The Immune System at Rest
- barrier establishment and evolution
- Leukocyte proliferation
- lymphocyte development
- complement production and circulation
- lymphocyte recirculation
- pre-emptive immunity at mucosal surfaces(Macs, DC, Mc cells)
components of the immediate innate response
antimicrobial peptides
complement
components of induced innate response
mac and DC cell activation
acute phase and interferon response
neutrophil infiltration
NK cell response
adaptive immunity components
T cell activation and differentiation
B cell activation and differentiation
antibody production by plasma cells
CD8 T cell cytotoxicity
what are the barriers that protect internal tissues
mucosal surfaces(GI, UG, respiratory tracts) epidermal
what are the three compartments of mucosal tissues
- epithelium
- lamina propria
- MALTs
what cells are in the epithelial layer of the mucosa
-Intraepithelial lymphocytes:
gamma/delta cells
CD8 alpha/alpha cells
memory CD8 T cells
what cells are in the lamina propria?
lymphatic tissue gamma/delta T cells CD8 CD4 (Th1 and Th17, T reg) plasma cells and memory B cells macs DCs
Mucosal-associated lymphoid tissue
specialized per mucosal tissue
lymph node-like organization
barriers produce antimicrobial Peptides to do what?
destroy pathogens
select commensal communities
initiate inflammation
what does calprotetin do?
binds and sequesters divalent cations to limit growth of bacteria and fungi
what do cathelicidins do?
disrupts membranes of bacteria: additional toxic effects intracellularly killing cells
what do surfactant proteins do?
block bacterial surface components and promotes phagocytosis
the common myeloid precursor gives rise to what side of the immune system cells?
innate cells
the common lymphoid precursor gives rise to what?
B cells, T cells and NK cells
lymphocyte circulation allows for what?
maximizes likelihood of antigen encounter
how long does it take for a single lymphocyte to completely circulate?
24 hours
DCs are probed by how many T cells per hour?
5000
once leaving the lymph nodes what percent of lymphocytes enter the lymph and blood?
52% lymph
48% blood
why strategy does our body employ for browsing in the immune system?
few specific cells that circulate for a long time rather than making a bunch of cells and wasting energy.
1:100,100 lymphocytes bind a presented antigen
where are most infections stopped?
at the epithelium and mucosal surfaces
what is the major difference in immunity at mucsoal surfaces compared to epithelium?
recruitment of neutrophils is not immediate
- inflammation is a last resort(chronic infxn, damage, large infxn)
- adaptive response is very local due to resident adaptive immune cells in the lamina propria
mucosal immunity is pre-emptive how?
adaptive immunity recruited prior to pathogen entry
- adaptive immune cells located at sites of potential infxn
- mucosal surface is shaped by ongoing immunity due to:
- -antimicrobial peptides
- -IgA secretion
- -Targeted killing
- -Epithelial cell immunity
- -commensal competition
initiation of inflammation is done by what?
pattern recognition
- TLRs
- complement
- CD14 (LPS)
- Mannose receptor
- SR-A/B (scavenger receptors)
what is exudate
fluid that contains complement, and antimicrobial peptides
what is the time line for immediate immune response
0-4 hours
what is the time line for induce immune response
4 hour to 4 days
what is the time line for adaptive immune response
4 days until pathogen is defeated or truce of chronic disease
what are the three compliment pathways
Classical
lectin
alternative
what are the three effector functions of C3b
opsonization
MAC
a components recruit phagocytic cells to site of infxn
what are the five inflammatory cytokines released by Macrophages to promote an inflammatory response?
IL-1B TNF-alpha IL-6 CXCL8 IL-12 (up regulates receptors, IFNs, proliferation in NK)
Inflammatory cytokines stimulate the liver to do what?
think of IL-6
make acute phase response
- CRP
- MBLs
- Complement components
- Clotting factors
- Lipopolysaccharide binding proteins
- inflammatory products like phospholipase A2
what does CXCL8 do and what is the receptor?
it is the primary neutrophil chemokine
neutrophil CXCL8 receptor is CXCL1/2 and causes the LFA-1 to be expressed
what are the three effector mechanisms of neutrophils?
phagocytosis
degranulation
NETs
where does the interferon response come from?
immune cells or infected cells
what are the 3 things IFNs do?
