More PSOR Abstractions and other NOTIONs
randall
What's in your genes that ISN'T in someone's without psoriasis?
http://www.ncbi.nlm.nih.gov/pubmed/20220767
J Invest Dermatol. 2010 Mar 11.
Assessment of the Psoriatic Transcriptome in a Large Sample:
Additional Regulated Genes and Comparisons with In Vitro Models.
Gudjonsson JE, Ding J, Johnston A, Tejasvi T, Guzman AM, Nair RP,
Voorhees JJ, Abecasis GR, Elder JT.
Department of Dermatology, University of Michigan Medical School, Ann
Arbor, Michigan, USA.
To further elucidate molecular alterations in psoriasis, we performed
a gene expression study of 58 paired lesional and uninvolved psoriatic
and 64 control skin samples. Comparison of involved psoriatic (PP) and
normal (NN) skin identified 1,326 differentially regulated transcripts
encoding 918 unique genes (549 up- and 369 downregulated), of which
over 600 are to our knowledge previously unreported, including
S100A7A, THRSP, and ELOVL3. Strongly upregulated genes included
SERPINB4, PI3, DEFB4, and several S100-family members. Strongly
downregulated genes included Wnt-inhibitory factor-1 (WIF1), beta-
cellulin (BTC), and CCL27. Enriched gene ontology categories included
immune response, defense response, and keratinocyte differentiation.
Biological processes regulating fatty acid and lipid metabolism were
enriched in the down-regulated gene set. Comparison of the psoriatic
transcriptome to the transcriptomes of cytokine-stimulated cultured
keratinocytes (IL-17, IL-22, IL-1alpha, IFN-gamma, TNF-alpha, and OSM)
showed surprisingly little overlap, with the cytokine-stimulated
keratinocyte expression representing only 2.5, 0.7, 1.5, 5.6, 5.0, and
1.9% of the lesional psoriatic dysregulated transcriptome,
respectively. This comprehensive analysis of differentially regulated
transcripts in psoriasis provides additional insight into the
pathogenic mechanisms involved and emphasizes the need for more
complex yet tractable experimental models of psoriasis.Journal of
Investigative Dermatology advance online publication, 11 March 2010;
doi:10.1038/jid.2010.36.
PMID: 20220767
I know what psoriasin (S100A7A) is.
http://en.wikipedia.org/wiki/S100A7
What is THRSP genetics?
http://en.wikipedia.org/wiki/THRSP
Thyroid hormone-inducible hepatic protein is a protein that in humans
is encoded by the THRSP gene.[1][2]
The protein encoded by this gene is similar to the gene product of
S14, a rat gene whose expression is limited to liver and adipose
tissue and is controlled by nutritional and hormonal factors. This
gene has been shown to be expressed in liver and adipocytes,
particularly in lipomatous modules. It is also found to be expressed
in lipogenic breast cancers, which suggests a role in controlling
tumor lipid metabolism.[2]
<sniP>
And ELOVL3 looks somewhat familiar?
Nope, don't see it in the group.
So?
We find it on pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&term=(elovl3[gene])
AND (Homo sapiens[orgn]) AND alive[prop] NOT newentry[gene]&log
$=genesensor5&logdbfrom=pubmed&sort=weight
1: ELOVL3 elongation of very long chain fatty acids (FEN1/Elo2, SUR4/
Elo3, yeast)-like 3 [ Homo sapiens ]
[...]
Also known as CIG30; CIG-30; MGC21435; ELOVL3
Summary ELOVL3 plays a role in fatty acid chain elongation and
formation of neutral lipids required for skin barrier function
(Westerberg et al., 2004 [PubMed 14581464]).[supplied by OMIM]
<sniP>
Not much is available on pubmed:
11 hits for ELOVL3
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=ELOVL3&log$=activity
And 7 hits for keywords: ELOVL* arachidonic acid
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=ELOVL*+AND+arachidonic+acid&log$=activity
116 hits for ELOVL* on pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=ELOVL*&log$=activity
Well for the time being, they should concentrate on evil elovl and AA
(arachidonic acid)
and how inflammation arises in autoimmune situations that entail LL37
(cathelicidin) and
vitamin D3.
That's my take on this gene.
Until then... we swim in the light and swallow vitamin D3 and think
that the media and THE vitamin D council understands our Plight.
And those mediots keep forcing D3 down our throats.
============
Things i can't figure OUT.
Oh REALLY?
How come vitamin D3 orally makes more plaques?
And natural sunlight, which is organic btw, slows immunity and clears
me up? LOL
http://www.ncbi.nlm.nih.gov/pubmed/20221619
Arch Dermatol Res. 2010 Mar 10.
Control of cutaneous antimicrobial peptides by vitamin D3.
Dombrowski Y, Peric M, Koglin S, Ruzicka T, Schauber J.
Department of Dermatology and Allergy, Klinik und Poliklinik für
Dermatologie und Allergologie, Ludwig-Maximilian-University,
Frauenlobstr. 9-11, 80337, Munich, Germany.
