secondary lymphoid organ many afferents; 1+ efferent encapsulated trabeculae
lymph node functions
nonspecific filtration by macrophages B and T cell storage immune response activation
lymph node follicle
B-cell localization and proliferation outer cortex: primary follicles: dense and dormant follicles secondary follicles: have pale germinal centers, are active
lymph node medulla
medullary cords = closely packed lymphocytes and plasma cells medullary sinuses communicate with efferent lymphatics and contain reticular cells and macrophages
lymph node paracortex
houses T cells between follicles and medulla T/B cells enter from blood via high endothelial venules poorly developed w/ DiGeorge syndrome enlarges in extreme cellular immune response (e.g. viral infection)
perforin and granzymes to induce apoptosis of virally infected and tumor cells induced to kill when exposed to nonspecific signal on target cell/absence of class on MHC on target cell surface also kills via antibody-dependent cell-mediated cytotoxicity (activated with CD16 binds Fc region of bound IgG)
NK cell activity is enhanced by____
IL-, 12 IFN-alpha, beta
NK cels belong to what immune system?
B cell function
antigen recognition; undergo somatic hypermutation to optimize antigen specificity produce antibody- differentiate into plasma B cells to secrete specific Igs memory B cells to accelerate future response to antigen
CD4+ T cell function
help B cells make antibodies produce cytokines to recruit phagocytes and active o/ leukocytes
CD8+ T cell function
directly kill virus-infected cells
what lymphocytes function in delayed cell-mediated hypersensitivity (IV)
what lymphocytes function in acute and chronic cellular organ rejection?
T cell rule of 8
MHC II x CD4 = 8 MCH I x CD8 = 8
T cell differentiation: cell type by location: bone marrow
T cell precursor
T cell differentiation: cell type by location: thymus (cortex)
CD4+CD8+ T cell
T cell differentiation: cell type by location: thymus (Medulla
CD8+ and CD4+ T cells
T cell differentiation: cell type by location: lympho node
cytotoxic T cells (from CD8+) helper T cells
cytotoxic T cells kill ____? and how?
virus-infected, neoplastic, and donor graft cells induce apoptosis by releasing cytotoxic granules containing preformed proteins (perforin, granzyme B)
what stimulates a T helper cell to become a Th1 cell?
what stimulates a T helper cell to become a Th2 cell?
what stimulates a T helper cell to become a Th17 cell?
TGF-beta + IL-6
positive selection in T cell differentiation
thymic cortex T cells expressing TCRs capable of binding surface self-MHC molecules survive
negative selection in T cell differentiation
medulla or thymus T cells expressing TCRs with high affinity for self antigens undergo apoptosis
TH1 cell: secretions
TH1 cell: activate___
macrophages cytotoxic T cells
TH1 cell: activated by ___
TH1 cell: inhibited by___
IL-4, IL-10 (fro Th2 cell)
TH2 cell: secretions
IL-4 IL-5 IL-10 IL-13
TH2 cell: recruits___
eosinophils for parasite defense
TH2 cell: promotes___
IgE production by B cells
TH2 cell: activated by___
TH2 cell: inhibited by___
INF-gamma (from Th1 cell)
what secretes IL-12 and what does IL-12 stimulate?
macrophages differentiation of T cells to Th1 cells
what secretes IFN-gamma to stimulate macrophages?
CD4 is expressed by what cells and it binds to what?
helper T cells MHC II on APCs
CD8 is expressed by what cells and it binds to what?
cytotoxic T cells MHC-I on virus-infected cells
regulator T cells maintain high immune tolerance y suppressing___
how many signals are required for T-cell activation, and B-cell activation and class switching?
Native T-cell activation steps
1. dendritic cell (specialized APC) samples/processes antigen 2. d.c. migrates to draining lymph node 3. foreign antigen presented to MHC II, recognized by TCR on CD4+ Th cell/MHCI on Tc (CD8+) cell 4. "costimulatory signal" given by B7-CD28 interaction (SIGNAL 2) 5. Th cell activates, produces cytokines; Tc activates and can recognize, kill virus-infected cell
B-cell activation and class switching steps
1. Th-cell activation 2. B-cell receptor-mediated endocytosis; foreign antigen presented on MHC II and recognized by TCR on Th cell (SIGNAL 1) 3. CD40 receptor on B cell binds CD40 ligand on Th cell (SIGNAL 2) 4. Th cell secretes cytokines (determine Ig class switching). B cell activates, switches class, affinity maturation, antibody production
Components of the Fab (variable) region of an antibody
light (L) and heavy (H) chains recognize antigens
function of Fc region of IgM and IgG
what chain contributes to both Fc and Fab?
what chain only contributes to Fab?
