innate response kicks in?
0-4 hours
The innate immune system is a system of pattern recognition. Name the two classes of molecular patterns, recognized by this system?
PAMPs (pathogen-associated molecular patterns)
DAMPs (damage-associated molecular patterns)
Name four types of pathogen associated molecular patterns
Lipopolysacharides (LPS)
Flagellin
Mannose sugars
Unmethylated cpG DNA
Name three types of damage associated molecular patterns
Heat shock proteins
Fibronectin
Chromatin
(Note that these all elicit different immune responses)
Name and define the three types of barriers pathogens must overcome in order to infect a host
Mechanical - such as epithelial cells preventing entry, flow of air or fluid, cilia (lungs)
Chemical - fatty acids on the skin, defensins in skin gut lungs (big role in oral cavity, and low pH in stomach
Microbiological - normal microbiota
Mechanical barriers are not passive. What does this mean?
The barriers are also constantly producing antimicrobial peptides and stuff
Explain how specialized immune tissues are integrated into barriers
Lymph tissue (simpler than lymph nodes) resides just beneath barriers such as payers patches in the gut (gut associated lymphoid tissue)
This is where localized B and T cell activation takes place
How do chemical barriers act on pathogens? Give examples
Isolation and physical removal… every mucosal tissue secretes a fluid (mucus) to trap the pathogen, then removes the pathogen. (Mucus and cilia in lungs)
Targeted destruction (lysozyme cleaves peptidoglycan.. only works on gram + cause it cannot penetrate the outer membrane of gram - )
Name 7 protein/peptides that are used as chemical barriers and some are especially important in the oral cavity.
Lysozyme Lactoferrin Defensins Cathelicidin Surfactant proteins Secretory leukocyte protease inhibitor S100 proteins (calprotectin and psoriasin)
What does lysozyme do?
Cleaves glycosidic bonds in peptidoglycan to lyse bacterial cells
What does lactoferrin do?
Binds and sequesters iron to limit growth and disrupt membranes
What do psoriasin and calprotectin do?
Disrupts membranes
Binds and sequesters divalent cations to limit growth
What do defensins do?
Disrupt membranes and has intracellular toxicity
Where are alpha defensins produced? What about beta?
Alpha - mostly neutrophils (some paneth cells) (HNP=human neutrophil peptide)
Beta - most mucosal cells (contiguously)
Some are constitutive and some are induced
Describe how defensins disrupt pathogen membranes. How is it selective?
Defensins are positively charged which integrate into the negatively charged membrane. Then the positive charge of the defensins repel each other to form pores in the membrane
It is selective because eukaryotic cells have more proteins in their membrane which are positively charged and repel the defensins
Note that defensins must have access to membrane in order to be effective, so lysozyme must cleave peptidoglycan first
What are some other things defensins can do besides disrupting pathogen membranes?
Signaling function to drive inflammatory response
Induce chemotaxis
Cause histamine release
Cause wound repair and cell migration
Interacts with complement and opsonization
Neutrophils ____ secrete __-defensins into GCF while stratified oral epithelim ____ secrete __-defensins
Are induced to
Alpha
Contitutively
Beta
What are some ways that mutualistic and commensal bacteria form barriers?
Protective functions by pathogen displacement, nutrient competition, receptor competition, and production of antibiotics
What are some other functions that mutualistic/commensal bacteria have?
Induction of IgA
Apical tightening of tight juncitons
Immune system development
Synthesize vitamins such as biotin and folate**
What role do antimicrobial peptides have in the mucosal flora? What other ways does our body interact with the mucosal flora?
They dictate the composition of the local gut flora (Note that commensal bacteria induce IgA and antimicrobial peptide secretion)
Dendritic cells constantly browse mucosal flora
Pattern recognition receptors detect commensal bacteria and prevent inflammation
What is the complement system and what four things does it do?
The complement system is an immune surveillance system of plasma proteins that act in cascades to selectively kill extracellular pathogens and diseased tissue, promote inflammation, clear tissue damage, and regulate tissue homeostasis
What are the three pathways of the complement system? Name them in the order in which they activate and describe how each is initiated.
Alternate - C3, properdin
Lectin - mannose - binding lectins
Classical - antibody/C1q complexes
Where is most of the complement produced?
Liver
Note that 15% of plasma globulin protein is complement
Name 7 components of the complement system
Initiators - initiate the complement pathways
Convertase activators - form convertases which labelantigens with C3b and C5b
Opsonins - coat pathogens to target them for phagocytosis
Anaphylotoxins - initiate and promote inflammation
Membrane attack complexes - form the MAC pore
Complement receptors - initiate signaling
Regulators - restrict or halt complement activity
What are some differences between the a and b complement fragments? Which complement is the exception?
A: small, no enzyme activity, anaphylotoxin, signalling activity
B: large, enzyme activty, opsonin, signaling activity
C2 is the exception to this rule
What initiates the alternative pathway?
Pathogen surface creates local environment conductive to complement activation
What initiates the lectin pathway?
Mannose-binding lectin binds to pathogen surface
How is the classical pathway activated?