Constant exposure to a wide variety of microbial pathogens represents
a major challenge for our skin. Antimicrobial peptides (AMPs) are
mediators of cutaneous innate immunity and protect primarily against
microbial infections. Cathelicidins were among the first AMPs
identified in human skin and recent evidence suggests that they exert
a dual role in innate immune defense: At first, due to their
antimicrobial activity they kill pathogens directly. In addition,
these peptides initiate a potent host response to infection resulting
in cytokine release, inflammation and a cellular response. Disturbed
cathelicidin expression and function was observed in several common
inflammatory skin diseases, such as psoriasis where cathelicidin
peptide converts inert self-DNA and self-RNA into an autoimmune
stimulus. In atopic dermatitis decreased levels of cathelicidin
facilitating microbial superinfections have been discussed.
Furthermore, abnormally processed cathelicidin peptides induce
inflammation and a vascular response in rosacea. Until recently, the
molecular mechanisms underlying cathelicidin regulation were unknown.
Recently, the vitamin D3 pathway was identified as the major regulator
of cathelicidin expression. Consequently, vitamin D3 entered the
spotlight as an immune modulator with impact on both innate and
adaptive immunity. Therapies targeting vitamin D3 signaling may
provide new approaches for infectious and inflammatory skin diseases
by affecting both innate and adaptive immune functions.
PMID: 20221619
It must be the retarded immune pathways that can't figure out a GOOD
thing. LOL
==============
More Hilarious foxp3 and psoriasis pathways then?
This time guttate versus plaque?
YeP..
http://www.ncbi.nlm.nih.gov/pubmed/20222932
Br J Dermatol. 2010 Mar 5.
Foxp3+ regulatory T cells and related cytokines differentially
expressed in plaque versus guttate psoriasis vulgaris.
Yan KX, Fang X, Han L, Zhang ZH, Kang KF, Zheng ZZ, Huang Q.
Department of Dermatology, Huashan Hospital, Fudan University,
Shanghai 200040, China.
Abstract Background The difference of the number in lesional skin and
peripheral blood and functioning of Foxp3+ regulatory T cells (Treg)
in plaque versus guttate psoriasis has not been reported. Objectives
To investigate whether Foxp3+Tregs and its regulation of inflammatory
cytokines is differentially expressed in plaque versus guttate
psoriasis vulgaris. Methods The number and the percentage of Foxp3+
cells in different phases of skin lesions of patients with plaque and
guttate psoriasis vulgaris were assessed by immunohistochemical
staining. The expression of Foxp3 and IL-17 protein in CD4 populations
were measured by flow cytometry. The inflammatory cytokines production
by TGF-beta1-induced Foxp3+ Tregs were assessed in in vitro study. The
cytokines in supernatant and serum were determined by ELISA. Results
The percentage of Foxp3+CD3+ cell in papillary layer was higher than
that in reticular layer of dermis and epidemis (p<0.05). The numbers
of Foxp3+Treg in skin lesions and peripheral blood were higher in
plaque than those in guttate psoriasis; whereas the percentage of
IL-17+CD4+ cells was higher in guttate than those in plaque
psoriasis(p<0.05). The numbers of Foxp3+ cell were positively
correlated with PSI score of skin lesions (p<0.0001), and the
percentages of Foxp3+CD4+ cell in peripheral blood were positively
correlated with PASI score of patients (p<0.05). The inhibitory
function of Treg to IL-17 and IL-6 in guttate psoriasis while TNF-
alpha in plaque psoriasis was deficient. Conclusion Differential
expression and regulatory functioning for inflammatory cytokines
production by Foxp3+Tregs may implicate different immunopathogenesis
of plaque and guttate psoriasis.
PMID: 20222932
==============
http://www.ncbi.nlm.nih.gov/pubmed/20224694
Dermatoendocrinol. 2009 Mar;1(2):114-8.
Overexpression of CXCL16 in lesional psoriatic skin.
Oh ST, Schramme A, Tilgen W, Gutwein P, Reichrath J.
BACKGROUND: Psoriasis is characterized as an autoimmune disease
resulting in an exaggerated innate immune response. The CXC-chemokine
ligand 16 (CXCL16) is described to function as an adhesion molecule, a
scavenger receptor or as a soluble molecule it acts as a
chemoattractant. CXCL16 has been reported to be expressed in a variety
of inflammatory diseases. However, no information has been reported in
the literature about the expression of CXCL16 in psoriatic skin.
PURPOSE: The present study was designed to analyze the expression and
localization of CXCL16 in human psoriatic skin tissues. RESULTS: In
normal skin, cytpoplasmic expression of CXCL16 was increased in
keratinocytes of upper epidermal cell layers as compared to the lower
epidermal cell layers. In lesional psoriatic skin, CXCL16
immunoreactivity was increased in the cytoplasm of keratinocytes of
lower epidermal layer kerartinocytes as compared to the normal
epidermis. Cytoplasmic CXCL16 expression was increased in the
capillary endothelial cells of psoriatic dermis as compared to
capillary endothelial cells of the normal dermis. Notably, almost all
inflammatory cells in the dermis were negative for CXCL16. MATERIALS
AND METHODS: Ten paraffinized specimens of human lesional psoriatic
skin and five paraffinized specimens of normal skin were studied using
an immunohistochemical streptavidinperoxidase technique. CONCLUSION:
We here report for the first time alterations in the
immunohistochemical staining pattern of CXCL16 in lesional psoriatic
skin compared to the normal skin. These results suggest that CXCL16
may play a role in the pathogenesis of psoriasis.
