say /what/ about psoriasis?

[Guest guest]

" New insights to the pathogenesis of psoriasis have been provided by a

recently developed mouse model (Zenz et al., 2005). Following the

observation that expression of the AP-1 subunit JunB is downregulated

in psoriatic lesions relative to normal skin, Zenz et al. (2005)

generated conditional knockout mice where both the JunB and c-Jun loci

are inducibly deleted in the epidermis upon tamoxifen-induced Cre

recombinase expression. Within 8–10 days of tamoxifen administration,

affected mice, in which both JunB and c-Jun were deleted, developed

skin lesions that were identical in appearance to psoriatic plaques of

human patients. Appearance of psoriatic lesions was associated with

appearance in 100% of the double-knockout mice of joint inflammation,

similar to psoriatic arthritis, which appears in 5%–40% of psoriasis

patients. "

Translation: two genes (JunB and c-Jun) were knocked out after the

mice were already grown up (at least I think that's what it means).

This is a nice trick because some genes are involved in development,

and knocking them out of the egg yields 6-headed mice, dead mice, or

something like that.

" Inactivation of the Rag2 locus, which prevents development of T and B

lymphocytes, which are believed to be important contributors to the

maintenance of psoriasis and RA (Feldmann and Maini, 2003), suppressed

development of psoriatic lesions less than deletion of TNFR1 but still

attenuated the development of subsequent arthritis (Zenz et al., 2005). "

Wow. Not all about adaptive immunity then. (I assume the Rag2 lesions

were created prior to the disease induction.)

Here's where it gets hot:

" The key question, however, is what causes the initial and deregulated

activation of myeloid cells in the skin of epidermally deleted

JunB/c-Jun knockout mice. Although the full mechanism remains to be

determined, Zenz et al. offer a few important clues. First, the

development of the disease is attenuated by application of a

broad-spectrum antibiotic, suggesting the involvement of bacteria,

most likely commensals that live on mouse skin. Second, one of the

first detectable changes in gene expression by epidermal keratinocytes

following inducible JunB/c-Jun deletion is upregulation of S100

proteins (S100A8 and S100A9), which have been shown to serve as

chemotactic factors for neutrophils (Rioux and Abbas, 2005). Rapid

upregulation of S100A8 and S100A9 was also seen upon deletion of JunB

and c-Jun in cultured keratinocytes, suggesting a close link between

the two (Zenz et al., 2005). As the two Jun proteins are important

regulators of keratinocyte proliferation (Zenz et al., 2003), it is

possible that their absence may result in increased exposure to

commensal bacteria due to accelerated loss of barrier function.

Together with the upregulation of S100 proteins and other yet-to-be

identified factors, this results in an exacerbated inflammatory

response that fails to resolve and eventually leads to activation of

lymphocytes that may propagate psoriatic arthritis through autoimmune

mechanisms. While it will be important to validate this hypothesis in

human subjects, it should be recognized that a patient suffering from

psoriasis may be far removed from the initial episode that exposed its

inflammatory cells to skin-born bacteria and therefore unlike the

inducible JunB/c-Jun knockout mice may no longer be responsive to

antibiotic therapy. "

As with all the barrier function theories (of asthma or Crohn's, for

example), you wonder why the barrier deficit persists. We know why it

might persist in the JunB/c-Jun mouse, but why would it persist in a

wild-type mammal?

[Guest guest]

'

Would you not think it's the toxins that are setting up the whole

sheebang...the cancer drug mentiuoned(tamoxifen) that's capable of

knocking around the genetics in the skin, is almost, if not 100% a

bacterial toxin produced item...

>

> " New insights to the pathogenesis of psoriasis have been provided

by a

> recently developed mouse model (Zenz et al., 2005). Following the

> observation that expression of the AP-1 subunit JunB is

downregulated

> in psoriatic lesions relative to normal skin, Zenz et al. (2005)

> generated conditional knockout mice where both the JunB and c-Jun

loci

> are inducibly deleted in the epidermis upon tamoxifen-induced Cre

> recombinase expression. Within 8–10 days of tamoxifen

administration,

> affected mice, in which both JunB and c-Jun were deleted, developed

> skin lesions that were identical in appearance to psoriatic plaques

of

> human patients. Appearance of psoriatic lesions was associated with

> appearance in 100% of the double-knockout mice of joint

inflammation,

> similar to psoriatic arthritis, which appears in 5%–40% of psoriasis

> patients. "

>

> Translation: two genes (JunB and c-Jun) were knocked out after the

> mice were already grown up (at least I think that's what it means).

