B6.026 Autoimmunity Flashcards
what is an allergen
antigen that is harmless and normal in the environment is perceived as abnormal
exposure causes a robust abnormal immune response
how are allergies mediated
IgE mechanisms
autoantigen
normal part of the body (protein, DNA or RNA) that is recognized by the immune system as abnormal leading to immune activation causing destruction and inflammation or activation of an organ
“allo”
non self antigen from members of the same species
examples of allo antigens
2 major: blood group antigens and histocompatibility antigens
highly polymorphic genes
alloimmunity
occurs when the body produces antibody against the new alloantigen to which it has been exposed
some features of innate immunity
- accumulation and activation of leukocytes and plasma proteins at site of infection
- prevents organisms from getting across barriers (mucous layer, epithelium)
- induces inflammation
- defends against intracellular (viral) infected cells
- kill extracellular microbes
- recognizing microbial structures to clear dead or injured cells
- germ line encoded
some features of adaptive immunity
- combats microbes via secretion of Abs from B cells that bind to microbes, block infection of host cells, and promote phagocytosis induced destruction
- helper T cells recruit leukocytes to elicit microbial destruction
- cytotoxic T cells kill microbial infected cells
time frame of innate immunity
0-12 hours primarily
time frame of adaptive immunity
1 day and forward
specificity of innate immunity
for structures shared by classes (PAMPs) or damaged cells (DAMPs)
receptors of innate immunity
encoded in germline
limited diversity
pattern recognition receptors
distribution of innate immunity receptors
nonclonal: identical receptors on all cells of the same lineage
discrimination of normal self and nonself in innate immunity
yes
healthy host cells are not recognized, or they may express molecules that prevent innate immune reactions
specificity of adaptive immunity
for structural detail of microbial molecules (antigens); may recognize nonmicrobial antigens
receptors of adaptive immunity
encoded by genes produced by somatic recombination of gene segments; greater diversity
distribution of adaptive immunity receptors
clonal: clones of lymphocytes with distinct specificities express different receptors
discrimination of normal self and nonself in adaptive immunity
yes
based on selection against self-reactive lymphocytes; may be imperfect (giving rise to autoimmunity)
microbial recognition in innate immunity
recognize structures shared by classes of microbes not present on host cells
enhanced function through the adaptive immune system
microbial recognition in adaptive immunity
lymphocytes express receptors (antibodies) on their cell surface that recognize specific antigens
utilize cells of innate immunity to eliminate microbes
antibody (adaptive) binds to a microbe, which activates phagocytes (innate) to ingest and destroy the microbe
cellular compartments with receptors on innate cells
cell surface to detect extracellular microbes
vesicles where microbes are ingested
cytosol to sense cytoplasmic microbes
what are PAMPs
pathogen associated molecular patterns
- microbial molecules, shared by microbes of the same type
- not on normal host cells
- stimulate innate immune response
- essential for survival/infectivity
examples of PAMPs
LPS- gram neg
peptidoglycans - bacteria
terminal mannose residues - opportunistic infections
unmethylated CG-rich DNA -intracellular viral infection
what are DAMPs
damage associated molecular patterns
- released from damaged or necrotic host cells
- present in injury (infarction) or infection
PRRs
pattern recognition receptors
innate immune receptors that recognize PAMPs and DAMPs
toll-like receptors
nod-like receptors
toll like receptors (TLRs)
specific for microbial components
activate transcription factors to stimulate expression of genes encoding cytokines, enzyme, and other proteins
TLR signaling process
- TLR engages and recruits protein
- proteins activate transcription factors (NFKP and IRFs)
- increased expression of: cytokines, adhesion molecules, co-stimulators (generating inflammation)
- production of type 1 interferon, antiviral activity
- stimulates adaptive immunity
nod like receptors (NLRs)
family of cytosolic receptors that sense DAMPs and PAMPs in the cytoplasm
NOD-1 and NOD-2
contain N-terminal CARD (caspase related domains)
bacterial peptidoglycans in the cell wall
activates NF-kB
NLRP-3
