Pathogenesis of Sjogren

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

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.

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

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.

36
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 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

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
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

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.

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

1. Neuropathyperipheral and central
2. Chronic fatigue and vague cognitive impairment
3. Lymphoproliferation
4. 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

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
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.