Test 2, deck 1 Flashcards
how is the classical complement pathway activated?
C1 recognizes immune complex formation (antigen-antibody) by binding to newly exposed site on constant region of antibody
difference in antigen activation with IgM and IgG?
IgG- monomeric- need lots of antigen bound to antibody close together to group C1q’s
IgM- pentameric- only need 1, has natural clustering of C1q’s
how is C4 activated in classic pathway?
C1 pathway!
1) binding of two C1q globular heads to antibody
2) C1r changes conformation & becomes enzymatically active
3) C1r cleaves C1s
4) Fully activated Cqrs can cleave C4
what is different in the C4 activation of the lectin pathway?
- have mannan binding lectin (MBL) & ficolins instead of C1q
- have MASP1 & 2 instead of C1r and C1s
1) MBL binds mannose/carbs on microbial pathogens
2) MASP1 & 2 become activated
what is the common pathway for classic and lectin pathways?
1) activated C1qrs/MBLmasp complexes cleave C4
2) C4b binds to surface of micro-organism
3) bound C4b binds C2
4) bound C2 is cleaved by C1
5) created C4b2a complex ** C3 convertase
6) C3 convertase cleaves C3 to make C4b2a3b complex ** C5 convertase
7) C5 cleaved to C5a&b
8) generation of C5b initiates the formation of the MAC
9) get association of C5b->9 & formation of a pore
what is an additional role of C3b
bound to antigen surface, important for opsonization & clearance of immune toxins
what are the two things cleaved by the C1/MBL complex? aka the two complements common to the lectin and classical pathway
C4 & C2
T/F Holes can only be punched in gram positive bacteria
FALSE- have too much peptidoglycan
what are the initial steps of the alternative pathway?
1) C3 undergoes spontaneous hydrolysis in plasma
2) C3(H20) binds factor B, is cleaved by factor D
3) C3(H20)Bb complex = C3 convertase
4) get lots of C3b
5) C3b only stable when bound to pathogenic surfaces
6) attached C3b binds factor B
7) attached factor B is cleaved- get C3bBb
8) binds to Factor P for stabilization, becomes C3 convertase
8) add another C3b- get C3bBbC3b= C5 convertase
9) cleave C5, make MAC
what are the complements unique to the alternative pathway?
factor D
factor B
properdin (factor P)
what receptor mediates C3b opsonization? what helps?
- macrophages carry receptors for C3b (CR1) (C4b assists with adherence, C5 enhances phagocytosis)
- assisted by antibodies bound to Fc receptors)
how are antigen-antibody complexes removed from circulation?
1) activation of complement leads to molecules of C3b on immune complex
2) CR1 receptor on erythrocytes binds the immune complex via C3b
3) in spleen & liver, phagocytes strip complexes off of RBCs
what are anaphylatoxis/some examples?
- fragments capable of binding to specific receptors on mast cells/basophils triggering granule release, increasing histamine concentrations and increasing vascular permeability
- what makes you red and inflamed
- includes C3a, C4a, C5a
what is an alternative role for C5a?
chemoattractant for neutrophils/eosinophils/basophils/monocytes
C1 inhibitors
1) C1 INH- acts by dissociating C1r&s from the C1 complex
C3 convertase inhibitors
1) DAF- decay-accelerating factor
2) C4 binding protein
3) complement receptor 1 (CR1)
4) membrane cofactor protein (MCP)
5) Factor I
C5 convertase inhibitors
1) Factor I
2) Factor H
3) Complement receptor 1 (CR1)
MAC inhibitor
CD59
deficiency in classical pathway
C1/C2/C4
immune-complex disease
deficiency in lectin pathway
frequent bacterial infections as a child
deficiency in alternative pathway
no immune complex disease, infections with pyogenic bacteria (bacteria that cause pus)
deficiency in C3b deposition
sometimes immune complex disease, infection with pyogenic bacteria
deficiency in membrane attack components
infection with Neisseria spp.
deficiency in C1 INH
failure to regulate C1- fluid accumulation, epiglottal swelling
deficiency in CD59
paroxysmal nocturnal hemoglobinurea - lack of regulation leads to RBC lysis and RBCs in urine
deficiency in early components of complement
poor clearance of immune complexes, resulting in increased immune complex disease
3 things all pathways do:
1) C3a and C5a recruit phagocytic cells to the site of infection & promote inflammation
2) phagocytes with receptors for C3b engulf & destroy pathogen
3) completion of cascade form MAC
complements that promote inflammation
C3A, 4A, 5A
complements that promote phagocytosis
C3B
complements that promote membrane attack
C5-9
components of mucosal immune system
GALT (GI) BALT (respiratory tract) NALT (nasal) genitourinary lacrimal glands salivary glands mammary glands
3 distinct anatomical features of mucosal system
1) lymphoid tissues are right below mucosal epithelia
2) have discrete compartments of both diffuse tissue & organized structures (Peyer’s patches)
3) have specialized uptake mechanisms (M cells
2 distinct effector mechanisms
1) activated/memory T cells predominate, even w/o infection
2) have a lot of regulatory t cells for tolerance (food antigens)
what do you find directly under single layer of epithelial cells?
