Shoemaker Conference_11-15_What is CIRS_Shoemaker_49 Slides.ppt

A New Paradigm in medicine. The effects of chronic inflammation in the body caused by the failure of the innate immune system to hand off the antigen danger signal to the adaptive immune system.

1. When Inflammation Becomes
Chronic
Introducing CIRS
Ritchie C. Shoemaker MD
Center for Research on Biotoxin Associated Illness
Pocomoke, Md
11/13/2015

2. CIRS? What is that?
•Chronic Inflammatory Response Syndrome
•Genomically based, multisystem, multi-
symptom illness
•Multi-factorial inflammatory responses
to environmental exposures/injury
*Initiators may be toxins, inflammagens
*Final common pathway for proteomics

3. What is CIRS-2
•Not acute (i.e., < 30 days)
•Inflammation is response to injury
•CIRS-Syndromes have similar proteomics
•Follows acute biotoxin-associated
inflammatory illness (and more)
•Follows effects of antigen-induced
inflammatory responses on genomics

4. Characteristics of CIRS
•Chronic illness, no self-healing
–Hygienic measures no help (don’t hurt)
–Supplements won’t do it
–Not dietary in origin
•Lack of regulation of innate inflammation
•Unchecked innate immune responses
•Lack of neuropeptide regulation
•Commonly associated with HLA

5. Multiplicity of system disorders
•Th 1: pro-inflammatory cytokines
•Th 2: anti-inflammatory cytokines
•Th 17: TGF beta-1 cytokines/gene
•Th 17/T reg imbalance (tissue based)
•Complement (split products!)
•Von Willebrand’s profile
•Hormonal disruption

6. And lest we forget
•HLA DR associations
•Multi-susceptible (4-3-53, 11-3-52B)
•Specific illness association
•Changes in nomenclature make HLA harder
to “see” than it needs to be
•Only need one copy to have problems
•Defective antigen presentation

7. HLA in illness
•4-3-53 and RA, malaria, PLS, auto-hepatitis
•11-3-52B and body habitus, auto-immunity
•“Celiac” genes are DR; associated with mold!
•Link from antigen recognition to antibody
formation; research is limited
•When made aware of genetic basis of
susceptibility women invariably think of kids

8. “Genomically based”
•Indeed. Anyone ignoring the far-reaching
gene effects of chronic inflammation will
fail to understand why diagnosis and
treatment of CIRS is so complex
•Treatment that leads to cure must be shown
to affect gene activation/suppression
•Here is where the predatory marketing in
CIRS ends: show us the genomic data

9. Before 2015, all we had was
proteomics
•Compare to 1997, there was exposure and
symptoms only!
•A whole lot of guessing going on!
•2000 CNMI
•2006 CBAI
•2008 Enter the TGF beta 1 literature
•2009 CIRS!

10. The Biotoxin Pathway
High levels of cytokines produce flu-like
symptoms: Headaches, muscle aches, fatigue,
unstable temperature, difficulty concentrating
and more. High levels of cytokines also result in
increased levels of several other immune-
response related substances, including TGF B-1,
MMP-9, IL-1B, and PAI-1. MMP-9 delivers
inflammatory elements from blood to brain,
nerve, muscle, lungs, and joints. It combines
with PAI-1 in increasing clot formation and
arterial blockage.
Inflammation-related
symptoms
Reduced
MSH
Hypothalamus
VIP
MSH
AVP
Leptin
receptor
Damaged leptin
receptors lead to
reduced production
by the hypothalamus
of MSH, a hormone
with many functions.
In genetically susceptible people, biotoxins bind to pattern receptors,
causing continuing, unregulated production of cytokines.
Dendritic
Cells
HLA-DR
Surface
Receptors
(Toll;
C-type
lectin;
mannose
& others)
I
n
c
r
e
a
s
e
d

C
y
t
o
k
i
n
e
s
I
n
c
r
e
a
s
e
d

L
e
p
t
i
n
Fat cells then
produce more
leptin, leading to
obesity (which
doesn’t respond to
exercise and diet).
Excessive cytokine
levels can damage
leptin receptors in
the hypothalamus.
B
o
d
y