recognizes microbial products, substances associated with cell damage, and endogenous substances in cells in large quantities (crystals)
enhances production of IL-1B
describe the inflammasome
- NLRP-3 oligomerizes with inactive form of caspase-1
- activation of inflammasome
- active caspase-1 cleaves pro-IL-1B
- activates IL-1B generates fever
inflammasome dysregulation associated conditions
gout- urate crystal deposit
auto inflammatory syndromes (familial periodic fear syndromes)
process of leukocyte recruitment
- rolling
- integrin activation by chemokines
- stable adhesion
- migration through endothelium (diapedesis)
characterize neutrophils
most abundant leukocyte in the blood
increase in number rapidly during infection
first cell to respond to infection (bacterial and fungal)
dominant cell of inflammation
function of neutrophils
phagocytose microbes in the blood and in tissues and destroy them through the oxidative burst
recruited to tissues to remove debris
lifespan of neutrophils
live for only a few hours
dead ones form pus
characterize monocytes/macrophages
found in all connective tissue and organs
prolonged survival in tissues
function of macrophages
activated by PRRs (TLR and NLR)
cytokine production regulates and induces inflammation
phagocytose microbes because of recognition of cell surface receptors
clear dead tissue
initiate tissue repair
classical macrophage activation
immune signals -TLRs -cytokine INFy from innate and adaptive immunity produces M1 activated macrophages destroy microbes and induce inflammation
alternative macrophage activation
cytokines IL-4 and IL-13 (same as associated w allergies)
produces M2 activated macrophages
tissue repair and termination of inflammation (downregulate immune system)
dendritic cells
APCs
initiation production of cytokines, and thus initiate inflammation
bridge innate and adaptive immunity
-stimulate adaptive immune responses
characterize mast cells
abundant cytoplasmic and vasoactive granules
located on skin and mucosal epithelium
how are mast cells activated
microbial products binding to TLRs (innate)
antibody dependent- typically IgE mediated type 1 hypersensitivity reactions
function of mast cells
vasoactive amines (histamine and tryptase)
-increased capillary permeability
-kill bacteria and inactivate microbial toxins
synthesize and secrete lipid mediators and cytokines
-stimulate inflammation
NK cell markers
CD16+/56+
primary function of NK cells
identify infected and stressed cells and kill them
- empty cytoplasmic granules into the extracellular space near the infected cell
- granules enter the cell and activate enzymes to induce apoptosis
other uses of NK cells
fight intracellular microbial infections
secrete IFN-y for macrophage activation
how are NK cells activated
by macrophages and dendritic cells
IL-15: development and maturation of NK cells
IL-12 and IFN type 1: enhance NK cell killing function
inhibition of NK cells
block signaling by receptor activation specific for self MHC 1 molecules to protect healthy cells via ITIMs
function of ITAMs
eliminate cells infected with intracellular microbes via antibody dependent cellular cytotoxicity (ADCC)
alternative complement pathway
triggered when activated complement proteins on microbial surfaces are uncontrolled due to lack of regulatory proteins
innate immunity
classical complement pathway
triggered by antibodies bound to microbes/antigens
adaptive immunity
lectin pathway
mannose binding lectin binds to terminal mannose residues
innate immunity
function of activated complement proteins
- opsonization and phagocytosis (C3b)
- inflammation (C5a, C3a)
- MAC cell lysis
plasma proteins of innate immunity
increase rapidly with infection = acute phase response
- collectins
- CRP
collectins
mannose binding lectin (MBL)
-recognizes microbial carbohydrates, coating them for phagocytosis
-activation of complement by the lectin pathway
surfactant
-protects lung from infective microbes
CRP
binds phosphorylcholine on microbes, opsonizes them for phagocytosis by macrophages
activates classic complement pathway proteins
non specific marker of inflammation
what are interleukins
soluble proteins that cause cell signaling to generate immune and inflammatory reactions - stimulated by infection
communication between cells
cytokines that stimulate APR protein synthesis from the liver (CPR and fibrinogen)
IL-6
cytokines for recruitment of neutrophils and monocytes
TNF
IL-1
chemokines
cytokines that cause fever by acting on the hypothalamus
TNF
IL-1
source of TNF
