Transcript - Dr. Robert Fox

Pathogenesis of
Sjogren’s Syndrome:
Translating Basic Science
from
“Bench to Bedside”
Sjogren’s Syndrome
• Increased mortality risk, particularly due to
lympho-proliferative complications
• Quality of life- equated with moderate angina
• “Disability” predominantly due to fatigue and cognitive
• “Limitations”:
 dry eyes (limits work- especially computer)
 dry mouth (limits sleep and social interactions around eating)
 extra-glandular manifestations, particularly neurologic
• Expense of artificial tears and dental decay
Background-1
Sjogren’s syndrome represents the interface of:
a) Immune and exocrine secretory functions (dryness)
b) Immune and neural function (neuropathy/cognitive)
c) Immune and hypothalamic-adrenal axis (autonomic)
d) Autoimmune proliferation and lymphoma
e) Lupus-like features of vasculitis and immune complex
Background-2
The Danger Signal
When we get “flu symptoms”
of arthralgia, fatigue, cognitive dysfunction—
it is a result of the cytokines/neurotransmitters
released by the innate immune system.
When these reactions persist due to a vicious
cycle perpetuated in genetically predisposed
individual by the acquired immune system,
the result is autoimmune disease.
Pathogenesis:
Take Home Lessons-1
1. Innate and Acquired Immune Systems are targets for
current therapy—including TNF, BAFF and IL-6
inhibitors, steroids, traditional DMARD’s and new
oral agents (Jak and syk inhibitors).
2. Functional circuit that controls immune and neural
function comprises the new “frontier” for therapy
from fibromyalgia to depression. The functional
circuit is the link between cytokines and symptoms.
Take Home Lesson - 2
The two arms of the immune system mutually interact
in the initiation and perpetuation of Sjogren’s Syndrome
Acquired System
 (HLA-DR)-memory
Traditional T-cell and
B-cell and their cytokines
 HLA-DR association
with autoantibody
production
Target of drugs such as
DMARDs and certain
biologics
Innate System

(Adaptive, immediate) - HLA independent
 Dendritic cells
 Cytokines-particularly
 Type I interferon
 Interferon-gamma
 BAFF, IL-6, IL-17
 Complement, CRP
Sensors of the innate system
 Toll receptors (TLR)-pathogen motiffs
 DAMP (damage recognition patterns)apoptosis
 RIG-1 (retinoid inducible genes)
 NOD/Card receptors-more than in colitis
Take Home Lesson 3:
The Functional Circuit
(Cytokines are not enough)
Control of tears or saliva flow are complex
processes that involve both afferent nerve
pathways that go to the midbrain and
efferent nerves that modulate glandular
function.
The midbrain signals are influenced by the
cortical outflow and the hypothalamic axis.
Normal tearing or salivation
secretion requires a functional unit
4. Stimulation
of gland
water
nutrients
hormones
3. Stimulation
of blood vessel
water
mucin
protein
3. Cortical
Outflow
Tracts
and
HPA
1. Ocular or oral surface
irritation
Nerves on mucosal
Afferent nerves
2. Midbrain of
central nervous
system
Lacrimatory or salivatory
nuclei
The functional circuit involves
known neural connections to the brain
*Pflugfelder SC, et. al. Dry Eye and Ocular Surface Disorders. NY: Dekker, 2004.
In Sjogren’s syndrome, the release of Ach and VIP
by efferent nerves to the glands
--and the response of the glands to neural transmitters-are impaired by lymphocytes
that enter the gland and release inflammatory factors
ocular and oral dryness
lymphocytes
Focal lymphocytic
infiltrates in the
glands
Gland dysfunction
•Autoantibodies
(anti-muscarinic antibody)
Cytokines (type I IFN, g-IFN)
•Metalloproteinases
(outside-inside signaling
molecules)
In Sjogren’s, only 50% of the acini and ducts are destroyed.
