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152 Cards in this Set
- Front
- Back
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Primary Lymphoid Organs
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Bone Marrow and Thymus
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Where does Primary Immune Response Occur?
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Lymph Nodes and Spleen
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How is diversity in Ag recognition accomplished?
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DNA rearrangement of Ig for Bcells and of TCR for Tcells
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How do we get secreted and transmembrane Ig's?
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alternative splicing of RNA
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Where does Ig rearrangement occur?
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Bone Marrow
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Where does TCR rearrangement occur?
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Thymus
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Professional APC's
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DC
Macrophage B-lympphyocyte |
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Characteristics of DC as APC?
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very efficient and can present any antigen
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Characteristics of macrophage as APC?
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less efficient than DC but also can present any antigen
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Characteristics of B-Cell as APC?
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only presents ONE antigen
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Functional Anatomy of Lymph Node:
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Primary Follicle are DENSE and mostly dormant Bcells
Secondary Follicles are PALE and have germinal centers and are active Medulla has cords (mostly Macrophages and Plasma cells) and sinuses (which are communications with the efferent lymphatics and also have macrophages) Paracortex is mostly Tcells and has HEV's through which T/B cells enter the blood |
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Flow though the Lymph Node
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APCs enter via Afferent Lymphatics
T cells enter via arterioles Effector Tcells enter via efferent lymphatics |
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What determines our individual response to different Antigen?
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MHC molecules, or rather the polymorphisms of the portions that interact with antigen and therefore cause different strength reactions
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What happens to virally infected cells?
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virus degraded in cytosol of any cell and peptide fragments presented on MHC I to CD8 CTL which kill the infected cell
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What happens to bacterially infected cells?
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bacteria is degraded in lysosomes of APCs and peptide fragments presented on MHC II to CD4 Tcells which secrete cytokines and activate Bcells
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What happens to extracellular pathogens and toxins?
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They are endocytosed and degraded by APC and presented via MHC II to CD4 which activates Bcells to secrete Ig's
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Anergy
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antigen presents to TCR without costimulatory molecule
recall the "Two-Signal Theory" of Tcell activation which requires both Ag (on MHC) and co-stimulatory molecules |
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CD4 T cell function
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activate macrophages, Bcells, and CD8 CTLs
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CD8 T cell function
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kill virally infected cells
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Innate Immunity
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aka natural immunity or native immunity
blocks entry of microbes and rapidly eliminates microbes that get in |
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Type of Adaptive Immunity
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Humoral
Cell-mediated |
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Humoral Immunity
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provides defense against extracellular microbes
mediated by antibodies produced by B cells |
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Cell-Mediated Immunity
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defense against intracellular microbes (viruses) and phagocytosed microbes in macrophages/APCs (bacteria)
mediated by CD4/CD8 T cells |
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What can T cells recognize?
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only microbial protein antigens presented by MHC, and only Primary structures
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What can B cells (and their Antibodies) recognize?
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many different types of microbial molecules, proteins, carbohydrates, and lipids. can also recognize primary, secondary, and tertiary structure.
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NK cells
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mediators of innate immunity
but dont express the clonaly distributed Ag-receptors that B and T cells do |
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What kind of Immunity do we have during the first 6 days of novel infection?
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ONLY INNATE
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Steps of Leukocyte Migration?
