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Pathogenesis of Sjogren’s Syndrome

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Title: Pathogenesis of Sjogren’s Syndrome


1
Pathogenesis ofSjogrens Syndrome
  • Translating Basic Sciencefrom Bench to Bedside

2
Sjogrens 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

3
Background-1
  • Sjogrens syndrome represents the interface of
  • Immune and exocrine secretory functions (dryness)
  • Immune and neural function (neuropathy/cognitive)
  • Immune and hypothalamic-adrenal axis (autonomic)
  • d) Autoimmune proliferation and lymphoma
  • e) Lupus-like features of vasculitis and immune
    complex

4
Background-2The 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.
5
Pathogenesis Take Home Lessons-1
  • Innate and Acquired Immune Systems are targets
    for current therapyincluding TNF, BAFF and IL-6
    inhibitors, steroids, traditional DMARDs and new
    oral agents (Jak and syk inhibitors).
  • 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.

6
Take Home Lesson - 2The two arms of the immune
system mutually interactin the initiation and
perpetuation of Sjogrens Syndrome
Acquired System
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
  • ? (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

7
Take Home Lesson 3The 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.

8
Normal tearing or salivation secretion requires a
functional unit
water mucin protein
  • Ocular or oral surface
  • irritation

4. Stimulation of gland
Nerves on mucosal
3. Cortical Outflow Tracts and HPA
water nutrients hormones
Afferent nerves
2. Midbrain of central nervous system
Lacrimatory or salivatory nuclei
3. Stimulation of blood vessel
9
The functional circuit involves known neural
connections to the brain
Pflugfelder SC, et. al. Dry Eye and Ocular
Surface Disorders. NY Dekker, 2004.
10
In Sjogrens 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
  • Gland dysfunction
  • Autoantibodies
  • (anti-muscarinic antibody)
  • ?Cytokines (type I IFN, g-IFN)
  • Metalloproteinases
  • (outside-inside signaling molecules)

lymphocytes
Focal lymphocytic infiltrates in the glands
11
In Sjogrens, 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
Normal
Sjogrens
12
In Sjogrens 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.

13
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.
14
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.
15
IFN Type I in salivary gland suggestsa role in
Sjogrens Syndrome
SS
SS SG biopsy with type I IFN gene profile
Non-SS sicca
NML
SS SG biopsy with type I IFN
16
Take home lesson-3Homing receptors determine
both glandular and extraglandular features
  • Salivary glands normally lack lymphocytes, so
    their mere presence in
  • an extraglandular tissues imply a
    lymphocyte aggressive process.
  • 2. Homing to the gland tissue is due to
    specific receptors/ligands controlled by
    chemokines/cytokines.
  • 3. Retention of lymphocytes in the tissue is
    due to specific ligands.
  • 4. Their apoptosis or expansion is regulated
    through Fas pathways
  • that are modulated by cytokines and
    bcl-2

17
Pathogenesis Take Home Lessons-4
  • Extraglandular manifestations are determined by
    lymphocyte homing to tissues-- factors that
    govern their retention in tissues and their
    apoptosis.
  • Factors governing their clonal expansion and
    lympho-proliferation lead to lymphoma-derived
    from B-cells themselves, T-cells, and dendritic
    cells.

18
1. Tissue Homing/Retention of lymphocytesis 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.
19
The endothelial cells attract T-cells by ICAMs
and Chemokines Sjogrens Lip Biopsy
B
20
The endothelial cells release B-cell
chemo-attractants
A
B
Ref 63
21
Endothelial cells attract dendritic cells
to home to the gland.
22
  • Take Home Points for Homing Receptors
  • Expressed by salivary glands in NOD.scid mice, so
    expression is independent of cytokines released
    from the lymphocytes.
  • b) Thus, the story of Sjogrens 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.

23
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).
24
Pathogenesis Take Home Lesson 4SS has
lymphoproliferative propertiesit lies on the
border between autoimmunity andlymphoma.
25
Sjogrens Syndrome with parotid enlargement
indicates lymphoproliferative tendency
26
  • Risk factors for lymphoma
  • Germinal centers on minor salivary gland biopsy
  • Low complement C4
  • 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
27
This provides a rational of
understanding for 1. anti-CD20 (rituximab) 2.
anti-BAFF and anti-TACI3. anti-CD22 antibody
therapies
28
Overview of the steps in pathogenesisthat help
explainrole of gender (TLR receptors)autoantibod
ies (anti-SS A)interferon-Type I
signatureHLA-DR association
29
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.