macrophages
T cells
mast cells
effects of TNF
endothelial cell activation neutrophil activation fever synthesis of APR in liver catabolism of fat and muscle apoptosis
source of IL-1
macrophages dendritic cells endothelial cells some epithelial cells mast cells
effects of IL-1
endothelial cell activation
fever
synthesis of APR in liver
TH17 differentiation
source of chemokines
macrophages dendritic cells endothelial cells T lymphocytes fibroblasts platelets
effects of chemokines
leukocytes: increased integrin affinity, chemotaxis, and activation
source of IL-12
dendritic cells
macrophages
effects if IL-12
INFy production and increased cytotoxic activity of T cells and NK cells
Th1 differentiation
source of IFN-y
NK cells
T lymphocytes
effects of IFN-y
activation of macrophages
stimulation of some Ab response
source of type 1 IFNs (a and B)
IFNa: dendritic cells, macrophages
IFNB: fibroblasts
effects of type 1 IFNs
antiviral state
increased MHC 1 expression
NK cell activation
source of IL-10
macrophages
dendritic cells
T cells
effects of IL-10
acts on dendritic cells and macrophages
inhibition of cytokine and chemokine production
reduced expression of co-stimulators and MHC 2 molecules
source of IL-6
macrophages
endothelial cells
T cells
effects of IL-6
synthesis of acute phase proteins in liver
proliferation of Ab producing B cells
source of IL-15
macrophages
effects of IL-15
proliferation of NK and T cells
source of IL-18
macrophages
effects of IL-18
IFNy synthesis in NK and T cells
source of TGF-B
many cell types
effects of TGF-B
inhibition of inflammation
differentiation of Th17 and Treg cells
how do innate immune cells discriminate against self antigens
receptors are specific for PAMPs and DAMPs, not for healthy substances
PRRs that recognize nucleic acids (present on normal cells) but they are located in cellular compartments where healthy cells are not accessible
normal mammalian cells express regulatory (protective) molecules
how do adaptive immune cells discriminate against self antigen
lymphocytes that recognize self undergo apoptosis or are inactivated when they encounter self antigen
primary function of B lymphocytes
neutralization of microbe, phagocytosis, and complement activation
VIA production of antibodies (IgD,A,M,G,E)
membrane bound antibodies
function as B cell receptor
which Ig is secreted onto mucosa
IgA
which Igs are present on naïve B cells
IgM and IgD
not as important for response to antigens
most abundant Ab in plasma
IgG
which Ig crosses the placenta
IgG
plasma cells
long living mature B cells
produce high affinity antibodies even after antigen removal in response to vaccines and infections
memory B cells
long living mature B cells
do not produce Ab
rapidly respond with antigen re-exposure
T cell dependent B cell response
protein antigens cause weak or absent Ab responses without T cell help APCs present to T lymphocytes that activate B cells to induce class switching and affinity maturation
T cell independent B cell response
polysaccharides, lipids, and other non protein antigens elicit Ab production without involvement of T cells
low affinity, short lived
primary antibody response
within days
IgM produced/wanes
low affinity
plasma cells go on to produce IgG long term
secondary antibody response
within days
larger response
IgG
higher affinity
describe B cell receptor signaling via complement receptors
B cells express complement receptor for activation when exposed to a microbial antigen
-microbial bound C3d (released from C3 during complement activation) binds to complement receptor 2 (CR2) on the B cell surface to activate B cells
C3d-CR2 binding enhances B cell activation as a part of the innate immune response
describe B cell receptor signaling via TLRs
promote B cell proliferation, differentiation, and antibody secretion
intracellular portion of BCR signaling
- Ab is bound to Ag
- tyrosine phosphorylation occurs
- activation of downstream enzymes via biochemical intermediates
- production of transcription factors leading to the immune response and inflammation (Myc, NFAT, NFKB, AP-1)
positive selection
selects for cells that express a BCR
negative selection
selects against cells with a BCR that binds self antigen with high affinity
-undergoes BCR editing or clonal deletion if self reactive
hypersensitivity type and test mnemonic
- A
- C
- I
- D
what is the general definition of hypersensitivity
injurious or pathologic immune reactions
exaggerated and abnormal reactions
2 mechanisms of hypersensitivity