- induce resistance to viral replication in all cells
- increase expression of ligands(stress) for receptors on NK cells
- activate NK cells to kill virus infected cells
what are the two cells that release perforin and granzyme?
CD8 T cells and NK cells
what are the 3 ways NK cells kill cells?
granule exocytosis release
death-receptors
IFN gamma and NO
what are the 3 classic antigen presenting cells?
DCs
Macs
B cells
what T cells can act as a antigen presenting cell?
gamma/delta T cell
what cells activate T cells
DCs
what cells can activate B cells
FDCs and Macs
what is the time line for T cell activation in a lymph node
min-24 hrs- Ag enters
1-24 hrs-T cell/APC interactions
24-96 hrs- T cell proliferation and differentiation
72-96 hrs: Egress of effector cells
what is the time line for B cell activation in a lymph node?
minutes: Ag enters
min-6 hrs- B cell/Ag interaction
6hrs- B cell migration to T cell zone
24-48 hrs-B cell prolif. and migrate to outer follicle zone
48-96 hrs- development of germinal center
72-96 hr: egress of effector cells
what are the 3 signals for T cell activation
MHC with TCR and co-receptor (activation)
B7 on APC with CD28 on T cell(survival)
cytokine signal (differentiation)
cytokinesis of activated T cells is how long
every 20 min
T cell differentiation is dependent upon what?
the pathogen that activated the APC
cytokines that induce the formation of Th1 cells
IL-12
IFN-gamma
cytokines that induce the formation of Th17
TGF-beta
IL-16
IL-23
cytokines that induce the formation of Th2
IL-4
cytokines that induce the formation of Tfh cells
IL-6
IL-21
cytokines that induce the formation of T reg cells
TGF beta
lack of inflammatory cytokines
what cells do B cells capture antigen from in lymph nodes
Macs and FDCs
B and Tfh cells form cognate pairs at what location in the lymph node
follicle boundary
how do Tfh cells aid in B cell activation?
stimulate proliferation
induce centroblast formation
induce class switching and SMH
provide survival signals to FDC selected centroblasts
induce plasma or memory cell differentiation
what is the primary focus?
proliferation of IgM secreting B cells for several days driven by IL-5 and IL-6
what is the secondary focus(germinal center)
B cells rapidly divide every 6 hours to form centroblasts and germinal centers driven by IL-6, IL-15 and BAFF
what are the four effector functions of antibodies
virus and toxin neutralization
opsonization
complement fixation (classical pathway)
antibody dependent cell-mediated cytotoxicity (NK and CD8 cells)
once a CD8 T cells is activate does it need a secondary signal to kill cells?
nope
cytokines released by Th1 cells?
IFN-gamma GM-CSF TNF-alpha LT IL-2
cytokines released by Th2
IL-4 IL-5 IL-10 IL-13 TGF-beta
cytokines released by Tfh
IL-21
IL-4
IFN-gamma
cytokines released by Th17
IL-17
IL-21
IL-22
IL-26
cytokines released by T reg
TGF-beta
IL-10
IL-35
Routes to cell death, there are 2
necrosis, induces inflammation(DAMPs) and PMN recruitment
-direct toxic effect
-indirect toxic effect
apoptosis, suppresses inflammation
The adaptive immune system improves with time how?
B cells: -increased Ab concentration -improved Ab affinity T cells: -memory T cells -population expansion -persistence
Immune resolution and repair process and cells involved
- inflammatory cytokine reduction
- anti-inflammatory cytokines produced
- T reg cell signaling and development
- T cell CTLA4 expression(bind B7 on DC to inhibit T cell activation)
inhibition of Th17 cells induces what type of T cell development?
T regulatory cells which release TGF-beta
the release of TGF-beta from T reg cells does what?
- Th1 secrete IFN-gamma which inhibit Th2 cells
- Th2 secrete TGF-beta and IL-10 to inhibit Th1 and Macs
