This document summarizes a debate between David Baker-For and Heinz Weindl-Against on whether B cells or T cells are the key pathogenic cell in multiple sclerosis (MS). It provides evidence from animal models, response to various MS therapies, and B cell and T cell biology to argue that memory B cells, not T cells, are the primary driver of MS pathology. Graphics show that treatments which reduce memory B cells in the blood correlate with decreased relapse rates and lesions in MS patients. The document concludes that while T cells may facilitate the disease, memory B cells are the main culprit in destroying myelin in MS.

1. DEBATE
David Baker- For
Heinz Weindl-Against
The Key Pathogenic Cell
in MS is a B cell
and is Independent of Antigen-
Presentation to T cells
To B or Not T-B, that is the Question?

2. AT THE LIMITS-MULTIPLE SCLEROSIS 2017
B CELLS ARE AN
A ACCOMPLICE
T CELLS ARE
FACILITATORS
THE IMPORTANT PATHOGENIC CELL IN MS
VICTIM: OLIGODENTROCYTE HAS BEEN MURDERED
B CELL
MEMORY B CELLS
ARE GUILTY
T CELLS ARE GUILTY

3. INFLAMMATORY PENUMBRA IN MS
MYELIN = BROWN
DEMYELINATION
PERIVASCULAR
LESION
RELAPSING MS
BIOLOGY OF MULTIPLE SCLEROSIS
Myelin=brown stainOligodendrocytes do not express MHC class II in vivo
ANTIBODY
CYTOKINE
CELL
HYPOXIA

4. MS is a T cell-mediated
Problem!
MS is a B cell-mediated
Problem!
Animal Models
Myelin-Reactive
T cells in MS
Dogma
Biology &
Available Data
Response to
Therapy
Treatments
EAE is T cell Mediated!
but, Animals Don’t Get MS
Healthy People Respond
to the Same Antigens.
Myelin-immunotherapy = FAILED
All active treatments
target B cells


Circumstantial
Evidence

AT THE LIMITS-MULTIPLE SCLEROSIS 2017
To B or Not T-B, that is the Question?

5. RESPONSE TO THERAPY
If MS is T Cell-Mediated, Why Does Ocrelizumab/Rituximab Work?
• Block B Cell Cytokines & Products
• Block Antigen-Presentation
Why evolve an extra APC Network?
• Block B Cell Follicles (& Pathogenic Antibodies)
Therapeutic Antibodies have very poor CNS penetration
Trophic Support-Cytotoxicity
DMT block peripheral Immune-Response
to block Lesion formation
Minor 5-20% T cells Population Important
• Block Pathogenic CD20 T Cells
Is their critical B cell APC function In vivo?
CD4 T cell depletion = FAILED
Marked CD8 depletion (Dimethyl fumarate) = Modest
(DMF has modest depletion of B cells)
To B or Not T-B, that is the Question?
Inebilizumab (anti-CD19) inhibits MS lesion
Agius et al. 2017 Mult Scler epub

6. T CELL SPECIFIC IMMUNOTHERAPY IN MS = FAILED
• CD4 T CELL (~70%) DEPLETION WITH cM-T412 MARGINAL EFFECT- PERCEPTION = FAILED
• Th1 (IL-12/IL-23) T CELL INHIBITION WITH USTEKINUMAB-PERCEPTION = FAILED
• Th17 (IL-17) T CELL INHIBITION WITH SECUKINUMAB MARGINAL EFFECT-PERCEPTION = FAILED
B CELL-DEPENDENT EAE = RUBBISH EAE
IT IS SUBOPTIMIZED…TO MAKE ANTIGEN
PRESENTATION IMPORTANT
B CELL-DEPENDENT EAE =
SUBOPTIMIZED EAE
• Disease Resistant Strain used
• Weak Immunogen for Strain
• Processing requiring antigen
• Low severity
TO MAKE ANTIGEN PRESENTATION
BY B CELLS APPEAR IMPORTANT
UCL-INSTITUTE OF NEUROLOGY
Queen Square
UCL-INSTITUTE OF NEUROLOGY
Queen Square
UCL-INSTITUTE OF NEUROLOGY
Queen Square
MULTIPLE SCLEROSIS: IS A CD4 Th17 T CELL-MEDIATED DISEASE?
Time Post-Induction (Days)
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
FrequencyofDisease(%)
0
10
20
30
40
50
60
70
80
90
100
Vehicle
CD4d mAb
CD8d mAb
CD20d mAb
Anti-CD20 in EAE does not work or has a marginal
effect, unless it depletes CD4 T cells.
RESPONSE TO THERAPY
B CELL SPECIFIC IMMUNOTHERAPY IN EAE = FAILED/MARGINAL
Sefia E et al. MSARDS 2017
Sefia E et al. MSARDS 2017
B cell Knockout
wildtype
Kuerten S et al. J Neuroimmunol.
2006 177:99-111

