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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)
– 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 System 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 are 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 Innate System
(HLA-DR)-memory (Adaptive, immediate) - HLA independent
Dendritic cells
Traditional T-cell and Cytokines-particularly
B-cell and their cytokines Type I interferon
Interferon-gamma
HLA-DR association with BAFF, IL-6, IL-17
autoantibody production
Complement, CRP
Target of drugs such as Sensors of the innate system
DMARDs and certain Toll receptors (TLR)-pathogen motiffs
biologics 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 tear or saliva flow is a complex
process that involves 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
water
1. Ocular or oral surface
mucin
6. Stimulation irritation
protein
of gland Nerves on mucosal
water 3. Cortical
nutrients Outflow
Tracts Afferent nerves
hormones And
HPA
2. Midbrain of
central nervous
5. Stimulation system
of blood vessel Lacrimatory or salivatory
nuclei
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)
is impaired by lymphocytes
that enter the gland and release inflammatory factors
ocular and oral dryness
Gland dysfunction
lymphocytes •Autoantibodies
(anti-muscarinic antibody)
Focal lymphocytic Cytokines (type I IFN, g-IFN)
infiltrates in the
glands
•Metalloproteinases
(outside-inside signalling
molecules)
In Sjogren’s, only 50% of the acini and ducts are destroyed .
Despite their retension 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. Salivary glands normally lack lymphocytes, so their mere presence in
an extraglandular tissues imply a lymphocyte aggressive process.
1. Homing to the gland tissue is due to specific receptors/ligands
controlled by chemokines/cytokines.
2. Retention of lymphocytes in the tissue is due to specific ligands.
3. 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.
Homing Receptors are up-regulated on
high endothelial venules in
Sjogren’s Lip Biopsy
A B
Peripheral Lymph Node Chemokine receptor CCL21
Addressin (PNA-d)
(peanut agglutinin) Ref 63
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.
The interesting point is that the homing
receptors expressed by salivary glands for
T-cells, B-cells, and dendritic cells occur in
NOD.scid mice so that they are independent
of cytokines released from the lymphocytes.
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.
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
In patients whose minor salivary glands develop germinal centers,
there is increased chance of lymphoma
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.
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 sex (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 Innate Auto-
Stress Immune system
antibodies
(virus-such as EBV) (Toll receptor)
(apoptotic fragment)
Immune
Type I IFN complex
Genetic
Genetic
Genetic
Genetic Acquired Disease
Factors
Factors
Factors
Factors Immune system
(including sex)
(including sex)
(including sex) Manifestations
(HLA-DR)
(HLA-DR)
(HLA-DR)
(HLA-DR)
T/B-cells
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
Summary
1. Ability to stimulate saliva or tears remains
inadequate involves a complex pathway.
2. Extraglandular manifestations reflect
homing pathways, as well as factors that
influence tissue retention and apoptosis.
3. Neuro-endocrine manifestations (cognitive
impairment and fatigue) remain the
frontier of research for the next decade.
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.
RobertFoxMD@mac.com
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 SS-A
Antibody tois complexed to hYRNA
To the innate immune
system (dendritic cells),
hYRNA
is a double-stranded RNA
and looks like a viral RNA
hYRNA
SS-A (ds RNA)
that binds to
a specific Toll receptor.
Salivary gland dendritic cells
bind to the Fcgreceptor to internalize the
immune complexes containing SS-A/hYRNA
3. Toll 3 receptor is in
1. Immune complex 2. Fc-g R located in the cytoplasm
antibody to SS-A
Plasmacytoid
Dendritic
4. IFN
hYRNA Cell Type 1
(ds RNA)
SS-A
--The Vicious Cycle --
of innate and acquired leads to IFN type I
(links genetic and autoantibody response)
6. B-cell
Anti-body response
4. Dendritic Cell 5. IFN-a Anti-SS-A
with in HLA-DR3
Toll Receptor pre-disposed female
and Fc-g Receptor
3. Toll receptor SS-A/hYRNA
Fc-gamma R
2. Immune
Complex
containing…
______ 1.Apoptotic Cell
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
The Functional Circuit involves
Known neural connections to the brain
*Pflugfelder SC, et. al. Dry Eye and Ocular Surface Disorders. NY: Dekker, 2004.
This 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 4. Pearl:
Failure to bind to homing
receptor in 72 hours
leads to obligate apoptosis
1. T- and B-cells have surface “homing of the lymphocyte.
receptors” when generated in node or This is why we do not become
marrow. one large lymph node.
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
Background 2
“The Danger Signal”
The immune system is the 6th sense of the brain.
Lymphocytes are sent out to detect foreign pathogens
and clean up debris from dead (apoptotic) cells.
Lymphocytes report back to the brain in the form of
neurokines and cytokines.
The Body’s 2 Distinct But Interconnected
Immune Systems
ACQUIRED INNATE
HLA-DR4–dependent: HLA-DR–independent:
T cells respond to peptide Dendritic cells respond to
specific structures found
antigens and generate 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.
Homing Receptors are up-regulated on
high endothelial venules in
Sjogren’s Lip Biopsy
A B
Peripheral Lymph Node Chemokine receptor CCL21
Addressin (PNA-d)
(peanut agglutinin) Ref 63