a
c
q
u
i
r
e
s
b
i
o
t
o
x
i
n
s

o
r

t
o
x
i
n
-
p
r
o
d
u
c
i
n
g

o
r
g
a
n
i
s
m
s

f
r
o
m

f
o
o
d
,

w
a
t
e
r
,

a
ir
,

o
r

b
u
g

b
it
e
s
Biotoxin
(HLA susceptible)
B
io
to
x
in
(
H
L
A

s
u
s
c
e
p
t
ib
le
)
B
i
o
t
o
x
i
n
Removal
from the
body
In most people,
biotoxins are
either removed
from the blood
by the liver or
attached by the
immune system,
broken down,
and excreted
harmlessly. In
people who don’t
have the right
immune
response genes,
however,
biotoxins can
remain in the
body indefinitely.
Nerve
cell/axon
Biotoxins have direct
effects, including
impairment of nerve
cell function.
Resistant Coag-negative
Staph Bacteria
Colonies of MARCoNS with resistance to multiple
antibiotics may develop in biofilm or mucus membranes.
The bacteria produce substances that aggravate both the
high cytokine levels and low MSH levels.
Reduced ADH
Reduced MSH can cause the pituitary to
produce lower levels of anti-diuretic
hormone (ADH), leading to thirst, frequent
urination, and susceptibility to shocks from
static electricity.
Reduced Androgens
Reduced MSH can cause the pituitary to lower its
production of sex hormones.
Changes in Cortisol
and ACTH levels
The pituitary may produce
elevated levels of cortisol and
ACTH in early stages of illness,
then drop to excessively low
levels later. (Patients should
avoid steroids such as
prednisone, which can lower
levels of ACTH)
Sleep Disturbance
Production of melatonin
is reduced, leading to
chronic, non-restorative
sleep.
Chronic Pain
Endorphin production is
suppressed. This can lead
to chronic, sometimes
unusual, pain.
Gastrointestinal
Problems
Lack of MSH can cause
malabsorption in the gut,
resulting in diarrhea. This is
sometimes called “leaky gut”
and resembles (but is not)
celiac disease. IBS is often
present.
White blood cells lose
regulation of cytokine
response, so that recovery
from other illnesses,
including infectious diseases,
may be slowed.
Prolonged Illness
c R. Shoemaker, 2011
Split Products of
Complement Activation
C4a: capillary hypoperfusion
C3a: bacterial membranes
Immune System Symptoms
Patients with certain HLA genotypes
(immune response genes) may develop
inappropriate immunity. Most common
are antibodies to:
-Gliadin (affects digestion)
-Cardiolipins (affects blood clotting)
Treg cells: Pathogenic T cells
High cytokine levels in the capillaries attract white
blood cells, leading to restricted blood flow, and lower
oxygen levels. HIF stimulates VEGF and TGF B-1.
Reduced VEGF leads to fatigue, muscle cramps, and
shortness of breath (may be over-ridden by
replacement with erythropoietin). TGF B-1 changes
cell type and interacts with Treg cells.
Capillaries
HIF
Increased Cytokines

12. Ciguatera
•Eaten any reef fish lately
•Careful about the grouper, snapper, jack
barracuda (and about 400 species)
•Pacific and Caribbean toxins are similar
•Well studied but chronic human health
effects now unveiled to be a typical CIRS
•And we know the genomics!

13. Lyme
•Can of wormy spirochetes
•What is PLS? And chronic Lyme?
•We now know from C3a, C4a, NQ, genomics
that PLS is a CIRS
•Antibiotics don’t fix CIRS
•I have argued about Lyme for years

14. Cyanobacteria
•Blue green algae blooms
•Not just Brazil and Australia any more!
•Cylindrospermopsis in lakes of Florida
•Microcystis just about everywhere in US
(including Ipswich!)
•Anabaena and who knows about Euglena?
•Copper and benomyl resistance!

15. Each of these categories of
illness can be acute and chronic
•CIRS is chronic!
•Labs ends up being similar
•Final common pathway!
•Treatment protocols are similar
•All have unique aspects of genomics
•Jumping to the end: VIP not only corrects
proteomics but genomics too

16. What about an exposure history?
•Do you live in a building that has water
intrusion? Leaks? A damp basement?
•Do you work in a building that has
condensation on windows and a humidity
problem? Schools with flat roofs?
•Did you develop this illness after you changed
buildings-home, work, church, school, more)
•What physician asked? NONE!

17. Treatment
•No self-healing in most I talked to
•Secretory diarrhea! Why, that’s easy to fix!
•Sure, use the good old bile salt binder,
cholestyramine (CSM)
•Diarrhea stopped; of course it did
•So did cough, memory loss and aching.
What did that mean?

18. Labeled for reducing cholesterol
•Off label use for years to stop bile salt
diarrhea
•Secretory diarrhea too
•Clostridia difficile
•Off label use by FP docs forever
•GI side effects common but clinical
improvement is often so rapid in
uncomplicated CIRS, as we now know

19. CSM is a binder of so many
compounds
•Call it glue
•Long polystyrene chain with side groups of
positively charge nitrogen (quaternary
ammonium, 1.43 Angstroms)
•The shape and size of the positive charge
interacts with a net negative charge found
in parts of biotoxins (1.41 Angstroms)

21. P-CTX-1
C-CTX-1
PbTx

25. Agent LD 50Molecular Weight Source
Botulinum Toxin0.001 150,000 Bacterium
Shiga Toxin 0.002 55,000 Bacterium
Diphtheria Toxin0.10 62,000 Bacterium
Maitotoxin* 0.10 3,400 Marine Dinoflagellate
Ciguatoxin* 0.40 1,000 Fish/Marine Dinoflagellate
Batrachotoxin*2.0 539 Arrow-Poison Frog
Ricin 3.0 64,000 Plant (Castor Bean)
Conotoxin* 5.0 1,500 Cone Snail
Tetrodotoxin* 8.0 319 Puffer Fish
α Tityustoxin9.0 8,000 Scorpion
Microcystin* 50.0 994 Blue-Green Algae
Sarin 100.0 140 Chemical Agent
Aconitine* 100.0 647 Plant (Monkshood)
T-2 Toxin* 1,210.0 466 Fungal Mycotoxin

26. 1998 first mold patient
•Initial use of VCS applied to Rx
•Differential diagnosis expands
•Improvement with Rx
•Relapse with re-exposure
•Improvement with Rx/removal only
•Was it toxins or what?