Despite their retention of neural innervation, the residual
glands do not function as a result of the inflammatory
environment
Foci of
lymphs
Sjogren’s
Normal
In Sjogren’s syndrome
The residual glandular cells are
paralyzed by the local
immune reaction.
Even though the acini/ducts
are 50% present, their innervation and
their receptors
for neurotransmitters are present.
Thus, the interesting question is:
Why are the residual glandular elements
not working?
This fundamental question of
how immune and neural systems interact
will be the “holy grail” of neuroscience
for the next decade.
Pathogenesis Take Home Lesson- 2
Although many complex interactions take place in the salivary
gland, a characteristic type I interferon gene signature is
noted repeatedly.
The relationship of autoantibody to SS-A/SS-B and type I
interferon signature has recently been suggested.
This links our blood tests (SS-A) and clinical features.
IFN Type I in salivary gland suggests
a role in Sjogren’s Syndrome
SS
SS SG biopsy with type I
IFN gene profile
SS SG biopsy with type I IFN
NML
Non-SS sicca
Take home lesson-3
Homing receptors determine
both glandular and extraglandular features
1.
2.
3.
4.
Salivary glands normally lack lymphocytes, so their mere presence in
an extraglandular tissues imply a lymphocyte aggressive process.
Homing to the gland tissue is due to specific receptors/ligands
controlled by chemokines/cytokines.
Retention of lymphocytes in the tissue is due to specific ligands.
Their apoptosis or expansion is regulated through Fas pathways
that are modulated by cytokines and bcl-2
Pathogenesis:
Take Home Lessons-4
1. Extraglandular manifestations are
determined by lymphocyte homing to
tissues-- factors that govern their
retention in tissues and their apoptosis.
2. Factors governing their clonal expansion
and lympho-proliferation lead to
lymphoma-derived from B-cells
themselves, T-cells, and dendritic cells.
1. Tissue Homing/Retention of lymphocytes
is the key process for accumulation of glandular infiltrates,
as virtually no mitotic cells are seen in the gland.
2. Subsequent migration from gland into efferent lymphatic
defines re-circulating memory lymphocyte pool.
The endothelial cells attract T-cells by
ICAM’s and Chemokines
Sjogren’s Lip Biopsy
B
The endothelial cells release B-cell
chemo-attractants
A
B
Ref 63
Endothelial cells attract dendritic cells
to home to the gland.
Take Home Points for Homing Receptors:
a)Expressed by salivary glands in NOD.scid
mice, so expression is independent of
cytokines released from the lymphocytes.
b) Thus, the story of Sjogren’s syndrome is
not a poor salivary gland that is “beaten
up” by the lymphocytes-- but that the
glands participate in the homing and
pathogenesis of inflammatory cells and
subsequent inflammation.
c) The problem with blockade of homing receptors
(whether Tsabri or Raptiva) has been the emergence
of rare but devastating problems due to reactivation
of papilloma viruses (such as JC) with clinical PML
(progressive multi-focal leukoencephalopathy).
Pathogenesis
Take Home Lesson 4
SS has
lymphoproliferative properties—
it lies on the border between
autoimmunity and
lymphoma.
Sjogren’s Syndrome – with parotid enlargement
indicates lymphoproliferative tendency
Risk factors for lymphoma
a) Germinal centers on minor salivary gland biopsy
b) Low complement C4
c) MGUS (esp. IgM-K with RF activity) and mixed cryoglobulin
The T-cells and dendritic cells drive B-cell clonal expansion, particularly
driven by BAFF, until a B-cell clone escapes to become a lymphoma.
Germinal Centers in Minor SG Biopsy
This provides a rational of
understanding for
1. anti-CD20 (rituximab)
2. anti-BAFF and anti-TACI
3. anti-CD22 antibody therapies
Overview of the steps in
pathogenesis
that help explain
role of gender (TLR receptors)
autoantibodies (anti-SS A)
interferon-Type I signature
HLA-DR association
SS: Hormonal Factors
(SS predominantly in women)
• X-chromosome location of Toll receptor;
• X-linked genes for apoptosis;
• X-linked genes for transcription promoter of
pro-inflammatory loci including NF-K;
• X-linked control of metalloproteinase
release under prolactin hormonal
regulation.
