652 terms

USMLE Immunology

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lymph node structure
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)
Lymph drainage (by lymph node cluster):
cervical
head and neck
Lymph drainage (by lymph node cluster):
hilar
lungs
Lymph drainage (by lymph node cluster):
mediastinal
trachea and esophagus
Lymph drainage (by lymph node cluster):
acillary
upper limb
breast
skin above umbilicus
Lymph drainage (by lymph node cluster):
celiac
liver
stomach
spleen
pancreas
upper duodenum
Lymph drainage (by lymph node cluster):
superior mesenteric
lower duodenum
jejunum
ileum
colon to splenic flexure
Lymph drainage (by lymph node cluster):
inferior mesenteric
colon from splenic flexure to upper rectum
Lymph drainage (by lymph node cluster):
internal iliac
lower rectum to anal canal (above pectinate line)
bladder
vagina (middle 1/3)
prostate
Lymph drainage (by lymph node cluster):
para-aortic
testes
ovaries
kidneys
uterus
Lymph drainage (by lymph node cluster):
superficial inguinal
anal canal (below pectinate line)
skin below umbilicus (except popliteal territory)
scrotum
Lymph drainage (by lymph node cluster):
popliteal
dorsolateral foor
posterior calf
duct that drains right side of body above diaphragm
right lymphatic duct
thoracic lymphatic duct drains___ and drains into___
everything except right side of body above diaphragm
drains into left subclavian and internal jugular veins
spleen sinusoid structure
long, vascular channels in red pulp (RBC filteration)
fenestrated "barrel hoop" basement membrane
location of T cells in spleen
periarteriolar lymphatic sheath (PALS) of white pulp (WBC filteration)
location of B cells in spleen
follicles in white pulp
characteristics of marginal zone of spleen
between red and white pulps
contains APCs and specialized B cells
APCs capture blood-borne antigens for recognition by lymphocytes
function of macrophages in spleen
remove encapsulated bacteria
splenic dysfunction causes___
dec. IgM = dec. complement activation = dec. C3b opsonizaton = inc. susceptibility to encapsulated organisms (SHiNE SKiS)
SHiNE SKiS
(encapsulated organisms)
Streptococcus pneumoniae
Haemophilus influenzae type B
Neisseria meningitidis
Escheria coli
Salmonela spp.
Klbesiella pneumoniae
group b Steptococci
postsplenectomy signs
Howell-Jolly bodies (nuclear remnants)
Target cells
Thrombocytosis (loss of sequestration and removal)
Lymphocytosis (loss of sequestration)
thymus is derives from___
third pharyngeal puch
thymus structure/function
T-cell differentiation and proliferation
capsule
cortex = dense w/ immature T cells
medulla = pale w/ mature T cells
Hssall corpuscles contain epithelial reticular cells
lymphocytes of thymus are derived from ___
mesenchyme
Innate immunity:
components
neutrophils
macrophages
monocytes
dendritic cells
NK cells (lymphoid origin)
complement
Innate immunity:
mechanism
germline encoded
Innate immunity:
resistance
persisits through generations
does not change over lifestime
Innate immunity:
response
nonfecific
rapid (min to hours)
Innate immunity:
physical carriers
epithelial tight junctions
mucus
Innate immunity:
secreted proteins
lysozyme
complemeny
C-reactive protein (CRP)
defensins
Innate immunity:
key recognition features
toll-like receptors (TLRs)
TLRs
toll-like receptors
pattern recognition receptors for pathogen-associated molecular patters (PAMPs)
ex: LPS (G-), flagellin (bacteria), ssRNA (viruses)
adaptive immunity:
components
T cells
B cells
circulating antibodies
adaptive immunity:
mechanism
viriation through V(D)J recombination during lymphocyte development
adaptive immunity:
resistance
microbial resistance not heritable
adaptive immunity:
response
highly specific
refined over time
develops over long periods
memory response is faster and more robust
adaptive immunity:
physical barriers
none
adaptive immunity:
secreted proteins
Igs
adaptive immunity:
key recognition features
memory cells: activated T and B cells
subsequent exposure to a previously encountered pathogen--> stronger, quicker immune response
MHC is encoded by ___ genes
HLA
MHC function (general)
present antigen fragments to T cells
bind T-cell receptors (TCRs)
MHC I:
loci
HLA-A, B, C
MHC I:
binding
TCR
CD8
MHC I:
expression
all nucleated cells
(not on RBCs)
MHC I:
function
present endogenously synthesized antigens (e.g. viral or cytosolic proteins) to CD8+ (cytotoxic) T cells
MHC I:
antigen loading
in RER after deliver via TAP (transporter associated with antigen processing)
MHC I:
associated protein
beta2-microglobulin
MHC II:
loci
HLA-DR,DP, DQ
MHC II:
binding
TCR and CD4
MHC II:
expression
expressed on APCs (macrophages, dendritic cells)
MHC II:
function
present exogenously synthesized antigens (e.g. bacterial proteins) to CD4+ helper T cells
MHC II:
antigen loading
following release of invariant chain in an acidified endosome
MHC II:
associated protein
invariant chain
HLA subtypes associated with diseases:
A3
hemochromatosis
HLA subtypes associated with diseases:
B27
PAIR (aka - seronegative arthropathies):
Psoriatic arthritis
Ankylosing spondylitis
arthritis of IBD
Reactive arthritis (formerly Reiter syndomr)
HLA subtypes associated with diseases:
DQ2/DQ8
celiac disease
HLA subtypes associated with diseases:
DR2
MS
hay fever
SLE
Goodpasture syndrome
HLA subtypes associated with diseases:
DR3
diabetes mellitus type 1
SLE
Graves disease
Hashimoto thyroiditis
HLA subtypes associated with diseases:
DR4
rheumatoid arthritis
diabetes mellitus type 1
"4 walls in a rheum"
HLA subtypes associated with diseases:
DR5
pernicious anemia-->vit B12 def, Hashimoto thyroiditis
NK cell function
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?
innate
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)
T cells
what lymphocytes function in acute and chronic cellular organ rejection?
T cells
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?
IL-12
INF-gamma
what stimulates a T helper cell to become a Th2 cell?
IL-4
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
IFN-gamma
TH1 cell:
activate___
macrophages
cytotoxic T cells
TH1 cell:
activated by ___
INF-gamma, IL-12
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___
IL-4
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?
Th1 cells
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___
CD4 and CD8 T cell effector functions
regulatory T cells express___
CD3
CD4
CD25
FOXP3
activated regulatory T cells produce___
anti-inflammatory cytokines
(e.g. IL-10, TGF-beta)
3 types of antigen-presenting cells
B cells
macrophages
dendritic cells
how many signals are required for T-cell activation, and B-cell activation and class switching?
2
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
fix complement
what chain contributes to both Fc and Fab?
heavy
what chain only contributes to Fab?
light
Fab function
(Fragment, antigen binding)
determines idiotype: unique antigen-binding pocket
only 1 antigen specifically expressed per B cell
Fc characteristics
Constant
Carboxy terminal
Complement binding
Carb side chains
determines idiotype (IgM, IgG, etc)
what drive antibody diversity?