PMID: 20224694
This is the only abstract with psoria* + cxcl16
And only 177 for cxcl16 on pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=CXCL16&log$=activity
Like this one:
http://www.ncbi.nlm.nih.gov/pubmed/20181724
J Leukoc Biol. 2010 Feb 24.
An alternatively spliced CXCL16 isoform expressed by dendritic cells
is a secreted chemoattractant for CXCR6+ cells.
van der Voort R, Verweij V, de Witte TM, Lasonder E, Adema GJ, Dolstra
H.
Departments of *Laboratory Medicine, Laboratory of Hematology,
andTumor Immunology andCentre for Molecular and Biomolecular
Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud
University Nijmegen Medical Centre, Nijmegen, The Netherlands.
DC are professional APCs that initiate and regulate adaptive immune
responses by interacting with naïve and memory T cells. Chemokines
released by DC play an essential role in T cell recruitment and in the
maintenance of antigen-specific T cell-DC conjugates. Here, we
characterized the expression of the T cell-attracting chemokine CXCL16
by murine DC. We demonstrate that through alternative RNA splicing, DC
not only express the previously characterized transmembrane CXCL16
isoform, which can be cleaved from the cell surface, but also a novel
isoform lacking the transmembrane and cytoplasmic domains.
Transfection of HEK293 cells shows that this novel isoform, termed
CXCL16v, is not expressed on the cell membrane but is secreted as a
protein of approximately 10 kDa. Quantitative PCR demonstrates that
CXCL16v is broadly expressed in lymphoid and nonlymphoid tissues
resembling the tissue distribution of DC. Indeed, CXCL16v mRNA is
expressed significantly by spleen DC and BM-DC. Moreover, we show that
mature DC have increased CXCL16v mRNA levels and express transmembrane
and soluble CXCL16 proteins. Finally, we show that CXCL16v
specifically attracts cells expressing the chemokine receptor CXCR6.
Our data demonstrate that mature DC express secreted, transmembrane,
and cleaved CXCL16 isoforms to recruit and communicate efficiently
with CXCR6(+) lymphoid cells.
PMID: 20181724
http://www.ncbi.nlm.nih.gov/pubmed/16547281
J Immunol. 2006 Apr 1;176(7):4431-9.
The vast majority of CLA+ T cells are resident in normal skin.
Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, Dowgiert
RK, Kupper TS.
Department of Dermatology, Brigham and Women's Hospital and Harvard
Skin Disease Research Center, Boston, MA 02115, USA.
Comment in:
J Immunol. 2006 Aug 1;177(3):1375-6; author reply 1376-7.
There are T cells within normal, noninflamed skin that most likely
conduct immunosurveillance and are implicated in the development of
psoriasis. We isolated T cells from normal human skin using both
established and novel methods. Skin resident T cells expressed high
levels of CLA, CCR4, and CCR6, and a subset expressed CCR8 and CXCR6.
Skin T cells had a remarkably diverse TCR repertoire and were mostly
Th1 memory effector cells with smaller subsets of central memory, Th2,
and functional T regulatory cells. We isolated a surprising number of
nonexpanded T cells from normal skin. To validate this finding, we
counted T cells in sections of normal skin and determined that there
are approximately 1 x 10(6) T cells/cm(2) normal skin and an estimated
2 x 10(10) T cells in the entire skin surface, nearly twice the number
of T cells in the circulation. Moreover, we estimate that 98% of
CLA(+) effector memory T cells are resident in normal skin under
resting conditions. These findings demonstrate that there is a large
pool of memory T cells in normal skin that can initiate and perpetuate
immune reactions in the absence of T cell recruitment from the blood.
PMID: 16547281
Can we imPlicate Th17 in these machinotions?
YeP..
CXCR6+ Th17 3 hits in pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=CXCR6%2B+Th17&log$=activity
http://www.ncbi.nlm.nih.gov/pubmed/19601882
Inflamm Allergy Drug Targets. 2009 Jul;8(3):221-8.
Migration and function of Th17 cells.
Kim CH.
Laboratory of Immunology and Hematopoiesis, Department of Comparative
Pathobiology; School of Veterinary Medicine, Purdue Cancer Center,
Purdue University, West Lafayette, IN 47907, USA. ch...@purdue.edu
T cells play central roles in regulation of the immune system in
mammals. T cell receptor alphabeta T cells that can produce the
cytokine IL-17 are called Th17 cells and form a lineage of effector T
cells that are distinct from Th1, Th2 and FoxP3(+) T cells. The
primary function of Th17 cells is to fight infection by bacterial and
fungal pathogens. Autoreactive Th17 cells are implicated in mediating
inflammation in the central nerves system, joints and other tissues.
Th17 cells express a number of chemokine receptors including a
secondary lymphoid tissue homing receptor (CCR7), the B follicle
homing receptor (CXCR5), and non-lymphoid tissue homing receptors
(CCR4, CCR5, and CXCR6). While these receptors are heterogeneously
expressed by Th17 cells and have the potential to guide the migration
of Th17 cell subsets into various tissues, CCR6 is uniformly expressed
by most Th17 cells regardless of their tissue tropism. CCR6 plays an
important role in migration of Th17 cells to inflamed tissues. Another
function of CCR6 is to localize Th17 cells close to CCL20 expressing
cells in the intestine, which would be important for the homeostasis
of Th17 cells. Thus, chemokine receptors appear to play complex roles
in the biology of Th17 cells.