peyer’s patches - lymphoid cells- where antigen response is initiated
what do you find in the lamina propria?
CD4+, CD8+ t-cells
what are IELs and what do they do?
intra epithelial lymphocytes; CD8+ t-lymphocytes; kill infected epithelial cells by recognizes their infected MHCI
what do you find in the lamina propria?
CD4+, CD8+ t-cells
CD8+ t cells in epithelial layer- IELs
inductive site for MALT; what is induction mediated by
peyer’s patch, isolated lymphoid follicle (areas exposed to intestinal lumen) ; induction mediated by M cells
where is 70%-80% of all antibody in the body made? what is it?
- mucosa
- IgA plasma cells
effector site MALT
lamina propria (where you find IgA plasma cells)
what do M-cells do?
take up antigen; have pockets with immune cells (DCs, Bs, Ts)so you can immediately start immune process
4 ways antigen uptake occurs with MALT
1) non-specific M cells
2) bacteria with antibody bound taken up by Fc receptors
3) bacteria that kills m-cell
4) dendrite sent through to luminal area
pathway of GALT activation
1) M cell takes up antigen, gets into DC (or other APC)
2) T-cells activated, go through lymph to mesenteric lymph node, thoracic duct, blood stream
3) use addressins to go back to lamina propria in gut
4) receptors for addressins, allows cell to squeeze through vessel and go from blood to lamina propria
4 key features of mucosal immunity:
1) antigen in mucosal site, antibody in lamina propria
2) B-cells in MALT produce dimeric IgA
3) T cells (CTLs) are important
4) mucosal immunity can give systemic immunity
T/F When you vaccinate against tetanus, you get mucosal immunity
False
what is the first line of defense in MALT?
epithelial cells provide innate defense
what are endocytosed bacteria recognized by and what signal does that produce?
- TLRs in intracellular vesicles, NODs in cytosol
- activates NfKB to induce inflammatory cytokines and chemokines
how do you keep commensals at bay?
coated by IgA to keep them from getting through epithelium
what other antibody is in mucosa?
IgM
what happens if you are deficient in IgA?
more susceptible to infection, however can see an increase in IgM and be symptomless
what does secretory component do?
protects IgA from digestion
how does IgA get across the membrane?
1) dimeric IgA binds polymeric Ig receptor on basolateral side of the epithelial cell
2) taken into cell, through cell, secreted on apical side of epithelial cell
3) receptor is cleaved, part of it stays part of IgA and is now the secretory component
3 IgA functions
1) binds and neutralizes pathogens & toxins in gut
2) able to bind an neutralize antigens while being transported in endosomes
3) can export toxins/pathogens from the lamina propria while being secreted
advantages/disadvantages to oral immunization
advantage: easily administered, gives both mucosal and systemic immunity
disadvantage: short lived response, difficult to elicit response b/c of tolerance
research example of how you induce tolerance instead of immunity
- feed mice with ovalbumin
- then inject ovalbumin + adjuvant to stimulate response
how do you induce mucosal immunity in the tolerogenic environment?
need to induce inflammation
what influences whether you get tolerance or immune response
- key is inducing dendritic cells to activate
- when commensals are taken up, get different cytokines which inhibit dendritic cell maturation and stimulates Tregs
key commensal immune function; what happens with c diff
- protect from pathogens
- antibiotics wipe out commensals, then exposed to c diff, c diff takes over and breaks epithelial barrier, causes terrible disease
central lymphoid tissue types and role
bone marrow (B-cells) & thymus (T-cells)
- lymphopoiesis (HSC gives rise to antigen specific lymphocytes)
- central tolerance (deletion of autoreactive lymphocyte)
peripheral lymphoid tissues
- specialized: lymph nodes, spleen, lymphatics
- regional: peyer’s patches, adenoids/tonsils, mucosal epithelial cells in respiratory system
4 purposes of lymphoid tissues
1) support lymphopoiesis
2) support development of diverse repertoire of antigen specific lymphocytes
3) central & peripheral tolerance
4) sustaining signals for lymphocyte survival
what kind of lymphocytes do you find in peripheral lymphoid tissues and what do they do?