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?
IgM
IgG
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
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
IgA
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
IgM
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
IgD
unclear function
found in serum and on surface of many B cells
IgE
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?
IgE
what antibody is the highest produced overall?
IgA
Thymus-independent antigens
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)
Thymus-dependent antigens
contain protein component (e.g. diptheria vaccine)
class-switching, immunologic memory occur due to B cell direct contact w/ Th cells (CD40-CD40L interaction)
acute-phase reactants
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
prolonged elevation --> amyloidosis
(-) downregulated acute-phase reactants:
albumin
reduction conserves AAs for + reactants
(-) downregulated acute-phase reactants:
transferrin
internalized by macrophages to sequester Fe
complement pathway
complement
system of hepatically synthesized plasma proteins that function in innate immunity and inflammation
membrane attack complex (MAC) defends against Gram negative bacterias
Complement Activation:
classic pathway
IgG or IgM
(GM makes classic cars)
(antibody-antigen complexes)
Complement Activation:
alternative pathway
microbe surfacce molecules
Complement Activation:
lectin pathway
mannose or other sugars on microbe surface
Complement: functions
C3b
opsonization
(b binds bacteria)
Complement: functions
C3a, C4a, C5a
Anaphylaxis
Complement: functions
C5a
neutrophil chemotaxis
Complement: functions
C5b-9
cytolysis by MAC
Complement: functions
opsonins
C3b and IgG = primary in bacterial defense
enhance phagocytosis
Cb3 also helps clear immune complexes
Complement: functions
inhibitors
decay-accelerating factor (DAF, aka CD55)
C1 esterase inhibitor
(prevent complement activation of self cells) (e.g. RBCs)
Complement Disorders:
C1 esterase inhibitor deficiency
hereditary angioedema
ACE inhibitors are contraindicated
Complement Disorders:
C3 deficiency
increases risk of severe, recurrent pyogenic sinus and respiratory infections
increased susceptibility to type III hypersensitivity rxns
Complement Disorders:
C5-C9 deficiencies
terminal complement deficiency increases susceptibility to recurrent Neisseria bacteremia
Complement Disorders:
DAF (GPI-anchored enzyme) deficiency
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
Cytokines secreted by macrophages:
TNF-alpha
mediates septic shock
activates endothelium
WBC recruitment
vascular leak
causes cachexia in malignancy
Cytokines secreted by all T cells:
IL-2
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
myeloperoxidase
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
superoxide dismutase
phagolysosome
enzyme of respiratory burst:
H2O2---> H2O + O2
bacterial catalase
phagolysosome
enzyme of respiratory burst:
H2O2 + Cl- ---> HClO+ (bleach, hypochlorote)
myeloperoxidase
phagolysosome
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
G6PD
neutrophil
P. aeruginose can make what that kills competing microbes?
ROS
what protein in secretory fluid and neutrophils inhibits bacterial growth via Fe chelation?
lactoferrin
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
TCR binds___
antigen-MHC complex
TCR location
T cell surface
CD3 location and associated receptor
T cell surface
TCR (for signal transduction)
CD28 location and function
T cell surface
binds B7 on APC
helper T cell surface proteins
CD4
CD40L
cytotoxic T cell surface proteins
CD8
regulatory T cell surface proteins
CD4
CD25
B cell surface proteins
Ig (binds antigen)
MHC II
CD19, 20, 21 (EBV receptor), 40
B7
macrophage surface proteins
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
CD34
anergy
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 ___
antigenic variation
3 bacteria, 3 viruses, 1 parasite that often exhibit antigenic variation
B: Salmonella (2 flagellar variants), Borrelia reccurentis (relapsing fever), N. gonorrhoeae (pilus protein)
V: flu, HIV, HCV
P: trypanosomes
Passive immunity:
acquisition
receive preformed antibodies
Passive immunity:
onset
rapid
Passive immunity:
examples
IgA in breastmilk
maternal IgG crossing placenta
antitoxin
humanized monoclonal Ab
Passive immunity:
after exposure to these dz(------) unvaccinated pt are given preformed antibodies(passive)
"To Be Healed Very Rapidly"
Tetanus toxin
Botulinum toxin
HBV
Varicella
Rabies virus
Active immunity:
acquisition
foreign antigen exposure
Active immunity:
onset
slow
Active immunity:
duration
long-lasting (memory)
Passive immunity:
duration
short span of antibodies
(1/2 life appx. 3 weeks)
Active immunity:
examples
natural infection
vaccine
toxoid
passive and active immunization can be given for exposure to what 2 diseases?
hep B
rabies
vaccination induces a ___ immune response
active
live attenuated vaccine:
description
microbe loses pathogenicity but retains capacity for transient growth in inoculated host
cellular AND humoral responses
live attenuated vaccine:
only one given to people HIV+
MMR
live attenuated vaccine:
Pros/Cons
pros: strong, often lifelong immunity
cons: may revert to virulent form; contraindicated w/ pregnancy, immunodeficiency
live attenuated vaccine:
examples
MMR
Sabian polio
intranasal flu
varicella
yelow fever
inactivated/killed vaccine:
description
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
IgG-antigen complex activates complement--> neutrophil attraction--->neutophils release lysosomal enzymes
Serum rxn
Arthus rxn
Serum reaction
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
Arthus reaction
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
immunofluorescent staining
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)
type I hypersensitivity disorders
(immediate, anaphylactic, atopic)
