- [Narrator] The university of Michigan,
Division of Gastroenterology,
and the Inflammatory Bowell Disease Program
host the IBD Visiting Professor Lecture Series
in Ann Arbor, Michigan.
This series presents the latest in clinical research
and basic science from IBD experts from around the world.
- So thank you and I had a great day yesterday
meeting everybody and today I'll meet a few more people.
It's been quite a whirlwind and today I did not wear
comfortable shoes based on your recommendations.
So I'm going to be talking about the role of immune markers
and predicting disease course and therapeutic outcome.
Really the way of the future is for us to be able to
move forward and I know a lot of work is being done on
imaging and looking at structural damage here,
so you're in the...
You have that same mantra of really prognostication
and thinking about natural history
and thinking about the right patient for the right therapy
and really attacking them early with
that more effective intervention.
So I'm going to take a different slant than the
radiologic and fibrostenosing perspective
and really talk about genetics or touch on genetics
but really focus on the immune reactivity
that individuals with IBD actually express
and whether these immune reactivity markers
could actually be used to think about
predicting outcome in patients with IBD,
particularity Crohn's Disease
but there's also some emerging data in Ulcerative Colitis.
So when we think of Inflammatory Bowel Disease
we as clinicians are on this end of the spectrum.
We see patients and we've realized
as you see more and more IBD patients
that there's really a spectrum of presentations.
You have some patients who present with very simple
non-penetrating, non-stricturing small bowel Crohn's Disease
and stay that way for a long time
and would have even stayed that way likely
if we gave no medications to be honest.
There's a certain subgroup of patients who just
live with mild abthi in the ilium and cecum.
A lot of you may find it when you do your
colon cancer screening and you don't know
really what to do with these patients,
they're asymptomatic but they have inflammatory changes
under the microscope as well as to your eye.
And so what we've come to understand,
there's no just one form of Inflammatory Bowel Disease,
there's many IBDs and each of these
Inflammatory Bowel Disease phenotypes
are actually represented by an underlying genetic
and/or immune reactivity that is specific to that phenotype
that that patient is presenting to you.
So a lot of us live over here but those of us who are in the
translational component of research,
we're really looking for surrogate markers or other ways
subclinical before a patient actually gets to be strictured
or penetrated where we can actually say,
you're on that path and therefore we'd like to
give you early effective intervention
and stop that progression in natural history
for you to develop stricturing or penetrating disease.
So my area of interest is really in the
immune response component.
There's a lot of individuals, including myself,
who are also interested in genetic susceptibility piece
but it's thought that maybe these immune reactivities
are actually an expression of the body,
of what was going on at the level of mucosa
as a gene defect was interacting with a specific bacteria
and you were spitting out an antibody against that bacteria.
That's the theory behind it.
Think about it like Celiac Disease,
you have a genetic defect, you have an underlying antigen
which is dietary as compared to IBD as bacterial
and you have an antibody response to this antigen.
It's kind of like that analogy in a very simple way
that you're actually expressing an antibody
against a specific bacterial antigen that may be causative.
Unfortunately we're not quite as sophisticated to actually
say that this particular antigen
that drives this this antibody response
is what causes Crohn's Disease.
If you go back in time historically, one of the antibodies,
which is ASCA, when it was first uncovered
which is Anti Saccharomyces cerevisiae,
they actually thought in Europe that
Saccharomyces cerevisiae was causative because we found
antibodies to a yeast in patients with Crohn's Disease.
So they eliminated yeast from the diet
and recognized that it has nothing to do with yeast
and that yeast was not the causative antigen
in these particular individuals.
But they realize that these must be some kind of
cross reactivity and what I mean by cross reactivity
is ASCA is what we measure a lot.
It's one of the most popular and most
significant markers of immune reactivity in Crohn's patients
but we don't really think that what is antigen or causative
or driving antigen in the body is actually the yeast.