(Fragment, antigen binding) determines idiotype: unique antigen-binding pocket only 1 antigen specifically expressed per B cell
1. random recombination of VJ (light chain) or V(D)J (heavy chain) genes 2. random combination of heavy and light chains 3. somatic hypermutation after antigen stimulation 4. addition of nucleotides to DNA during recombination by terminal deoxynucleotidyl transferase(TdT)
what do mature B cells express on surface?
where does isotype switching of B cells occur?
germinal centers of lymph nodes (gene rearrangement, mediated by cytokines and CD40L) differentiate into plasma cells that secrete IgA, IgE, IgG
main Ab in secondary (delayed) response to antigen most abundant isotype in serum fixes complement crosses placenta (passive immunity of infants) opsonizes bacteria neutralizes bacterial toxins and viruses
prevents bacteria/virus attachment to mucus membranes does not fix complement monomer in circulation; dimer when secreted crosses epithelial cells via transcytosis Peyers patches of GI tract secrete-->protects against gut infections most produced antibody overall but lower serum conc. released into tears, saliva, breast milk, mucus
produced in primary (immediate) response to antigen fixes complement cannot cross placenta antigen receptor on mature B cells monomer on B cell; pentamer when secreted
what is the function of the pentamer structure of secreted IgM?
enables avid antigen binding while humoral response evolves
unclear function found in serum and on surface of many B cells
binds mast cells and basophils cross-links when exposed to allergen --> type I hypersenstivity response via release of inflam. mediators (ex- histamine) mediates immunity to worms via eosinophil activation
what antibody has the lowest serum conc?
what antibody is the highest produced overall?
lack peptide component (e.g. LPS) cannot be presented by MHC to T cells weakly or nonimmunogenic vaccines require boosters and adjucants (e.g. pneumococcal polysaccharide vaccine)
contain protein component (e.g. diptheria vaccine) class-switching, immunologic memory occur due to B cell direct contact w/ Th cells (CD40-CD40L interaction)
factors whose serum conc. change greatly in response to inflammation made by liver in both acute and chronic inflammatory states notably induced by IL-6
(+) upregulated acute-phase reactants: C-reactive protein (CRP)
opsonin fixes complement facilitates phagocytosis measured clinically as sign of ongoing inflammation
(+) upregulated acute-phase reactants: ferritin
binds to and sequesters Fe to inhibit microbial Fe scavenging
(+) upregulated acute-phase reactants: fibrinogen
coagulation factor promotes endothelial repair correlates with ESR
(+) upregulated acute-phase reactants: hepcidin
prevents release of Fe bound to ferritin --> anemia of chronic disease
(+) upregulated acute-phase reactants: serum amyloid A
complement-mediated lysis of RBCs paroxysmal nocturnal hemoglobinuria
Important Cytokines: mnemonic
Hot T-bone stEAK" IL-1: fever (hot) IL-2: T cell stimulation IL-3: Bone marrow stimulation IL-4: IgE production stimulation IL-5: IgA production stimulation IL-6: aKute-phase protein production stimulation
Cytokines secreted by macrophages: IL-1
aka-osteoclast-activating factor fever, acute inflammation activated endothelium to express adhesion molecules induces chemokine secretion for WBC recruitment
Cytokines secreted by macrophages: IL-6
fever stimulates acute-phase protein production
Cytokines secreted by macrophages: IL-8
major chemotactic factor for neutrophils "clean up on aisle 8: neutrophils clear infections"
Cytokines secreted by macrophages: IL-12
induces T cell differentiation into Th1 cells activates NK cells
stimulates growth of helper, cytotoxix, and regulatory T cells, and NK cells
Cytokines secreted by all T cells: IL-3
supports growth and differentiation of bone marrow stem cells functions like GM-CSF
Cytokines secreted by Th1 cells: interferom-gamma
secreted by NK cells in response to IL-2 from macrophages stimulates macrophages to kill phagocytosed pathogens activates NK cells to kill virus-infected cells increases MHC expression and antigen presentation by all cells
Cytokines secreted by Th2 cells: IL-4
induces differentiation into Th2 cells promotes frowth of B cells enhances class switching to IgE and IgG
Cytokines secreted by Th2 cells: IL-5
promotes B cell differentiation enhances class switching to IgA stimulates growth and differentiation of eosinophils
Cytokines secreted by Th2 cells: IL-10
modulates inflammatory response decreases expression of MCH II and Th1 cytokines inhibits activated macrophages and dendritic cells also secreted by regulatory T cells
what two substances are major attenuators of the immune/inflammatory response?