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Rolling Adhesion
Firm Adhesion Diapedesis Migration |
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Rolling Adhesion Step of WBC Migration
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mediated by E and P selectin (on endothelium) and Sialyl Lewis X Acid (on leukocyte)
this can be upregulated by TNFa and IL-1 released from macrophages "sentinel mode" |
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Firm Adhesion Step of WBC Migration
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triggered by IL8/CXCL8, which is send from the basement membrane
mediated by ICAM-1/VCAM-1 (on endothelium) and LFA-1,VLA-4 (on WBC) |
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Diapedisis Step of WBC Migration
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crawling through the endothelial junctions into tissue
mediated by PECAM-1 (found on both WBC and vessel) |
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Migration Step of WBC Migration
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this is where the WBC travels through interstitium into site of injury/infection
mediated by chemokines/cytokines |
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TLR's
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Toll-Like Receptors
impt in innate immunity recognize many parts of microbe and responsible for gene induction (esp NF-kB) |
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TLR4
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recognizes LPS of gram negatives
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TLR2
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recognizes gram positive
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Lectin
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class of carb binding proteins present on wbc, etc
import in INNATE immunity, complement activation, phagocytosis, chemotaxis |
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Mast Cells
what do they do? what activates them? |
rapid phagocyte of innate immunity
contains preformed granules which release cytokines (histamine, TNFa, etc) that cause inflammation impt in allergies activated by IgE |
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Granulocytes
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"BEN"
Basophils Eosinophils Neutrophils have granules which contain toxins to kill phagocytosed bacteria/microbes |
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Monocyte
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precursor to DC and macrophage
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Dectin
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lectin on macrophage that recognizes glucagon on YEAST wall
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Pathways of Complement Activation (Basics)
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Classical: Ag-Ab complex activates C3/C5 convertase (IgG, IgM)
"GM makes Classic Cars" Alternative: Pathogen surface activates C3/C5 convertase MB Lectin: lectin binds to pathogen |
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Results of Complement Activation
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MAC: C5b-C9
Opsonization: C3b, C3bi Chemotaxis of Inflammatory Cells: C3a, C4a, C5a (C3a+C5a are anaphylactics because cause histamine release) B Cell Activation: C3d on CR2/CD21 |
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Defensins
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secreted by epithelial cells into lumen (gut) forming pores and killing bacteria
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Components of Innate Immunity
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Epithelial Barriers
Intraepithelial Lymphocytes (gamma-delta Tcells, B-1 cells) Phagocytes (PMN, Eos, Monos, Macros) NK Cells Complement Cytokines |
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gamma delta T cells
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intraepithelial cells component of innate immune system
sentinels |
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B-1 Cells
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found in peritoneal cavity and respond to microbes/toxins that pass through the walls of the intestine
secrete natural antibodies (IgMs) which are specific to carbs on walls of many bacteria |
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What do Macrophages secrete? and what does that do?
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TNFa and IL-1, which causes upregulation E/P-selectins in vasculature and firmer binding of WBC.
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NF-kB
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transcription factor activated by TLR's that stimulates production of cytokines, etc involved in phagocyte function
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NK Cell function?
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secrete IFN-gamma
induce apoptotic death of virally infected cells that no longer express MHC I |
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IFN-gamma
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secreted by NK cells and T cells (both CD8 and TH1 CD4)
activated Macrophages |
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what activates NK cells?
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IL-12
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IL-12?
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secreted by Bcells and macrophages
activates NK and TH1 cells |
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How does innate immunity stimulate adaptive immunity?
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provides the "second signal"
ex: IFNg from NK cells stimulate DC/Macrophages to express costimulatry molecules (ie B7) and secrete lL-12 ex: C3d, which binds CR2 on Bcells acts as costimulator for B cells |
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Genes encoding MHCI, II?
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I= HLA A, B, C
II= HLA - DR, DQ, DP remember that each gene has many many alleles |
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Where does development of "central tolerance" take place?
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thymus and bone marrow
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Structure of MHCI
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ends of antigen binding cleft are closed, so can only bind peptides of 8-11 aa in length
1 chain, 3 alpha (1, 2, 3) subunits and 1 extrinsic beta-2 microglobulin alpha 1 and 2 form antigen binding cleft |
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Structure of MHCII
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ends of antigen binding cleft are open so can bind variable length peptides
2 chains of 2 subunits, (alpha 1, 2 and beta 1, 2) alpha 1, beta 1 form the antigen binding cleft |
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How does innate immunity stimulate adaptive immunity?
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provides the "second signal"
ex: IFNg from NK cells stimulate DC/Macrophages to express costimulatry molecules (ie B7) and secrete lL-12 ex: C3d, which binds CR2 on Bcells acts as costimulator for B cells |
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Genes encoding MHCI, II?
