Superantigens
Pete
Superantigens - Concepts, clinical disease and therapy
Indian Journal of Medical Microbiology
Year : 2004 | Volume : 22 | Issue : 4 | Page : 204-211
Hemalatha V, Srikanth P, Mallika M
Department of Microbiology, Sri Ramachandra Medical College and Research
Institute, Porur, Chennai - 600 116, India
Abstract
The term superantigen was introduced in microbiology and immunology only
a decade ago. The unique feature of superantigen is that it bypasses the
antigen processing mechanism and specifically binds to TCR v segment and
forms a trimolecular complex along with major histocompatibility complex
class II. Since its discovery, several studies have been carried out to
unravel the properties of superantigens. They are implicated in the
pathogenesis of diseases of bacterial, viral and fungal origin. They are
also known to play a role in autoimmune diseases. Therapy for these
superantigens is being worked upon. Studies have shown that intravenous
gamma globulin containing specific antibodies to these superantigens
inhibits the activation of T-Cells and also the cytokine production by
them resulting in dramatic recovery from superantigen mediated diseases.
The use of superantigen in the therapy of cancer is being explored.
Full Text
Historically, as early as1960, the US weaponised staphylococcal
enterotoxin as incapacitating biological element.[1] When given by
inhalational route, much lower quantities produced the desired
incapacitating effects than with synthetic chemicals. The clinical
effects were fever, malaise, myalgia, respiratory symptoms like cough,
dyspnoea and gastrointestinal symptoms.[1] But the exact pathogenesis of
these staphylococcal enterotoxins and their superantigenic property was
not known then. Only in 1990, Kappler and Marrack coined the term
superantigen and its properties were described.[2] Following this, other
types of superantigens, having characteristic property, were described.
One such antigen was a B cell ''superantigen'' which stimulated the B
cells as exemplified by the gp 120 moiety of human immmunodeficiency
virus (HIV).[3] This is believed to be due to binding of gp 120 moeties
to v(H) immunoglobulin family.[3] Another set of antigens called prenyl
pyrophosphate antigens, which stimulated the T cells were also
discovered.[4]
However, superantigens, which selectively bind the v element of T cell
receptor, are of primary interest today. These superantigens escape the
conventional antigen processing mechanism and selectively bind to TCR v
region and MHC class II molecule.[5] This superantigen family includes
bacterial, viral and fungal components. They are also known to play a
role in allergy and autoimmune mechanisms. Superantigens can be broadly
classified as exogenous - comprising bacterial toxins and
endogenous -comprising virally encoded superantigens. Endogenous
superantigens have not been identified so far in humans.
The aim of this article is to review the recent concepts in
superantigens - its structure, biological effects, the immunological
response of the host and to elucidate the role of superantigens in the
pathogenesis of superantigen mediated diseases. The changing concepts
over the last decade have resulted in the use of different modalities in
the therapy of diseases such as toxic shock syndrome [TSS] and Kawasaki
syndrome and also the use of genetically engineered superantigen in the
therapy of cancer. Other aspects such as isolation and detection of
superantigens have also been dealt with in this review.
T-cell receptor and superantigen
Knowledge of the structure of a TCR is important in understanding the
site of antigen binding of a conventional antigen vis-à-vis a
superantigen. TCR is a heterodimer composed either of and chains or of
and chains. chain has three regions coded by three different genetic
segments - variable V, junctional J and diversity D,while the chain
consists of four regions - variable, junctional, diversity and constant
regions. The germ line TCR gene locus consists of 20-30 variable
regions. The variable region of this chain is our main focus since this
is the site where the superantigen binds. Conventionally, both v and v
regions of TCR interact with the antigenic peptide whereas only the v
region is used for the superantigen interaction.[5] The basic difference
between a conventional antigen and a superantigen is that the former
after antigen processing interacts with both v and v regions of TCR
while the latter bypasses the antigen processing mechanism and interacts
only with TCR v region. As a result, a specific antigen can stimulate
only a small amount of T cells while a superantigen can stimulate a
large clone of T cells. Therefore, the action of a specific antigen is
MHC restricted and that of superantigen is not MHC restricted.[5] The
differences between a conventional antigen and a superantigen are
highlighted in [Figure:1].