- mixed B & T cells (not specific like only T-cells in thymus)
- supports circulating lymphocyte survival
- activates naive lymphocytes
- useful for peripheral tolerance
_____ cells in bone marrow are critically important to B-cell development; they are found in the ______
stromal; trabeculae
_____ go to thymus to develop
thymocytes
where do early stem cells hang out? where do they migrate to?
- start in endosteum, just below inner cavity of long bones
- migrate to stromal cells
- then central sinus of marrow
- then circulation
4 possibilities for B-cell central tolerance
1) no self reaction- migrates out
2) reacts strongly to mulltivalent self molecule- receptor editing or clonal deletion
3) reacts to soluble self molecules- becomes anergic
* * dangerous 4) low affinity non-cross linking self molecule- migrates out, but if enough self-protein becomes abundant, b-cell can be set off
what are two lymphoid structures found only in the periphery?
lymphoid follicles & germinal centers
what are the two lymphoid structures common to the thymus and lymph node?
cortex & medulla (and cortico-medullary junction)
what maturation factors are provided by stromal cells for immature B cells?
FLT3 ligand, IL7, stem-cell factor, CXCL12
what are the two lymphoid structures common to the thymus and lymph node?
cortex & medulla (and cortico-medullary junction)
what is the difference between stroma and parenchyma?
stroma: non-leukocytes
parenchyma: leukocytes
whats in the cortex of the thymus?
immature thymocytes, scattered macrophages (eat up apoptotic thymocytes) (is darker)
what’s in the medulla of the thymus?
more mature thymocytes, dendritic cells, macrophages (lighter)
T/F the thymus is fully developed at birth
TRUE
describe positive selection and how stringent it is
- more that recognize peptide in MHC with low affinity
what type of selection is AIRE important for?
negative selection
how do APCs (DCs) get into lymph node?
afferent lymphatic vesicle- subcapsular sinus- tracebulae/cortical sinus- paracortical areas (mainly T-cells)
how to naive lymphocytes get into lymph node?
lymph arterioles- nodular/cortical follicle area- high endothelial venules (HEV) where lymphocytes squeeze out and go into the paracortical areas (again, mainly T-cells)
what determines “b-cell areas” of lymph node
follicular dendritic cells (FDC)
what happens when free antigen enters a lymph node via afferent lymphatics ?
- picked up by macrophages in sub-capsular region
- trap antigen on surface, present directly to B cells
- OR pass antigen to FDCs (which enhance the B- cell response via B-cell maturation)
- OR present antigen to T-cells in paracortical area in traditional manner
where do plasma cells go? memory b’s?
plasma cells- stay in medullary cord (short lived) or go out to bone marrow/gut
memory b cells- circulate through lymphoid organs
T/F Spleen receives afferent lymphatics
FALSE BLOOD BORN PATHOGENS
3 Functions of spleen?
1) RBC disposal & recycling iron (red pulp)
2) immune responses to blood borne pathogens (white pulp)
3) hematopoiesis if needed
Describe the blood supply of the spleen
splenic artery- trabecular artery- central arteriole OR marginal sinus OR vascular sinusoids- fenestrated in red pulp next to macrophages which take out old/damaged RBCs
what would happen to patient who had traumatic loss of spleen? sickle cell?
would get babesiosis or other RBC-borne pathogens; w/ sickle cell would get enlarged spleen
what are marginal b-zone cells (macs, B’s) sensitive too?
blood antigens, bacterial polysaccharides & other circulating peptides
what is the exception to the secretion of IgA in MALT tissues?
genitourinary = IgG
clonal selection hypothesis- 4 postulates
1- lymphocytes have receptor with unique specificity
2- foreign molecule + receptor actives lymphocytes
3- differentiated effector cells have same receptors as parent cell
4- receptors specific for self molecules are deleted early
B cell vs t cell vs plasma cell area of lymph node
B cells- follicle (have developing plasma zones- germinal centers)
T cells- parafollicular cortex
plasma cells- medullary cords
what does the spleen do?
- immune response to blood-borne pathogens (white)
- RBC disposal & Fe recycling ** majority (red)
- secondary hematopoiesis
organization of cells in spleen
- PALS- around arteriole- T cells
- follicles- next to PALS, B cells
- marginal zone- next to follicles, macrophages, stationary B cells, where filtering happens
what is spleen good at clearing?
infections with encapsulated bacteria & babesiosis (parasite which reproduces in RBCs)