29. Defining mold illness
•Potential for exposure
•GAO 2008 Same symptoms as published
•Same labs as in published experimental
animals and humans
•Response to therapy
•Superseded 2003 two-tiered definition
from CRBAI

30. Say it in a lot of words
•Acute and chronic illness acquired
following exposure to interior of WDB with
resident microbes including but not limited
to fungi, bacteria, actinomycetes,
mycobacteria; and inflammagens including
beta glucans, mannans, lectins,
hemolysins, spirocyclic drimanes, mVOCs
(and more)
•See Table 2 in handouts

31. Who gets sick?
•Defective antigen presentation is under
control of HLA DR
•6 (of 54 types) haplotypes of HLA show up
with elevated relative risk (incidence in
cases divided by incidence in controls)
•Relative risk: total is 24% of the
population
•% is constant in many studies

32. Genetics of inflammatory illness
•Why is there no dose response?
–A few molecules of toxin make some people
deathly ill
–A pound of toxin doesn’t make some people ill
•Why do some people have no symptoms
and others a lot? HLA DR.
•What does HLA screening mean for children
(and schools, homes)?

33. What is a “moldy” building?
•You hear these words all the time
•What about toxin-forming bacteria and
actinomycetes (and mycobacteria)?
•What about all the inflammagens?
•What does it cost to assess every antigen
that makes people sick?

34. Or, what is a building health index?
•Environmental Relative Mold Index
•EPA, 2006
•1000 homes; dry/water-damaged
•Groups I (moldy) and II (not-moldy)
organisms identified by DNA (QPCR)
•Add sum of logs, subtract II from I
•Voila, ERMI

35. HERTSMI-2
•Simple, effective and fast
•Based on hard data
•Based on environmental conditions
•Mycologists begrudgingly say “maybe”
•Patients love it
–They see the source of the problem
–They can figure out what is wrong

36. What tells you someone is ill
•Symptoms
•Visual contrast sensitivity (VCS)
•Labs (what you have and don’t)
•Sequential steps of therapy
•Transparent results of testing as each step
is completed
•Caution re lack of transparency

37. So we know what to do, how do we
know when to do it?
•Potential for exposure
•Presence of typical symptoms
•Presence of typical labs
•Absence of confounders
•Differential diagnosis
•Prospective exposure studies give poof of
causation

38. Defining what is wrong brings
effective treatment
•Lowering levels of inflammagens: C3a, C4a,
MMP9 and TGF beta-1
•Correct hormonal dysregulation
•Deal with auto-immunity
•Improve capillary hypoperfusion
•Eradicate commensal staphs
•Correct cellular immunity

39. Genomics-1
•Preserve WBC
•Extract mRNA
•Analyze with NextGen sequencing
•Compare to controls
•Compare to cases
•Look for responsiveness to meds

40. Genomics-2
•Look at microRNA
–Policemen of nuclear membrane
•Look at long noncoding RNA
–Nuclear bodies
–Here lies epigenetics??
•We are looking at regulation of regulation!
•These were genes called “Junk”
•The illness is fixed when genes are “normal”

41. Genomics-3
•Pathways, before and after
•We aren’t just looking at a static gene
•We are looking at genes interacting into
physiology
•We are looking at regulatory aspects of gene
control from LNC to microRNA to mRNA
•We look at the basics of what is wrong in
disease

46. Summing up
•Lots to think about tonight
•When I come back in 5 more years, just
imagine what we will be talking about
•CIRS is so common, so easy to define, so
vitally important to the future of medicine
•We cannot make assumptions
•We cannot guess about Lyme, fibromyalgia
and CFS

47. Follow the data!
•Science will find a way
•Until we show the naysayers all we need
them to know, we will just keep following
our ideas and our dreams
•We are close to such incredible
breakthroughs, I ask you to keep paying
attention.
•But stay out of moldy buildings

48. Treatment steps
VIP
TGF beta-1
Correct C4a
Correct C3a
Correct VEGF
Correct MMP9
Correct ADH/osmolality
Correct androgens
Correct antigliadin
Eradicate MARCoNS
CSM/Welchol
Remove from exposure

49. For more information:
www.survivingmold.com
State of the Art Answers to 500 Mold
Questions 2014 (ebook)
Surviving Mold December, 2010; ebook
Mold Warriors 2005, 2007, 2010 ebook
Desperation Medicine 2001, 2006, 2009
Lose the Weight You Hate 2002, 2005