Structure and biological effects of superantigen
The structure of a superantigen contributes to its biological
properties. Superantigens are medium sized 22-29 kDa globular compact
proteins. Structurally they all show conserved 2-domain architecture (N
and C terminal domains and helix in the center of the molecule). The N
terminal domain is characterized by presence of hydrophobic residues in
solvent exposed regions and determines the lethality of the toxin. C
terminal domain has four stranded sheet capped by the central helix and
determines the superantigenicity of the toxin.[6] Another common feature
is the presence of disulphide loop formed by the cystinyl residues
(except in TSST - I) in the N terminal domain, which is implicated in
the emetic properties of the enterotoxins. Subtle differences in the
structures of different superantigens [Figure:2]a and [Figure:2]b result
in varied biological effects. The chain of HLADR I is involved in the
bindings of most of the superantigens. But in the case of TSST- I, the
chain of DR I molecule is involved in binding. Also TSST-I binds in the
presence of a peptide antigen so that a trimolecular complex is formed
with chain of HLADR1, peptide antigen and TSST-I.[6] TSST-I does not
possess any extrastructural characters [Figure:2]a and so gets cleaved
by pepsin, therefore, has no role in the causation of staphylococcal
food poisoning. Its unique property of mucosal invasion plays a role in
the causation of a systemic disease like TSS.[7] Staphylococcal
enterotoxins (SE) and Streptococcal pyrogenic superantigens (SPE) have
extra structural characters like lengthy amino terminal [Figure:2]b,
which help them to resist the peptide digestion in the stomach resulting
in Staphylococcal food poisoning. The presence of cystinyl residues in
SEs and SPEs contribute to their emetic property, which TSST-I lacks.
The emetic property of the former can also be due to their
enterotoxigenic activity.[6] Zinc and histidine ions are also known to
play a role in this interaction of superantigens.[6]
A superantigen with a difference
Recently it has been found that Mycoplasma arthritidis mitogen (MAM)
interacts with the TCR v region not just at complimentarity determining
region (CDR) 1 and 2 (which are germline coded) but also at CDR3, which
is generated by somatic mutation. As a result, MAM does not produce a
characteristic superantigen v signature or massive T cell expansion.[8]
Thus it appears that v expansion may not be the only mechanism of action
of superantigens in the pathogenesis of diseases and that some
superantigens may lack the v signature itself and yet plays a role in
the pathogenesis of infections.[8]
Effects of superantigen stimulation
Following the interaction of superantigen with the v region a large
number of T cells are stimulated resulting in elaborate production of
cytokines involved in various inflammatory processes associated with the
disease. For e.g., the expression of IL - I and TNF bring about the
vascular endothelial injury in TSS.[9] The expression of IL- 6, GM-CSF
and E-selectin elicit pro-inflammatory and prothrombic responses in
Kawasaki syndrome.[10] The interaction of superantigen with T cell can
also perform an inhibitory function as anergy, deletion and suppression.
The repetitive application of small amounts of superantigen leads to
deletion of specific v repertoire without initial proliferation for
example, in case of endogenous superantigens like HIV gp 120, the viral
encoded superantigen leads to deletion of specific v T cell
population.[11]
Apoptosis of v bearing T cells is another effect brought about by
increased FAS expression induced by superantigens. The presence and the
type of cytokines, which modulate this T cell immune response, govern
apoptosis. For example, IFN is supposed to prevent apoptosis in
superantigen treated cells.[12]
Superantigens have property of enhancing the endotoxin activity by
100,000 folds in rabbits.[13] This enhancement causes the release of
monokines like TNF , which contributes to the endothelial toxicity. The
endotoxin superantigen synergy has a clinical impact in two ways.