- an immune response to a microbe or environmental allergy causes tissue injury due to repeated or poorly controlled reactions
- failure of self tolerance when an immune response is generated to self (autologous) antigens = autoimmunity
4 types of hypersensitivity
- immediate mediated by IgE binding to mast cells
- Ab (non IgE) mediated cell or tissue destruction
- Ab/Ag complex deposition causing inflammation and tissue injury
- T cell mediated
describe type 1 hypersensitivity
true allergy or atopy
IgE antibody-mast cell mediated in response to an antigen
examples of type 1 hypersens
allergic rhinitis/conjunctivitis food/med allergies asthma anaphylaxis atopic dermatitis venom
symptoms of type 1 hypersens
hives difficulty breathing swelling hypotension anaphylaxis
describe type 2 hypersens
Ab that is directed against cell surface markers or the ECM
- complement and Fc receptor-induced recruitment and activation of leukocytes (bring in neutrophils and macrophages eliciting tissue damage)
- opsonization and phagocytosis
- cell function abnormalities by competitive inhibition or activation
discuss the mechanisms of complement and Fc receptor mediated type 2 hypersens
Abs bind to activate the neutrophil
complement activation releases C3a and C5a to activate the neutrophil
neutrophils generate ROS and lysosomal enzymes that cause inflammation/injury
can occur after strep infection due to antibody cross reacting with myocardium and myocarditis
discuss the mechanisms of opsonization and phagocytosis mediated type 2 hypersens
complement activation occurs releasing C3b that opsonizes the cell
Fc receptor on phagocytes recognizes C3b on an opsonized cell and phagocytoses the infected cell
type 2 hypersens against blood products
may occur with erythrocytes and platelets causing anemia and thrombocytopenia
discuss cell function abnormalities by competitive inhibition or activation that occur w type 2 hypersen
Abs generated against hormone receptors competitively inhibit hormone production
- graves
- myasthenia gravis
graves
thyroid stimulation even in the absence of TSH leading to hyperthyroidism
myasthenia gravis
MSK paralysis disease where Abs are made against the Ach receptor and inhibit transmission of signals to muscle to move
type 3 hypersens
disease is caused by deposition of circulating Ab/Ag complexes in blood vessels
- activation of complement
- activation of inflammatory cascade
symptoms of type 3 hypersens
systemic or localized
vasculitis
nephritis
inflammatory skin reaction
arthus rxn
localized Ag/Ab complex deposition
due to vaccine, local vasculitis
example of arthus rxn
tetanus vaccine
- pt gets the tetanus vaccine
- development of normal Abs to tetanus toxoid
- repeat vaccination occurs within a short time
- pre-formed antibodies complex with additional vaccine antigen and deposit in the subQ tissue
- localized inflammation, pain, swelling
examples of type 3 hypersens diseases
SLE polyarteritis nodosa post-strep glomerulonephritis serum sickness arthus rxn
type 4 hypersens
T lymphocyte mediated delayed hypersens
T cells can cause disease by causing tissue injury
4 types of type 4 hypersens
- local autoimmune reaction with T cells directed against cellular antigens within that local tissue
- persistent response to environmental triggers
- T cell response to microbes
- response to superantigens
classic type 4 hypersens microbe
tuberculosis- granulomatous inflammation because of persistent infection causing local tissue injury
superantigens
bacterial and viral toxins that bind to T cell receptors regardless of specificity causing inflammation trough excessive cytokine production
mechanism of type 4 hypersens
same as for attacking microbes, but antigen may never be cleared
CD4+ cells targeting cell or tissue Ags presented by APCs
CD8+ cells targeting host cells
may work together
type 4 hypersens diseases
multiple sclerosis rheumatoid arthritis DM1 IBD (crohns) contact sensitivity (poison ivy, metal allergy) chronic infection (tuberculosis) viral hepatitis (hep B and C) toxic shock
how do DTH skin tests work
must have prior exposure to develop sensitivity
T cells home to the site
-respond to the antigen
-T cells and monocyte infiltration
-CD4+ cytokine production causes increased vascular permeability, leading to edema and fibrin deposition
-leukocyte products lead to tissue damage
type 2 hypersens diseases
autoimmune hemolytic anemia autoimmune thrombocytopenic purpura goodpastures graves disease myasthenia gravis pemphigus vulgaris pernicious anemia rheumatic fever