> This is a nice trick because some genes are involved in development,

> and knocking them out of the egg yields 6-headed mice, dead mice, or

> something like that.

>

> " Inactivation of the Rag2 locus, which prevents development of T

and B

> lymphocytes, which are believed to be important contributors to the

> maintenance of psoriasis and RA (Feldmann and Maini, 2003),

suppressed

> development of psoriatic lesions less than deletion of TNFR1 but

still

> attenuated the development of subsequent arthritis (Zenz et al.,

2005). "

>

> Wow. Not all about adaptive immunity then. (I assume the Rag2

lesions

> were created prior to the disease induction.)

>

> Here's where it gets hot:

>

> " The key question, however, is what causes the initial and

deregulated

> activation of myeloid cells in the skin of epidermally deleted

> JunB/c-Jun knockout mice. Although the full mechanism remains to be

> determined, Zenz et al. offer a few important clues. First, the

> development of the disease is attenuated by application of a

> broad-spectrum antibiotic, suggesting the involvement of bacteria,

> most likely commensals that live on mouse skin. Second, one of the

> first detectable changes in gene expression by epidermal

keratinocytes

> following inducible JunB/c-Jun deletion is upregulation of S100

> proteins (S100A8 and S100A9), which have been shown to serve as

> chemotactic factors for neutrophils (Rioux and Abbas, 2005). Rapid

> upregulation of S100A8 and S100A9 was also seen upon deletion of

JunB

> and c-Jun in cultured keratinocytes, suggesting a close link between

> the two (Zenz et al., 2005). As the two Jun proteins are important

> regulators of keratinocyte proliferation (Zenz et al., 2003), it is

> possible that their absence may result in increased exposure to

> commensal bacteria due to accelerated loss of barrier function.

> Together with the upregulation of S100 proteins and other yet-to-be

> identified factors, this results in an exacerbated inflammatory

> response that fails to resolve and eventually leads to activation of

> lymphocytes that may propagate psoriatic arthritis through

autoimmune

> mechanisms. While it will be important to validate this hypothesis

in

> human subjects, it should be recognized that a patient suffering

from

> psoriasis may be far removed from the initial episode that exposed

its

> inflammatory cells to skin-born bacteria and therefore unlike the

> inducible JunB/c-Jun knockout mice may no longer be responsive to

> antibiotic therapy. "

>

> As with all the barrier function theories (of asthma or Crohn's, for

> example), you wonder why the barrier deficit persists. We know why

it

> might persist in the JunB/c-Jun mouse, but why would it persist in a

> wild-type mammal?

>

[Guest guest]

I'm not 100% sure, but I think they set this up so that tamox

activated a special enzyme (encoded by a gene they'd pre-inserted)

that cuts out the target genes. So tamox is just used as a " switch, "

and the choice of tamox is pretty arbitrary. I would guess that the

concentrations of tamox used are probably too low for it to have any

of its usual cytotoxic/anticancer effect.

Specifically, tamoxifen (actually, a metabolite thereof) inhibits the

estrogen receptor. The estrogen receptor is a transcription factor,

meaning that it binds to DNA and alters the production of proteins -

but only after estrogen binds to it. How they managed to set it up so

that blocking the estrogen receptor triggers this special gene-cutting

enzyme, I'm not sure.

Doxy is sometimes used in a kind of similar way to control events in

weird genetically modified animals. In that case, I think there are

certain bacterial transcription factors that can bind, and thus sense,

tetracyclines. These transcription factors can be put into a mouse

genome in order to obtain doxy-dependent production of certain

proteins. This is usually " leaky " though, in that there is usually

some production of those proteins even in the absence of doxy - so I

was told in school. So in practice it's not as kick ass as it sounds.

> '

> Would you not think it's the toxins that are setting up the whole

> sheebang...the cancer drug mentiuoned(tamoxifen) that's capable of

> knocking around the genetics in the skin, is almost, if not 100% a

> bacterial toxin produced item...

>