7. T CELL SPECIFIC IMMUNOTHERAPY IN MS = FAILED
• CD4 T CELL (~70%) DEPLETION WITH cM-T412 MARGINAL EFFECT- PERCEPTION = FAILED
• Th1 (IL-12/IL-23) T CELL INHIBITION WITH USTEKINUMAB-PERCEPTION = FAILED
• Th17 (IL-17) T CELL INHIBITION WITH SECUKINUMAB MARGINAL EFFECT-PERCEPTION = FAILED
B CELL-DEPENDENT EAE = RUBBISH EAE
IT IS SUBOPTIMIZED…TO MAKE ANTIGEN
PRESENTATION IMPORTANT
B CELL-DEPENDENT EAE =
SUBOPTIMIZED EAE
• Disease Resistant Strain used
• Weak Immunogen for Strain
• Processing requiring antigen
• Low severity
TO MAKE ANTIGEN PRESENTATION
BY B CELLS APPEAR IMPORTANT
UCL-INSTITUTE OF NEUROLOGY
Queen Square
UCL-INSTITUTE OF NEUROLOGY
Queen Square
UCL-INSTITUTE OF NEUROLOGY
Queen Square
MULTIPLE SCLEROSIS: IS A CD4 Th17 T CELL-MEDIATED DISEASE?
Time Post-Induction (Days)
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
FrequencyofDisease(%)
0
10
20
30
40
50
60
70
80
90
100
Vehicle
CD4d mAb
CD8d mAb
CD20d mAb
Anti-CD20 in EAE does not work or has a marginal
effect, unless it depletes CD4 T cells.
RESPONSE TO THERAPY
B CELL SPECIFIC IMMUNOTHERAPY IN EAE = FAILED/MARGINAL
75% T cell
Depletion
Sefia E et al. MSARDS 2017
Sefia E et al. MSARDS 2017
B cell Knockout
wildtype
Kuerten S et al. J Neuroimmunol.
2006 177:99-111
B cell
Depletion

8. Plasma cell
CD19-, CD20-
CD27+,
CD38+, CD138+
CD8 memory
CD19+ B CELLS ARE NOT A SINGLE SUBSET
CD4 naive CD4 memory
Th1/Th17
CD8 Naive
CD8 cytotoxic
CD8 suppressor
CD4 T regulatory cell
Tr1 regulatory cell
CD19+
B cell
T Cell Biologists World View
of B Cell Biology

9. BLOOD
Memory Cell
(Guilty in MS)
CD19+, CD27+
Unswitched
IgD+
CD19+, CD27+
Class switched
IgD-
Plasmablast
CD19+, CD20-
CD27+,
CD38+
Immature
CD19+, CD20+
CD27-,
CD38+, CD10+
Pre-B Cells
CD19+, CD20+
Plasma cell
CD19-, CD20-
CD27+,
CD38+, CD138+
BONE MARROW
Germinal Centre Cell
CD19+, CD20+
CD27+, CD269+
LYMPHOID
TISSUE
Primary Follicle Cortex
(B cell Area)Secondary
Follicle
T cell
Area
Follicular
Dendritic
Cell
Pro-B Cells
CD19-/+, CD20+, CD34+
Naïve/Mature
CD19+, CD20+
CD27-,
CD38+, CD10-
Regulatory Cell
CD19+, CD20+
CD5+, CD24+
CD19+ B CELLS ARE NOT A SINGLE SUBSET

