Transcript MCs

«Real»-Biological Proposals for
IRBD 2013 talk
December
2013 REVISION
new paths to bipolarity, mixity,
fibromyalgia, and migraine.
G.Treviranus, Berne (CH) www.biposuisse.ch
 CNS regulates itself: its «psychosomatoses» occur
after breach of mast cell-guarded barriers under
conjoint co-evolved pluri-site microbial «influence»
 PNE-Immunology matures from «Solutes» to
«Conduits, Cauldrons & Pellets» monitored by PNS to
explain LOCAL small-arterial «change» by Mast cells
 Concatenated Conduits: lymphatics, fascial spaces,
adventitial nerves and neural vessels, vessel-vessels,
micro-conduits, nerves, sinus cavernosus …
 Carrying: fluid signals, cells, MCs and their cytokine
pellets (Kunder 2008)
 Mast cells (MCs) are "kanban-hubs" at every stage.
Present CRISIS OF RESEARCH:
Glahn DC (2008): pathways, through which .. remote riskconferring and … influence on brain … are unknown. Maes
M (1995, 2012): a bad, chronic … (neuro)inflammation and
(neuro) degenerative processes following less well defined
triggers. Whalley (2012) polygenetic risk profiling, …
model… in vitro, individuals from the extremes .. to identify
the cellular process that underlie imaging findings.
500+
Mio. Yrs.
old
a MC from Malaga
1.) PterygoPalatineGanglion:
calms BRAIN MAST CELLs (MCs)
2.) BRAIN MCs: in meninges,
thalamus, putamen, habenula
are «psychodynamic migrants»,
damage & heal the BBB and
Gray matter & White mattter.
3.) Peripheral MC-borne TNFa«XR» pellets leak from final
curve of THORACIC DUCT &
reach centripetal adventitial
vessels of CAROTIDE Art. &
VETEBRAL branches causing
local BBB damage e.g. from MCs
4.) MC-made pellets beforehand
trickle from PNS-influenced
LYMPHATIC CAULDRONS cause
FIBROMYALGIA/other psychoSOMATIC STRESS DISORDERS
5.) BARTONELLA  ungueal Cat
scratch Disease, Morgellons etc.
a Genome-hijacker & -modifier
 ?CNV , Chromosome anomalies, MASTOCYTE mutations ?
-
Bartonella-caused mutation triple hypothesis: a
genetic link to Mastocyte activation syndromes & BPAD?
2012: PPG calms brain MCs? SYSTEMIC MAST Various mutations in Mastocyte
activation syndrome (with anaphylaxia)
A “NEW TWIST for BPAD?” (Hagop) CELL ACTIVATION
2013:“Mastocyte Activation Syndrome
Syndromes” – a PARADIGM 1991 Metcalfe: MILD
Systemic MASTOCYTOSIS
DISORDER for BPAD?
with NORMAL SKIN
2014 ? Peru-Brazil migrants
mission for Bartonella bac. with
additional B.henselae -PCR &
HCl-33 for BPAD?
? Infect MCs w/ Bartonella ?
? Skin test for BH in
Mastocyte Activation Syndromes
? HCl-33 in common depression
2007 Akin: aberrant mast
cell population with
idiopathic ANAPHYLAXIS
2009 Bonadonna:
CLONAL mast cell
disorders in systemic
reactions to BEE-stings
and serum TRYPTASE
2010 Alvarez-Twose:
… with SYSTEMIC MAST
CELL ACTIVATION
Full circle?
ImmuneR weak
BART-like germs invade, lymphatics,
CNS…  Behavior: «thrive & don’t fear cats»
& BONE MARROW  mutations  
 MC-activation syndrome & IR MC D
 IR-deficiency  more infections.
Rogers MP, HMS 1985
What kind of
rhinosinusitis?
«Mickey’s cheek» lesions
of DORSAL MIDBRAIN :
1 Bartonella henselae BH
Peri red nucleus =O SCAR or ?
ongoing Bartonellosis ? 
with +potential for angiomas?
MC extracelluar traps?
Thoracic duct
& Venositis?
M, 1964:
TY-Kurd
Anergic
BPAD-2
Cthymia,
OH ++
M, 1936:
Generalized,
Early vertebralis
arteriitis SCAR?