1. allergic, atopic disorders (rhinitis, hay fever, eczema, hives, asthma)
2. bee sting, food/drug allergy
type II hypersensitivity disorders
(specific to tissue where antigen is)
acute hemolytic transfusion rxns
autoimmune hemolytic anemia
bullous pemphigoid
erythroblastosis fetalis
Goodpasture syndrome
Graves disease
Guillain-Barre syndrome
idiopathic thrombocytopenia purpura
myastenia gravis
pemphigus vulgaris
pernicious anemia
rheumatic fever
type III hypersensitivity disorders
(possible vasculitis and systemic manifestations)
Arthus rxn (swelling, inflammation post tetanus vaccine)
SLE
polyarteritis nodosa
poststreptococcal glomerulonephritis
serum sickness
type IV hypersensitivity disorders
(delayed)
contact dermatitis (poison ivy/oak, nickel allergy)
graft-vs-host disease
MS
PPD test for M tuerculosis
blood transfusion reactions: allergic
pathogenesis
type I hypersensitivity against plasma proteins in transfused blood
blood transfusion reactions: allergic
clinical presentation
urticaria
pruritis
wheezing
fever
blood transfusion reactions: allergic
treatment
antihistamines
blood transfusion reactions: anaphylactic
pathogenesis
severe allergic rxn
IgA-deficient pts must receive blood products without IgA
blood transfusion reactions: anaphylactic
clinical presentation
dyspnea
bronchospasm
hypotension
respiratory arrest
shock
blood transfusion reactions: anaphylactic
treatment
epi
blood transfusion reactions: febrile nonhemolytic transfusion rxn
pathogenesis
type II hypersensitivity rxn
host Abs against donor HLA antigens and WBCs
blood transfusion reactions: febrile nonhemolytic transfusion rxn
clinical presentation
fever
headaches
chills
flushing
blood transfusion reactions: acute hemolytic transfusion rxn
pathogenesis
type II hypersensitivity rxn
intravascular hemolysis (ABO type incompatibility)
or extravascular hemolysis (host Ab rxn against donor RBC antigen)
blood transfusion reactions: acute hemolytic transfusion rxn
clinical presentation
fever
hypotension
tachypnea
tachycardia
flank pain
hemoglobinuria (intravascular hemolysis)
jaundice (extravascular hemolysis)
autoantibodies by associated disease:
myasthenia gravis
anti-ACh receptor
autoantibodies by associated disease:
Goodpasture syndrome
anti-basement membrane
autoantibodies by associated disease:
SLE, antiphospholipid syndrome
aticardiolipin
lupus anticoagulant
autoantibodies by associated disease:
limited scleroderma (CREST syndrome)
anticentromere
autoantibodies by associated disease:
pemphigus vulgaris
antidesmosome (anti-desmoglen)
autoantibodies by associated disease:
SLE
anti-dsDNA
anti-Smith
autoantibodies by associated disease:
type I diabetes mellitus
anti-glutamic acid decarboxylase (GAD-65)
autoantibodies by associated disease:
bullois pemphigoid
antihemidesmosome
autoantibodies by associated disease:
drug-induced lupus
anti-histone
autoantibodies by associated disease:
polymyositis, dermatomyositis
anti-Jo-1
anti-SRP
anti-Mi-2
autoantibodies by associated disease:
primary biliary cirrhosis
antimitochondrial
autoantibodies by associated disease:
Hashimoto thyroiditis
antimicrosomal
antithyroglobulin
autoantibodies by associated disease:
SLE, nonspecific
antinuclear antibodies
autoantibodies by associated disease:
pernicious anemia
antiparietal cell
autoantibodies by associated disease:
scleroderma (diffuse)
anti0Scl-70 (anti-DNA topoisomerase I)
autoantibodies by associated disease:
autoimmune hepatitis
anti-smooth muscle
autoantibodies by associated disease:
Sjorgen syndrome
anti-SSA
anti-SSB
(anti-Ro, anti-LA)
autoantibodies by associated disease:
Graves disease
anti-TSH receptor
autoantibodies by associated disease:
mixed connective tissue disease
anti-U1 RNP (ribonucleoprotein)
autoantibodies by associated disease:
celiac disease
IgA anti-endomysial
IgA anti-tissue transglutaminase
autoantibodies by associated disease:
microscopic polyangitis, eosinophilic granulomatosus with polyangitis (Churg-Strauss syndrome)
MPO-ANCA/p-ANCA
autoantibodies by associated disease:
granulomatosis with polyangitis (Wegner syndrome)
PR3-ANCA/c-ANCA
autoantibodies by associated disease:
rheumatoid arthritis
rheumatoid factor (IgM that targets IgG Fc region)
anti-CCP (more specific)
Immunodeficiencies: B cell disorders:

X-linked (Bruton) agammaglobulinemia
defect
in BTK (a tyrosine kinase gene)---> no B cell maturation
Immunodeficiencies: B cell disorders: X-linked (Bruton) agammaglobulinemia
inheritance
X-linked
Immunodeficiencies: B cell disorders: X-linked (Bruton) agammaglobulinemia
presentation
recurrent bacterial, enteroviral infections after 6 mos (dec. maternal IgG)
Immunodeficiencies: B cell disorders: X-linked (Bruton) agammaglobulinemia
findings
no B cells in peripheral lood
dec Ig all classes
absent/scanty lymph nodes, tonsils
Immunodeficiencies: B cell disorders: selective IgA deficiency
defect
unknown
most common primary immunodeficiency
Immunodeficiencies: B cell disorders: selective IgA deficiency
presentation
usually asymptomatic
Airway, GI infections
Autoimmune disease
Atopy
Anaphylaxis to IgA-containing products
Immunodeficiencies: B cell disorders: selective IgA deficiency
findings
normal IgG, IgM
decreased IgA
Immunodeficiencies: B cell disorders: common variable immunodeficiency:
defect
many causes
affects B-cell differentiation
Immunodeficiencies: B cell disorders: common variable immunodeficiency:
presentation
can be acquired in 20s-30s
inc. risk autoimmune disease, brochiestasis, lymphoma, sinopulmonary infections
Immunodeficiencies: B cell disorders: common variable immunodeficiency:
findings
dec plasma dells
dec immunoglobulins
Immunodeficiencies: T cell disorders: thymic aplasia (DiGeorge syndrome)
defect
22q11 disease
failure to develope 3rd, 4th pharyngeal pouches-->no thymus, parathyroids
Immunodeficiencies: T cell disorders: thymic aplasia (DiGeorge syndrome)
presentation
tetany (hypocalcemia)
recurrent viral/fungal infections (T cell def.)