10. CD19+, CD27+
Class-Switched
IgD-
Germinal
Centre Cell
CD19+,CD20+
CD27+,
CD269+
BLOOD
Memory Cell
(Guilty in MS)
CD19+, CD27+
Unswitched
IgD+
Plasmablast
CD19+, CD20-
CD27+,
CD38+
Naïve/Mature
CD19+, CD20+
CD27-,
CD38+, CD10-
Immature
CD19+, CD20+
CD27-,
CD38+, CD10+
Pre-B Cells
CD19+, CD20+
BONE MARROW
CD34+ stem Cell
HUMAN B CELLS
Pro-B Cells
CD19-/+, CD20-
CD34+
BLOOD
LYMPHOID TISSUE
Plasma cell
CD19-, CD20-
CD27+,
CD38+,
CD138+

11. Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
MeanPercentageChangefromBaseline
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
40
Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
MeanPercentageChangefromBaseline
0
20
40
60
80
100
120
140
160
180
200
Immatute B cellsCD19 B cells
Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
MeanPercentageChangefromBaseline
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
140
Mature
Naive B cells
Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
MeanPercentageChangefromBaseline
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
Memory B cells
Alemtuzumab Targets memory B cells
overshoot
overshoot
MEMORY B CELLS IN MS-THERAPY
Baker D et al. JAMA Neurol. 2017;74:961.
Environment for Secondary B cell Autoimmunities (about 50% at 5 Years)

12. Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
MeanPercentageChangefromBaseline
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
40
Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
MeanPercentageChangefromBaseline
0
20
40
60
80
100
120
140
160
180
200
Immatute B cellsCD19 B cells
Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
MeanPercentageChangefromBaseline
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
140
Mature
Naive B cells
Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
MeanPercentageChangefromBaseline
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
Memory B cells
Alemtuzumab Targets memory B cells
overshoot
overshoot
MEMORY B CELLS IN MS-THERAPY
Baker D et al. JAMA Neurol. 2017;74:961.
Alemtuzumab
hCD52 Tg
mice kills by
ADCC-needs
both antibody
& natural
killer cells/
PMN to kill.
(Hu et al.
2009)
Bone marrow
Not purged
Environment for Secondary B cell Autoimmunities (about 50% at 5 Years)

13. MS Treatment Memory B cells in the
Blood
Availability of B cells to
enter CNS
Relapse Rate/
MRI Lesions
Glatiramer acetate
Beta Interferon
Dimethyl fumarate
Mitoxantrone
Fingolimod
Natalizumab
Alemtuzumab
Daclizumab*
Rituximab
Atacicept*
Infliximab*
HSCT
Cladribine
Reduced
Reduced
Reduced
Reduced
Reduced
Increased
Reduced
Reduced*
Reduced
Increased*
Increased*
Reduced
Reduced
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased*
Decreased
Increased*
Increased*
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Increased
Increased
Decreased
Decreased
* Non-MS data
Loss of B memory Cell function in Efficacious Treatments
MEMORY B CELLS IN MS-THERAPY
Baker D et al. EBioMedicine 2017; 16:41.

14. Mitoxantrone
Fingolimod
Beta Interferon Hierarchy of Responsiveness
Loss of B memory Cell function in Efficacious Treatments
Dooley J et al. Neurology N2 2016 3 (e240).Baker D et al. EBioMedicine 2017; 16:41.
MEMORY B CELLS IN MS-THERAPY

15. Natalizumab
Loss of B memory Cell function in Efficacious Treatments
MEMORY B CELLS IN MS-THERAPY
CD19+, CD27+ B Memory
Anti-CD20
Ocrelizumab Phase II extension (Baker et al EbioMedicine 2017; 16:41)
Palanichamy A et al. J Immunol. 2014; 193:580
6 months
1 year

