2 types of synovial lining cells
A: resemble macrophages with lots of organelles
B: resemble fibroblastas with lots of ER
What is the unique feature of synovial lining?
No basement membrane
What are the components of synovial interstitium?
collagen fibrils and proteoglycans with abundant fenestrated microvessels
What is the most rapidly destructive form of bone and joint disease?
How do bacteria spread in septic arthritis?
typically hematogenous spread
also direct puncture/surgical procedures/animal bites
Why is the joint susceptible to septic infection?
- abundant vascular supply
- lack of limiting basement membrane
What are the main categories of septic arthritis causing bacteria?
Gonoccal (N. gonorrhea) vs. Nongonococcal (S. aureus)
What are 4 key risk factors of bacterial arthritis?
- age (80+)
- pre-existing joint disease/damage (osteo/rheumatoid arthritis)
- chronic systemic disease (diabetes)
- immunosuppression (steroids)
- prosthetic joint
- drug use
mechanisms which infectious organsms have evolved to enhance immune evasion
What do MSCRAMMs bind and what do they do?
microbial surface components recognizing adhesive matrix molecules
- bind host matrix proteins like collagen, elastin, etc.
In what organism is the agr relevant and what does it do?
accessory gene regulator
- regulate S. aureus surface proteins and exotoxins
- upregulates proteins early in infection to promote attachment and upregulates exotoxins later in infection
How does N. gonorrhea (G+cocci) attach to cell surfaces?
How does N. gonorrhea avoid complement and phagocytosis?
Protein IA binds to factor H --> inactivates complement 3b
3 ways septic arthritis leads to joint damage
- direct bacterial effect/toxins
- host immune response to LPS/cytokines --> autodigestion of cartilage by metalloproteases
- mechanical effects from joint effusion pressure
Cytokines implicated in immune-mediated damage in septic arthritis
IL1beta and IL6 --> recruit neutrophils and macrophages --> produce TNFalpha, IL1,6,8 --> production of proteases and free radicals
How does joint exudate lead to ischemia in septic arthritis?
purulent exudate increases intra-articular pressure --> ischemia in avascular cartilage
Septic arthritis-clinical features
Gonococcal arthritis-clinical features
inflammatory arthritis of multiple joints
Classification of joint effusions
normal- clear, viscous (<200 leukocytes/mm3)
noninflammatory- clear/yellow, viscous (200-2000)
inflammatory-cloudy/yellow, thin (2000-100,000)
septic-purulent, thin (>50,000)
Stages of Lyme disease
early localized-rash, erythema migrans, viral symptoms
early disseminated-cardiac, neurologic
late disease-neurologic, inflammatory arthritis
Borrelia arthritis-late disease-clinical features
spirochetes invade synovium --> accumulation of neutrophils, complexes, complement, cytokines
fluid count < 50,000 leukocytes/mm3
- monoarticular knee
Why is joint damage slow-onset with lyme disease?
Borrelia does not produce its own proteases so must wait for immune response to generate damage
Molecular mimicry hypothesis for Lyme resistance
T cell epitope mimicry between spirochete and host protein --> borrelia mediated autoimmunity
Phenomenon of autoreactive t cell possing TCR for foreign peptide that also recognizes self-peptide
Molecular mimicry phenomenon
Observations that support molecular mimicry hypothesis
- certain MHC II types predisposed to Lyme arthritis --> HLA DRB1*0401/0101
- presence of ab to borrelia out surface protein in pts with lyme arthritis
- id of autoantigen with sequence homology
Which Borrelia protein is the target of Lyme arthritis autoantibodies?
OspA surface protein
Which human autoantigen has sequence homology with the Borrelia antibody target
LF1alpha - adhesion molecule on inflamed tissues
Primary issue with molecular mimicry hypothesis re: antibiotic resistant Lyme arthritis
- LF1-alpha is a weak agonist to OspA reactive tcells
What kinds of patients with antibiotic resistant Lyme arthritis have a strong immune response to OspA and LFA-1alpha?