Time course of autoimmune response*
1. Environmental stress is interpreted in context of genetic
factors.
2. Antibodies precede disease.
3. Presence of antibody does not mean disease.
Environmental
Stress
(virus-such as EBV)
(apoptotic fragment)
Innate
(Toll receptor)
Type I IFN
Genetic
Genetic
Genetic
Genetic
Factors
Factors
Factors
Factors
(including
(including
(includingsex)
sex)
sex)
(HLA-DR)
(HLA-DR)
(HLA-DR)
(HLA-DR)
Autoantibodies
Immune system
Immune
complex
Acquired
Immune system
(HLA-DR)
T/B-cells
Disease
Manifestations
Time period of years
Ref. 32-33
Genetic Predisposition in SS
to Type I Interferon
In genome wide screens, association of IRF5
alleles and Stat 4, with predisposition to
development of SS*
* Refs 36-38
Other Factors in Pathogenesis
• Gender - SS is a predominantly a disease
of women.
• Onset and increase of dryness with
menopause.
• Increased risk of Klinefelter (XXY) in male SS*
—Toll receptor translocation (BXB model).
• Aromatase knockout mouse gets SS.
• RbAp48--estrogen dependent apoptosis.
• DHEA and CRISP-role in glandular processing.
* Refs 34-40
At this point …
• I want to stop for questions and see if you
would like to break or stay for new
approaches to therapy
• Thanks again for inviting mel.
Treatment of Sjogren’s in 2010:
Opportunities and Challenges
a) Treatment of Dry Eyes and Mouth
b) Treatment of Extraglandular
Manifestations-• Lupus like symptoms-arthralgia, rash
• Neuropathy (central and peripheral)
• Cognitive and myalgia (fibromyalgia)
• Lymphoproliferative
Take Home Points-1
1. Topical therapy of dry eyes and dry mouth:
new targets include water transport,
mucins, and topical small molecules such
as jak 3.
2. Dry mouth symptoms may be “burning”
mouth and require treatment as a local
neuropathy.
Take Home Point-2
1. Poor correlation of symptoms and
objective findings of both dryness and
neuropathic symptoms.
2. This poor correlation is the greatest
challenge since it involves cortical
perception of discomfort
3. The neuro-endocrine circuit in Sjogren’s
may provide insight into “fibromyalgia”
Take home points-3
• Systemic Manifestations for lupus like symptoms
DMARDs
Hydroxychloroquine
Methotrexate
Leflunomide
Small molecules-Jak3
and Jak ½
Filomodulin (MS
approved)
Biologic Agents
Anti-CD20 rituximab
and new variants
Anti-BAFF (Benlysta)
Anti-CD22 (Eprumazab)
Taci-Ig and
ICOS
Homing receptors
New Approaches to Dryness
1. Topical Ocular Dryness
“smart artificial
tears”
Mucin
Androgen
Micro-iRNA
Anti-IL-17*
Jak 3 inhibitor*
Metalloproteinase
inhibitor
* Currently
cyclosporin is water
insoluble and
irritating
New Approaches to Dryness-2
Oral Agents are better than pilocarpine or cevimeline
… since the gland is not destroyed but is paralyzed by
cytokines and metalloproteinases
• Improved secretagogues
(new muscarinic agents in trial)
• Anti-cytokine therapy has
modest effect only in patients
with early disease
New Approaches to Dryness-3
Novel methods of water conservation
•
1. Transport water across the conjunctiva (diquafasol)
p2Y2 purine receptor agonist
2. Decrease evaporative loss
(muc 3, muc 5A, lipid)
3.Decrease water reabsorption
through membranes of eye
by blocking trans-epithelial salt
(and water) channels that drain
orbit (compound P552-02)
p2Y2 receptor
directly
transport
water across
conjunctiva
Tear film
Membranes at the base of the
orbit are a major site of ‘water
exit” (in addition to the puncta)
Electrical Stimulation with intra-oral device
Strietzel et al (2011) Arth Rheum pg. 63—Abstract misleading
Results: “The active intervention performed better than sham for some
secondary outcome measures for dryness frequency. No statistical significance
for the parameters oral discomfort, sleeping difficulty, resting salivary flow rate,
and stimulated salivary flow rate.”