30
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.
Auto- antibodies
Innate Immune system (Toll receptor)
Environmental Stress (virus-such as
EBV) (apoptotic fragment)
Immune complex
Type I IFN
Genetic Factors (including sex) (HLA-DR)
Genetic Factors (including sex) (HLA-DR)
Genetic Factors (including sex) (HLA-DR)
Genetic Factors (including sex) (HLA-DR)
Disease Manifestations
Genetic Factors (including sex) (HLA-DR)
Acquired Immune system (HLA-DR) T/B-cells
Time period of years
Ref. 32-33
31
Genetic Predisposition in SSto Type I Interferon
  • In genome wide screens, association of IRF5
    alleles and Stat 4, with predisposition to
    development of SS
  • Refs 36-38

32
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

33
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.

34
Treatment of Sjogrens in 2010Opportunities and
Challenges
  • Treatment of Dry Eyes and Mouth
  • Treatment of Extraglandular Manifestations--
  • Lupus like symptoms-arthralgia, rash
  • Neuropathy (central and peripheral)
  • Cognitive and myalgia (fibromyalgia)
  • Lymphoproliferative

35
Take Home Points-1
  • Topical therapy of dry eyes and dry mouth new
    targets include water transport, mucins, and
    topical small molecules such as jak 3.
  • Dry mouth symptoms may be burning mouth and
    require treatment as a local neuropathy.

36
Take Home Point-2
  • Poor correlation of symptoms and objective
    findings of both dryness and neuropathic
    symptoms.
  • This poor correlation is the greatest challenge
    since it involves cortical perception of
    discomfort
  • The neuro-endocrine circuit in Sjogrens may
    provide insight into fibromyalgia

37
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
38
New Approaches to Dryness
  • 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
39
New Approaches to Dryness-2Oral 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

40
Novel methods of water conservation
New Approaches to Dryness-3
  • 1. Transport water across the conjunctiva
    (diquafasol)
  • p2Y2 purine receptor agonist
  • 2. Decrease evaporative loss
  • (muc 3, muc 5A, lipid)
  • 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)
41
Electrical Stimulation with intra-oral
deviceStrietzel et al (2011) Arth Rheum pg.
63Abstract 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.
42
Reminiscent of Electrical Stimulation (Salitron)
in 1980sStellar (1988) Daniels (1992)
  • 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

43
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.

44
Systemic Therapies-1
  • Traditional DMARDs- alone and combination.
  • Hydroxychloroquineworks 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

45
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 toxicity-however, 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).

46
Systemic Therapies-2Leflunomide and mycophenolic
acid-both 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.

47
Take home lessonfor 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.

48
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 steroidslotemax-like for
    effect on NFK-b this was the basis of p38 map
    kinase
  • Novel IKKB inhibitors that lack effect on weight,
    bone, etc.

49
Biologics and Cytotoxics
  • Biologic Agentsthe 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 cyclophosphamidealthough 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 diseasewe must reset
    the repertoire using cyotkines and growth
    factors. There will probably be a role for
    cyclophosphamide in this process.

50
Available biologic therapy for Sjogrens-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

51
Rituximab (anti-CD20 antibody)-numerous reports
in Sjogrensthat 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.

52
Rituximab failed the two pivotalFDA trials in
lupusboth 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).

53
Rituximab Most Consistent Rolefor Hematologic
Features in SS lymphadenopathy,
pseudolymphoma, thrombocytopenia
mixed cryoglobulin low grade lymphomaAs 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.
54
Rituximab Treatment
  • Only small changes in tear/saliva flow and only
    in patients with early disease
  • Changes in salivary gland biopsy with improvement
    in foci score
  • B-cell depletion as expected
  • Change in T-cell repertoire (CD25 T-reg) in some
    patients.

55
Important lesson about biologicsfrom Rituximab
  • When you deplete B-cells (rituximab)
  • Create an excess of circulating BAFF in
    comparison to the number of B-cells that bear
    BAFF-Receptor
  • This excess of ligand stimulates a round of cell
    division not only of B-cells but of B-cells
  • Any round of cell division leads to activation
    induced cell death (AICD) and opportunity to
    re-shape the repertoire.

56
The cure of autoimmune disease
  • will depend on changing the repertoire--
  • T-regs to modulate auto-immune cells
  • Alteration of homing receptors
  • Regeneration of damaged target organs.

57
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).

58
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.

59
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.