C-reactive protein or antibody binds to specific antigen on pathogen surface
____ initiates the classical pathway by binding to the ___ portion of ___. Attached to C1q are ___ and ___, which have a ___ activity, thus initiating the complement cascade
C1q
Conservative portion of antibodies
C1r and C1s
Proteolytic
True or false… a single plasma cell can produce both IgG and IgM antibodies, as long as they have the same variable region. The first antibody that they typically produce is IgM
True
True or false.. C1q only needs to bind to one IgM or IgG
False.. although it must only bind to one IgM molecule, it must bind to multiple IgG
Once C1q binds to antibodies and recruits 2 C1r and 2 C1s, the complex is called ___. This complex cleaves ___ into ___ and ___
C1qr2s2
C4
C4a
C4b
Once C4 is cleaved into C4a and C4b by c1qr2s2, ___ stays on the surface of the pathogen to recruit ___ which is cleaved by ____ to form ___ (___).
C4b
C2
C1qr2s2
C4b2a (C3 convertase)
Note that this complex is made up of C4b and C2a
C4b2a will cleave ___ into ___ and ____. ____ remains attached to the complex to become ____ (____).
C3
C3a
C3b
C4b2a3b
Note that C3b opsonizes the pathogen too
C4b2a3b (C5 convertase) cleaves ___ into ____ and ____. ___ functions to opsonizes the pathogen
C5
C5a
C5b
C5b
Name the order of complexes of the classical pathway
C1qr2s2
C4b2a (C3 convertase)
C4b2a3b (C5 convertase)
The lectin pathway is initiated by the binding of two different proteins, ___ and ____
Mannose binding lectins
Ficolins
What are MASP-1 and MASP-2? They cleave ___
MBL(Mannose binding lectin) associated serine proteases
They cleave C4
MASP-2 cleaves ___ into ___ and ____. ___ stays on the pathogen surface. Then, MASP-2 also cleaves ____ into ___ and ____. ____ binds to ____ forming ___ (____)
C4
C4a
C4b
C2
C2a
C2b
C2a binds to C4b forming C4b2a (C3 convertase)
In the lectin pathway, C4b2a cleaves ___ into ___ and ___ which can bind to ____ or ____.
C3
C3a
C3b
C3b can bind to the microbial surface (opsonization) or the convertase itself to become a C5 convertase, coating the cell with C5b
What three things can activate the alternative pathway?
Spontaneous C3 hydrolysis
Properdin-pathogen binding and C3 recruitment
Proteolytic C3 cleavage (thrombin and clotting cascade proteases)
C3, while floating around the bond will spontaneously expose its ___ bond to allow attack by ___ to cleave C3 into ___ and ___
Thioester
Water
C3a
C3b
Once C3 is spontaneously cleaved into C3a and C3b, C3b has two different fates. What are they?
It can turn into iC3b (inactive C3b) or it can label the surface of pathogen and self cells
Once C3 is spontaneously cleaved, ____ can bind to iC3b. Then ___ can cleave ___ to form ____
Factor B
Factor D can cleave factor B to form iC3Bb
IC3Bb functions as a ____ to ____
Soluble C3 convertase
Initiate the alternative pathway by cleaving C3 to C3a and C3b.. C3b will bind to cell membranes
Describe the formation of the alternative C3 convertase (C3bBb) on a pathogen membrane
Factor B binds to C3b (already located on pathogen membrane). Then Factor D cleaves factor B to form the C3 convertase, C3bBb . C3bBb then continues to cleave C3, depositing more and more C3b on the membrane (opsonization)
What does properdin do?
Stabilizes the C3 convertase C3bBb on a pathogen and recruits additional C3b
C3bBb will recruit another C3b to form the ____
Alternative C5 convertase
C5 is cleaved by this to form C5a and C5b. When C5b accumulates on membrane, it forms pores
The Ca’s are the ____. These function on the ____ and surrounding cells to cause ____
Anaphylotoxins
Vasculature
Permeability to allow extravesation of inflammatory cells. The Ca’s also induce the immune cells.
How do C3a and C5a influence immune cells?
Anaphylotoxins interact with discrete receptors on innate immune cells to Cause chemotaxis, degranulation, and phagocytosis
True or false.. in order for phagocytosis to occur, the phagocyte must have its CR1 receptor bound to C3b and its C5a receptor bound to C5a
True.
This is important so you dont destroy things you aren’t supposed to.
How does complement work with blood borne pathogens?
Antibodies bind to pathogen. C3b binds to these antibodies. Erythrocytes bind to the complement. This whole structure is sent to a macrophage where phagocytosis occurs
What are the three ways in which complement eliminates pathogens?
Anaphylotoxins recruit inflammatory cells
Opsonization of pathogen, targeting for phagocytosis
Formation of pores to lyse bacteria
Describe the formation of membrane attack complexes
Once C5b is on pathogen, it will recruit C6, then C7, the C8.
This complex then recruits the last complement, C9 which forms the pore
How can healthy self-cells block the formation of membrane attach complexes?
CD59 blocks C5b678 to prevent it from recruiting C9
What are the roles of factor H, I, DAF, and MCP?
Leads to complement depletion
DAF-decay accelerating factor
MCP-membrane co-factor protein
What is the significance of P. Gingivalis and complement?
It hijacks the complement system to create the anaphylotoxins to cause recurrent inflammation to use the inflammatory cells as a food source. Also to disregulate the toll-like receptor to tone down the direct killing of p. Gingivalis
Molluscum contagiosum is caused by ____
The pox virus
Describe the alternate C5 convertase
C3b2Bb. The C3bBb cleaves a C3 and the C3b remains attached