Firstly, the circulation of bacterial superantigens reduces the
threshold of endotoxicity to an extent that circulation of endogenous
endotoxins may be sufficient to contribute to shock. Secondly,
coexistence of gram positive and gram negative organisms, even as
colonisation in critically ill patients, may through this synergy of
endotoxin and superantigen, result in shock in the absence of typical
focus of bacterial infection.[14]
Superantigens and clinical disease
Superantigens are being implicated in pathogenesis of several diseases
of bacterial, viral and few of fungal origin [Table:1]. Some examples
are discussed below.
Bacterial superantigens
Toxic shock syndrome
Toxic shock syndrome is an acute fatal illness characterized by high
fever; diffuse erythematous rash, desquamation of skin 1-2 weeks after
the onset, hypotension and involvement of three or more organ
systems.[9] The absence of detectable bacteraemia in TSS suggested the
role of toxins produced by the organisms. Both Staphylococcus aureus and
Streptococcus pyogenes can cause TSS.
TSST-I is the major toxin producing TSS.[9] It is isolated in all cases
of TSS associated with tampon usage. Staphylococcal enterotoxins A, B, C
are also isolated in minority of cases not associated with tampon usage.
TSST-I production needs certain conditions like the presence of an
animal protein, low levels of glucose, temperature of 37-400 C, pH
6.5-8.0 and oxygen. In a normally anaerobic vagina, the hyper absorbable
tampons introduce good oxygenation favoring TSST-I production by the
colonising S.aureus. TSS can also occur in the absence of tampon usage.
This is due to the proteases produced by the colonizing S.aureus, which
bring about the proteolytic cleavage of menstrual blood releasing
sufficient oxygen. This phenomenon favours TSST-I production and thus
the initiation of the disease.[9]
Due to its inherent ability to cross the mucosal surface TSST-I enters
the systemic circulation and stimulates the T cells bearing v 2 subsets.
This results in the release of cytokines like IL-1, IL-2, IFN- and TNF ,
which cause the capillary leakage inducing hypotension.[15] Also the
inherent property of TSST-I to enhance the endogenous endotoxin activity
causes the release of monokines like TNF resulting in endothelial cell
death. In low doses, TSST-I is not cytotoxic but causes the release of
albumin resulting in hypotension. TSST-I induces the expression of
glucocorticoid receptor - an endogenous inhibitor of classic
glucocorticoid receptor suggesting superantigen induced glucocorticoid
resistance.[15] TSST-I also renders the normal peripheral mononuclear
cells highly resistant to dexamethasone.[16] Hence steroids are not used
for the treatment of TSS. The first case of TSS due to Streptococcus was
reported in 1987.[17] Several virulence factors of S.pyogenes like
streptococcal pyrogenic toxins A, B, C and exotoxin F and several other
novel streptococcal superantigens, including streptococcal mitogenic
exotoxin Z (SMEZ), SMEZ-2, SPE-G, SPE-H,[18] SPE-J, and SPE-I.[19] All
these possessing typical superantigen features with high mitogenic
potential on human T cells are likely to be involved in the
pathogenesis. These virulence factors stimulate T cells resulting in
elaborate production of cytokines like TNF and IFN which contribute to
invasion of soft tissues and skin and necrotizing fascitis of TSS.[17]
Food poisoning
Staphylococcal enterotoxins A, B, C, D, E and H are implicated in the
causation of staphylococcal food poisoning.[9] The disease is
characterized by emesis with or without diarrhea and results from
ingestion of one or more preformed toxins or food contaminated with
S.aureus. Systemic manifestations like fever and hypotension is rare.
The action of superantigen leads to elaborate production of cytokines,
which act as inflammatory mediators resulting in inflammation of the gut
mucosa with neutrophilic infiltrates. The source of these inflammatory
mediators is undetermined. Some studies identify the mast cells
secreting substance p as the source in the manifestation of food
poisoning.[9]
Atopic dermatitis
Superantigen secreting S.aureus has been isolated from patients with
atopic dermatitis (AD). Out of 74 patients, 53% of them were proven to
have been colonized by TSST-I producing S.aureus.[20]
The superantigen involved penetrates the inflamed skin and binds with
langerhan cells, the professional antigen presenting cell of the skin,
stimulating the release of cytokines like IL- I, TNF, IL-12. IL-1 and
TNF induce the expression of E- selection on vascular endothelium
allowing an influx cutaneous lymphocytic antigen memory effector cells.