We feel what's happening is that
on the cell wall of this yeast, of Saccharomyces,
there must be cross reactivity with a bacterial sugar,
a sugar on the cell wall of bacteria
and what this antibody is is representative of some overlap
or cross reactivity with another antigen on the cell wall of
a very important bacteria and I say important
when I show you how critical ASCA is
in terms of predicting outcome.
So the ones that are actually commercially available
in the U.S., are most of them actually
but the ones we are familiar with are the top five here,
pANCA, ASCA, OmpC and C-Bir.
These are actually available through Prometheus Labs.
ASCA and pANCA's often available through other labs.
The pANCA's different based on different labs
but ASCA's essentially the same wherever you get it.
These antibodies which are called anti-glycan antibodies
are by a company called Glycomed
which is based out of Israel.
They're actually not a commercial lab with a sales force
but they go through LapCorp
so I don't know if you have access...
Peter do you have access Glycomed or...?
- [Peter] (mumbles)
- Okay so, Glycomed because they're not a you know,
a company that markets they just actually go through LabCorp
so some labs if they have contracts with LabCorp and not,
wouldn't send somewhere else you would get the anti-glycan
antibodies as a result.
So these are anti-glycans which is very similar to ASCA
which means an antibody gains a sugar in the cell wall
of bacteria and/or yeast in this particular situation.
This in an antibody against a flagellin,
this is an antibody against a specific
outer membrane foreign known to be localized on E. coli.
pANCA was actually thought to be an auto-antibody
but now actually people think that it's truly an
antibody against a bacterial component.
So there's increasing interest in understanding
what these antibodies represent
because maybe there's actually a causative antigen.
As we know there's not... it's not very simple in IBD
where you have one antigen, one gene, one phenotype
or else we wouldn't be here right.
So the reality is it's much more complex than that
so that's why the knowledge of multiple immune reactivities
is actually interesting because it means and it talks to
the multifactorial natural of IBD.
And to think that each of these probably represents
some kind of gene bacterial interaction is very interesting
because it lends itself to the hypothesis that we believe,
IBD results from a genetic susceptibility
and an inappropriate handling of our bacteria.
So it's kind of interesting to think that
we may have actually markers of this abnormal handling
of bacteria in specific gene defects.
So, if we're gonna phenotype patients or classify patients
much deeper than just clinically meaning,
you have small bowel, you have stricturing,
you have penetrating, you have a family history,
you're diagnosed below the age of 16,
these are all classifications systems we use to phenotype.
We could think about actually phenotyping patients
at a subclinical level meaning at the immunotype
rather than the clinical phenotype.
We can think about classifying patients at the immune level.
And so back in 2002, Carol Landers group
they actually started to think about,
how do Crohn's patients kind of end up in terms of
how many antibodies each of them have
and what's the combination of these markers
that an individual can have.
And what you can see here,
is that there's about a quarter of patients who are positive
for all three of these bacterial driven antigens
or antibodies against bacterial driven antigens.
The question will be,
which I'll say with you in a few moments is,
what does that mean to be positive for all of these markers?
Does that impact the way I view my patient
and does that impact the progression of disease,
meaning is it a bad thing or is it a good thing
and I'll share with you the data on that.
And then you can see there are patients who have overlap
of two of these and then there are individual patients
who have the remaining difference of the antibodies
that are individually positive.
Then in 2005, C-Bir came along.
C-Bir was interesting because it was actually found in an
animal model at Chuck Elsen's lab in Alabama
and then he said hey, take this antigen
and actually test it in your humans
and see whether or not your human Crohn's patients actually
have antibodies against this antigen
and 50% of Crohn's patients were positive for this antibody.
But it was actually identified in an animal model
that got Inflammatory Bowel Disease.
So we thought wow, this could be causative,
there could be something about this flagellin
and it's a Clustridiath flagellin, it's not C. diff
'cause everyone got excited but it is not,
it's actually the family of Clustridias huge
and this is just one of the family of
or species of Clustridias.