conotruncal abnormalities (tetralogy of Fallot, truncus arteriosus, etc)
Immunodeficiencies: T cell disorders: thymic aplasia (DiGeorge syndrome)
findings
dec T cells
dec PTH
dec Ca2+
absent thymic shadow in CXR
22q11 deletion detected by FISH
Immunodeficiencies: T cell disorders:IL-12 receptor deficiency
defect
dec Th1 response
Immunodeficiencies: T cell disorders:IL-12 receptor deficiency
inheritance
AR
Immunodeficiencies: T cell disorders:IL-12 receptor deficiency
presentation
disseminated mycobacterial and fungal infections
may present after BCG vaccine
Immunodeficiencies: T cell disorders:IL-12 receptor deficiency
findings
dec INF-alpha
Immunodeficiencies: T cell disorders: autosomal dominant hyper-IgE syndrome (Job syndrome)
defect
Th17 cell def. due to STAT3 mutation---> impaired neutrophil recruitment to infection sites
Immunodeficiencies: T cell disorders: autosomal dominant hyper-IgE syndrome (Job syndrome)
presentation
FATED:
Facies
cold (noninflammed) staph. Abcesses
retained primary Teeth
inc. IgE
Dermatologic problems (eczema)
Immunodeficiencies: T cell disorders: autosomal dominant hyper-IgE syndrome (Job syndrome)
findings
inc. IgE
dec. INF-gamma
Immunodeficiencies: T cell disorders: chronic mucocutaneous candidiasis
defect
T-cell dysfunction
many causes
Immunodeficiencies: T cell disorders: chronic mucocutaneous candidiasis
presentation
noninvasive Candida albicans infections of skin and mucous membranes
Immunodeficiencies: T cell disorders: chronic mucocutaneous candidiasis
findings
absent in vitro T-cell proliferation in response to Candidia antigens
absent cutaneous rxn to Candida antigens
Immunodeficiencies: B and T cell disorders: SCID
defect
several types:
defective IL-2R gamma chain (most common, X-linked)
adenosine deaminase def. (AR)
Immunodeficiencies: B and T cell disorders: SCID
presentation
failure to thrive
chronic diarrhea
thrush
recurrent viral, bacterial, fungal, protozoal infections
Immunodeficiencies: B and T cell disorders: SCID
treatment
bone marrow transplant (no concern for rejection)
Immunodeficiencies: B and T cell disorders: SCID
findings
dec T-cell receptor excision circles (TRECs)
absent thymic shadow on CXR, germinal centers (lymph node biopsy), T cells (flow cytometry)
Immunodeficiencies: B and T cell disorders: ataxia-telangiectasia
defect
in ATM gene --->DNA ds breaks repair failure -->cell cycle arrest
Immunodeficiencies: B and T cell disorders: ataxia-telangiectasia
presentation
triad:
cerebellar defects (ataxia)
spider angiomas (telangiectasia)
IgA def
Immunodeficiencies: B and T cell disorders: ataxia-telangiectasia
findings
dec IgA, IgG, IgE
inc. AFP
lymphopenia
cerebellar atrophy
Immunodeficiencies: B and T cell disorders: hyper-IgM syndrome
defect
most common: deefective CD40L on Th cells---> class switching defect
(X-kinked R)
Immunodeficiencies: B and T cell disorders: hyper-IgM syndrome
presentation
severe pyogenic infections early in life
opportunistic infections w/ Pneumocystis, Crptosporidium, CMV
Immunodeficiencies: B and T cell disorders: hyper-IgM syndrome
findings
inc. IgM
ddec. IgG, IgA, IgE
Immunodeficiencies: B and T cell disorders: Wiskott-Aldrich syndrome
defect
X-linkedR mutation of WAS gene
T cells can't reorganize actin in cytoskeleton
Immunodeficiencies: B and T cell disorders: Wiskott-Aldrich syndrome
presentation
thrombocytopenic purpura
eczema
recurrent infections
(WATER)
inc. risk autoimmune disease and malignancy
Immunodeficiencies: B and T cell disorders: Wiskott-Aldrich syndrome
findings
dec to normal IgG, IgM
inc IgE, IgA
fever
smaller platelets
Immunodeficiencies: phagocyte dysfunction: leukocyte adhesion deficiency (type I)
defect
in LFA-1 integrin (CD18) proteins
impaired migration and chemotoxis
Immunodeficiencies: phagocyte dysfunction: leukocyte adhesion deficiency (type I)
inheritance
AR
Immunodeficiencies: phagocyte dysfunction: leukocyte adhesion deficiency (type I)
presentation
recurrent bact. infections of skin, mucosa
absent pus formation
impaired wound healing
delayed (>30) separation of umbilical cord
Immunodeficiencies: phagocyte dysfunction: leukocyte adhesion deficiency (type I)
findins
inc neutrophils, but none at infection sites
Immunodeficiencies: phagocyte dysfunction: Chediak-Higashi syndrome
defect
in LYST (lysosomal trafficking regulator gene)
microtubule dysfunction in phag-lysosome fusion
Immunodeficiencies: phagocyte dysfunction: Chediak-Higashi syndrome
ineritance
AR
Immunodeficiencies: phagocyte dysfunction: Chediak-Higashi syndrome
presentation
recurrent pyrogenic infections by staph, strep
partial albinism
peripheral neuropathy
progressive neurodeeneration
infiltrative lymphohistocytosis
Immunodeficiencies: phagocyte dysfunction: Chediak-Higashi syndrome
findings
giant granules in granulocytes and platelets
pancytopenia
mild coagulation defects
Immunodeficiencies: phagocyte dysfunction: chronic granulomatous disease
defect
of NADPH oxidase-->dec ROS and dec respiratory burst in neutrophils
Immunodeficiencies: phagocyte dysfunction: chronic granulomatous disease
most common inheritance
XR
Immunodeficiencies: phagocyte dysfunction: chronic granulomatous disease
presentation
inc susceptibility to catalase + (Need PLACES):
Nocardia
Pseudomonas
Listeria
Aspergillus
Candida
E. coli
S. aureus
Serratia
Immunodeficiencies: phagocyte dysfunction: chronic granulomatous disease
findings
abnormal dihydrorhodamine (flow cytometry) test
nitroblue tetrazolium dye reduction test is -
Bacterial infections in immunodeficiency:
dec. T cells
sepsis
Bacterial infections in immunodeficiency:
dec. B cells
encapsulated (SHiNE SKiS)
Bacterial infections in immunodeficiency:
dec granulocytes
Staphylococcus
Burkholderia cepacia
P. aeruginosa
Serratia
Nocardia
Bacterial infections in immunodeficiency:
dec complement
encapsulated species with early component deficiencies
Niesseria with late component (MAC) deficiencies
Viral infections in immunodeficiency:
dec T cells
CMV
EBV
JCV
VZV
chronic GI/respiratory viral infections
Viral infections in immunodeficiency:
dec B cells
enteroviral encephalitis
poliovirus (live vaccine contraindicated)
Viral infections in immunodeficiency:
dec granulocytes
N/A
Viral infections in immunodeficiency:
dec. complement
N/A
Fungal/Parasitic infections in immunodeficiency:
dec T cells
Candida (local)
PCP
Fungal/Parasitic infections in immunodeficiency:
dec B cells
GI giardiasis (no IgA)
Fungal/Parasitic infections in immunodeficiency:
dec granulocytes
Candida (systemic)
Aspergillus
Fungal/Parasitic infections in immunodeficiency:
dec complement
N/A
with immunodeficiencies, deficiencies of T cells tend to produce more of what sorts of infections? of B cells?