IL -12 secreted by the T cells in response to superantigen effect
migrates to the skin associated lymph nodes and upregulate the
expression of cutaneous lymphocytic antigen and stimulate the virgin T
cells. The combination of both the memory and effector cells amplifies
the process of AD.[21] Drugs against Staphylococcus have been found
effective in chronic AD. Superantigens also augment allergen specific
IgE response and induce corticosteroid resistance suggesting that
several mechanisms exist by which superantigen could aggravate the
severity of AD. Studies have shown that patients who suffered from TSS
also developed chronic eczematoid dermatitis whereas no patients
recovering from grams negative sepsis had AD. Malassezia furfur has also
been implicated in the pathogenesis of AD.[21] It will be discussed
under fungal superantigens. Recent studies have found that superantigens
also play a role in allergic rhinitis and sinusitis.[22]
Kawasaki syndrome
Kawasaki syndrome is an acute febrile illness associated with multiple
vasculitis primarily affecting infants and young children.[10] TSST-I,
SPE-B and SPE-C have been isolated from different anatomic sites of
these patients.[10] These strains were mainly from the mucosal
colonisation of gastrointestinal tract. The toxin produced by them is
absorbed via the mucosal surface and results in the stimulation of the
local and circulating T cells and mononuclear cells. This is followed by
the production of cytokines like IL-1, IL-6, IL-10, GM-CSF and
E-SELECTIN that bring about the proinflamatory and prothrombic
responses. This ultimately leads to the endothelial cell activation
accompanied by infiltration of activated CD4 and CD8 cells as well as
the monocytes and macrophages resulting in the initial vascular insult
in kawasaki syndrome.[10]
The involvement of a superantigen is supported by the expansion of v 2 T
cells to a greater extent and v 8 T cells in minority of cases.[10] The
increased levels of T cells decreased with convalesence.
Psoriasis
Toxin producing S.aureus has been isolated from 50% of patients having
psoriasis.[23] Streptococcal throat infection plays an important role in
guttate psoriasis. Skin biopsy of these patients has shown increase in v
bearing T -cells. The probable mechanism is stimulation of skin
keratinocyte, T-cell and monocyte producing keratinocyte proliferation
and endothelial cell activation.[23]
Scalded skin syndrome
It is typically a non-fatal disease of newborns and is characterized by
a specific intraepidermal separation of layers of skin. Exfoliative
toxin of Staphylococcus has been implicated in this disease.[9]
Fungal superantigens
Malassezia furfur has also been described as a pathogen in AD. It is a
lypophilic yeast commonly present in seborrheic areas of skin. IgE
antibodies against M. furfur are commonly found in AD patients.
Antifungal agents have decreased the severity of AD in these
patients.[21]
Viral superantigens
Human immunodeficiency virus (HIV)
HIV is characterized by the selective CD4 cells depletion. The discovery
that the pathogenesis of murine leukemia virus induced immunodeficiency
syndrome in mice was linked to the presence of virally encoded
superantigen lead to the investigation of a similar scenario in HIV
infection.[11] The varied effects in HIV include the following.
Clonal deletion
HIV encoded superantigen, which is expressed on actively infected cells
in conjunction with MHC II molecules, brings about the elimination of
responsive noninfected cells resulting in depletion of cells. Analysis
of v polyelements by PCR revealed that v 14, 15, 16, 17,18,19,20 are the
subsets commonly deleted.[11] Studies were carried out to investigate
whether v depletion was caused directly by HIV or by some of the
opportunistic infections that arise during the disease. The asymptomatic
HIV patients without malignancy or opportunistic infections with CD4
levels Rabies
The nucleocapsid of rabies virus is an exogenous superantigen specific
for v 8 T-lymphocytes, which binds to HLA class 2 chain. The
superantigen activity of the rabies virus resides in the N-protein
component of the nucleocapsid of rabies virus and this can have
considerable effects on vaccine strategy, by producing enormous
neutralizing viral antibodies following its interaction with T cells
(nucleocapsid consists of N, NS and L protein). The expansion of these T
cells is believed to be responsible for the transmission of the virus to
the nerve endings.[25]
Epstein Barr Virus (EBV)
More than 90% of adults are latently infected through out their lifetime
with EBV. In vitro analysis showed that EBV infected B cells stimulated
T cells v 13 family.[26] The evidence of EBV superantigenic activity is
the occurrence of autoimmune disorders like Sjogren syndromes in
patients with EBV disease.