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I= HLA A, B, C
II= HLA - DR, DQ, DP remember that each gene has many many alleles |
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Where does development of "central tolerance" take place?
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thymus and bone marrow
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Structure of MHCI
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ends of antigen binding cleft are closed, so can only bind peptides of 8-11 aa in length
1 chain, 3 alpha (1, 2, 3) subunits and 1 extrinsic beta-2 microglobulin alpha 1 and 2 form antigen binding cleft alpha 3 is binding site for coreceptor CD3 |
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Structure of MHCII
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ends of antigen binding cleft are open so can bind variable length peptides
2 chains of 2 subunits, (alpha 1, 2 and beta 1, 2) alpha 1, beta 1 form the antigen binding cleft Beta 2 is the binding site of corceptor CD4 |
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Langerhans cells
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epidermal DCs
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Genetics of MHCs
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mendelian
co-dominantly expressed |
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Omen Syndrome
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mutation in RAG-1 needed for VDJ recombination so kids have SCID (lack B+Tcells) and die early of infection unless get BMTx
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CDR3
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3rd hypervariable region which is special in that base pairs can be added at this point randomly causing what is known as "JUNCTIONAL DIVERSITY"
must be added in multiples of 3 otherwise causes frameshift nonsense mutation |
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What determines the class of Ig?
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heavy chain C regions
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IgA
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secreted Ab that mediates mucosal immunity and neonatal passive immunity
monomer or dimer |
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IgM
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naive B cell antigen receptor
main antibody in primary reponse fixes complement doesnt cross placenta can be monomer of B cell or pentamer |
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IgG
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main antibody in secondary response
monomer fixes complement, opsonization, ADCC, neonatal immunity, feedback inhibits Bcells crosses placenta |
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IgD
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naive B cell receptor with unknown function
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IgE
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mediates type I immediate hypersensitivity in inducing release of mediators from mast cells and basophils when exposed to allergen and activates eosinophils
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which Ig's are involved in passive neonatal immunity?
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IgG and IgA "GA GA"
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Which Ig's are involved in complement activation?
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IgG and IgM "GM makes classic cars" ....so activate the classical pathway
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Second signal for B cell activation?
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C3d binding CR2 (aka CD21)
CD40L (from CD4 Tcell) binding CD40 |
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What activates CD4 T cells?
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APC presentation via MHC
costimulation: B7 (on Bcell) binding |
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What initiates class switching?
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CD40L from T cell binding CD40 on B cell
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What determines which class to switch to?
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remember that CD40L/CD40 initiates the switch but cytokines needed to direct it:
IgG= IFN gamma from TH1 cells IgE= IL-4 from TH2 cells IgA=TGF-B from mucosal tissue |
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Hyper IgM Syndrome
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defect in CD40L on CD4 Helper T cell which results in inability to class switch from IgM
High IgM, low everything else X-linked |
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IL-5
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secreted by TH2
stimulates Eosinophils |
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Where do plasma cells reside?
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in the medullary cords of lymph nodes
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How do B cells become deactivated?
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IgG feedback (binds to Fc-gamma-RII)
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Bruton's Agammaglobulinemia
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X-linked defect in Bruton's Tec Kinase which blocks B cell development in the pre-B cell stage
results in no B cells and no antibodies X-linked |
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RAG proteins
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needed for light chain editing (if B cell is too self reactive) and VDJ recombination
not class swithing |
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Ig with highest serum concentration
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IgG
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Main defense against encapsulated bacteria?
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opsonization then phagocytosis
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How are helminths killed?