Tx of antibiotic resitant Lyme arthritis
Viral arthritis-clinical features
symmetric polyarticular small joint
Example of immune complex mediated viral arthritis
Example of antigenic persistence related viral arthritis
How does HepB produce arthritis?
HepB SA + antibodies form complexes that deposit in synovium --> complement activation, neutrophils --> inflammatory arthritis
Most common viral arthritis in the US
What molecule communicates with Parvovirus B19 to allow its entry to the synovium?
glyocsphingolipid Gb4 on synovium
various pieces of infectious agent can cause ongoing immune response even in absence of whole organism
multisystem inflammatory arthritides involving the spine, synovium, and enthesis
associated with HLAB27
Which HLA is associated with spondyloarthropathies?
asymmetric polyarticular peripheral arthritis
new bone formation
Tx: TNF alpha inhibitor, Ibuprofen, PT
What are three defining features of spondyloarthropathies?
simultaneous bone catabolism/anabolism
What process precedes synovitis in SpA?
Cytokines that stimulate RANKL
TNFalpha, IL1, 6 --> RANKL --> osteoclast activation
and--> Dkk-1 and sclerostin --> osteoblast inhibition
Three important pathways in pathologic bone formation
BMP, Wnt, and PGE
The pathogenic function of HLAB27 is related to antigen presentation to what kinds of cells?
Relationship between HLAB27 and bacteria
HLAB27 rats need colonic bacteria to get SpA
Three theories explaining role of HLA-B27 in SpA
misfolding and unfolded protein response
Cytokine linchpin in unfolded protein response related to SpA and HLA-B27
IL 23 --> IFNbeta, IL 17,22,1,6,TNFalpha --> osteproliferation, inflammation, ethesitis
systemic autoimmune condition with antibodies to components of cell nucleus + protean clinical manifestions
SLE-key clinical features
ANA --> antiDNA or anti-smith or APLA
Environmental contributors to Lupus
When do SLE autoantibodies appear?
long before clinical manifestations
antinuclear antibody --> binds to antigens found in nucleus --> immunofluoresence, ELISA (via Hep-2 cells)
Autoantibodies specific for lupus
Pathogenic modalities of SLE
apoptosis --> nuclear antigens
inf-alpha stimulation of immune system
What molecule has been found in association with apoptosis defects in SLE?
BLyS --> B lymphocyte stimulator --> Belimumab (Anti-BLyS Ab)
Newest lupus drug
Which autoantibodies mediate neonatal lupus?
Anti-Ro/La (SSA/SSB) --> passive transfer from maternal system
Neonatal lupus-clinical features
- complete congenital heart block
Clinical measure for immune complexes
C3 and C4 levels --> if low, lots of disease activity
immune complex mediated sequelae of lupus
Which TLRs activate innate immune system and generate IFN in lupus?
TLR 7 and 9 --> recognize immune complexes
Which cytokine is thought to be most important in mediating scleroderma?
Triad of conditions defining scleroderma
diffuse (above knees/elbows)
Diffuse cutaneous scleroderma-clinical features
early visceral organ involvmeent
absence of anticentromere antibodies
Limited cutaneous scleroderma-clinical features
- esophageal dysmotility
Anti-centromere antibodies are found in what kind of scleroderma?
Which autoantibodies are associated with scleroderma?
anti-Scl-70 in AA//HLA-DQ7
anti-centromere in caucasians
Which virus is associated with scleroderma?
Genes associated with scleroderma
COL1A2 (type 1 collagen)
Which ANA is associated with rapidly progressive scleroderma?
How does TGF-beta mediate SSc/Scleroderma
sensitizes fibroblasts to stay persistently activated
decreases function of collagen degrading proteases
SMAD pathway in Scleroderma
TGFbeta binding --> SMAD 2/3 phosphorylation -> SMAD4 translocation to nucleus --> collagen gene upregulation
Which SMAD downregulates collagen formation in SSc and which cytokines mediate this inhibition?