TGF-beta(she act beta so she attenuate d response) IL-10
function of respiratory burst
ROS production from respiratory burst --> neutralized by NADPH, which also creates them
blue-green heme-containing pigment that colors sputum associated with respiratory burst
respiratory burst diagram
disease characterized by NADPH oxidase def.
chronic granulomatous disease
enzyme of respiratory burst: O2-->O2-1 (free radical)
NADPH oxidase phagolysosome
enzyme of respiratory burst: O2 free radical --> H2O2
enzyme of respiratory burst: H2O2--> H20 and GSH ---> GSSG
glutathione peroxidase req. Se neutrophil
enzyme of respiratory burst: GSSG--->GSH and NADPH---> NAD+
glutathione reductase req. Se neutrophil
enzyme of respiratory burst: NAD+--->NADPH and glucose-6P--->6-phosphogluconate
P. aeruginose can make what that kills competing microbes?
what protein in secretory fluid and neutrophils inhibits bacterial growth via Fe chelation?
phagocytes of pt with CGD have no H202 so what do they do
they can utilize H202 generated by invading organisms and convert it to ROS. so pt are at risk of catalase+ species capable of neutralizing their own H202, leaving phagocytes without ROS for fighting infections
interferons alpha and beta
defense against DNA and RNA viruses act locally on unifected cells; secreted glycoproteins of infected cell help other cells selectively degrade viral DNA/RNA and proteins cause apoptosis-->stop viral amplification
CD14 CD40 MHC II B7 Fe and C3b receptors (enhanced during phagocytosis)
NK cell surface proteins
CD16 (binds Fe, IgG) CD56 (unique to NK)
hematopoietic stem cell surface protein
state in which cell cannot become activated by exposure to its antigen happens to T/B cells when exposed to their antigen w/o costimulatory signal (signal 2) mechanism of self-tolerance
effects of bacterial toxins
superantigens (S. pyogenes, S aureus) = massive cytokine release via APC's MHC II cross-linking w/ beta region of TCR, which can then activate and CD4+ T cell LPS/endotoxins directly stimulate endotoxin receptor TLR4/CD14 on macrophages
DNA rearrangement and RNA segment reassortment are mechanisms of ___
3 bacteria, 3 viruses, 1 parasite that often exhibit antigenic variation
inactivated by heat or chemicals epitopic structure of surface antigens maintained mainly humoral response
inactivated/killed vaccine: pros/cons
pros: safer than live vaccine cons: weaker immune response; boosters usually req.