Reminiscent of Electrical Stimulation (Salitron) in 1980’s
Stellar (1988); Daniels (1992)
a)
b)
c)
d)
Approved by FDA as a “device”
Denied by insurance due to “efficacy”
Price precluded use by patients
About the same benefit as use of a vibrator
(used intra-oral) or electric toothbrush to
stimulate tongue and buccal mucosa
Importance of mechanical stimulation,
including the use of lozenges
The standard joke about therapy
• Rheumatologists only have one drug:
steroids.
• The training of a rheumatologists is how to
get the patient to a lower dose of steroids or
off them entirely.
Systemic Therapies-1
• Traditional DMARDs- alone and combination.
• Hydroxychloroquine—works on “antigen processing”
by raising pH of antigen loading compartment.
• Hydroxychloroquine is a weak diprotic base that diffuses into
compartment for loading and raises the pH of the “endosome.”
• This effect prevents the “loading” of low affinity (autoantigens)
onto nascent DR molecules.
• Also, affects the ability to bind to Toll receptors in the lysosome.
• Using this model, new through-put screening of new and better
drugs
Systemic Therapies-2
• Traditional DMARDs- What is new with methotrexate?
• Alone or in combination with hydroxychlorquine to taper
steroids;
• Methotrexate polyglutamate may predict efficacy and toxicityhowever, methotrexate polyglutamate levels are still in trial in
SLE and SS;
• Most exciting are the reports of new SNPs to predict
methotrexate responsive patients in RA;
• (all the SNPs are in the de novo adenosine pathway).
Systemic Therapies-2
Leflunomide and mycophenolic acidboth have mechanism of action that are similar and
analogous to methotrexate
• Methotrexate works on de novo synthesis for purine
ribonucleotide pathway.
• Leflunomide and Mycophenolic acid on de novo pyrimidine
ribonucleotide pathway.
• These ribonucleotides serve as energy source (mostly for
glycosylation) that is required for cell division.
• Unless, adequate rUMP, impaired G1-S transition.
Take home lesson
for Methotrexate, Azathioprine, Leflunomide,
mycophenolic acid
• All work by inhibiting synthesis of ribonucleotides that
serve as an energy source (de novo synthesis pathway)
required for G1-S transition of maturation.
• This pathway links p52 and p21 driven apoptosis; p52 is
the “sensor” for adequate ribonucleotide level.
• Ribonucleotide synthesis as an energy source for cell
membrane synthesis and glycosylation.
• In future, it is likely that we can use SNPs to predict
response to these agents based on their enzyme
polymorphisms.
Systemic Therapies-3
• Traditional steroids:
• Prednisolone and methylprednisolone)—cheap and
work but side effects
• In general, the issue with steroids is the dose
(less than prednisone 7.5 and duration of therapy)
• Development of “soft steroids”—lotemax-like for
effect on NFK-b ; this was the basis of p38 map
kinase
• Novel IKKB inhibitors that lack effect on weight,
bone, etc.
Biologics and Cytotoxics
• Biologic Agents—the new “holy target” based on success
in RA; however, biologics have been disappointing in SLE
and SS (we will deal with these later in talk).
• Cytotoxics such as cyclophosphamide—although we
worry about cyclophosphamide, we need to ask how much
is actually justified if we use carefully and limit cycles.
• We worry about marrow depletion but yet hematologists
use it to mobilize “stem cells” into the periphery.
• In order to “cure” immune disease—we must reset the
repertoire using cyotkines and growth factors. There will
probably be a role for cyclophosphamide in this process.