INF-gamma and TNF alpha
Which important SSc related factors are stimulated by TGF-beta?
CTGF: fibroblast, vascular smooth muscle, endothelium
PDGF: skin, lungs, vasculature
Initiating event in scleroderma
t cells migrate to vessel wall --> cytokines/growth factors --> fibrosis and transdifferentiation of fibroblasts to myocytes --> tissue hypoxia --> ischemia
Major organ consequences of SSc
scleroderma renal crisis --> renovascular damage from fibrosis
pulmonary hypertension --> fibrosis and hypertrophy
Key histological feature of cutaneous SSc
thickened dermis with increased collagen bundles
group of immune mediated disorders causing inflammation and damage to vessel walls leading to tissue ischemia and organ failure
Classificiation of vasculitis
Dx of vasculitis
leukocyte vessel wall infiltrate (inflammation)
vessel wall damage
immune complex deposition (in immune-complex mediated small vessel vasculitis)
Medium vessel vasculitis- Polyarteritis nodosum (PAN)-clinical features
Dx of classical PAN by angiogram requires
transmural inflammatory cell infiltrate
intimal proliferation (destroying elastic laminae)
resulting in vessel occlusion
Which organs are spared by PAN?
glomeruli and lungs
Renal consequences of PAN
reduced blood supply --> renin --> salt/water retention --> hypertension
Virus associated with PAN
Where in arteries does PAN tend to manifest?
bifurcation sites --> increased sheer stress results in buildup of endothelial adhesion molecules and proinflammatory tf (e.g. NFkB)
What pathologic features are absent in PAN?
immune complexes and autoantibodies (incl. ANCA)
anti-neutrophil cytoplasmic antibodies
associated with small vessel vaculitides
recognize neutrophil lysosomes
c-ANCA vs. p-ANCA
cytoplasmic: least common, most specific, PR-3
perinuclear: most common, least specific, MPO
test to confirm c-ANCA
test to confirm p-ANCA
Organ tropism of ANCA Associated Vasculitides (AAV)
microcirculation --> lungs and kidneys
Pathology of cresentic glomerulonephritis
injury to glomerular capillary wall --> plasma protein/fibrinogen leakage --> macrophages/Tcells --> IL1, TNFalpha --> fibroblast proliferation, collagen deposition, crescent formation --> glomerular nephritis
whole body edema (due to renal involvement, here b/c of AAV)
Role of ANCAs in AAV
cytokines prime neutrophils to express ANCA antigens --> bind to Fab and Fc ANCA--> neutrophil activation --> endothelial cell damage in capillaries via lytic enzymes, ROS
Environmental consequences on ANCA production
can trigger anti-PR3 in patients with subacute bacterial endocarditis or amoebiasis --> will disappear with antibiotics
What bacterial antigen makes AAV worse?
Small Vessel Vasculitis- Immune Complex-clinical features
skin rash - palpable purpura
tropism for dermal vessels
In what conditions do we find circulating immune complexes?
connective tissue disorders (lupus)
malignancy (hairy cell leukemia)
hypersensitivity drug reactions
Under what condition do ICs precipitate?
Immune Complex SSV-morphology
Which venules are most susceptible to immune mediated injury due to hypoxia and stasis in SSV?
postcapillary venules --> leukocyte adherence best in small vessels with stasis
Why does IC SSV cause palpable purpura?
thrombosis --> C3a/5a/histamine --> widens EC jxns --> leakage --> palpable purpura
Acute Gouty Arthritis-clinical features
severe monoarthritis (one joint)
1st mtp joint, ankles, knees
acute + gradual resolution
middle aged males
hyperuricemia and urate crystal shedding in synovial
Dx of Acute Gouty Arthritis
hyperuricemia (>6.8mg/dL) + MSU crystal dposition
What dietary elements are associated with gout?
