4.6 Immunopath 1 Flashcards
Host defense
Inate immunity – barriers + inflammation, Adaptive immunity –humoral + cellular
innate immunity
barriers–>epithelia–> mechanical barriers + secretory products, inflammation–> cells + complement
cells of innate immunity in inflammation
neutrophils, macrophages, NK cells, DCs
innate immunity
no specificity, linked to adaptive immunity, molecular pattern recognition receptors (eg. Toll like receptors) which recognize molecules unique and critical to microbes (proteins we don’t have), or cellular stress proteins (like heat shock proteins)
innate immunitiy recognizes
pathogen related molecular patterns (microbes) or Danger associated molecular patterns (stress proteins) and recognition results in leukocyte activation, opsonization, and direct microbial killing
adaptive immunity
humoral immunity –> B cells/Plasma cells, Cellular immunity –> T cells, there is crss talk btw these two branches
Adaptive immunity is
specific, and macrophages and DCs are also involved (along with innate)–>APCs
Cells of the Adaptive Response
T cells –CD8 and CD4 (Th1,2,17), Bcells–Plasma cells
where do you find B and T cells
they are anatomically separated until they need to interact
what makes up the majority of circulating lymphocytes
T cells (60-70%)
Where are T cells found
paracortical areas of lymphnodes and in the arteriorlar sheaths of the spleen
What are T cells programmed to do
each t cell is programmed to recognize a single antigenic component via its T-cell receptor
what are non variable accessory molecules associated with TCR
CD3 – they help transduce the signal after binding –CD3 is occasionally found on NK cells
what are the signals involved with Tcells and APCs
Signal 1–>CD4/8 and MHC II/I, TCR, CD3, Signal 2–> CD28–CD80/86
TCR
each receptor specific for a single antigenic determinant, diversity through gene rearrangement via RAG 1 and 2, remember all cells have TCR genes but they are only rearranged in a T cell
CD4 and CD8 on T cells
markers and functional surface proteins that separate T cells into 2 distingce populations: CD4–helper and CD-8–killer
of CD3 positive cells
CD4 cells represent 60%, CD8 cells represent 30%
CD4s further divided into
Th1, Th2, Th17 by cytokine markers
Th1
induced by IFN gamma and IL12, cytokines produced are IFN gamma, actions–Macrophage activation, IgG production, Host defense against–intracellular microbes, role in disease–immune mediated chornic inflammatory diseases (often autoimmune)
Th2
induced by IL4, cytokines produces are IL4, 5, 13, Actions: IgE production eosinophil activation, Host defense against –helminthic parasites, role in disease–allergies
Th17
Induced by TGFbeta, IL6, 1, 23, Cytokines produced IL 17, 22, Actions: Recruit monocytes and neutrophils, host defense against –extracellular bacteria, fungi, role in disease–immune mediated chronic inflammatory diseases (often autoimmune)
B Cells make up
10-20% of peripheral circulating pool
B cells are found in
lymphnodes and spleen infollicles, in submucosa of GI tract
on stimulation B cells turn into
plasma cells, the Ab factories
B cell receptors
unique receptors, surface IgM and IgD ab is the ag binding moiety
B cell non variable accessory molecules
Ig alpha and Ig beta (CD79 a and b) similar to CD3 molecuels that help transduce the signal
B cells have receptors for
complement, Fc, and CD40
Bcells have abundant
C’2 receptors (CD21) which is the receptor for EBV
B cell markers
CD19, CD20, CD22
B cell activation
B cells are activated by a number of ag but mostly require T-cells for a robust response (especially protein ag), some ag are T independent
T cells secrete
stimulatory cytokines for b cells, and express the ligand for CD40.
B cell T cell interaction via CD 40
essential for secretion of IgG A E (hyper-IgM syndrome)
B cell signals
Signal 1– Ab-Ag w/ Igbeta &alpha, Signal 2–CD 21 - complement - Ag
Antibodies
IgM, G (subtypes IgG1, IgG2), IgA, IgE, Each Ab is specific for a single antigenic determinant, diversity achieved through gene rearrangement (RAG1 and 2)
how can you tell if you have B cell leukemia and not just an infection
the antiboides will all be the same in B cell leukemia bc the b cells are monoclonal
IgM structure
like a star of 5 Abs
IgG, D, E structure
a sing Y shaped structure
Ig A structure
two Abs
IgE
binds to receptors on mast cells, histamine released when Ag is bound, works with eosinophils to kill works, responsible for hay fever and anaphylactic shock
IgA
secreted onto mucosal surfaces – if there is an IgA deficiency pt will survive and is often non symptomatic bc back up systems work well in this case
how does the hep B vaccine work
first injection produces an IgM response that takes 3-4w to subside (need to wait till these Ab go down before you give the next dose to ensure that the initial Abs don_t eat up the 2nd dose of the vaccine), the second dose is small to produce a highly selective subset of ab with the higherst affinity, and the 3rd shot is to boost titer leves so you have Ab floating around that can respond if necessary. Need to check titers even if vaccinated to ensure that you have ab floating around and are protected
The mononuclear Phagocyte System
monocytes, macrophages, Kupffer cells, microglia, mesangial cells, DCs, langerhans cells, major interaction in adaptive immunity is Ag presentation, Dendritic cells are professional APC especially for primary responses. Macrophages can present ag but usually recall Ags/ ones that you’ve seen before
Monocyte becomes
a resident macrophage or an activated macrophage, remember they have the ability fo fine tune their functions so they can function without damaging self
IFN gamma and LPS
alone they both produce a response (IFN>LPS), but together they are synergistic meaning when you have both you’ll have stronger responses even if at lower doses
TLR2
ligand–lipoproteins, peptidoglycan, zymosan, LPS, GPI anchor, Lipoarabinomannan, Phosphatidylinositol dimannosied, Microbial source–Bacteria, Gram positive bacteria, Fungi, Leptospira, Trypanosomes, Mycobacteria
TLR 3
Ligand–DS RNA, Microbial source –Viruses
TLR 4
Ligand –LPS, HSF00, Microbial source–Gr neg bacteria, Chlamydia
TLR 5
Ligand–flagellin, Microbial source–various bacteria
TLR 6
ligand–CpG DNA, Microbial source–bacteria, protozoans
Activated Macrophages
increased surface expressin of Class II MHC, increased phagocytosis, incresaed secretion of O2-, H2O2, proteases etc, increased secretion of cytokines (esp TNF, IL1, 12, 8, and sometiems IL 10), Secretion of NO, Increased killing of intracellular pathogens, increased ADCC, killing of some types of tumor cells
ADCC
ab dep cellmediated cytotoxicity – monocytes activated, target cells coated with AB, they can kill (NK cells do this)
slide 30??