inactivated/killed vaccine: examples
"RIP Always" Rabies Influenza (injection) Polio (Salk) hep A
Type I hypersensitivity
anaphylactic, atopic free antigen cross-links IgE on presensitized mast cells and basophils --> immediate vasoconstrictive amine release (eg histamine) acting on post-capillary venules rapid due to preformed antibody delayed response due to production of arachidonic acid metabolites (eg leukotrienes)
test for type I hypersensitivity
IgE-specific skin test
antibody-mediated hypersensitivity types
I II III
type II hypersensitivity
cytotoxic (Ab mediated) IgG, IgM bind fixed antigen on enemy cell--> cell destruction mechanisms: opsonization+phagocytosis; complement+Fc-receptor mediated inflammation; Ab-mediated cellular dysfunction Ab+ complement = MAC
tests for type II hypersensitvity
1. direct Coombs: test: detects Abs that have been adhered to patient's RBCs 2. indirect Coombs' test: detects serum Abs that can adhere to other RBCs
type III hypersensitivity tissue damage when Ab-foreign protein complexes are deposited on cell membranes, where they fix to complement more common than Arthus rxn can be caused by drugs acting as haptens
serum sickness presentation
5-10 days after exposure fever urticaria arthralgia proteinuria lymphadenopathy
type III hypersensitivity local, subacute, Ab-mediated intrademal antigen injection ---> complexes form in skin
Arthus rxn presentation
edema necrosis activation of complement
Arthus rxn test
type IV hypersensitivity rxn
delayed T-cell mediated sensitized T cells encounter antigen and release cytokines---->macrophage activation no Ab involvement not transferable by serum test: patch test, PPD
4 Ts of type IV hypersensitivity rxn
T cells Transplant rejections TB skin tests Touching (contact dermatitis)
hypersensitivity rxns: ACID
Anaphylactic, Atopic (I) Cytotoxic (Ab mediated) (II) Immune complex (III) Delayed (cell mediated) (IV)
grafted immunocompetent T cells proliferate in immunocompromised host, reject host cells w/ foreign proteins--->severe organ dysfunction
transplant rejections: graft-vs.-host disease: features
maculopapular rash jaundice diarrhea hepatosplenomegaly usually in bone marrow, liver transplants (rich in lymphocytes) potentially beneficial in bone marrow transplant for leukemia (raft-vs-host tumor effect)
block lymphocyte activation and proliferation suppress cellular immunity to reduce acute transplant rejection frequently combined for inc efficacy with dec toxicity chronic use = inc infection, malignancy risk
immunosuppressants: cyclosporine mechanism
calcineurin inhibitor binds cyclophilin blocks T cell activation by preventing IL-2 transcription
loss of what complement protein leads to bacterial infections?
loss of what complement proteins leads to susceptibility to bacterial meningitis?
loss of what component of the complement cascade leads to edema? how?
C1 inhibitor impacts fixation, clotting, and kinin pathways
in an acute phase reaction, the liver increases secretion of what proteins? what molecules stimulate it to do so? what molecules decrease secretion?
1. C-reactive protein, serum amyloid, ceruloplasmin, complement factor-3, haptoglobin, fibrinogen, alpha1-antitrypsin 2. cytokines from macrophages at inflammation site (IL-1,6, TNF-alpha) 3. albumin, transferrin
Fe-binding protein secreted by exocrine glands and some granules in neutrophils deprives bacteria of iron
bactericidal oxidoreductase from mucosal glands, including salivary and mammary catalyzes oxidation, H20 production using H2O2
anaphylotoxin function and associated complements
potent stimulator of phagocytosis C3a, C4a, C5a
serine endoprotease that converts quiescent proprotein complement to highly reactive form ex: C3 and C5 convertases
opsonization w/ C3b causes...
directs macrophage phagocytosis
opsonization w/ C5b causes...
directs formation of MAC
bactericidal oxidoreductase expressed in neutrophils, stored in asurophilic granules Cl- oxidation using H2O2, forming HCl catalytic cofactor has heme-->green pus
hypoxanthine--->xanthine w/ H2O2 from H2O xanthine then converted to uric acid + H2O2 acts of alipatic compounds producing ROS major constituent of globules in breast milk
C-X-C chemokines (alpha)
have 2 cysteines separated by 1 AA attract neutrophils potent ones: IL-8, platelet factor 4, IFN-gamma, inducible protein 10, macrophage activation factors
C-C chemokines (beta)
have 2 adjacent cysteines most attract monocytes, T cells (some attract eos., baso., NK cells) via MCPs, MIP, RANTES
difference between monokines and lymphokines
produced by lymphocytes vs. monocytes/macrophages
effector cells of innate immunity are referred to as...
granulocytes or PMN cells
function of chemokines in innate immune system
function of cytokines in innate immune system
illicit specific physiological responses
function of selectins
on most leukocytes steady-state lymphocyte entry into immune organ directs secondary tethering of neutrophils binding partners: E-selectin, CLA
cutaneous lymphocyte antigen
on endothelial cells induced by IL-1beta, TNF-alpha, TNF-beta, LPS NF-KB regulation (pro-inflammatory TF) downregulated by internalization, routed to lysosome
on endothelial cells prepackaged in Weibel-Palade bodies histamine, thrombin, O radicals-->rapid surface expression rapid down-reg via internalization recycled from endosomes to secretory granules expression induced by TNF-alpha, LPS
NK cytotoxic T cell screens for missing MHC I; antiviral perforin, granzyme
alpha-beta T cell receptor
on thymus-derived T cells recognize peptides presented by MHC II
gamma-delta T cell receptor
on mucosal epithelial T cells recognize free peptides does not need antigen presentation
mucosal areas Abs to bacterial polysaccharides and LPS limited repertoire to different antigens
produced in germinal centers undergo Ig rearrangements, somatic hypermutation, class-switching differentiate into plasma cells produce large amts of Abs
immature dendritic cells
accumulate and identify foreign substances at site of inflammation PAMP exposure-->maturation and migration to draining lymph node (adjacent to mature naive T cells in paracortex)
mature dendritic cells present antigen to what?