beer, meats, fructose
PRPP synthase and gout
increased PRPP (x linked) results in more purine synthesis --> hyperuricemia
HGPRT and gout
deficiency (x linked) --> less salvage --> hyperuricemia
Xanthine Oxidase and gout
target of inhibitors allopurinol and febuxostat
Uricase and gout
not in humans --> Pegloticase porcine uricase can treat hyperuricemia
reabsorbs filtered urate in proximal tubules
- organics: lactate/b-hydroxybutyrate,acetoacetate
HGPRT deficiency (x linked)
PRPP synthetase superactivity (x linked rare)
Diseases featuring HGPRT deficiency and primary hyperuricemia
Lesch-Nyhan (total def w/neuropathy)
Kelle-Seegmiller (partial def w/o neuropathy)
excessive dietary intake
accelerated ATP degradation (acute illness)
URAT stimulators-pyrazinamide, nicotinate, organic acids
- URAT stimulators-pyrazinamide, nicotinate, organic acids
- cyclosporine-decreased GFR
- low-dose salicylate
Alcohol and hyperuricemia
accelerated hepatic ATP breakdown -->overproduction
increased lactic acid --> URAT1 stimulation
dehydration --> underexcretion
high guanosine content
Chronic Tophaceous Gout-clinical features
inability to eliminate urate as rapidly as produced --> Tophi deposits in olecrenon, ear, forearm, fingers
Chronic Tophaceous Gout-morphology
granulomas of mononuclear and multinucleated macrophages surrounding debris + MSU crystals + connective tissue
Renal failure/Kidney Stones
uric acid deposition in renal tubules --> acute renal failure
uric acid deposition in collecting ducts/ureters--> stones
Pathogenesis of Acute Gout
MSU crystal phagocytosis --> NLRP3 inflammasome activation --> IL1beta --> induce inflammatory cytokines --> neutrophil influx
End pathological event in acute gout
Tx of acute gout
Tx of chronic gout
progressive degenerative changes in shape, composition, and mechanical properties of weight bearing joint tissues, especially articular cartilage
Most common cause of arthritis
Cartilage in joints is composed of
matrix (80% water)
type II collagen
_______ provides tensile strength in joints.
Type II collagen
_______ resist compression in joints.
negatively charged proteoglycans
Force in joints is dissipated by ________.
water efflux from cartilage matrix
Rate and nature of OA progression
slow "wear and tear" over time with low-grade chronic inflammation
Cytokines involved in low-grade chronic inflammation in OA and consequence.
TNFalpha, IL1b, IL6 --> recruit matrix metalloproteases --> inflammation, tissue damage, suppressed repair
Matrix metalloproteases are regulated by _______.
TIMP: tissue inhibitor of metalloproteases
decreased range of motion
worse with use
variable presentation (worse in women)
- decreased range of motion
Bony outgrowths in OA and types
- bouchard's node ("body of finger") = pip
- heberden's node ("head of finger") = dip
Cartilage compression results in
fluid pressure increase
change in osmolarity
trigger of mechanoreceptors (stretch-activated)
normal load = maintenance
abnormal load = decreased proteoglycan synthesis
- normal load = maintenance
- abnormal load = decreased proteoglycan synthesis
Abnormal load on cartilage results in
decreased proteoglycan synthesis
subchondral eburnation (loss)
matrix fragments triggers
clustering of chondrocytes "clones" --> "confused proliferation of chondrocytes"
replacement of type II with type I collagen -->fibrocartilage
- repeated microtrauma (fibrillation/clefts)
- abnormal matrix composition
- calcified cartilage growth
- increase in water
- subchondral bone thickening --> less dense
- decrease in number
In ______ osteoarthritis, formation outpaces resorption of bone.
Angiogenesis in OA
dependent on VEGF
increase fluid flow
increase inflammatory mediators
Subchondral sclerosis is a feature of _________.
In OA, synovial features include
decreased mw of hyaluronic acid
Links between obesity and OA
chemical: leptin --> stimulates inflammation in chondrocytes
mechanical: weight, load pattern
______ is a cardinal feature of OA.
Does synovium become thinner in OA?