recurrent bacterial
fungal/parasitic
aUTOgraft
from self
synergic graft (isograft)
from clone or identical twin
allograft
from nonidentical twin of same species
xenograft
from different species
transplant rejections:
hyper acute: onset
within minutes
transplant rejections: hyperacute:
pathogenesis
pre-existing recipient Abs react to donor antigens (type II hypersensitivity rxn)
activate complement
transplant rejections: hyperacute:
features
widespread thrombosis of graft vessels-->ischemia, necrosis
graft must be removed
transplant rejections:
acute:onset
weeks to months
transplant rejections: acute:
pathogenesis
cellular: CD8+ T cells activated against donor MHCs
humoral: similar to hyperacute, but Abs develop after transplant
transplant rejections: acute:
features
vasculitis of graft vessels with dense interstitial lympocyte infiltrate
prevent/reverse with immunosuppressants
transplant rejections: chronic:
onset
months to years
transplant rejections: chronic:
pathogenesis
CD4+ T cells respond to recipient APCs presenting donor peptides, incl allogenic MHC
cellular and humoral components
transplant rejections: chronic:
features
recipient T cells react, secrete cytokines-->proliferation of vascular SM and parenchymal finrosis
dominated by ateriosclerosis
transplant rejections: graft-vs.-host disease:
onset
varies
transplant rejections: graft-vs.-host disease:
pathogenesis
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)
immunosuppressants
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
immunosuppressants: cyclosporinse
use
transplant rejection prophylaxis
psoriasis
rheumatoid arthritis
immunosuppressants: cyclosporine
toxicity
nephrotoxicity
hypertension
hyperlipidemia
neurotoxicity
gingival hyperplasia
hirstutism
immunosuppressants: tacrolimus (FK506)
mechanism
calcineurin inhibitor
binds FK506 binding protein (FKBP)
blocks T cell activation by preventing IL-2 transcription
immunosuppressants: tacrolimus (FK506)
use
transplant rejection prophylaxis
immunosuppressants: tacrolimus (FK506)
toxicity
similar to cyclosporine
inc risk diabetes, neurotoxicity
no gingival hyperplasia or hirstutism
toxicity of calcineurin inhibitors
nephrotoxic
immunosuppressants: sirolimus (Ripamycin)
mechanism
mTOR inhibitor
binds FKBP
lock T cell activation and B cell differentiation by preventing response to IL-2
immunosuppressants: sirolimus (Ripamycin)
use
kidney transplant rejection prophylaxis
synergistic w/ cyclosporine
immunosuppressants: sirolimus (Ripamycin)
toxicity
anemia
thrombocytopenia
leukopenia
insulin resistance
hyperlipidemia
NOT nephrotoxic
what immunosuppressant is used in drug-eluting stents?
sirolimus (Ripamycin)
immunosuppressants: daclizumab, basiliximab
mechanism
monoclonal Abs
block IL-2R
immunosuppressants: daclizumab, basiliximab
use
kidney transplant rejection prophylaxis
immunosuppressants: daclizumab, basiliximab
toxicity
edema
hypertension
tremor
immunosuppressants: azathioprine
mechanism
antimetabolite precursor of 6-mercaptopurine
inhibits lymphocyte proliferation by blocking nucleotide synthesis
immunosuppressants: azathioprine
use
transplant rejection prophylaxis
rheumatoid arthritis
Crohn disease
glomerulonephritis
o/ autoimmune conditions
immunosuppressants: azathioprine
toxicity
leukopenia
anemia
thrombocytopenia
(increased by allopurinol)
immunosuppressants: glucocorticoids
mechanism
inhibit NF-kB
suppress both B and T cell function by dec transcription of many cytokines
immunosuppressants: glucocorticoids
use
transplant rejection prophylaxis (immunisuppression)
inflammation
many autoimmune disorders
immunosuppressants: glucocorticoids
toxicity
hyperglycemia
osteoporosis
central obesity
muscle breakdown
psychosis
acne
hypertension
cataracts
avascular necrosis
what immunosuppressant can cause iatrogenic Cushing syndrome?
glucocorticoids
immunosuppression targets
diagram
recombinant cytokines by clinical use:
renal cell carcinoma, metastatic melanoma
Aldesleukin (IL-2)
recombinant cytokines by clinical use:
anemias (esp in renal failure)
Epoietin alfa (erythropoietin)
recombinant cytokines by clinical use:
bone marrow recovery
Filgrastim (G-CSF)
Sargramostim (GM-CSF)
recombinant cytokines by clinical use:
chronic hep B an C, Kaposi sarcoma, malignant melanoma
INF-alpha
recombinant cytokines by clinical use:
MS
INF-beta
recombinant cytokines by clinical use:
chronic granulomatous disease
INF-gamma
recombinant cytokines by clinical use:
thrombocytopenia
Romiplostin, eltrombopag
Oprelvekin (IL-11)
Therapeutic Antibodies: Cancer Therapy: Alemtuzumab
target
CD52
Therapeutic Antibodies: Cancer Therapy: Alemtuzumab
clinical use
CLL
"lym" - a"lym"tuzumab
Therapeutic Antibodies: Cancer Therapy: bevacizumab
target
VEGF
Therapeutic Antibodies: Cancer Therapy: bevacizumab
clinical use
colorectal cancer
renal cell carcinoma
Therapeutic Antibodies: Cancer Therapy: cetuximab
target
EGFR
Therapeutic Antibodies: Cancer Therapy: cetuximab
clinical use
stage IV colorectal cancer
head and neck cancer
Therapeutic Antibodies: Cancer Therapy: retuximab
target
CD20
Therapeutic Antibodies: Cancer Therapy: retuximab
clinical use
B-cell non-Hodgkin lymphoma
CLL
rheumatoid arthritis
ITP
Therapeutic Antibodies: Cancer Therapy: trastuzumab
target
HER2/neu
Therapeutic Antibodies: Cancer Therapy: trastuzumab
clinical use
breast cancer
Therapeutic Antibodies: Autoimmune Disease Therapy: adalimumab, infliximab
target
soluble TNF-alpha
(etancercept is a decoy TNF-alpha receptor, not monoclonal Ab)
Therapeutic Antibodies: Autoimmune Disease Therapy: adalimumab, infliximab
clinical use
IBD
RA
ankylosing spondylitis
Therapeutic Antibodies: Autoimmune Disease Therapy: eculizumab
target
complement protein C5
Therapeutic Antibodies: Autoimmune Disease Therapy: eculizumab
clinical use
paroxysmal nocturnal hemoglobinuria
Therapeutic Antibodies: Autoimmune Disease Therapy: natatlizumab
target
alpha-4 integrin (WBC adhesion)
Therapeutic Antibodies: Autoimmune Disease Therapy: natatlizumab
clinical use
MS
Crohn disease
Therapeutic Antibodies: Autoimmune Disease Therapy: natatlizumab
risk
of PML in patients with JC virus
Therapeutic Antibodies: other: abciximab
target
platelet glycoproten IIb/IIIa
(2x3="cix")
Therapeutic Antibodies: other: abciximab
clinical use
antiplatelet agent--> prevention of ischemic complication in pts undergoing percutaneous coronary intervention
Therapeutic Antibodies: other: denosumab
target
RANKL
Therapeutic Antibodies: other: denosumab
clinical use
osteoporosis
inhibits osteoclast maturation (mimics osteoproterin)
Therapeutic Antibodies: other: digoxin immune Fab
target
digoxin
Therapeutic Antibodies: other: digoxin immune Fab
clinical use
digoxin toxicity antidote
Therapeutic Antibodies: other: omalizumab
target
IgE
Therapeutic Antibodies: other: omalizumab
clinical use
allergic asthma
prevents IgE binding to FceRI
Therapeutic Antibodies: other: palivizumab
target
RSV F protein
"vi" for viris
Therapeutic Antibodies: other: palivizumab
clinical use
RSV prophylaxis for high-risk infants
Therapeutic Antibodies: other: ranibizuma, bevacizumab
target
VEGF
Therapeutic Antibodies: other: ranibizuma, bevacizumab
clinical use
neovascular age-related macular degeneration
interstitial T lymphocytes release ___ to disrupt tight junctions
IFN-gamma
IL-4
IL-10
DAMPs
damage associated molecular patterns
antimicrobial proteins
general characteristics
12-50 AAs-long peptides collection
many stored in neutrophils
net + charge: disrupt membrane integrity
antimicrobial compounds: collectins
site and properties
extracellular
collage-like domain
antimicrobial compounds: defensins
site and properties
extracellular-vernix caseos, amniotic fluid
or intracellular
cysteine-rich, cationic
antimicrobial compounds: cathelicidins
site and properties
lysosomes of PMN and macrophages
cationic, release elastase
antimicrobial compounds: saposin
site and properties
CTL, NK cells
acts on sphingolipids
antimicrobial compounds: mucins
site and properties
saliva
highly glycosidic proteins
eicosanoids that function in inflammation
prostaglandins
thromboxanes
leukotrienes
lipoxins
(all membrane derived lipids)
enzyme that plays major role in eicosanoids synthesis
phospholipase A2
eicosanoids regulate what?