PMID: 19601882
For the next two:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=CXCR6%2B+Th17&log$=activity
In the mean time:
http://en.wikipedia.org/wiki/CXC_chemokine_receptors
http://en.wikipedia.org/wiki/CXCR6
Symbols CXCR6; BONZO; CD186; STRL33; TYMSTR
C-X-C chemokine receptor type 6 is a protein that in humans is encoded
by the CXCR6 gene.[1][2][3]
CXCR6 has also recently been designated CD186 (cluster of
differentiation 186).
<snip>
Bonzo? LOL
http://en.wikipedia.org/wiki/CXCL16
Alt. symbols SCYB16, SR-PSOX, CXCLG16
Chemokine (C-X-C motif) ligand 16 (CXCL16) is a small cytokine
belonging to the CXC chemokine family. Larger than other chemokines
(with 254 amino acids), CXCL16 is composed of a CXC chemokine domain,
a mucin-like stalk, a transmembrane domain and a cytoplasmic tail
containing a potential tyrosine phosphorylation site that may bind SH2.
[1] These are unusual features for a chemokine, and allow CXCL16 to be
expressed as a cell surface bound molecule, as well as a soluble
chemokine.[2] CXCL16 is produced by dendritic cells found in the T
cell zones of lymphoid organs, and by cells found in the red pulp of
the spleen.[1] Cells that bind and migrate in response to CXCL16
include several subsets of T cells, and natural killer T (NKT) cells.
[1] CXCL16 interacts with the chemokine receptor CXCR6, also known as
Bonzo.[3][1] Expression of CXCL16 is induced by the inflammatory
cytokines IFN-gamma and TNF-alpha.[2] The gene for human CXCL16 is
located on chromosome 17.[1]
<sniP>
So we expand the Th17 and cxc search:
And we expand the cxc and psoria* (103 hits pubmed)
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=CXC*+AND+psoria*&log$=activity
And CXCL + psoria* (80 hits on pubmed)
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=CXCL*+AND+psoria*&log$=activity
And CXCL11 + psoria* (11 hits on pubmed)
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=CXCL11+AND+psoria*&log$=activity
Front loaded for IFN expression? Another inflammation hair trigger?
30 hits on pubmed: CXC* AND IFN AND psoria*
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=CXC*+AND+IFN+AND+psoria*&log$=activity
=============
http://www.ncbi.nlm.nih.gov/pubmed/20223157
Actas Dermosifiliogr. 2010 Mar;101(2):151-155.
Production of interleukin-8 by circulating CLA+ T cells with skin
tropism in patients with psoriasis and in healthy controls.
Ferran M, Ferran M, Galván AB, Giménez-Arnau A, Giménez-Arnau A, Pujol
RM, Pujol RM, Santamaría-Babi LF, Santamaría-Babi LF.
Servicio de Dermatología, Hospital del Mar-IMIM, Barcelona, España.
BACKGROUND: Psoriasis is an immune-mediated disease typically
associated with cutaneous neutrophilic infiltration and Munro
microabscesses. Interleukin (IL)-8 is one of the main neutrophil-
attracting chemokines. Although keratinocytes have traditionally been
considered to be the principal source of IL-8 in psoriasis, we present
data that suggest that cutaneous lymphocyte associated antigen (CLA) +
T lymphocytes synthesize this cytokine. MATERIAL AND METHODS: Six
patients with psoriasis and 6 healthy controls were studied.
Immunomagnetic separation was used to isolate CLA+ and CLA- T
lymphocytes and IL-8 and interferon (IFN)-gamma production was
quantified for each cell subpopulation using enzyme-linked
immunosorbent assay. Finally, gene expression of IL-8 was analyzed by
reverse transcriptase-polymerase chain reaction. RESULTS: CLA+ and
CLA- T lymphocytes from patients with psoriasis and from controls
showed a significantly increased production of IFN-gamma when
activated, whereas only activated CLA+ T lymphocytes (from patients
and controls) synthesized IL-8. The higher level of expression of IL-8
and IFN-gamma by CLA+T lymphocytes in comparison to CLA- cells was
confirmed. DISCUSSION: Previous studies have confirmed IL-8 production
by T lymphocytes in inflammatory skin diseases with neutrophil-rich
infiltrates, such as acute generalized exanthematous pustulosis,
Behçet disease, and pustular psoriasis. We have confirmed the role of
the subset of T lymphocytes with skin tropism (CLA+) in IL-8
production in nonpustular psoriasis.
PMID: 20223157
Other ways to skew Th1 and 2:
http://www.eurekalert.org/pub_releases/2010-03/uop-pri031110.php
Penn researchers identify immune cells that fight parasites may
promote allergies and asthma
PHILADELPHIA –- Millions of people in both the developing and
developed world may benefit from new immune-system research findings
from the University of Pennsylvania School of Veterinary Medicine.