BH caused oculoglandular syndrome of dorsal
midbrain of
Parinaud 1898 !
clinical,
serological,
antibioticresponsive
Bartonella
henselae:
Where is your
clinical data?
P. Grof
pyoderma
gangrenosum
Angioma & Zoonotic psychosis (sheep).
Periungueal tenderness & ascending
along lymphatics is «difficult data» …
Lhermitte
.
Alice In Wonderland Syndrome
PEDUNCULAR HALLUCINOSIS
M, 1977: Italian.RC-BPAD1 since
childhood, CSA, OH++, sex++
Spectacular hallucinations:
devils all around him, micro- /
macropsia,TLE-like. Talented.
NOT psychotic , insight.
Univ. depart.: F20 & Xeplion i.m.
rTMS: L DFPC: halluc. STOPPED !
He refuses further TMS because
”I NEED the “Fire in my legs”
as FEEDBACK from GOD”
Small serie’s clusters are chance,
but 5 independent recent cases
had clinico-serological and/or MRT
signs ++ suggestive of BARTONELLA
1. BPAD  SYSTEMIC AUTOINFLAMMATION Leboyer 2012 CONFLICT
= trigger Grunze 2012 - ? via MAST CELLS (MCs) ?
2. Classical dimensions THOUGHT-ACTION-MOOD MAP ONTO
Cortico-SubCortical-Circuits Anderson 1986 which are BUNDLED at
the THALAMUS GT. IRBD 2012 ? in order to receive MC-signals?
3. NASAL Ganglion [PPG] ? exerts TONIC A Ch-anti-inflammatory
APPROACH
CYCLES
.
PARASYMPATHETIC BRAKE ON MC otherwhise opening BBB? IRBD 2012
4. TRIGEMINAL afferents or STOP of biting (TG mot)? inhibit NASAL
PPG-brake  ? MCs open BBB  ACUTE SHAME: STOPS ostracism.
5. HABENULAR MCs brake VTA/SEARCH-system CHRONIC SHAME:
Bearden: CX 2007
STOPS rivalry. GT. IRBD 2013 Can ISTDP (H.Davanloo) REVERT SHAME TO GUILT ?
GM loss & rescue
6. MRI: LEFT hemisphere-LITHIUM-rescue: does it STOP MCs ? 
LITHIUM acts
as MC7. THREAT signals of co-evolved microbes act via LYMPH-conduits
Inhibitor ?
through MC-pellets on ? own vessels of Carotide etc.  MCs open
R Li ÷ no LEFT
BBB along SMALL ARTERIES 8. MRI reveils “environmental” GMlosses :
HIPPOCAMPUS xxxMCs ?

RIGHT:    non-shared (mostly) environmental damage
HC 2008
R
R
R
MIDBRAIN ?
GM x BPAD in TWINS
NON-shared environment Van den Schot, 2010
Bundled
 Lenticulostriate
SMALL ARTERY
C1)i.
D
o
n’
t
P
P
G
B
I
T
E
Parasympathetic PPG = 2 x 70T cells, of which 5.6T to
brain ARTERIES: ? APPROACH network: its VTA has 2 x 400T cells
MIGRAINE: ii.Cortex is hyper-responsive because of low
Thalamo-Cortical drive – bc. of MCs? ii. ET1 or kynurenin
Dreier 2002,
CSD-oligemia via ? Pericytes Chauvel 2012 iii.CGRP-receptors only on MCs
(but NO axon reflex!) iv. CAUSE of MIG.= Unknown trouble of TG!
brainstem!2 x 2.8T cells 
OUTPUT=
BRAIN ARTERIES (? MCs)
minor part opens to
liquid ? from CAROTIS
ALL HEADACHES show LOCAL GM-loss &
WM-loss corr. general COGNITIVE 
& Sinus
Cavernosus Ggl.
PPG-brake
of BBB-MCs
braked by ?
TG-baskets 
Frequent
GM 
MIGRAINEURS
PUTAMEN  May 2009
Maleki 2011
CFS

COGNITION
/ Memory 
Headaches
Ravindran 2011
TENS CLUST MIG
HealthyControls
Severity MIG±AURA
Subj. severe TENSION
Post-nodal
Collectors
lung
COLLECTING vessel
T
NALT, BALT, GALT, H
R
GERALT
E
A
Cell migration
can overcome
T
interstitial flow
s
~.1-4 µm/s
i
g
BARRIERS
n
PATHOGENS
a
PHYSICAL
l
needs &threats
L~ NODE
Margaris 2012
TNF-a fosters :
- lymphatic
growth
- leukocyte &
MC
transmigration
- MC attraction
in lung: Baluk 2009
Could pellets cross the barrier of lymphatic collectors or ducts? NO?