vascular tone
SM contraction
(also: anaphylaxis, asthma, inflammation)
eicosanoids are responsible for what 4 of the 5 signs of inflammation?
calor
rubor
dolor
tumor
3 molecules that immediately and rapidly stimulate vascular dilation
bradykinin
histamine
prostaglandins
arachnoid acid--->prostaglandin G2
enzyme (constitutive), regulators, result
COX-1 (constitutive)
(-): aspirin, ibuprofen, indomethacin
pain and edema
enzyme that synthesizes arachnoid acid from membrane derivative
phospholipase A2
arachnoid acid--->prostaglandin G2
enzyme (inducible), regulators, result
COX-2 (inducible)
(-): glucocorticoids, IL-4
(+): IL-1, TNF-ALPHA, GFs
pain and edema
arachnoid acid--->leukotriene A4
enzyme
lipoxygenase
leukotriene A4--->leukotriene B4
enzyme, result
leukotriene A4 hydrolase
SM contraction and cell infiltration
Lewis trip response
Flush: capillary dilation
Flare: arteriolar dilation
Wheal: exudation, edema
where are complement proteins synthesized?
liver
generation of what 3 things facilitates macrophage clearance of foreign object?
anaphylatoxin
opsonin
membrane attack complex (MAC)
loss of what complement protein leads to bacterial infections?
C3
loss of what complement proteins leads to susceptibility to bacterial meningitis?
C5-9
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
lactoferrin
Fe-binding protein
secreted by exocrine glands and some granules in neutrophils
deprives bacteria of iron
lactoperoxidase
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
convertase
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
myeloperoxidase
bactericidal oxidoreductase
expressed in neutrophils, stored in asurophilic granules
Cl- oxidation using H2O2, forming HCl
catalytic cofactor has heme-->green pus
xanthine oxidoreductase
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
recruit leukocytes
function of cytokines in innate immune system
illicit specific physiological responses
function of selectins
cell-cell adhesion
L-selectin
on most leukocytes
steady-state lymphocyte entry into immune organ
directs secondary tethering of neutrophils
binding partners: E-selectin, CLA
CLA
cutaneous lymphocyte antigen
E-selectin
on endothelial cells
induced by IL-1beta, TNF-alpha, TNF-beta, LPS
NF-KB regulation (pro-inflammatory TF)
downregulated by internalization, routed to lysosome
P-selectin
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
IL-1 (alpha, beta)
major cell souce
macrophages
endothelial cells
dendritic cells
Langerhans cells
IL-1 (alpha, beta)
major immunologic action
Il-2 receptor emergence on T cells
B-cell activation enhancement
fever, acute phase reaction, IL-6 induction
increase nonspecific resistance
inhibited by endogenous IL-1 receptor agonist
IL-2
major cell source
Th1 cells
IL-2
major immunologic action
T-cell GF
activates NK, B cells
IL-3
major cell source
T cells
IL-3
major immunologic action
stimulates hematopoiesis
IL-4
major cell source
T cells
IL-4
major immunologic action
stimulate B-cell synthesis of IgE
down regulation of IFN-gamma
IL-5
major cell source
T cells
IL-5
major immunologic action
growth, differentiation of eosinophils
B-cell growth factor
enhances IgA synthesis
IL-6
major cell source
monocytes
T cells
endothelial cells
IL-6
major immunologic action
induces acute phase reactants, fever, B cell differentiation
IL-7
major cell source
bone marrow
IL-7
major immunologic action
stimulates pre-B and pre-T cells
IL-8
major cell source
monocytes
endothelial cells
lymphocytes
fibroblasts
IL-8
major immunologic action
chemotactic factor for neutrophils and T cells
IL-9
major cell source
Th cells
IL-9
major immunologic action
T-cell antigen
IL-10
major cell source
Th2 cells
IL-10
major immunologic action
inhibits IFN-gamma synthesis by Th1 cells
suppress synthesis of other cytokines
IL-11
major cell source
bone marrow
IL-11
major immunologic action
hematopoiesis stimulation
enhance acute phase reaction protein synthesis
IL-12
major cell source
macrophages
B cells
IL-12
major immunologic action
promote Th1 differentiation, IFN-gamma synthesis
stimulates NK cells and CD8+ T cells to cytolysis
acts synergistically w/ IL-2
IL-13
major cell source
Th2 cells
IL-13
major immunologic action
inhibits inflammatory cytokines:
ILs 1, 6, 8, 10; MCP
IL-15
major cell source
T cells
IL-15
major immunologic action
T-cell mitogen
enhance growth of intestinal epithelium
IL-16
major cell source
CD8+ T cells
eosinophils
IL-16
major immunologic action
increase MHC II, chemotaxis, CD4+ T-cell cytokines
dec antigen-induced proliferation
IL-17
major cell source
T cells
IL-17
major immunologic action
inc inflammation
IL-18
major cell source
activated macrophages
IL-18
major immunologic action
in IFM-gamma production, NK cell action
TNF-alpha
major cell source
macrophages
B cells
T cells
large granular lymphocytes
TNF-alpha
major immunologic action
cytotoxic for tumors
cachexia
mediates bacterial shock
TNF-beta
major cell source
T cells
TNF-beta
major immunologic action
cytotoxic for tumors
transforming GF-beta
major cell source
almost all normal cell types
transforming GF-beta
major immunologic action
inhibits B and T cell proliferation
reduces cytokine receptors
leukocyte chemotactic agent
mediates inflammation and tissue repair
NBS-LRR proteins
nucleoside-binding site and leucine-rich repeats
cell receptor that detects intracellular pathogens
TLR-1
subcellular location, ligand, cell types
cell surface
lipoprotein
monocytes, macrophages, dendritic cells, B cells
TLR-2
subcellular location, ligand, cell types
cell surface
glycolipid, lipotechoic acid, HSP-70
monocytes, macrophages, dendritic cells, mast cells
TLR-3
subcellular location, ligand, cell types
intracellular compartment
dsRNA, polyl:C
dendritic cells
TLR-4
subcellular location, ligand, cell types
cell surface
LPS, HSP, fibrinogen
monocytes, macrophages, dendritic cells, mast cells, B cells
TLR-5
subcellular location, ligand, cell types
cell surface
flagelli
monocytes, macrophages dendritic cells
TLR-6
subcellular location, ligand, cell types
cell surface
diacyl lipopeptide
monocytes, macrophages, mast cells, B cells
TLR-7
subcellular location, ligand, cell types
intracellular compartment
ssRNA
monocytes, macrophages, plasmacytoid cells, B cells
TLR-8
subcellular location, ligand, cell types
intracellular compartment
ssRNA
monocytes, macrophages, dendritic cells, mast cells
TLR-9
subcellular location, ligand, cell types
intracellular compartment
unmethylated CpG DNA
monocytes, macrophages, dendritic cells, B cells
TLR-10
subcellular location, ligand, cell types
intracellular compartment
unknown
TLR-11
subcellular location, ligand, cell types
intracellular compartment
profilin
monocytes, macrophages
TLR-12
subcellular location, ligand, cell types
intracellular compartment
unknown
TLR-13
subcellular location, ligand, cell types
intracellular compartment
bacterial RNA
monocytes, macrophages, dendritic cells
C-lecithin receptor
subcellular location, ligand, cell types
cell surface
mannose, galactose
macrophages, dendritic cells
NOD-like receptor
subcellular location, ligand, cell types
cytoplasm
peptidoglycan, muramyl dipeptide
RIG-I-like receptor
subcellular location, ligand, cell types
cytoplasm
dsRNA
how long is a neutrophil in circulation?