16. Natalizumab
Loss of B memory Cell function in Efficacious Treatments
MEMORY B CELLS IN MS-THERAPY
CD19+, CD27+ B Memory
Anti-CD20
Ocrelizumab Phase II extension (Baker et al EbioMedicine 2017; 16:41)
Palanichamy A et al. J Immunol. 2014; 193:580
6 months
1 year

17. Developmental Repopulation of B cells is Slow
in Western Europe
Classswitched
MEMORY B CELLS IN MS-AETIOLOGY
Duchamap et al.
Immun Inflamm 2014:2:131
Absolute NumbersPercentages
Induction therapy using CD20-B cell depletion in non-MS autoimmune
________________________________________________________________________________
Total Memory B cells Class switched memory B cells
________________________________________________________________________________
Healthy Control 30.5 ± 6.9%; P = 0.001 18.3 ± 5.8% P = 0.001
Responder 6.3 ± 0.9% 3.6 ± 0.5% (5 year)
Non-Responder 51.1 ± 23.2% P = 0.009 42.8 ± 18.1% P = 0.036; (3-5 year)
________________________________________________________________________________
Amolik JH et al. Athritis rheum 2007; 56:3044
Myasthenia gravis (Lebrun et al. 2016), NMO (Kim et al. 2015), Lupus (Vital et al. 2011), Arthritis (Trouvin et al. 2015)
Audia S et al. Blood. 2011; 118:4394

18. Childhood
(1-13year)
PercentageofMemoryBcells+SD
0
10
20
30
40
50
60
Healthy
multiple sclerosis
Adolescent
(14-17year)
Adult
(25-55 year)
Adult
Onset
Paediatric
Onset
Memory B cells appear in paediatric MS more rapidly than during aging
Schwartz A et al. 2017. Neurol Neuroimmunol Neuroinflamm 4:e309
MEMORY B CELLS IN MS-PATHOLOGY

19. ________________________________________
CD19+, CD27+ Memory B cells
Blood CSF
MS Type Remission Relapse Remission
________________________________________
Paediatric MS 30.1% 20.9% 66.4%
Adult MS 32.2% 26.7% 75.9%
________________________________________
MEMORY B CELLS IN MS-PATHOLOGY
Schwartz A et al. 2017. Neurol Neuroimmunol Neuroinflamm 4:e309
Memory B cells drop in Blood during relapse and accumulate in CNS

20. T CELLS OUTNUMBER MEMORY B CELLS
MYELIN = BROWN
DEMYELINATION
PERIVASCULAR
LESION
RELAPSING MS
BIOLOGY OF MULTIPLE SCLEROSIS
DISPRUPTIVE
INFLUENCE
AN
MS LESION
T CELLS = 7-24% OF LEUCOCYTES MEMORY B CELLS = 0.2-1.7% OF LEUCOCYTES

21. Genetic Association with B Cell Activating Factor (BAFF) in Sardinian MS
CD24+, CD27+ = Unswitched and Class-Switched memory B cells are increased
Northern European MS may use a different Genetic Pathway
MEMORY B CELLS IN MS-AETIOLOGY
HLA-DRB1*1501: Expressed
by B cells
IL2RA (CD25) Expressed
by memory B
IL7RA (CD127) Expressed
by pre-B cells
Many MS Susceptibility Genes with
presumed T cell function are present in or
acts of B cell lineages
HLA-DRB1*1501: Expressed by B cells
IL2RA (CD25) Expressed by memory B
IL7RA (CD127) Expressed by pre-B cells
TNFRSF1A Expressed by pre B cells
STAT4 Expressed by pre B cells
IL12A Expressed by Immature B cells
BCL10 Expressed by Immature B cells
CXCR5 Expressed by Memory B cells