Available biologic therapy for Sjogren’s-1
•
•
TNF antagonists- one initial report of
success with infliximab*
Repeat studies not replicate early success
Repeat infliximab study (multi-center,
more patients)*
Etanercept*
•
*Refs 43-47
•
•
Rituximab (anti-CD20 antibody)numerous reports in Sjogren’s
that are multi-center and controlled
• B-cell depletion efficient in periphery;
• Decreased lymphocytes in gland biopsy;
• Surprisingly, little change in serum
BAFF or IgG levels;
• Well tolerated.
Rituximab failed the two pivotal
FDA trials in lupus—
both renal and non-renal
•
•
•
•
These trials were poorly designed.
The steroid dose was too high.
The patients were too heterogeneous.
The drug worked, but so did the placebo
(standard of care).
• The finding of several cases of PML
(progressive neurodystrophy due to JC virus).
Rituximab Most Consistent Role
for
Hematologic Features in SS
*lymphadenopathy,
*pseudolymphoma,
*thrombocytopenia
* mixed cryoglobulin
*low grade lymphoma
As it will not have “FDA label,” it will be an off-label use,
and expense in US
will limit its use-- as insurance will not cover.
Rituximab Treatment
1. Only small changes in tear/saliva flow and
only in patients with early disease;
2. Changes in salivary gland biopsy with
improvement in foci score;
3. B-cell depletion as expected;
4. Change in T-cell repertoire (CD25+ T-reg)
in some patients.
Important lesson about biologics
from Rituximab
When you deplete B-cells (rituximab):
1. Create an excess of circulating BAFF in comparison to
the number of B-cells that bear BAFF-Receptor;
2. This excess of ligand stimulates a round of cell division
not only of B-cells but of B-cells;
3. Any round of cell division leads to activation induced cell
death (AICD) and opportunity to re-shape the repertoire.
The “cure” of autoimmune disease
will depend on changing the repertoire-a) T-regs to modulate auto-immune cells;
b) Alteration of homing receptors;
c) Regeneration of damaged target organs.
Humanized anti-CD20
(ocrelizumab)
• Higher Affinity for B-cells;
• Had Fc receptor for complement and B-cell
depletion;
• Clinical trials halted due to increased
infection (although mostly at non-US sites).
Other Biologics-1
• Anti-BAFF (Benlysta) antibody;
• Approved for SLE by FDA;
• The SS subset of SLE (SS-A) did not show
significant improvement compared to SLE cohort;
• Although the Benlysta subset did better than with
no treatment, the patient and physician Global
Assessment was not significantly different from
placebo and marginally different than low dose.
Other Biologics-2
• Anti-CD22 (Epratuzumab)—another B-cell marker;
• Initial clinical trials in SS (and SLE) plagued by
production of a uniform product (problems in
glycosylation), so 6 different lots needed with interruption
of protocol;
• New Drug Manufacturer and preliminary studies indicate
safety;
• Any FDA approval for SS will require increased saliva and
tears. Expect at best, results similar to rituximab.
Other therapies in trial (biologic)
1
2
3
5.
6.
7.
Anti-CD22 antibody: initial results inconclusive and
repeat trials in progress*
Antibody to IFN-a (Medi 545) in SLE*
(Dan Wallace at ACR (2007) and recruiting in Japan)
Antibody to type II (gamma) IFN (fontolizumab)
Antibody to BAFF-R, April and TACI-Ig*
Benlysta (free BAFF) and Ly2127399 (Lilly’s antiBAFF)(membrane and free)
Bortezomib (protesome inhibitor)
*Refs 60-61 and clinicaltrials.gov
Additional Trials
•
•
•
•
•
Raptiva (stopped)
Thalidomide (stopped)
DHEA—past NIH trial vs. SLE trial
Mycophenolic Acid
Rituxan and biogeneric
Fingolimod- a novel approach
• The molecular biology of phosphofingolimod is thought to lie in its activity at
one of the five sphingosine-1-phosphate
receptors
Stromal cell has
Sphingosine
receptor
Lymphocyte is
retained in the
lymph node until
the sphingosine
ligand is
“removed”
Fingolimod-2
(recently approved for multiple sclerosis)
• It can sequester lymphocytes in lymph nodes, preventing
them from moving to the central nervous system for autoimmune responses in multiple sclerosis, and was originally
proposed as a anti-rejection medication indicated posttransplantation.