The Penn Vet researchers, studying how the immune system operates,
have discovered a previously unidentified cell population that may be
the body's double-edged sword, fighting off parasitic infections but
also causing the harmful immune responses that can lead to allergies
and asthma.
This cell population, termed multipotent progenitor cells, or MPP,
appears to be activated in the context of allergies or infection with
parasitic worms and may be one of the earliest cellular events in the
developing immune response. The research published by David Artis,
assistant professor in the Department of Pathobiology at Penn Vet, and
colleagues may identify an important process in the immune response to
helminth parasites and allergies.
A better understanding of what regulates the development of this cell
population and what promotes its activation and function may aid in
the development of drugs.
The research could benefit two patient populations: Those in
developing countries still wrestling with parasitic worm infections
and those in more industrialized environments where parasites are less
prevalent but where immune responses can run amok, leading to a higher
prevalence of allergies and asthma.
Millions worldwide struggle with health problems due to parasitic
worms. These helminth worm parasites thrive in unsanitary conditions,
in uncooked meat and in contaminated water. In more sanitary regions
with fewer helminth parasites, the immune response that evolved to
fight these infections may be redundant. It has been proposed that,
due to reduced exposure to helminth parasites, the inactive immune
response may inappropriately respond to substances like pollen,
pollutants and some contents of food, resulting in exaggerated rates
of asthma and allergy.
The National Institutes of Health estimates that as many as 40 to 50
million Americans suffer from allergic diseases. Consistent with this
theory of redundancy, there are reports that show equatorial regions
with an abundance of helminth parasites have populations that
encounter lower rates of asthma and allergies.
"From an evolutionary perspective, it is likely that we evolved a
complex immune response to fight parasitic worms, but our more
sanitized environment no longer has this same population of
parasites," Artis said. "This newly identified cell population could
represent one of the earliest events in this type of immune response,
which offers potential new targets for treatment of infection and
allergic inflammation."
The research team demonstrated that a molecule called IL25, a member
of the IL17 cytokine family, promotes the accumulation of a lineage-
negative multipotent progenitor cell population in the intestine that
promotes T cell responses associated with asthma and helminth
infection. The resulting cell population gives rise to cells of
macrophage and granulocyte lineages. The ability of IL25 to induce the
emergence of an MPP cell population identifies a link between the IL17
cytokine family and extramedullary haematopoiesis and suggests a
previously unrecognized innate immune pathway that promotes TH2
cytokine responses at mucosal sites.
<snip>
What exactly are mmp's (multipotent progenitor cells)?
http://en.wikipedia.org/wiki/Multipotency
And their wormy why does it haPPen abstract?
OK,
http://www.ncbi.nlm.nih.gov/pubmed/20200520
Nature. 2010 Mar 3.
IL25 elicits a multipotent progenitor cell population that promotes
T(H)2 cytokine responses.
Saenz SA, Siracusa MC, Perrigoue JG, Spencer SP, Urban Jr JF, Tocker
JE, Budelsky AL, Kleinschek MA, Kastelein RA, Kambayashi T, Bhandoola
A, Artis D.
Department of Pathobiology.
CD4(+) T helper 2 (T(H)2) cells secrete interleukin (IL)4, IL5 and
IL13, and are required for immunity to gastrointestinal helminth
infections. However, T(H)2 cells also promote chronic inflammation
associated with asthma and allergic disorders. The non-haematopoietic-
cell-derived cytokines thymic stromal lymphopoietin, IL33 and IL25
(also known as IL17E) have been implicated in inducing T(H)2 cell-
dependent inflammation at mucosal sites, but how these cytokines
influence innate immune responses remains poorly defined. Here we show
that IL25, a member of the IL17 cytokine family, promotes the
accumulation of a lineage-negative (Lin(-)) multipotent progenitor
(MPP) cell population in the gut-associated lymphoid tissue that
promotes T(H)2 cytokine responses. The IL25-elicited cell population,
termed MPP(type2) cells, was defined by the expression of Sca-1 (also
known as Ly6a) and intermediate expression of c-Kit (c-Kit(int)), and
exhibited multipotent capacity, giving rise to cells of monocyte/
macrophage and granulocyte lineages both in vitro and in vivo. Progeny
of MPP(type2) cells were competent antigen presenting cells, and
adoptive transfer of MPP(type2) cells could promote T(H)2 cytokine
responses and confer protective immunity to helminth infection in
normally susceptible Il25(-/-) mice. The ability of IL25 to induce the
emergence of an MPP(type2) cell population identifies a link between
the IL17 cytokine family and extramedullary haematopoiesis, and
suggests a previously unrecognized innate immune pathway that promotes
T(H)2 cytokine responses at mucosal sites.
PMID: 20200520
And ONLY 25 hits for IL25 so far on pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=IL25&log$=activity
And induces a Th2 skew which could balance out our Th1 response one
may suppose.
http://www.ncbi.nlm.nih.gov/gene/64806?
====================
http://www.ncbi.nlm.nih.gov/pubmed/20218931
Expert Opin Ther Pat. 2010 Mar 11.
Itk inhibitors: a patent review.
Lo HY.
Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd,
Ridgefield, CT 06877, USA +1 203 798 4923 ; +1 203 791 6072 ; ho-
yin...@boehringer-ingelheim.com.