Cytomegalo virus (CMV)
V 7 T cells were found to be increased in CMV disease. But the overall
response is very weak and existence of a superantigen is still in
question.[27]
Acute disseminated encephalomyelitis
It is usually preceded by immunization or by viral or bacterial
infection. Recently, it is thought to be due to autoimmunity mediated by
T- lymphocytes with specificity for myelin antigen such as myelin basic
protein, proteolipid protein, myelinoligodenterocyte and
glycoprotein.[28] The reason is supposed to be a molecular mimicry of
myelin antigen with viral and bacterial peptides (superantigens) derived
from Streptococcus and Staphylococcus spp. and molecular studies have
revealed that v 1, 2, 4 and 10 were expanded.[28]
Superantigens and autoimmunity
The basis of autoimmune disorders due to superantigen is due to greater
stimulation of T-lymphocytes and elaborate cytokine production.[29]
Molecular mimicry of certain peptides to the human protein component may
play a role. As a result of T-cell activation, polyclonal B cells are
also activated leading to autoantibody production resulting in
autoimmunity. Superantigen causes a flare up of disease in patients who
have undergone remission.
Detection of superantigens
Superantigens are stable proteins. The isolation of superantigens is
done as the first step, followed by the methods to detect them.
The organisms producing these superantigens are grown till the
stationary phase in dialyzable beef heart medium with high aeration at
370 C at pH 7-8. All cultures are treated with 4 volumes of cold (40 C)
ethanol to precipitate the toxins. Toxins are then resolubilised in
pyrogen free water and subjected to preparative thin layer isoelectric
focusing first at pH 3-10 and then in a narrow range encompassing the
isoelectric pI of the toxin. The toxin is eluted from the gel and
ampholytes are removed by dialysis. Very small amounts of toxin can be
obtained depending on the type of the toxin.[7] If staphylococcal
enterotoxins enter via the inhalational route, nasal swabs of these
patients taken after 12-24 hours of exposure can yield toxins. This was
the best approach to early diagnosis in cases of biological warfare.
Polymerase chain reaction can detect c-DNA of a specific sequence of the
toxins. Primers are available for DNA sequences of various
staphylococcal and streptococcal toxins. Immunoassays can detect minute
quantities (picograms) of toxins in the environmental samples.[30]
Antibodies to the toxins are very nonspecific since they show lot of
variation in their levels during the course of the disease.[30]
Therefore, this method may not be very specific in confirming the
superantigen-mediated disease. Recently western blot analysis has been
adopted for the detection of streptococcal superantigens in toxic shock
syndrome.[31]
Therapy of superantigen mediated diseases
Antibiotics and supportive therapy may be used in the treatment
depending on the toxin isolated from various samples such as
staphylococcal superantigen in TSS. Antibiotics, especially
clindamycin,[32] is seen to be effective in the treatment of TSS.
Clindamycin downregulates the expression of penicillin binding proteins
and streptococcal M protein, inhibiting bacterial cell wall synthesis
and aiding phagocytosis. Steroids have no role in the therapy as the
superantigen induces the corticosteroid inhibitory receptor and also
renders the peripheral blood mononuclear cells resistant to
dexamethasone.