No. Only subchondral bone in early OA and cartilage throughout.
polyarticular small joint inflammatory arthritis of the synovium with systemic symptoms -->synovitis unexplained by other diseases
What happens to synovium in RA?
early: synovium thickens by hypertrophy and hyperplasia --> distension of joint capsule due to inflammatory fluid/cells
advanced: inflammation causes bony destruction and cartilage damage--> "pannus"/wet bread appearance
In contrast to osteoarthritis, bony destruction in RA is a ____ process.
production of metalloproteases
migration of inflammatory cells
erosion of bone and collagen
Disease of weight bearing joints is
Disease of small joint synovia
Disease of cartilage
Disease of synovium and enthesis
Implications of "Shared Epitope" hypothesis in RA
epitopes in HLA-DR are shared by alleles associated with RA --> autoimmune implications
Smoking and RA
increases risk of ACPA+ RA
Which antibodies are associated with smoking and periodontis in RA?
anti-cyclic citrullinated peptide (CCP) antibodies
- targeted against citrulline residues in Type II collagen
- marker of severe disease
Periodontis is associated with
RA via anti-CCP antibodies
Citrullination hypothesis in RA
increased citrullination --> binding with MHC II --> antigen presentation --> antibody development --> immune complex --> inflammation
Where in the synovium of many patients do immune cells gather?
lymph-node like structures withn autoimmune environment
Cytokines produced by macrophages
TNF alpha, IFN gamma, IL1, IL6
Cytokines produced by dendritic cells
TNF alpha, IL1, IL6
Autoantibodies associated with RA
rheumatoid factor -
Rheumatoid Factor (RF)
IgM antibody that binds to Fc portion of IgG --> immune complexes --> B cell presentation of any antigen bound by IgG --> widespread inflammation
*also complement fixation and cytokine mediated inflammation
Cytokines produced by B cells
TNFalpha, IL6, IFN gamma, Lymphotoxin
Main cytokine in RA
How do cytokines upregulate bone and collagen destruction in RA?
Cytokines --> collagenase, RANKL
- cartilage destruction can be inside/out or outside/in
Where is RANKL found?
stromal cells, osteoblasts, T cells, synovial fibroblasts --> activate RANK on osteoclasts
RANK antagonist: binds RANKL
Systemic sequelae of RA
Increased mortality in RA patients associated with
cardiovascular events due to atherosclerosis
Classes of drugs used in tx of RA
Disease modifying anti rheumatic drugs (DMARDs)
Early treatment of RA
NSAIDs, aggressive DMARDs (MTX)
window of opportunity to prevent damage
increasing tolerability of DMARDs
First line treatment for RA and MOA
- inhibits DHFR (inhibit lymphocytes)
- increases adenosine (reduces inflammation)
- reduce TNFalpha and IL1
- SE: abdominal pain, mouth sores, myelosuppresison, teratogenic in utero
Alternative first line treatment for RA and MOA
- inhibits orotic acid dehydrogenase --> pyrimidine synthesis
- alters cell growth and inflammation
- SE: weight loss, abdonminal pain, diarrhea, teratogenic
fully human mabs
receptor fusion proteins
anti-TNF alpha drugs
binds soluble TNF and cell bound TNF (antibody or receptor clone on human Fc + Pegol) --> reduce inflammation, reduce infiltration
SE: injection site rxn, infection, anti-pregnancy, MS-like, tolerance, neoplasms
e.g. etanercept, glimumamb, inflixumab
- block IL6 cytokine receptor --> maturation of T/B cells, osteoclasts, macrophages
- reduces immune response
- used after TNFalpha inhibitor
- SE: liver, pregnancy, infusion, infections
- block IL-1 receptor --> reduce immune response
- lower response rates
- not common in RA
- SE: infection, pregnancy
like belatacept: anti CD80/86
SE: infection, anaphylaxis, pregnancy, infusion rxn, neoplasms
bind CD20 on B cells --> destruction --> depletion of B cells
antibody dependent cell cytoxicity (ADCC)
complement dependent cytotoxicity (CDC)
used after failure of TNFalpha
- antibody dependent cell cytoxicity (ADCC)
- complement dependent cytotoxicity (CDC)
RA treatment plan
Wait and see
Add-in TNFalpha inhibitor like Etanercept
if failure, then Anti-IL6 like Tocilizumab
if failure, then Abatacept
if failure, then Rituximab
chronic, autoimmune inflammatory disorder with lymphocytic infiltration of exocrine glands resulting in reduced glandular/salivary/lacrimal secretion (sicca) in associatein with anti-SSA/SSB
Types of Sjogren's
sicca symptoms develop in healthy person
sicca symptoms in person w/connective tissue disease (e.g. RA)
Clinical stages of Sjogren's
1st stage: sicca, m/s pain
2nd stage: internal organs, vasculitis
3rd stage: NHL of salivary glands
injury to exocrine glandular epithelia --> apoptosis --> exposure of autoantigens
infiltration of glands with lymphocytes/inflammatory cells --> cytokines --> autoantibody production --> destruction --> loss of function
What kind of cells produce watery saliva and what enzyme does this contain?