Importance of field: IL-2 inducible T-cell kinase (Itk) is a non-
receptor tyrosine kinase of the Tec family. It plays an important role
in T cell signaling and the production of various pro-inflammatory
cytokines such as IL-2, IL-4, IL-5, IL-10 and IL-13. Inhibition of Itk
has been a target for the treatment of diseases related to
inflammation disorders such as psoriasis and allergic asthma. Rich
resources on the structural information for Itk made discovery of
novel selective Itk inhibitors blossom in the past decade. Areas
covered in this review: In this report, distinct structural classes of
specific Itk inhibitors are summarized and their in vitro/in vivo
properties are discussed. What the reader will gain: A summary of 21
patents including 16 different chemical structure classes of Itk
inhibitors. The in vivo efficacies of some of the inhibitors in animal
models are also discussed. Take home message: Although some of the
inhibitors show efficacy in different animal models, which implies
potential for therapeutic use in human, there is not yet a chemical
entity reported in clinical trials. The prospects for Itk inhibitors
will rely on the quality of the compound and the validity of the
target in patients within the selected therapeutic area.
PMID: 20218931
http://en.wikipedia.org/wiki/ITK_(gene)
IL2-inducible T-cell kinase, also known as ITK, is a protein which in
humans is encoded by the ITK gene.[1]
Function
This gene encodes an intracellular tyrosine kinase expressed in T-
cells. The protein is thought to play a role in T-cell proliferation
and differentiation.[2][3]
Structure
This protein contains the following domains, which are often found in
intracellular kinases:[4]
N-terminus – PH (pleckstrin homology domain)
BTK – Bruton's tyrosine kinase Cys-rich motif
SH3 – (Src homology 3)
SH2 – (Src homology 2)
C-terminus – tyrosine kinase, catalytic domain
<sniP>
REACTs with:
http://en.wikipedia.org/wiki/FYN
http://en.wikipedia.org/wiki/Linker_of_activated_T_cells
[...]
Function
The protein encoded by this gene is phosphorylated by ZAP70/SYK
protein tyrosine kinases following activation of the T-cell antigen
receptor (TCR) signal transduction pathway. This transmembrane protein
localizes to lipid rafts (also known as glycosphingolipid-enriched
microdomains or GEMs) and acts as a docking site for SH2 domain-
containing proteins.[3] Upon phosphorylation, this protein recruits
multiple adaptor proteins and downstream signaling molecules into
multimolecular signaling complexes located near the site of TCR
engagement.[2]
<snip>
http://en.wikipedia.org/wiki/PLCG1
http://en.wikipedia.org/wiki/Lymphocyte_cytosolic_protein_2
http://en.wikipedia.org/wiki/KHDRBS1
http://en.wikipedia.org/wiki/Wiskott-Aldrich_syndrome_protein
<plus others>
randall.... bored cept for that eLOVL gene...
JRStern
wrote:
>Hi,
>
>
>
>What's in your genes that ISN'T in someone's without psoriasis?
No, I don't think that's what it says.
I think they took skin samples from one person in clear and psoriasis
areas and compared those.
>http://www.ncbi.nlm.nih.gov/pubmed/20220767
>J Invest Dermatol. 2010 Mar 11.
>
>Assessment of the Psoriatic Transcriptome in a Large Sample:
>Additional Regulated Genes and Comparisons with In Vitro Models.
>
>Gudjonsson JE, Ding J, Johnston A, Tejasvi T, Guzman AM, Nair RP,
>Voorhees JJ, Abecasis GR, Elder JT.
>
>Department of Dermatology, University of Michigan Medical School, Ann
>Arbor, Michigan, USA.
>
>To further elucidate molecular alterations in psoriasis, we performed
>a gene expression study of 58 paired lesional and uninvolved psoriatic
>and 64 control skin samples.
...
J.
randall
> On Sat, 13 Mar 2010 13:32:12 -0800 (PST), randall <ranhu...@aol.com>
> wrote:
>
> >Hi,
>
> >What's in your genes that ISN'T in someone's without psoriasis?
>
> No, I don't think that's what it says.
OK....
>
> I think they took skin samples from one person in clear and psoriasis
> areas and compared those.
OK, now that i ACTUALLY took time to read it. YOUR RIGHT. LOL
> J.
J
Before we go off half cocked, lets think about this.
What does it mean to have expressed versus NON expressed genes for
instance?
http://en.wikipedia.org/wiki/Gene_expression
Which being rather BASIC, we can go directly to:
http://en.wikipedia.org/wiki/Epigenetics
I would go even beyond to:
http://en.wikipedia.org/wiki/Epigenetics#Evolution
And this being even.... gruntingly slow.... like a bad Bm...
wE can do this:
Why your DNA isn't your destiny
http://www.time.com/time/health/article/0,8599,1951968,00.html
(Your thinking is in the matrix read this and escaPe. no
really...LOL)
OK we look at those genes uPregulated and down regulated in that
abstract.
For grins of course.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&term=(serpinb4[gene])
AND (Homo sapiens[orgn]) AND alive[prop] NOT newentry[gene]&log
$=genesensor5&logdbfrom=pubmed&sort=weight
SERPINB4
http://www.ncbi.nlm.nih.gov/gene/6318?ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum
SERPINB4
provided by HGNC
Official Full Name serpin peptidase inhibitor, clade B (ovalbumin),
member 4
[...]