Macs–classical IL12, Exposure to Steroids, IL4, or immune complexes IL10; T cells –IFN gamma and Th1, IL4 and TH2
Dendritic cells
1 DC can present to many T cells due to all its dendrites
Types of dendritic cells
interdigitating DCs (or just DC), Follicular DC
Interdigitating DCs (or just DC)
located throughout body at portals of entry, Ag capture receptors, express same chemokine receptors as T cells recruited to T cell areas of lymphid organs, high levels of MHC II and costimulatory molecues so Ag presented to CD4 cells – only takes 15 seconds to get DC going to LN
Follicular DCs
in splenic and LN follicles, Fc and C3b receptors–capture Ab bound Ag, APC to B-cells and selection for inc affinity
NK cells
aka the larger granular lymphocyte, have innate ability to kill virally infected cells and some tumor cells, 10-15% of circulating lymphocytes, CD3 negative but CD16 (Fc receptor) positive thus perfroming ADCC and CD56 positive, NK cells kill virally infected cellls that have low MHC I molecule, increased MHC I inhibits NK cells, NK cells recognize certain stress proteins not normally expressed on cells unless virally infected
NK cells work by
secreting IFN gamma and TNF, IFN gamma activates macrophages and induces CD4 cells to differentiate toward TH1 responses, virally infected cells and newly formed tumor cells often have low MHC 1 molecules and certain stress/triggering molecuels on surface
cytokines and chemokines
communication molecules of the immune response
innate immunity cyto/chemo kines
TNF alpha, IL 1, 6, IFN alpha, beta
Lymphocyte activation and growth cyto/chemokines
IL 2, 4, 5, 12, 15, TGF beta, IL 10
Activation of inflammatory cells cyto/chemokines
IFN gamma, TNF alpha and beta, IL 17, 22
Stimulation of hematopoesis cyto/chemokines
GM-CSF, M-CSF
Leukocyte movement cyto/chemokines
CXC or C-C: IL8 and MCP1
MHC
major histocompattibility complex, class I and II, major antigenic determinants on tissues, necessary for humoral and cellular immune responses,
where are MHC genes coded
all coded from a small region on chromosome 6 called the MHC complex
MHC function
MCH domains and peptides are highly polymorphic, many alleles in the population, major function is to display antigens, polymorphism associated with binding of different antigens, diversity ensures in whole population all ag can be presented (but not by all individuals), no 2 individuals have the same MHC haplotype so transplantation is a problem
MHC I domains
alpha 2 alpha 1, alpha 3, beta2 microblobulin
MHCII domaines
alpha1 beta1, alpha2 beta 2
Class I MHC
present on all nucleated cells in body including platelets, a major transplantation barrier, HLA (human leukocyte antigetn), Three loci HLA-A, B, C, Binds and presents intracellular ag—mainly viruses that we are concerned about
MHC I restricted functions
MCH has to bind self CD8 in order to kill, if it has nonself CD8 it won’t kill
Why do we have MHC restricted functions
bc during a viral infection, the virus sheds proteins, those proteins coat cells. T-cells are not just going to kill a protein coated cell bc there would be no purpose in that. It wants to kill a cell that is infected. So to know it is infected the particles must be presented on MHC I.
Class II MHC
on macrophages, dendritic cells, and some B-cells, major transplantation barrier, HLA-D region, subregions DP, DQ and DR, Major role – Processed exogenous ag presentation. Karatinocytes can start expressing class II but under most cases MHC II is only on APCs. binds CD4 T cells.
Mac/DC stimulates T cells by producing
IL1 and IL12
T cell stimulates Mac/DC bye producing
IFN gamma
CD4 T cells self stimulate by
IL2
CD4 T cells also produce
IL2 for B cell factors, and other T cell factors
Macs/DCs also produce
TNF and other chemical mediators
Costimulatory molecules on APC
B7 1 and 2 (CD80 and 86), CD40
Costimulatory molecules on CD4 t cell
CD 28 and CD40L
Why do we need MHC restriction and Costimulation
they help us select for clones that don’t react to self in the thymic epithelia and BM
Diseases Associated with HLA
inflammatory diseases –Ankylosing spondylitis, HLA-B27 have 90 fold inc chance of disease, Metabolic genetic disease several metabolic genes map within HLA locus, Autoimmune disease MHCI and II associations