More recently, patients with TSS appear to benefit with treatment with
pooled intravenous immunoglobulins (IVIG).[33] The use of pooled
intravenous imunoglobulins in the therapy of streptococcal toxic shock
syndrome has been documented to be effective. Though there are no
randomized controlled trials on the use of immunoglobulins in
superantigen mediated disease, in a small study of 21 cases, the use of
IVIG was associated with improved survival when compared with historical
controls.[34] The rationale behind the use of IVIG is that, in early or
persistent low-grade infection IVIG can neutralize the infectious agents
and superantigens by binding to these toxins. IVIG have high titres of
antibodies against the superantigens and these inhibit the T cell
responses in toxin specific manner.[35] Studies conducted in vitro
demonstrated the neutralizing effect of IVIG against eight toxins of
Staphylococcus.[35] They also reduce the cytokine secretion and alter
the cytokine antagonist production. These properties are applied in the
treatment of TSS and Kawasaki syndrome. IVIG is the main stay of
treatment in Kawasaki syndrome. It is effective in preventing the
formation of coronary artery aneurysms in Kawasaki syndrome.[10] They
are also used in the treatment of autoimmune diseases.[36]
Superantigen as a therapeutic agent
Studies have been conducted to design new treatment for tumors.
Genetically engineered staphylococcal enterotoxin A (SEA) was fused with
a Fab fragment specific for tumor cells in the lung of rabbits which
activated 10% of T-cells, almost the strength of activation of a toxic
superantigen, and targeted these cells against antigen positive tumor
cells. Fab fragment specifically bound to these tumor cells while SEA
bound to MHC I on the tumor cells. This stimulated the immune response
against the tumor cells and activated T cells to induce cytotoxicity of
the tumor cells.[37] Another study in human non-small cell lung
carcinoma has shown that the Fab fragment of antibodies against the
oncofetal antigen (antigen commonly seen in many carcinomas), when fused
with the engineered superantigen and directed to the carcinoma cells,
resulted in cytotoxicity in these cells.[37]
Conclusion
More than a decade of research on superantigens has revealed fascinating
facets of its structure, properties and biological effects.
Superantigens can no longer be associated only with the causation of
TSS. Several studies reviewed here have implicated its role in the
pathogenesis of other diseases of bacterial, viral and fungal origin as
well as in autoimmune and allergic disorders. The armamentarium against
superantigens range from antibiotics like clindamycin to the use of IVIG
giving a new dimension to the treatment of infectious diseases.
Superantigen as a therapeutic agent in the treatment of cancer is a
promising aspect to be explored in the future.
References
1Arora DR, Gautam V, Arora B. Biological Warfare: Bio Terrorism. Ind J
Med Microbiol 2002; 20 (1): 6-11.
2Marrack P, Kappler J. Staphylococcal enterotoxins and their relatives.
Science 1990; 248:705-711.
3Neshat MN. Mapping of B cell superantigen binding site for HIV - 1, GP
120 on a V(A)3 gene. Int immunol 2000; 12 (3): 305-12.
4Morita CT, Li H, Lamphear JG, Rich RR, Fraser JD, Mariuzza RA, Lee HK.
Recognition of superantigens by ?d T cell. SEA recognition site for V? 2
T-Cell receptors. Immunity 2001; 14:331-344.
5Imboden JB, Seaman WE. T lymphocytes and natural killer cells in
Medical Immunology 10 th ed. (Eds.) DP Stites, AI Terr, TG Parslow.
(Inc. Appleton and Lange) 2001.132.
6Earhart CA, Mitchell DT, Murray DL Shlievert PM, Ohlendorf DH. TSST -
I: molecular structure and basis for T cell recognition in:
Superantigens - molecular biology, immunology and relevance to human
disease. (Eds.) Leung DYM, Huber BT, Schlievert PM, (Marcel Dekker, Inc:
NewYork) 1997: 127-148.
7Dinges MM, Orwin PM, Schlievert PM. Exotoxins of Staphylococcus aureus.
Clin Microbiol Rev 2000; 13:16-34.
8Holdstev AS, Choi Y, Spanopolou E, Posnett DN. Mycoplasma superantigen
is a CDR3-dependent ligand for the cell antigen receptor, J Exp Med
1998; 187: 319-27.
9Bohach GA, Jablonski L, Roggiani M, Sadler I, Schlievert PM, Mitchell
D, Ohlendorf D. Biological activity of pyrogenic toxins delivered at the
mucosal surface in J. Arbuthnott, B. Fuman (Eds). European conference on
Toxic shock syndrome. International congress and symposium series 229.