• It has been reported to stimulate the repair process of glial
cells and precursor cells after injury.
• Fingolimod has also been reported to be useful in murine
lupus and Sjogren’s.
Problem will again be the risk of PML—
a rare but devastating complication
• May be acceptable in life threatening
diseases such as multiple sclerosis;
• Unclear if the FDA will approve such drugs
for “quality of life” issues such as dryness
or fatigue;
• The global assessment by physician and
patient has been the huge limitation in FDA
approval.
Fingolimod provides rationale for new
therapies that interfere with homing
3. When the homing receptor encounters
vascular adhesive molecules,
the lymphocyte enters tissue.
CD4+
Blood
2. Lymphs
migrate
through blood
to tissues.
B cell
1.
T- and B-cells have surface “homing
receptors” when generated in node or
marrow.
4. Pearl:
Failure to bind to homing
receptor in 72 hours
leads to obligate apoptosis
of the lymphocyte.
This is why we do not become
one large lymph node.
Caution:
PML (progressive multifocal leukoencephalopathy)
• Due to reactivation of polyoma virus (JC) in CNS
• We have seen with agents: that alter homing:
–
–
Natalazumab (Tsabri)
Efalizumab (Raptiva),
and
• B-cell depleting agents (Rituximab);
• SS and SLE patients already handle polyoma poorly, as
evidenced by higher frequency pap smear abnormalities.
Our most difficult problems
1. Neuropathy—peripheral and central;
2. Chronic fatigue and vague cognitive
impairment;
3. Lymphoproliferation;
4. Accelerated cardiovascular complications.
Neuropathy
• Poor correlation between symptoms and
objective findings:
– Eye pain- does not correlate with tear flow;
– Mouth pain-not correlate with saliva;
– Peripheral neuropathy-not correlate with nerve
biopsy;
– Cognitive-not correlate with acute phase
reactants.
Fibromyalgia:
The elephant in the Room
Fatigue
Cognitive
Dry eyes and
dry mouth
Nerve
pain
As rheumatologists
• We will need to learn a new vocabulary
about the perception of pain and how it is
modulated by cytokines.
• The key term is the “plasticity” of the
nervous system. How the perception of
pain is modulated by cytokines of the
“stress axis.”
Neuroplasticity in Pain Processing1-3
100
Pain Sensation
80
Hyperalgesia3
Cytokines
alter pain
perception
60
40
Pain state
Allodynia
20
0
innocuous
noxious
Stimulus Intensity
1. Woolf CJ, Salter MW. Science. 2000;288:1765-1768.
2. Basbaum AI, Jessell TM. The perception of pain. In: Kandel ER, et al, eds.
Principles of Neural Science. 4th ed. 2000:479.
3. Cervero F, Laird JMA. Pain. 1996;68:13-23.
Normal
The Pain Roadmap: Peripheral and
Central Nervous System Landmarks
• The neural
processing of pain
involves the:
– peripheral
nervous system
– spinal cord
(central nervous
system)
– brain (central
nervous system)
Central
Nervous
System
Brain image courtesy of ATI
Peripheral Nervous
System
Brain Regions that May Modulate Pain and
1-4 and Mouth:
Central Amplification ofEmotion
Pain from Eyes
Regions Found on Functional MRI
Both
Somatosensory Cortex
Pain
Insular Cortex
Prefrontal Cortex
Thalamus
Hippocampus
Take Home Lesson 1
1. Topical therapy and ability to stimulate
saliva or tears remains inadequate.
2. Treatment of extraglandular manifestations
such as arthritis, rashes, hemolytic
anemia, or lymphomas is rapidly
improving.
3. The treatment of the neuro-endocrine
manifestations (cognitive impairment and
fatigue) remains inadequate.