60
Other therapies in trial (biologic)
  • 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)
  • 3 Antibody to type II (gamma) IFN
    (fontolizumab)
  • Antibody to BAFF-R, April and TACI-Ig
  • Benlysta (free BAFF) and Ly2127399 (Lillys
    anti-BAFF)(membrane and free)
  • Bortezomib (protesome inhibitor)
  • Refs 60-61 and clinicaltrials.gov

61
Additional Trials
  • Raptiva (stopped)
  • Thalidomide (stopped)
  • DHEApast NIH trial vs. SLE trial
  • Mycophenolic Acid
  • Rituxan and biogeneric

62
Fingolimod- a novel approach
  • The molecular biology of phospho-fingolimod is
    thought to lie in its activity at one of the five
    sphingosine-1-phosphate receptors

Lymphocyte is retained in the lymph node until
the sphingosine ligand is removed
Stromal cell has Sphingosine receptor
63
Fingolimod-2(recently approved for multiple
sclerosis)
  • It can sequester lymphocytes in lymph nodes,
    preventing them from moving to the central
    nervous system for auto-immune responses in
    multiple sclerosis, and was originally proposed
    as a anti-rejection medication indicated
    post-transplantation.
  • 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 Sjogrens.

64
Problem will again be the risk of PMLa 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.

65
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.
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.
B cell
  • 1. T- and B-cells have surface homing
    receptors when generated in node or marrow.

66
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.

67
Our most difficult problems
  • Neuropathyperipheral and central
  • Chronic fatigue and vague cognitive impairment
  • Lymphoproliferation
  • Accelerated cardiovascular complications.

68
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.

69
Fibromyalgia The elephant in the Room
Fatigue Cognitive
Dry eyes and dry mouth
Nerve pain
70
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.

71
Cytokines alter pain perception
72
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73
Brain Regions that May Modulate Pain and
Emotion1-4
Central Amplification of Pain from Eyes and
Mouth Regions Found on Functional
MRI
Both
Pain
Somatosensory Cortex
Insular Cortex
Prefrontal Cortex
Thalamus
Hippocampus
74
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.

75
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
  • RobertFoxMD_at_mac.com

76
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77
Rituximab (anti-CD20)
  • 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

78
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79
How does the process start?There may be many
different triggers in the genetically predisposed
individual
  • Defective apoptosis of glandular cells and
    clearance of these autoantigens
  • Viral infection including EBV (in Caucasion and
    Japanese) and Coxsackie (in Greek patients)
  • Other viral infections (examples of Hep C, HIV
    and HTLV-1) can mimic SS
  • Activation of endogenous retroviral fragments.

Ref 1
80
Role of Autoantibody Anti-SS A
Anti-SS A antibody (associated with
HLA-DR3) binds to SS-A which is complexed to
hYRNA
Antibody to SS-A
To the innate immune system
(dendritic cells), hYRNA is a
double-stranded RNA and looks like a viral RNA
that binds to a specific Toll
receptor.
hYRNA (ds RNA)
SS-A
81
Salivary gland dendritic cells bind to the
Fc??receptor to internalize the immune complexes
containing SS-A/hYRNA
3. Toll 3 receptor is in located
in the cytoplasm
2. Fc-? R
1. Immune complex antibody to SS-A
Plasmacytoid Dendritic Cell
4. IFN Type 1
hYRNA (ds RNA)
SS-A
82
--The Vicious Cycle -- of innate and acquired
leads to IFN type I(links genetic and
autoantibody response)
6. B-cell Anti-body response Anti-SS-A in
HLA-DR3 pre-disposed female
5. IFN-a
  • 4. Dendritic Cell
  • with
  • Toll Receptor
  • and Fc-g Receptor

3. Toll receptor Fc-gamma R
SS-A/hYRNA
2. Immune Complex containing ______
  • Apoptotic Cell

83
Pearl Rituxan does more than
deplete B-cells
  • 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

84
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85
Typical Clinical Features of dry eyes, dry
mouth and swollen glands
86
Dryness results in the clinical appearance of
keratoconjunctivitis sicca (KCS)characteristic
of Sjogrens 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
87
For exampleIL-17 plays a key role in decreased
secretion of water, proteins and mucin required
in tears and saliva
88
Severe Xerostomia with dry tongue
89
Sjogrens Syndrome- Cervical Dental Caries
90
The Bodys 2 Distinct But Interconnected Immune
Systems
  • ACQUIRED

INNATE
HLA-DR4dependent T cells respond to peptide
antigens and generate memory cells
HLA-DRindependent Dendritic cells respond to
specific structures found on bacteria and
apoptotic Products (Toll receptors)
Lymphyocytes (Type 2 interferon signature)
Dendritic Cells (Type 1 interferon signature)
Beutler B et al. Blood Cells Mol Dis.
199824216-230.
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