Th cells (using MHC II)
marginal zone B cells
in spleen produce Abs to polysaccharides
location of gamma-delta T cells
boundary areas of gut mucosa and epithelia
NK cells target cells with....
Ab labels complement labels aberrant MHC I
NK cells have receptors for...
complement (C3a,b and C5a) IgG, IgA
killer inhibitory receptor expressed on NK cells binds to normal MHC I-->deactivated NK--->no rxn NK causes apoptosis if KIR is not engaged by cell
2 ways in which NK cell causes apoptosis
1. granule exocytosis 2. TNF pathway
NKT cells have receptors for..., recognize...
alpha-beta TCR and NK lecithin receptor (NK1.1.) glycolipids displayed by CD1
leukocyte (< 1% abundance) lymphocyte-derived important in viral infections produces large amts interferons alpha and beta no complement receptor (CD110) or LPS receptor (CD14) has TLR-7 to detect ssRNA; TLR-9 tod etect CpG
what happens to an antigen that enters intravenously?
phago- or pinocytosed in spleen
what happens to an antigen that enters by a route that is not intravenous?
trafficked to lymph node draining site of entry
CD28 on T cell + B.71 on APC--->
inc IL-2 synthesis
development of Ab synthesis B cell differentiation IgE production suppress CMI by down-reg IFN-gamma by Th1
B cell differentiation w/ IL-2,4 eosinophil differentiation IgA synthesis
activate macrophages, NK cells HLA antigen presentation by endothelial cells down-reg IL-4-->dec Ab synthesis
activate macrophages acute phase response w/ IL-1
which ILs from dendritic cells and macrophages aid in transition of macrophages, Tc, NK cells to CMI?
inhibits Th1 secretion of IFN-gamma (reduced macrophage activation) and IL-2
inhibits Th1 secretion of IFN-gamma (reduced macrophage activation) and IL-2
which IL influences terminal differentiation of a B cell into a plasma cell and IgM secretion?
IL-4 and IFN-gamma stimulate switch to which Ig type?
IgG IL-4 also stimulates switch to IgE
TGF-beta stimulates switch to which Ig type?
binding of ___ on B cell to ___ on Th cell is necessary for switching to occur
affinity vs avidity
1. binding energy b/w Ab and univalent epitope 2. total " " and multivalent antigen
donor cells + recipient serum determines whether anti-RBC Abs are present in recipient's serum slide agglutination test
donor serum + recipient cells less severe resultant transfusion reaction would occur than in major crossmatch b/c minimal donor serum Abs compared to donor serum slide agglutination test
what is the Coombs direct test used to detect?
weak or nonagglutinating anti-Rh Ab (add antihuman Ig directly to infant's RBCs) (indirect detects Abs in maternal circulation)
immunoelectrophoresis is used to detect specific what?
RIST (radioimmunosorbent test) is used for what?
measure total (nonspecific) IgE in allergic patients' serum
RAST (radioallergosorbent test) is used for what?
measure IgE in pt serum specific for a given allergen
Type O blood terminal epitope genotype (Rh+ and -)
fructose, galactose Rh+: DCe Rh-: dce
Type A blood terminal epitope genotype (Rh+ and -)
N-acetylgalactosamine Rh+: RcE Rh-: dCe
Type B blood terminal epitope genotype (Rh+ and -)
galactose Rh+: DCE Rh-: dcE
Type AB blood terminal epitope genotype (Rh+ and -)
n/a Rh+: Dce Rh-: dCE
transient physiologic hypogammaglobulineia
normal infants 3-6 mos caused by diaappearance of maternal IgG (1/2 life 22-28 days) and infant's early slow rate if synthesis of secretable IgG
dec levels selective Ig (usually IgA) mucosal surface protection diminished or lost increased incidence AI diseases normal # IgA-bearing cells, but they fail to differentiate into screening plasma cells