(Royal society of Medicine press Ltd., NY) 1998. 170-172.
10Leung DYM, Schlievert PM, Meissner HC. The immunopathogenesis and
management of Kawasaki syndrome. Arthritis Rheum 1998; 41:1538.
11Imberti L, Bettinardi SA, Puoti M, Primi D. Selective depletion in HIV
infection of T Cells that bear specific T cell receptor vß sequences.
Science 1991; 254: 860-862.
12Weber AK. Superantigen induced T cell death by apoptosis: analysis on
a single cell level and effect of IFN - and IL - 4 treatments. Int arch
allergy immunol 2000; 121(3): 215-223.
13Schlievert PM. Enhancement of host susceptibility to lethal endotoxin
shock by staphylococcal pyrogenic exotoxin type C. Infect Immun 1982;
36:123-128.
14Laupland KB, Davies HD, Low DE, Schwartz B, Green K. Invasive group A
Streptococcal disease in children and association with varicella zoster
virus infection. Ontario Group A Streptococcal study Group. Pediatrics
2000; 105: E60.
15Choi Y, Lafferty JA, Clements JR, Todd JK, Gelfand EW, Kappler J,
Marrack P, Kotzin BL.Selective expansion of T cells expressing V 2 in
toxic shock syndrome. J Exp Med 1990; 172: 981-984.
16Hauk PJ. Induction of Corticosteroid insensitivity in human PBMCS by
microbial superantigen. J Allergy Clin Immunol 2000; 105(4): 782-787.
17Madeleine W. Cunningham. Pathogenesis of Group A Streptococcal
infections. Clin Micro Rev 2000; 13 (3): 470-511.
18Proft T, Moffatt S, Berkahn C, Fraser J. Identification and
characterization of novel superantigens from Streptococcus pyogenes. J
Exp Med 1999; 189: 89-101.
19Proft T, Arcus V, Handley V, Baker E, Fraser J. Immunological and
biochemical characterization of Streptococcal pyrogenic exotoxins I and
J (SPE-I and SPE-J) from Streptococcus pyogenes. J Immun 2001; 166:
6711-9.
20Leung DYM, Nelson HS, Szefler SJ. S.aureus derived exotoxin in Atopic
dermatitis - Clinical and therapeutic implications. J Allergy Clin
Immunol 2000; 105(4): 649-650.
21Leung DYM. Atopic dermatitis. New insights opportunities for
therapeutic interventions. J Allergy clin immunol 2000; 105(5): 860-876.
22Schubert MS. A superantigen hypothesis for the pathogenesis of chronic
hypertropic rhinosinusitis, allergic fungal sinusitis and related
disorders - Ann allergy Asthma Immunol. 2001; 87(3): 181-188.
23Prodanovich S, Kirsner RS, Taylor JR. Treatment of patients
hospitalized for psoariasis. Dermatology clinics 2000; 18(3): 425-435.
24Groux H, Torpier G, Monte D, Mouton Y, Capron A, Ameisen JC. Activated
induced death by apoptosis in CD 4 T Cells from HIV infected
asymptomatic individuals. J Exp med 1992; 175: 331-340.
25Monique L, Mireille L, Arends AM, Ramirez R, Vuillier F, Charron D,
Lotteau V, Algara DS. Evidence for a viral superantigen in humans.
Nature 1992; 358:507-510.
26Hubert BT, Hsu P.N, Sutkowski M. Virally encoded superantigens. Micro
Biol Rev 1996; 60: 473-482.
27D Dobrescu, S Kabak, K Mehta, CH Suh, A Asch, PU Cameron, AS Hodtsev,
DN Posnett. Human immunodeficiency virus I reservoir in CD 4 T cells is
restricted to certain v subsets. Proc Natl Sci USA 1995; 92: 5563-5567.
28Jorens PG - Encephalomyelitis associated antimyelin autoreactivity
induced by streptococcal exotoxins. Neurology 2000: 54(7): 1433-41.