Thank you
for your time and attention
I would be happy to entertain any questions
now or later.
The slides are available to you
for your use
at
[email protected]
Rituximab (anti-CD20)*
1.
2.
•
•
•
3.
4.
•
Multiple studies of small number of patients and single center trials
General Conclusion-a) useful in extra glandular manifestations including:
-- mixed cryoglobulinemia
-- pseudolymphoma (glands or lung)
-- hemolytic anemia and thrombocytopenia
b) results in tear/saliva flow not significant except in group of patients
with early SS, where increase saliva was statistically increased but
still modest improvement and biopsies showed improvement;
Among SLE patients treated with anti-CD20, SS-A subset responded
less frequently and had shorter remissions;
After an NIH multi-center trial, company is not pursuing indication.
*Refs 47-59
How does the process start?
There may be many different triggers in the
genetically predisposed individual…
1. Defective apoptosis of glandular cells and
clearance of these autoantigens;
2. Viral infection including EBV (in Caucasion
and Japanese) and Coxsackie (in Greek patients);
3. Other viral infections (examples of Hep C, HIV
and HTLV-1) can mimic SS;
4. Activation of endogenous retroviral fragments.
Ref 1
Role of Autoantibody:
Anti-SS A
Anti-SS A antibody
(associated with HLA-DR3)
binds to SS-A
which
complexed to hYRNA
Antibody
toisSS-A
To the innate immune
system (dendritic cells),
hYRNA
SS-A
hYRNA
(ds RNA)
is a double-stranded RNA
and looks like a viral RNA
that binds to
a specific Toll receptor.
Salivary gland dendritic cells
bind to the Fcg receptor to internalize the
immune complexes containing SS-A/hYRNA
1. Immune complex
antibody to SS-A
hYRNA
(ds RNA)
2. Fc-g R
3. Toll 3 receptor is in
located in the cytoplasm
Plasmacytoid
Dendritic
Cell
SS-A
4. IFN
Type 1
--The Vicious Cycle -of innate and acquired leads to IFN type I
(links genetic and autoantibody response)
6. B-cell
4. Dendritic Cell
5. IFN-a
with
Toll Receptor
and Fc-g Receptor
3. Toll receptor
Fc-gamma R
2. Immune
Anti-body response
Anti-SS-A
in HLA-DR3
pre-disposed female
SS-A/hYRNA
Complex
containing…
______
1.Apoptotic Cell
Pearl: Rituxan does more
than deplete B-cells
a)
•
Alteration of T-cell subsets (especially appearance of
CD25+/FoxP3 T-regs) after treatment
indicates a role in “rebooting the computer.”
•
•
•
b) Lymphocytes remain present in the SG
biopsy, probably due to BAFF secreted by
dendritic cells.
•
*Refs 57-59
Typical Clinical Features of
dry eyes, dry mouth
and swollen glands
Dryness results in the clinical appearance of
keratoconjunctivitis sicca (KCS)
characteristic of Sjogren’s syndrome
The upper lid
literally sticks to
the surface epithelial
surface and pulls
surface mucin layers off.
The Rose Bengal
dye retention
is like
“rain water pooling
in a street pothole”
This test can be
done at bedside
and allows
“triage” and rapid
referral of patients
to Ophthalmology
For example
IL-17 plays a key role in decreased secretion of water, proteins
and mucin required in tears and saliva
Severe Xerostomia with dry tongue
Sjogren’s Syndrome- Cervical Dental Caries
The Body’s 2 Distinct But Interconnected
Immune Systems
ACQUIRED
INNATE
HLA-DR4–dependent:
HLA-DR–independent:
T cells respond to peptide
antigens and generate
Dendritic cells respond to
specific structures found
on bacteria and apoptotic
memory cells
Products (Toll receptors)
Lymphyocytes
Dendritic Cells
(Type 2 interferon signature)
(Type 1 interferon signature)
Beutler B et al. Blood Cells Mol Dis. 1998;24:216-230.