Homo sapiens
Lineage Eukaryota; Metazoa; Chordata; Craniata; Vertebrata;
Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates;
Haplorrhini; Catarrhini; Hominidae; Homo
Also known as PI11; SCCA1; SCCA2; LEUPIN; SCCA-2; SERPINB4
<sniP>
Nothing is sending up fireworks regarding SRPINB4.
Let's look on pubmed and see.
What we see.
I only see six boring hits including the one we cited. :(
Do what then?
http://en.wikipedia.org/wiki/SERPINB4
Serpin B4 is a protein that in humans is encoded by the SERPINB4 gene.
[1][2][3]
And maybe more can be had here:
http://en.wikipedia.org/wiki/Serpin
Other then avoiding SCC and inflammation in general, i'm not seeing
IT.
http://en.wikipedia.org/wiki/Serpin#Serpins.2C_serpinopathies_and_human_disease
===================
I guess we LOOK at strongly uPregulated PI3.
Nine hits for PI3 + psoria* on pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=PI3+psoria*&log$=activity
And NO WONDER i LOVE resveratrol. it inhibits PI3.
Good work resveratrol. LOL
http://www.ncbi.nlm.nih.gov/pubmed/20012470
Mol Cell Biochem. 2010 Apr;337(1-2):201-12. Epub 2009 Dec 11.
FOXO transcription factors and VEGF neutralizing antibody enhance
antiangiogenic effects of resveratrol.
Srivastava RK, Unterman TG, Shankar S.
Department of Pharmacology, Toxicology and Therapeutics, The
University of Kansas Medical Center, Kansas City, KS, 66160-7410, USA.
Resveratrol (trans-3,5,4'-trihydroxystilbene), a compound found
largely in the skins of red grapes and wines, possesses anti-cancer
and anti-angiogenic properties and protects the cardiovascular system.
However, the molecular mechanisms by which resveratrol inhibits
angiogenesis are currently subjects of intense investigation. The
purpose of this study was to examine whether FOXO transcription
factors mediate anti-angiogenic effects of resveratrol, and whether
vascular endothelial growth factor (VEGF) neutralizing antibody can
enhance these effects of resveratrol. Inhibition of PI3 kinase (PI3K)/
AKT and MEK/ERK pathways synergistically inhibited migration and
capillary tube formation of Human Umbilical Vein Endothelial Cells
(HUVECs) and further enhanced the anti-angiogenic effects of
resveratrol. Inhibitors of AKT and MEK kinase synergistically
inhibited cytoplasmic FOXO3a phosphorylation, which was accompanied by
its nuclear translocation in HUVECs. Interestingly, inhibition of PI3K/
AKT and MEK/ERK pathways synergistically induced FOXO transcriptional
activity and inhibited cell migration and capillary tube formation.
Antiangiogenic effects of resveratrol were enhanced by inhibitors of
AKT and MEK. Phosphorylation-deficient mutants of FOXOs induced FOXO
transcriptional activity, inhibited HUVEC cell migration, and
capillary tube formation, and also enhanced antiangiogenic effects of
resveratrol. Finally, VEGF neutralizing antibody enhanced the anti-
proliferative and anti-angiogenic effects of resveratrol. In
conclusion, regulation of FOXO transcription factors by resveratrol
may play an important role in angiogenesis which is critical for
cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, and
cardiovascular disorders.
PMID: 20012470
I guess we look closer at PI3 now.
http://en.wikipedia.org/wiki/Phosphoinositide_3-kinasPhosphoinositide
3-kinases (PI 3-kinases or PI3Ks) are a family of enzymes involved in
cellular functions such as cell growth, proliferation,
differentiation, motility, survival and intracellular trafficking,
which in turn are involved in cancer.
PI3Ks are a family of related intracellular signal transducer enzymes
capable of phosphorylating the 3 position hydroxyl group of the
inositol ring of phosphatidylinositol (PtdIns).[2] They are also known
as phosphatidylinositol-3-kinases. The pathway, with oncogene PIK3CA
and tumor suppressor PTEN (gene) is implicated in insensitivity of
cancer tumors to insulin and IGF1, in calorie restriction.[3][4]
[...]
http://en.wikipedia.org/wiki/Phosphoinositide_3-kinase#PI_3-kinases_as_protein_kinases
OK, close enough.
============
DEFB4
So we look at related articles for psoriais and DEFB4
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=20220767
380 hits for DEFB4
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=DEFB4&log$=activity
And 28 of these 380 hits have keyword: psoria*
There is a TON of info to be gleaned in this search:
This is interesting:
http://www.ncbi.nlm.nih.gov/pubmed/20152900
J Steroid Biochem Mol Biol. 2010 Feb 10.
1alpha-Hydroxylase and innate immune responses to 25-hydroxyvitamin D
in colonic cell lines.
Lagishetty V, Chun RF, Liu NQ, Lisse TS, Adams JS, Hewison M.
Department of Orthopaedic Surgery, David Geffen School of Medicine,
University of California Los Angeles, Los Angeles, CA 90095, USA.