6 hours
longer in spleen
what hormones cause an increase in neutrophil secretion?
glucocorticoids
neutrophils phagocytize cells marked with what?
C3b, IgG, or collectins
process triggered by anaphlatoxins C3a, C4a, C5a
3 types of secretory granules of neutrophils
1. azurophilic (defensins, myeloperoxidase, lysozyme)
2. specifics (lactoferrin, lysozyme)
3. gelatinase (acetyltransferase, gelatinase, lysozyme)
basophils express __ receptors for IgE and ___ receptors for antigen presentation to Th2 cells
Fc
MHC II
what cells direct cell-mediated cellular cytotoxicity (CMCC)?
eosinophils
eosinophils express __ receptors for IgG and IgE, and __ for activation of CD4+ T cells.
Fc receptors
MHC II
cell-mediated cellular cytotoxicity (CMCC)
delivers toxic free radicals and proteases to parasite
release of cytotoxic agents also damages host tissues
directed by eosinophils
T or F: mast cells normally are circulating
false
T or F: mast cells can be found past the BBB
true
mast cell functions
phagocytosis
antigen presentation
regulate inflammation, adaptive immune responses
control vascular integrity, neutrophil recruitment
screen DAMPs, PAMPs
mast cell secretions
histamine
heparin proteoglycan
serine proteases tryptase and chymase
reactive lipids: thromboxane, prostaglandin D2, leukotriene, platelet-activating factor
macrophage functional states:
M1
respond to bacteria and inhibit cancer growth
macrophage functional states:
M2
support angiogenesis, suppress immunity, promote cancer growth
immature myeloid-derived dendritic cells (mDC)
process antigen for presentation to T helper cells
endocytose antigen, process in lysosome, present in MCH II
mature when exposed to PAMP and migrate to lymph node
mature myeloid-derived dendritic cells (mDC)
reduce endocytosis activity
inc MHC II expression
inc coreceptors CD80/88
depending on identity of triggering PAMP, release IL-12
different AA sequences in which Ab chain determine the type?
H chains
(L chains the same for all; H and L both have constant and variable domains)
T or F: IgA is usually found as dimer in serum
true
molecule that stimulates B cells to switch to IgE production
IL-4
IgE binds to IL-5 of eosinophils--->
elimination of parasitic helminths
IgD function
receptor on B-cell membranes for antigen
HLA types associated with disease (and risk):
B 27
ankylosing spondylitis (87)
Reiter's syndrome (40)
HLA types associated with disease (and risk):
DR 3
dermatitis herpetiformis (56)
SLE (5)
HLA types associated with disease (and risk):
DR 3/DR 4
insulin-dependent diabetes (33)
HLA types associated with disease (and risk):
C 6
psoriasis vulgaris (13)
HLA types associated with disease (and risk):
DR 2
Goodpasture's syndrome (13)
aka anti glomerular basement membrane disease
HLA types associated with disease (and risk):
Dw 4/DR 4
rheumatoid arthritis (10)
HLA types associated with disease (and risk):
DR 5
pernicious anemia (5)
HLA
human leukocyte antigen
controls discrimination b/w self and non-self antigen presentation to T cells
determines individual susceptibility to immunologic disorders and infectious agents
HLA class I
glycoproteins on surface of most nucleated cells
can bind to several different peptidic epitopes and present them to Tc cells (class I restriction)
HLA class II
glycoproteins on surface of macrophages, dendritic cells, activated T cells, B cells
present prptidic epitopes to Th cells (class II restriction)
can bind several epitopes
HLA class III
control serum proteins, including several complement components and TNFs
which HLA classes are a major obstacle to organ transplantation? on what chromosome are many of their alleles located?
classes I and II
chromosome 6
T or F: in regards to genes encoding HLAs, the haplotypes from each parent are expressed codominantly
true
TCR
T-cell antigenic receptor
recognize peptidic fragments bound to HLA classes I and II on APCs
TCR coreceptors and link to immune response
1. class II HLA + CD4 receptor-->humoral immunity
2. class I HLA + CD8 receptor--->cell-mediated immunity
function of RAG-1 and RAG-2 enzymes
recombinase enzymes that are required for heavy and light chain rearrangements in early B and T cell antigen receptor expression
mature B cells express what Ig on their PMs? receptors for which Ig?