YES, IF neurogenic nerves & MCs OPEN LYMPHATICS to hasten the
SIGNAL DELIVERIES to LYMPH-NODES required for immune response
- at the expense of FLUID DRAINAGE – WHILE microbes are present.
Rat tail Suami 2011
Rat tail Hagedoorn 2004
Initial LV
0.03 mm
r & LEFT
Thoracic
ducts
Conduits for lymph-borne signals to the BRAINSTEM?
LEFT – more than right - Thoracic DUCT drains a «cauldron»
FROM LYMPHATIC «catchment areas»: face, skin, GIT/UGT, CNS
VA
Thoracic
duct
Thoracic duct
Subclavia
Seeger 2009
Subclavia
VAGAL N.
through cephalad curves the thoracic DUCTS
come to lie within the carotide sheath close to
the CAROTIDE and VERTEBRAL art. and to the
VAGAL N.: here TNFa-pellets could cross from
the LYMPHATICS to the former’s micro-arteries
Pellet TNFa acts on the vasa vasorum
of the CAROTIDE branches and causes
? MC-modifying «arteriitis» of BBB.
The VERTEBRAL ARTERIES fuse to the
Basilar Art. preserving LATERALITY of
ist walls. The left VA is crossed by the
Thoracic Duct, which lies inside the
carotid sheath with the IJV and the
vagal nerve which are also inflamed
via the proper micro-arteries.
The transversa colli Art. could inflame
the brachial plexus.
.
thoracic duct pelletleaks maybe reach
the brachial
plexus perineural
veins behind the
ant. scalene, then
the radicular veins
and Bateson’s
plexus.
Seeger 2009
Inflammatory VEIN stenoses of
IJV in MSclerosis? 91% or of
Azygos 86% (Zamboni 2009) with  Type III
collagen; but no myofibroblast (Coen 2013).
R Thorac duct
MC-mediated
? Reversible
cerebral vasoconstriction
syndrome
MC-mediated ?
inflammatory
VASA VASORUM
dissections
Lymphatic & MC-mediated?
VARICOSE VEINS driven by C-fibres & MC-mediated? Rupture
mast cells (Vital 2010) ;C5a activation (deVries 2013). of atherosclerotic plaque
Willems 2013
nano biomechanics
KLC2 lowers AMPA: TAT-KLCpCDK inhibits
GSK3b-P~ylation of KLC2 needed for (rat)
AMPAR-trafficking and «mood-stabilizing»
in the rat (Du, Manji 2009).
But KLC2 is ALSO needed to fetch the
pump Na+/K+-ATPase when MCs fill
with Na+ after any release (± IgE).
OH intake  in amygdalar k.o.-143-3ζ which is needed by KLC2 …
«The pump» Na+/K+-ATPase neuro-ISO-FORM 3
is candidate for mood swings
micro biomechanics
Good
or
bad
guy ?
F10
& BP
Only BPAD patients already stabilized on LI:
 the pump and  oxidative stress Bannerjee 2012
Hennion, El-Mailakh 2002
Icv.-Ouabaïne-Mania-rats release more
DA in mPFC – LI no use!
Sui (Shanghai) 2013
AMPH  the pump in rats – unless on LI or VPA
MAMPH and pro-inflammatory CKs
 pump isoform3 bc. of downstream Erk
Pendyala 2012
«pump» ISOFORM 3 is related to MIGRAINE
Trzewik
2001
Trzewik 2001
LYMPHATIC «open end»
El-Mailakh 1983.
Ouabaïne-like cardenolides from adrenals e.g.
INHIBIT the pump causing TNF-related (TRAIL)
apoptosis Panayiotidis 2010
brain-slice «irritability», stress-hypertension
and damages healed by LITHIUM (not VPA)
LYMPHATIC
microvalves
ABC-C1 transporter = multidrug-resistance
MDR1:
carries S1P –
Fingolimod –
targeted prime
modulator of
MC functions.
Particle
inside!