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IgE opsonizes the bug and then binds FcgRI on eosinophil which releases granules that kill it
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CRP
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an acute phase protein which can activate complement via C1q (without involving Ab)
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Leukocyte Adhesion Deficiency
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abscence of LFA-1 on phagocytes
presents with recurrent bacterial infection, absent pus formation, delayed separation of the umbilicus |
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Acquired Complement Deficiency
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cirrhosis; complement made in liver
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Where does thymus arise from? (embryologically)
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ventral portion of 3rd pharyngeal pouch
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DiGeorge Syndrome
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22q11 syndrome (CATCH-22)
lack of thymic development (no T cells) and parathyroid hormone (hypocalcemia..tetany) |
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CRP
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an acute phase protein which can activate complement via C1q (without involving Ab)
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Leukocyte Adhesion Deficiency
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abscence of LFA-1 on phagocytes
presents with recurrent bacterial infection, absent pus formation, delayed separation of the umbilicus |
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Acquired Complement Deficiency
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cirrhosis; complement made in liver
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Where does thymus arise from? (embryologically)
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3rd pharyngeal pouch
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DiGeorge Syndrome
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22q11 syndrome (CATCH-22)
lack of thymic development (no T cells) and parathyroid hormone (hypocalcemia..tetany) due to failure of separation of 3rd and 4th pharyngeal pouch |
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Familial Mediteranean Fever
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vasculitis with PMN infiltrate caused by mutation in pyrin
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Link between CRP and MI
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CRP interacts with jeopardized myocardium and activates more complement making the MI worse
Give phosphocholine-analog (competitive inhibitor) to decrease infarct size during MI |
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Wiscott Aldrich Syndrome
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X-linked recessive
defect in ability to launch IgM response against capsular polysacchrides of bacteria high IgA (think A for Aldrich), low IgM Infections Purpura (thrombocytopenic) Eczema "WIPE" ...w=wiscott's |
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Ataxia Telangiectasia
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mutation in DNA repair protein
results in ataxia and teleangiectasias and B cell immunodeficiencies |
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Causes of congenital SCID
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adenosine deaminase def
IL-2 receptor defect etc |
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CTLA-4
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receptor on T cell that binds B7 aka CD80/86 on APC and inactivates T cell
opposite of CD28 |
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Cytokines which inhibit T cell response?
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IL-10
TGF-B secreted by Tregs |
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B7
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aka CD80/86
on APC activates CD4 cells via CD28 inhibits T cells via CTLA4 |
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What does oral administration of antigen do?
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creates TH3 cells (Treg) which secrete TGF-B
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IL 2
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"clonal expander"
secreted by helper T cells causing growth of all T cells |
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TH1 cells
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secrete IFN-gamma, IL2, and TNF-a
stimulate phagocyte mediated killing |
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TH2 cells
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secrete IL4, IL5, etc
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What kind of hypersensitity is a PPD
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delayed type
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IL-12
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secreted by B cells and macrophages
activated NK cells promotes TH1 differentiation |
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Cause of Chrohns Dz
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too much IFN-gamma secreting TH1 cells resulting in too much IgG
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IgA Deficiency
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most common primary immunodeficienty
low serum IgA pretty benign |
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CVID
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common variable immunodeficiency
defect in B cell maturation so normal B cell levels but low plasma cell levels can be acquired |
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Types of Grafts?
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autologous=from self
syngenic=from twin allogenic=from another human (not twin) xenogenic=from animal |
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Chronic Mucocutaneous Candidiasis
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Tcell dysfunction specifically against Candida
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IL-12 receptor Deficiency
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low TH1 response presenting as disseminated mycobacterium infections
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Types of Transplant Rejection?
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Hyperacute: within mins due to preformed antibodies in host
Acute: within weeks, due to cytotoxic T cells reacting against foreign MHCs. reversible with immunosuppresents Chronic: in months/years due to antibody-mediated vascular damage (fibrinoid necrosis). irreversible |
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Autoimmune Disorders associated with HLA B27?
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Psoriasis
Ankylosing Spondylitis IBD Reiter's Syndrome |
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Reiter's Syndrome symptoms?
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conjunctivitis
urethritis arthritis "Can't see, can't pee, can't climb a tree' |
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Sjogren's Autoantibodies?
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anti SS-A (Ro)
anti SS-B (La) |
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SLE autoantibodies?
