TLRs - example and mechanism
CD14 (coTLR4) on machrophages binds LPS (a PAMP)
TLR cranks up NF-kB - nuclear transcription factor
mediators of pain
PGE2 and bradykinin
PGI2 / D2 / E2
dilation, permeability
LTC/D/E 4
vasoconstriction, bronchospasm, permeability
slow part of anaphylaxis (MAST cells)
Mast cell activation - 3
- tissue trauma
- C3a and C5a
- IgE cross linking antigen
neutrophil go-go
LTB4
C5a
IL-8
bacterial products
classic complement pathway
C1 binds IgG or IgM that is already bound to antigen
C3b
opsonin
Hageman factor XII - source, trigger, and 3 mechanisms
from liver; collagen exposure
- coagulation AND fibrinolysis
- comlement
- Kinin system (HMWK –> brady)
fever mechanism
IL-1 and TNF from macrophages ramp up COX, PGE2 raises temperature set point
rolling - ? binds ?
selectins (speed bumps) on endothelium bind sialyl lewis X on WBC
2 selectin types and stimuli
P-selectin - Weibel-Palade - histamine
E-selectin - TNF and IL-1
adhesion - ? binds ? and stimuli for each
ICAM and VCAM on endothelium - TNF and IL-1
Integrins on WBC - C5a and LTB4
leukocyte adhesion deficiency - cause and Sx
integrin defect - CD18
- delayed separation of umbilical cord
- tons of neutrophils in blood
- recurrent bacterial infections that LACK PUS
site of transmigration
post-capillary venules
Chediak-HIGAshi
protein traffic defect - cannot make PHAGOLYSOSOME Hemostasis defect Infections Giant granules in WBCs Albino neutropenia, periph neuropathy
O2-dependent killing
O2 –> NADPH oxidase (CGD) – oxidative burst of superoxide radicals –> SOD –> H2O2 –> MPO –> HOCl
anti-inflammatory cytokines
IL-10 and TGF-B
2nd signal for CD4 Tcells
B7 on APC binds CD28 on CD4 Tcell
Th1 subset
IL-12 is stimulus, secrete IFN-y (IgM –> IgG) and IL-2
Th2
IL-4 IL-5 IL-10 IL-13
IgE, IgA, eosinophils
CD8+ 2nd signal and 2 killing mechanisms
IL-2 from Th1 cells
1. perforin and granzyme
2. espression of FasL
both trigger apoptosis
MHC-I
A3
B8
B27
all nucleated cells + platelets
presents INTRAcellular antigens i.e. cytosol, viral
Ag peptide delivered to RER by TAP then loaded on MHC-I [1 long chain, 1 short chain]
B2-microglobulin
A3 = hemochromatosis, B8 - MG
MHC-II
DR2 vs 3 vs 4
on APCs
presents EXTRAcellular antigens (foreign protein ie bacteria)
Ag is loaded after release of invariant chain in an acidic endosome
DR2 - MS and Goodpasture
DR3 - SLE
DR4 - RA
CD40
B cells; 2nd signal - binds CD40L on CD4 helper T cell
also on macrophages
defining trait of a granuloma
epithelioid histiocytes (macrophages with lots of PINK cytoplasm) – surrounded by giant cells and rim of histiocytes
non-caseating granuloma - definition and 4 examples
do NOT have central necrosis aka still have nuclei, not as dark as caseating in middle
- rxn to foreign material
- sarcoid // berrylium
- Crohn
- bartonella (cat scratch - neck, star-shape)
granuloma formation
macrophage presents antigen to CD4 via MHC-II –> macrophage secretes IL-12 –> Th1 subtype –> IFN-y –> macrophage converts to histiocyte or giant cells
TNF-a maintains granuloma in TB
viral and fungal infection - main cells
T cells
bacteria or protozoa
B cells
SCID pathology
lack of ADA leads to buildup of adenosine and deoxyadenosine (ie cannot breakdown into hypoxanthine) – toxic to WBCs
X-linked agammaglobulinemia
pre/pro-B cells cannot mature thus you get total lak of immunoglobulin
mutated Bruton tyrosine kinase “brutal tyrant” on chromosome 20
presents at 6mo w/ bacterial, enterovirus, giardia
absent lymph nodes / tonsils
avoid live vaccines
CVID
low immunoglobulin, similar infections but will present later in childhood
IgA deficiency
most common one but usually chill; esp. at risk to viruses. anaphylaxis to blood transfusion**
CELIAC
Hyper IgM syndrome - cause
defect in CD40 - no class switching thus all other types will be low - can't opsonize well no germinal centers
Wiskott-Aldrich
WATER thrombocytopenia, eczema, recurr infection
bloody diarrhea, nosebleeds
X-linked – “WiXott-Aldrich”
WASP gene - anchors membrane receptors - cannot present antigens. actin.
major cause of death = bleeding
hereditary angioedema
C1 inhibitor deficiency edema esp. around EYES and mucosa unregulated activation of kallikrein --> elevated bradykinin, low C4 Tx includes Danazol ACE-inhibitors CONTRAindicated
hyper IgE (Job)
STAT3 mutation - no/low Th17 –> cant recruit neutrophils
eczema, bones break easy, keep baby teeth
face deformities, cold abscesses
eosinophilia
AIRE
autoimmune regulator – presents self-antigens in medulla for negative selection
autoimmune polyendocrine syndrome 1
C2 deficiency
lupus
anti-dsDNA or anti-Sm
lupus
2 main antiphospholipid antibodies
- anti-cardiolipin (false + VDRL and RPR)
2. lupus anticoagulant – falsely elevated PTT (they’re actually hypercoagulable - clot a lot)
HSR type in lupus vs sjogren
Lupus - type III - antigen-Ig comlexes
Sjogren - type IV - lymphocyte mediated
anti-ribonucleoprotein
Sjogren’s
anti-SSA/Ro or anti-SSB/La
pregnant woman with + anti-SSA
baby at risk for congenital heart block and neonatal lupus
anti-centromere (Dx and Sx)
limited scleroderma - CREST:
calcinosis/centromere, raynaud, esophagus dysmotility, sclerodactyly, telangiectasia
anti-topoisomerase 1
anti-Scl 70 – diffuse scleroderma – crest + early visceral
lungs - MCCD - fibrosis and HTN
GI
kidneys - scleroderma crisis
anti U1 ribonucleoprotein
mixed - lupus + sclerosis + polymyositis
CD34
hematopoeitic stem cells in bone marrow
granulation tissue
fibroblasts - lay down type III collagen + capillaries + myofibroblasts
type III collagen
granulation tissue, keloid, uterus, embryo (very pliable)
what requires 1. zinc 2. Vitamin C 3. copper
- collagenase - replaces type III collagen w/ type I
- hydroxylation of proline and lysine residues on procollagen in the RER (early step)
- lysyl oxidase - forms covalent crosslinks in final step (between lysine and hydroxylysine of tropocollagen strands)
regenrative liver nodules - 2 key traits
- twin cell plates 2. No portal triads - just rows
growth factors for 1. fibroblasts 2. angiogensis
- TGF and PDGF
- FGF and VEGF
((TGF-a = epithelium))
((FGF = bone dev.))
PDGF stims growth of ? 3 things
fibroblasts, endothelium, smooth muscle
PNH
defect in PIGA –> cannot make anchors for complement inhibitors (CD55/DAF or CD59). RBCs get gobbled by complement.