serous acinar cells
What kind of cells produce thick saliva and what is the key component?
mucous acinar cells
mucin --> lubrication of food
Where do inflammatory cells localize to in early Sjogren's lymphoepithelial lesions?
periacinar and periductal (focal lymphocytic sialadenitis) distribution of
- B cells
- plasma cells
Late stage Sjogren's-morphology
chemokine CXCL12 overexpression --> attracts lymphocytes and dendritic cells
CXCL13 expression -->attracts B cells
SGECs act more like APCs --> express MHC, adhesion molecules, costimulatory
What chemokine is overexpressed in Sjogren's and what is its function?
CXCL12 --> attracts t cells and dendritic cells
What aberrant chemokine is expressed in Sjogren's and what is its function?
CXCL13 --> attract B cells
What aberrant molecules are expressed by SGECs in Sjogren's?
BAX --> more apoptosis of SGECs
What aberrant molecules do lymphocytes express in Sjogren's?
BCLX1 --> reduced apoptosis of lymphocytes
Which viruses are sialotropic --> cause salivary gland disease?
HIV, Hep C --> activation of type 1 INF system
Role of Type 1 Interferon system in Sjogren's
persistence of plasmacytoid dendritic cells (INF1 producing) in salivary glands in ABSENCE of virus
interferon signature in blood leukocytes
can be stimulated by viral infection (TLR recognitio nby plamacytoid dendritic cells)
Main explanation for dryness in Sjogren's
parenchymal loss due to loss of salivary epithelia
Alternative mechanism of drness in Sjogren's
anti-M3R antibodies --> inhibit binding of AcH to M3R receptors on acinar cells --> no IP3 --> no Ca release --> no opening of Ca and K channels --> no water flow
- associated with Type 1 SS
- could aslo be acceerated degradation of AcH
3 immune mechanisms for dryness in Sjogren's
blocking antibodies (M3R)
Factors contributing to MALT in late Sjogren's
CXCL13 recruits B cells --> Baff stimulates proliferation, neoplastic formation of ectopic lymphoid structures --> B cells escape peripheral checkpoints-->A20/NFkB final oncogenic event
- B cell hyperactivity --> autoantibodies
- increased Ig
- formation of ectopic lymphoid follicles and germinal-like centers
- increased BAFF/BLyS in blood/salivary glands (anti-apoptotic)
- Tx: rituximab
What is the common final oncogenic event in BAFF mediated lymphomagenesis in Sjogren's?
A20 mutations --> abnormal NFkB expression --> uncontrolled B cell proliferation and survival
Cytokine that sparks progression to lymphomagenesis in Sjogren's
2 hit hypothesis for Sjogren's suggests what kinds of mutations necessary for lymphomagenesis?
NALP3 Inflammasome in gout
- uric acid -->intracellular PRP-->caspase 1 --> cleaves and activates IL1beta and IL18 --> recruits neutrophils and macrophages