Vitamin D-insufficiency is a prevalent condition in populations
throughout the world, with low serum levels of 25-hydroxyvitamin D
(25OHD) linked to a variety of human health concerns including cancer,
autoimmune disease and infection. Current data suggest that 25OHD
action involves localized extra-renal conversion to 1,25-
dihydroxyvitamin D (1,25(OH)2D) via tissue-specific expression of the
enzyme 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-hydroxylase). In
cells such as macrophages, expression of 1alpha-hydroxylase is
intimately associated with toll-like receptor (TLR) recognition of
pathogens. However, this mechanism may not be exclusive to extra-renal
generation of 1,25(OH)2D. To investigate the relationship between TLR-
mediated pathogen recognition and vitamin D-induced antibacterial
activity, intracrine responses to 25OHD metabolism were explored in
vitro using the established colonic cell lines Caco-2 and Caco-2 clone
BBe. Analysis of antibacterial factors such as cathelicidin (LL37) and
beta-defensin-4 (DEFB4) was carried out following co-treatment with
TLR ligands. Data indicate that, unlike macrophages, Caco-2 and BBe
colonic cell lines are unresponsive to TLR-induced 1alpha-hydroxylase.
Alternative activators of 1alpha-hydroxylase such as transforming
growth factor beta were also ineffective at priming intracrine
responses to 25OHD. Thus, in common with other barrier sites such as
the skin or placenta, colonic epithelial cells may require specific
factors to initiate intracrine responses to vitamin D. Copyright ©
2010 Elsevier Ltd. All rights reserved.
PMID: 20152900
And besides the LL37 LINKAGE, we have crohn's in this next one.
http://www.ncbi.nlm.nih.gov/pubmed/19809410
Am J Gastroenterol. 2010 Feb;105(2):354-9. Epub 2009 Oct 6.
Association of higher DEFB4 genomic copy number with Crohn's disease.
Bentley RW, Pearson J, Gearry RB, Barclay ML, McKinney C, Merriman TR,
Roberts RL.
Department of Pathology, University of Otago, Christchurch, New
Zealand. robert....@otago.ac.nz
Comment in:
Am J Gastroenterol. 2010 Feb;105(2):360-2.
OBJECTIVES: Human beta-defensin 2 (hBD-2 or DEFB4) is a highly
inducible, antimicrobial peptide, which may have an important role in
the innate immune response at epithelial surfaces. Genomic copy number
of DEFB4 is polymorphic, with most individuals possessing 3-5 copies.
Increased DEFB4 copy number is a susceptibility factor for psoriasis,
whereas a single study in a Crohn's disease (CD) cohort reported that
decreased DEFB4 copy number is associated with colonic inflammation.
Here, we analyze association of DEFB4 copy number with CD in a New
Zealand case-control cohort of European origin. METHODS: DEFB4 gene
copy number was determined using TaqMan quantitative PCR in 466 CD
patients and 329 controls. DNA samples, independently genotyped for
DEFB4 copy number by alternative methods, were used to validate the
assay. RESULTS: Increased DEFB4 genomic copy number was seen in CD
patients compared with controls. Individuals with >4 copies had a
significantly higher risk of developing CD than those with <4 copies
(odds ratio 1.54; 95% confidence interval 1.13-2.09, P=5e-05). DEFB4
genomic copy number did not differ by disease location within the CD
cohort (P=0.948), nor did analysis of CD patients who had undergone
surgery detect association of decreased DEFB4 genomic copy number (<4)
in colonic CD compared with ileal CD (P=0.120). CONCLUSIONS: Our
results indicate that elevated DEFB4 copy number is a risk factor for
CD (irrespective of intestinal location), and challenge previous data
supporting positive association of lower DEFB4 genomic copy number
with colonic CD.
PMID: 19809410
============
OK, so I'm really looking at that last one and it being uPregulated
screws us pretty good.
What's down regulated?
How about wIF1 next.
http://en.wikipedia.org/wiki/WIF1
Wnt inhibitory factor 1 is a protein that in humans is encoded by the
WIF1 gene.[1][2]
WNT proteins are extracellular signaling molecules involved in the
control of embryonic development. This gene encodes a secreted
protein, which binds WNT proteins and inhibits their activities. This
protein contains a WNT inhibitory factor (WIF) domain and 5 epidermal
growth factor (EGF)-like domains. It may be involved in mesoderm
segmentation. This protein is found to be present in fish, amphibia
and mammals.[2]
<sniP>
This sounds important:
**5 epidermal growth factor (EGF)-like domains**
But if this
http://en.wikipedia.org/wiki/Wnt_signaling_pathway
was downregulated wouldn't we get more cancer? And
I can't see a thing in the pathway leading to or away
from any psoriasis pathway:
http://en.wikipedia.org/wiki/File:Signal_transduction_pathways.png
Ok back to pubmed:
Wif1 -- 102 hits on pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=wif1&log$=activity
OK, so maybe folks with a Th1 skew are protected from cancer by a WIF1
down regulation?
I haven't a clue otherwise. LOL
===========
Next is beta-cellulin (BTC)
With a total of three hits in pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=beta-cellulin+AND+(BTC)&log$=activity
But with beta-cellulin we get 15 hits on pubmed.
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=beta-cellulin&log$=activity
===========================
randall.... boy was that fun or what?