Bonghan
Rabbit
ventricle
Bonghan «primo-vessels» slide freely on
brain surfaces
& within vessels
MCs (MAST CELLS) live-t1/2 30 mo at barriers, where they
mature, react on ~100 receptors often to threat signals
MCs in ALLERGY-ANAPHYLAXIA & ALL stages of IMMUNE
RESPONSE via co-stimulatory, cell-cell, cell-matrix, «immunothrombosis» signaling. kiss-and-run exocytosis: transient pore; full exocytosis:
membrane fusion; compound exocytosis; homotypic fusion; cell to cell channels etc.
Ehrlich 1875
Dropp 1972-76
Goldschmidt 1985-Dimitriadou 1990Theoharides 1990Manning 1994
Silver, Silverman,
Zhuang 1992-
In BRAIN MCs «represent», migrate & modulate processes:
often randomly clustered along blood vessels
in different areas in different rodent strains
Leptomeninges (++++) & cerebral cortex (++) seem to map
«peripheral immune states»
Hypothalamus (+++) - ? Satiety/hunger – ? defence system
mesencephalon (++)
«psychodynamic» processes: approach / hoarding / aggression
Med. habenula: parenting, courtship dominance/defeat
Thalamus: erogenic zones
MCs hold 90% of brain histamine (cognition research!)
& much of NAA: confounder of MRS-research!
Dandekar
2003
s
Neurites join MCs Nakanishi 2008
MCs Basophils
Paul Ehrlich
MC & BBB: MC are longlived (wks-mo), but
migrate within hour from blood to brain:
TNF-a essential 1st contact with EC (Kneilling 2009)
18541915
BBB
Leuk
MCs steer
Leukocyte
& own
entry ±
similarly
T
N
EC F
Leuk
a
Leuk
ONGOING CAUSE  OLD or NEW SYMPTOMS
RR-MS: Flares: days, Remission: weeks; 70%  progressive
TREAT ONGOING CAUSE  RECOVERY
BPAD
R. Post
Theoharides
N.Y.
MCs in ASD
MCs in MS
etc.
Rudich et
2012
B.2) BRAIN MCs:
open, damage &
seal BBB: are hubs
MCs are long-living
hubs w/ convergent
divergent signals on
 ~100 /  ~40 receptors
resonating with Stress-axes
HPA, HThyrA,Ntroph/peptA
Addictive
signals calm (CB,
Nicotine, BZD) or
release + H (OH,
Op.) or via MKLC
(OH) AMPH ??
Bartonella H-like bacteria CAUSE «epigenetic»
hijacking of the histone acetylase and repair systems
Schizophr Bull. 1995;21(2):167-71.
& genetic changes to the human genome incl. CNV
BIPOLAR & Rheumatism
“Gelenkrheumatismus”:
E. Kraepelin
SCHIZOPHRENIA & RA:
Fuller Torrey & Yolken
++ >HCO cats in
childhood
Similarities:
class II HLA Ag.
? infectious etiology:
retroviruses, HERPES
viruses (EBV, HSV)
Toxoplasma gondii
Inverse correlation “once
a person gets one (..) 
relatively immune to the
other.” Torrey EF, Yolken RH,
2001
FM:  sensitivity (detection ok) in noxious & multiple
sensory modes: sounds; even pleasant odors, which
parallels tenderness – and ? Irritability ?
Ceko et al.(McGill) 2012 «4 possible factors»: 1) ongoing peripheral
source of input from C nociceptors other than applied S ;
2) sensitized NMDA-R (Staud: Can be dampened in HCO too: post-NMDA-R ..
3) (..) descending modulation of DH DNIC MOR, a2ADR etc. pp.!; 4) supraspinal level.
? ANTICIPATION
Ceko, Bushnell,
Gracely (2012)
Tran, Casey 2010
Potvin 2008, 2009
Lévesque 2012
r= - 0.70 PANNS+
Thalamic MCs?
F20
5, 10, 20 s & 20 s HEAT perception intensity
MCs unleashed by PPG … LI case reports; VALP: none.
LIMBIC DA Striatal D2/D3+:pain;
COMTval/val (DA -):pain .- FM: DRD3-SNP.
Qrost-v. BRAIN
gyrus rectus
{SHAME – GUILT}
Qpost.-d. BRAIN
QThalamus
CR QThalamus
www.bipoSuisse.ch
MC
Research Gate
www.Prezi.com
MC
Muchas gracias!
PC
EC
AC