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ANA
Anti-dsDNA Anti-Smith "ANA nicole SMITH has Double Dates" |
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Scleroderma autoantibodies
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CREST=anticentromere
Diffuse=anti-Scl-70 |
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p-ANCA
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vasculitides other than Wegner's
Polyarteritis Nodosa |
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c-ANCA
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Wegner's autoantibody
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Job's Syndrome
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failure of IFN-gamma production by T-helper cells
PMN's fail to respond to chemotactic stimuli Facies (coarse) Abscesses (cold non-inflammed staph) Teeth (retained primary teeth) E=IgE elevated Dermatologic Issues "FATED" |
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Types of Hypersensitivity Reactions
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I=Immediate Type, Anaphylactic/Atopic IgE mediated activation of mast cells, basophils.
II=Antibody mediated, IgG or IgM bind to anitigen on "enemy cell" leading to lysis or phagocytosis III=immune complex mediated, activates complement IV=Delayed, T-cell-mediated. sensitized T cells encounter antigen and then release lymphokines "A C I D" c=cytotoxic |
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Interferons
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alpha and beta inhibit viral protein synthesis (degrade viral mRNA not hosts)
gamma NK cells activation and APC activation |
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Mellitin
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present in bee venom and directly causes mast cell degranulation (no hypersentitivity rxn necessary, although one does exist as well)
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HIV testing
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first step is ELISA
confirmation by westen blot (look for gp120, gp41, p24) if 2/3 are present, patient is HIV+, if 0/3 HIV-, if 1/3 indeterminate. need to do repeat of a PCR |
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What is the cause of Lupus Nephritis?
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high titers of the anti-dsDNA antibodies
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CREST Syndrome
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variant of scleroderma that has autoantibodies to centromeres
Calcinosis Raynauds Esosopageal Dismotility Sclerodactyly Teleangiectasia usually more benign that diffuse scleroderma |
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Disease(s) associated with HLA DR2
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MS
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Disease(s) associated with HLA DR3, Dr4
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Type 1 DM
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Where are class I MHC complexes found?
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all nucleated cells
not mature RBC present on platelets |
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Desensitization Therapy
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repeated injectinos of increasingly greater amt of allergen, resulting in prodction of IgG's that attach to allergens and present them from binding mast cells
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Arthus Reaction
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localized immune complex rxn
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Type 4 Hypersensitivity RXN
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antibody indept T-cell mediated rxn (cellular immunity)
includes delayed type hypersensitivity rxns and cell mediated cytotoxicity |
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Type 2 Hypersensitivity RXN
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antibody dept reactions
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Hyperacute graft rejection
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type II
can be due to abo incompatibility or pre-formed anti-hla antibodies irreversible and immediate causes vessel thrombosis |
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Acute Graft Rejection
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Type IV and II
days-weeks potentially reversible with immunosuppresants |
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Chronic Rejection
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pathogenesis not well understood
months-yrs vascular injury with intimal fibrosis and thickening |
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Drug Induced Lupus
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procainamide, hydralazine
antihistone antibodies goes away after stopping drugs |
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SLE antibodies
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anti-ANA (more sensitive)
anti-dsDNA (more specific) anti-Sm (more specific) antiphospholipid antibodies (anticardiolipin, anticoagulant....damage vessels causing thrombosis, false positive on vrdl) |
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CREST Syndrome
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C=calcification, centromere antibody
R=raynaud's E=espophageal dismotility S=sclerodactyly (tapperd, claw like fingers) T=teleangiectasia limied sclerosis |
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Systemic Sclerosis
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excess collagen production
crest symptoms plus more anti-topoisomerase antibodies, scl-70 |
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HIV Testing
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screen=ELISA for anti gp120. almost 100% sensitive
Confirmation=western blot, positive if 2/3; p24, gp21, gp120/gp160 |
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p24
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inidcates active HIV replication
presents before anti-gp120 antibodies positive prior to seroconversion and when AIDs is diagnosed (2 distinct peaks) |
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CD 56
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NK cell marker (specific)
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CD 16
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NK, Macrophage, PMN marker
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CD30
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marker for Reed Sternberg cells, diagnositic of Hodgkins Lymphoma
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CD15
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marker for Reed Sternberg cells, diagnositic of Hodgkins Lymphoma
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