IgD
IgM
positive selection
screens for functional antigen receptors on developing lymphocytes
negative selection
removes lymphocytes with receptors that recognize host-specific antigens
activation induced cytosine deaminase (AID)
deaminates C to U in the process of somatic hypermutation, which is responsible for generating the vast array of different Abs
U is then removed by U-DNA glycosylase
naive T cell CD4+ or CD8+
symbol, function, secretory cytokines
Th0
quiescent, progenitor, activated by DC
none
activated helper T cell
symbol, function, secretory cytokines
Th0*
activated progenitor, receptive to cytokine control
IL-2
helper T1
symbol, function, secretory cytokines
Th1
intracellular bacteria and virus
IFN-gamma, LT-alpha
helper T2
symbol, function, secretory cytokines
Th2
extracellular parasites
IL-4,-5,-13,-25
helper T9
symbol, function, secretory cytokines
Th9
immunity to helminths
IL-9,-10
helper T17
symbol, function, secretory cytokines
Th17
extracellular bacteria, fungi; mucosay
IL-21,-17a,-17f,-22
natural regulatory T cell CD4+ CD25+
symbol, function, secretory cytokines
Treg
tolerance, regulation, homeostasis
TGF-beta
regulatory 1 T CD4+ CD25+
symbol, function, secretory cytokines
Tr1
suppress naive and memory T cells; inducible
IL-10
anergic T CD4+ CD25+
symbol, function, secretory cytokines
Th3
mucosal immunity, inducible
TGF-beta
suppressor T CD8+ CD28+
symbol, function, secretory cytokines
Ts
regulation, mucosal immunity
IL-10, TGF-beta; upregulates ILT3 on monocytes
cytotoxic T cell
symbol, function, secretory cytokines
Tc
cell-mediated immunity
perforin granzyme
(gamma-delta)T
symbol, function, secretory cytokines
(gamma-delta)T
mucosal, respiratory tract
IFN-gamma, TNF-alpha, IL-4
natural killer T cell
symbol, function, secretory cytokines
NKT
detect glycolipid antigen presented by CD1
IFN-gamma, TNF-alpha, IL-4
natural killer cell
symbol, function, secretory cytokines
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
B1 cells
mucosal areas
Abs to bacterial polysaccharides and LPS
limited repertoire to different antigens
B2 cells
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
KIR
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
plasmacytoid cells
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
IL-4 function
development of Ab synthesis
B cell differentiation
IgE production
suppress CMI by down-reg IFN-gamma by Th1
IL-5 function
B cell differentiation w/ IL-2,4
eosinophil differentiation
IgA synthesis
IFN-gamma function
activate macrophages, NK cells
HLA antigen presentation by endothelial cells
down-reg IL-4-->dec Ab synthesis
TNF-alpha function
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?
12
18
IL-10 function
inhibits Th1 secretion of IFN-gamma (reduced macrophage activation) and IL-2
IL-13 function
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-6
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?
IgE
binding of ___ on B cell to ___ on Th cell is necessary for switching to occur
CD40
CD40L
affinity vs avidity
1. binding energy b/w Ab and univalent epitope
2. total " " and multivalent antigen
major crossmatch
donor cells + recipient serum
determines whether anti-RBC Abs are present in recipient's serum
slide agglutination test
minor crossmatch
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?
antigens
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
dysagammaglobulinemia
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
3 ways self-tolerance is developed
1. clonal deletion
2. clonal anergy
3. peripheral suppression
self-tolerance mechanisms:
clonal deletion
immature CD4+ cells that have receptors for endogenous antigens are deleted in neonatal thymus after binding self-antigen
(same for immature B cells in bone marrow)
self-tolerance mechanisms:
clonal anergy
loss of B- and T-cell function after exposure to antigens in absence of costimulatory signal or exposure to cells lacking MHC II
self-tolerance mechanisms:
peripheral suppression
occurs if CD8+ T cells or macrophages secrete cytokines that down-reg immune response or if high- or low-dose antigen produces anergic state
carcinoembryonic antigen (CEA)
present on fetal GI tract, liver cells
disappears at birth
reappears ins erum of most pts w/ colorectal cancer
beta-fetoprotein
low levels in normal adults
high levels in pts w/ hepatomas and testicular teratocarcinomas
cons of recombinant DNA vaccines
continuous stimulus ---> tolerance, autoimmunity may develop
which type of vaccines seem to be associated with the fewest safety concerns overall?
recombinant vaccines
IL-1
source
macrophages
endothelial cells
dendritic cells
Langerhans cells
IL-1
function
stimulate IL-2 receptor emergence on T cells
enhance B cell activation
fever
acute phase reactants
IL-6 induction
increase nonspecific resistance
IL-2
source
Th1
IL-2
function
T cell growth factor
activate NK and B cells
IL-3
source
T cells
IL-3
function
stimulate hematopoiesis
IL-4
source
T cells
IL-4
function
B cell synthesis of IgE
downregulation of IFN-gamma
IL-5
source
T cells
IL-5
function
eosinophil growth and differentiation
B cell growth factor
enhance IgA synthesis
IL-6
source
monocytes
T cells
endothelial cells
IL-6
function
induce acute phase reactants, fever, and late B cell differentation
IL-7
source
bone marrow
IL-7
function
stimulate pre-B and pre-T cells
IL-9
source
Th cells
IL-9
function
T cell mitogen
IL-8
source
monocytes
endothelial cells
lymphocytes
fibroblasts
IL-8
function
neutrophil and T cell chemotaxis
IL-10
source
Th2 cells
IL-10
function
inhibit IFN-gamma synthesis by Th1 cells
suppress synthesis of other cytokines
IL-11
source
bone marrow
IL-11
function
stimulate hematopoiesis
enhance acute phase protein synthesis
IL-12
source
macrophages
B cells
IL-12
function
promote Th1 differentiation and IFN-gamma synthesis
stimulate cytolysis by NK and cytotoxic T cells
synergist of IL-2
IL-13
source
Th2 cells
IL-13
function
inhibit inflammatory cytokines
(IL-1, 6, 8, 10, MCP)
IL-15
source
T cells
IL-15
function
T cell mitogen
enhance growth of intestinal epithelium
IL-16
source
CD8+ T cells
eosinophils
IL-16
function
increase class II MHC, chemotaxis, CD4+ chemotaxis
decrease antigen-induced proliferation
IL-17
source
T cells
IL-17
function
increase inflammatory response
IL-18
source
activated macrophages
IL-18
function
increase IFN-gamma production and NK cell action
TNF-alpha
source
macrophages
T cels
B cells
large granular lymphocytes
TNF-alpha
function
cytotoxic for tumors
cachexia
mediates bacterial shock
TNF-beta
source
T cells
TNF-beta
function
cytotoxic for tumors
TGF-beta
source
almost all normal cell types
TGF-beta
function
inhibit B and T cell proliferation
reduce cytokine receptors
leukocyte chemotactic agent
mediate inflammation and tissue repair
ThO*
activated, but not yet differentiated, helper T cell
receptive to cytokine control
secretes IL-2
Th1 cell
function
secretions
intracellular bacteria and viruses
IFN-gamma
Th2 cell
function
secretions
extracellular parasites
IL-4, 5, 13, 25
Th9
function
secretions
extracellular helminthes
IL-9, IL-10
Th17
function
secretions
extracellular bacteria, fungi, mucosay
IL-21, 17, 22
Treg (CD4+CD25+)
function
secretions
tolerance, regulation, homeostasis
TGF-beta
Tr1 (CD4+CD25-)
function
secretions
inducible; suppress naive and memory T cells
IL-10
Th3 (anergic T CD4+CD25-)
inducible; mucosal immunity
TGF-beta
Ts (suppressor CD8+CD28-)
function
secretions
regulation, mucosal immunity
IL-10, TGF-beta, upregulate ILT3 on monocytes
Tc
function
secretions
cell-mediated immunity
perforin, granzyme
(gamma-delta)T
function
secretions
mucosal, respiratory tract
IFN-amma, TNF-alpha, IL-4
NKT
function
secretions
detect glycolipid antigen presented by CD1
IFN-gamma, TGF-alpha, IL-4
NK cell
function
secretions
screens for MHC I; antiviral activity
perforin, granzyme