22. MEMORY B CELLS IN MS-AETIOLOGY
Antibody Secretion
Cytokine
Secretion
APC
Function
B cell
CD22MHC
Y
EBV
Memory

23. EBV Drives Memory B Cell FormationEBV PROMOTES HUMAN IMMUNITY
van den Heuvel D et al.
J Leukoc Biol. 2017; 101:
949-956
Evolutionary Advantage
• Life-long B cell Immunity to help prevent infections
EBV drives proliferation & differentiation of
memory B cells and blocks plasma cell differentiation.
Latent EBV virus reservoir in circulating memory B cells
Viral reactivation & shedding in saliva for transmission
Immune mechanisms can limit viral activity
Evolutionary Price
• B cell Lymphomas (Burkitts & Hodgkins) Lymphoma
• Glandular Fever (B cell proliferation & CD8 T cell killing)
• Autoimmunity (Historically post-reproductive age)
MEMORY B CELLS IN MS-BIOLOGY

24. CONCLUSIONS
B Cells appear to be the Major Target for Activity in MS
• Limited evidence that T cells control MS (Trial failures).
(CD4 depletion, Th1, Th17 cytokine therapy)
• Efficacy across with a range of different agents via a common B cell mechanism
Treatment Hierachy based on Memory B Cell Depletion Potential
• Memory B cell depletion is a major, common, mediator for relapse control in MS
• Memory B cell function, cytokine activity and EBV activity are interlinked
• There is pathogenic autoantibody in MS (May be secondary to damage)
Unifying mechanism consistent with (a) Aetiology (b) Pathology (c) Therapy

25. VAGAL NERVE STIMULATION?
MONOCLONAL
ANTIBODIES
SMALL MOLECULE
INJECTABLES
REMOVAL OF
SURVIVAL FACTORS
MOLECULES
VIA THE MOUTH
GUILTY-VERDICT
GIVE THE
MEMORY B CELL
THE
“DEATH PENALTY”

26. DEBATE SUMMATION
David Baker
Heinz Weindl

27. SUMATION
B IS FOR BIOLOGY = RESPONSE TO THERAPY
Unifying mechanism incorporating: (a) Aetiology (b) Pathology (c) Therapy

• Rodents have complicated B cell biology/ do not get infected with EBV
Experimental Autoimmune Encephalomyelitis is Not MS
• Treatment Hierachy based on: Memory B Cell Depletion Potential
Memory T cell Depletion Potential
• Response to Therapy. Fingolimod enhances CCR7-, CD45RO+ cells
(This would contain the pathogenic population…. if MS was T cell-mediated)
Song ZY et al. PoS One. 2015;10(4):e0124923.
CD45RO’s
Increase
CD45RO’s increase in the CNS of MS
• Prevention of Rebound after Natalizumab withdrawal = CD20 B cell depletion

28. WEINDL ARGUMENTS
NO COMPELLING EVIDENCE PRESENTED
TO CAST DOUBT ON THE CENTRAL ROLE OF
MEMORY B CELLS IN MULTIPLE SCLEROSIS
THERE IS REASONABLE DOUBT
AGAINTS IT BEING THE T CELL
(Response to therapy)
JUST BECAUSE A CELL IS PRESENT
DOES NOT MEAN IT IS IMPORTANT (GUILTY)
MOST IMMUNE CELLS IN LESIONS ARE IRRELEVANT THEY
ACCUMULATE BECAUSE OF INFLAMMATORY SIGNALS
The Chewbacca defence: the aim to deliberately confuse the jury rather
than to factually refute the case of the other side.
The concept of disguising a flaw in one's argument by presenting large amounts
of irrelevant information
T Cells Control MS….It does not make Sense!
Vote for the B’s…B cells = Biology of MS

29. THANKS FOR LISTENING WITH AN OPEN MIND
Do not acquit the B cell
The Memory B cell is Guilty
Give the T cell a suspended sentence for facilitation
GIVE THE
MEMORY B CELL
THE
“DEATH PENALTY”
Injectable Oral Antibody
magic bullet
The Chewbacca defence: the aim to deliberately confuse the jury rather
than to factually refute the case of the other side.
The concept of disguising a flaw in one's argument by presenting large amounts
of irrelevant information
T Cells Control MS….It does not make Sense!
Vote for the B’s…B cells = Biology of MS