spontaneous models of autoimmunity - the NOD mouse

[Guest guest]

I've been reading this long Ann Rev review on the NOD mouse:

http://arjournals.annualreviews.org/doi/pdf/10.1146/annurev.immunol.23.021704.11\

5643?cookieSet=1

It's pretty good.

Though knowing vaguely that they are supposed to be homozygous, I had

never looked up the definition of an inbred mouse before, so I did.

It's discussed in this Nature Group review:

www.nature.com/ng/journal/v24/n1/full/ng0100_23.html

But I didn't get much out of that one that I didn't already get faster

here:

" An inbred strain is one that has been maintained by sibling (sister x

brother) matings for 20 or more consecutive generations. All of the

standard JAX® Mice inbred strains have far surpassed 20 generations of

inbreeding. "

Ewww!

" Except for the sex difference, mice of an inbred strain are as

genetically alike as possible, being homozygous at virtually all of

their loci. "

http://jaxmice.jax.org/info/inbred.html

The Nature Group paper says:

" At 20 generations, on average at least 98.6% of the loci in each

mouse are homozygous. Many strains have been bred for more than 150

generations and are essentially homozygous at all loci. Each inbred

strain is also isogenic (genetically identical) because all

individuals trace back to a common ancestor in the twentieth or a

subsequent generation. "

So, the NOD mouse has generally elevated immune disease potential, for

both spontaneous and experimental immune diseases. It's missing one

HLA locus. It also seems to have a non-wild-type single-aa variation

at another HLA locus, one which carries quite a lot of the excess

diabetes risk. That seems dreadfully artificial in one sense, but on

the other hand there appears to be a comparable single-aa substitution

that confers serious risk in humans, which is quite striking.

The NOD could also be a pretty messed up little guy in general

considering it is almost fully homozygous. What's interesting is that

much of the genetic risk, other than that conferred by the mutant HLA

allele, is not well characterized. The specificity of the pathogenic T

cells also doesn't seem to have been the subject of much progress.

That makes you wonder.

You have to wonder if these varmints could have a vertically

transmitted infection in the pancreas. The mice's isogenicity would

certainly facilitate it's vertical transfer. The penetrance of

diabetes in the NOD mouse is actually better under germ-free

conditions (an interesting bit of evidence for the hygeine

hypothesis). Germ-free mouse lines are propagated in sterile

facilities and initially isolated by cesarean delivery of a germ-free

progenitor infant, but what might that infant have acquired

transplacentally?

[Guest guest]

Humans will become extinct and the mouse will live on since they get

cured with every treatment they are given.

a

>

> I've been reading this long Ann Rev review on the NOD mouse:

>

>

http://arjournals.annualreviews.org/doi/pdf/10.1146/annurev.immunol.23

..021704.115643?cookieSet=1

>

> It's pretty good.

>

> Though knowing vaguely that they are supposed to be homozygous, I

had

> never looked up the definition of an inbred mouse before, so I did.

> It's discussed in this Nature Group review:

>

> www.nature.com/ng/journal/v24/n1/full/ng0100_23.html

>

> But I didn't get much out of that one that I didn't already get

faster

> here:

>

> " An inbred strain is one that has been maintained by sibling

(sister x

> brother) matings for 20 or more consecutive generations. All of the

> standard JAX® Mice inbred strains have far surpassed 20 generations

of

> inbreeding. "

>

> Ewww!

>

> " Except for the sex difference, mice of an inbred strain are as

> genetically alike as possible, being homozygous at virtually all of

> their loci. "

>

> http://jaxmice.jax.org/info/inbred.html

>

> The Nature Group paper says:

>

> " At 20 generations, on average at least 98.6% of the loci in each

> mouse are homozygous. Many strains have been bred for more than 150

> generations and are essentially homozygous at all loci. Each inbred

> strain is also isogenic (genetically identical) because all

> individuals trace back to a common ancestor in the twentieth or a

> subsequent generation. "

>

> So, the NOD mouse has generally elevated immune disease potential,

for

> both spontaneous and experimental immune diseases. It's missing one

> HLA locus. It also seems to have a non-wild-type single-aa variation

> at another HLA locus, one which carries quite a lot of the excess

> diabetes risk. That seems dreadfully artificial in one sense, but on

> the other hand there appears to be a comparable single-aa

substitution

> that confers serious risk in humans, which is quite striking.

>

> The NOD could also be a pretty messed up little guy in general

> considering it is almost fully homozygous. What's interesting is

that

> much of the genetic risk, other than that conferred by the mutant

HLA

> allele, is not well characterized. The specificity of the

pathogenic T

> cells also doesn't seem to have been the subject of much progress.

> That makes you wonder.

>

> You have to wonder if these varmints could have a vertically

> transmitted infection in the pancreas. The mice's isogenicity would

> certainly facilitate it's vertical transfer. The penetrance of

> diabetes in the NOD mouse is actually better under germ-free

> conditions (an interesting bit of evidence for the hygeine

> hypothesis). Germ-free mouse lines are propagated in sterile

> facilities and initially isolated by cesarean delivery of a germ-

free

> progenitor infant, but what might that infant have acquired

> transplacentally?

>

[Guest guest]

> What's interesting is that

> much of the genetic risk, other than that conferred by the mutant HLA

> allele, is not well characterized.

Meaning, the risk-conferring regulatory or structural sequences

associated with most of the known markers, have not been identified.

> The specificity of the pathogenic T

> cells also doesn't seem to have been the subject of much progress.

> That makes you wonder.

Well, that was much too strongly worded. It sounds like they do have T

cell clones able to transfer disease. See also

http://www.nature.com/nm/journal/v5/n6/pdf/nm0699_601.pdf

(There may be a question, however, of whether a given adoptive

transfer gives a realistic T cell dose, or instead a supra-realistic one.)

What they don't seem to be sure of is which T cell clones initially

break tolerance.