29Morshed S, Mercadante MT, Lombroso PJ. Genetics of childhood disorders
XXVIII. Auto immunity part I. J Am Acad adolesc psychiatry 2000; 40(7):
855-858.
30Miwa K, Fukuyama M, Kunitomo T, Igarashi H. Rapid assay for detection
of toxic shock syndrome toxin 1 from human sera. J Clin Microbiol 1994;
32: 539-542.
31Proft T, Sriskandan S, Yang L, Fraser JD. Superantigens and
Streptococcal Toxic Shock Syndrome. Emerg infect Dis 2003; 9(10):
1211-1218.
32Sriskandan S, McKee A, Hall L, Cohen J. Comparative effects of
clindamycin and ampicillin on superantigenic activity of streptococcus
pyogenes. J Antimicrob Chemother 1997; 40: 275-77.
33Rich RR. Intravenous immunoglobulins - Supertherapy for superantigens.
Editorial. J Clin Invest 1993; 91:378.
34Kaul R, McGeer A, Teglund AN, Kotb M, Schwartz B, O'Rourke K, Talbot
J, Low DE, The Canadian Streptococcal Study Group. Intravenous
immunoglobulin therapy for streptococcal toxic shock syndrome-a
comparative observational study. The Canadian Streptococcal Study Group.
Clin Infect Dis 1999; 28: 800-07.
35Takei YK, Walker SM. Intravenous immunoglobulins contain specific
antibodies inhibitory to activation of T Cells by Staphylococcal toxin
superantigens. J Clin Invest 1993; 91: 602-607.
36Colsky AC. Intravenous immunoglobulins in autoimmune disorders and
Inflammatory Dermatosis. Dermatology Clinics. 2000; 18:447-457.
37Forsberg G. Therapy of human non-small cell lung carcinoma using
antibody targeting of a modified superantigen. Br J Cancer 2001; 85(1):
129-136.
--
All the best,
Pete
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randall
> An interesting read with some relevance to Psoriasis
>
> http://www.ijmm.org/article.asp?issn=0255-0857;year=2004;volume=22;issue=4;spage=204;epage=211;aulast=Hemalatha
>
> Superantigens - Concepts, clinical disease and therapy
<sniP>
Like your Pantothenic acid synthesized by intestinal microflora, we
have
more then a few gut hunches here.
If it all doesn't connect at one time or another in the gut then what
does?
Don't the scientist guys need to connect Jun proteins and ap1 with some
uPstream suspects?
What if it's downstream hiding under our nostrils?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15158604
Commensal bacteria (normal microflora), mucosal immunity and chronic
inflammatory and autoimmune diseases.
Tlaskalova-Hogenova H, Stepankova R, Hudcovic T, Tuckova L, Cukrowska
B, Lodinova-Zadnikova R, Kozakova H, Rossmann P, Bartova J, Sokol D,
Funda DP, Borovska D, Rehakova Z, Sinkora J, Hofman J, Drastich P,
Kokesova A.
Department of Immunology and Gnotobiology, Institute of Microbiology,
Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague
4, Czech Republic. tlas...@biomed.cas.cz
Commensal microflora (normal microflora, indigenous microbiota)
consists of those micro-organisms, which are present on body surfaces
covered by epithelial cells and are exposed to the external environment
(gastrointestinal and respiratory tract, vagina, skin, etc.). The
number of bacteria colonising mucosal and skin surfaces exceeds the
number of cells forming human body. Commensal bacteria co-evolved with
their hosts, however, under specific conditions they are able to
overcome protective host responses and exert pathologic effects.
Resident bacteria form complex ecosystems, whose diversity is enormous.
The most abundant microflora is present in the distal parts of the gut;
the majority of the intestinal bacteria are Gram-negative anaerobes.
More than 50% of intestinal bacteria cannot be cultured by conventional
microbiological techniques. Molecular biological methods help in
analysing the structural and functional complexity of the microflora
and in identifying its components. Resident microflora contains a
number of components able to activate innate and adaptive immunity.
Unlimited immune activation in response to signals from commensal
bacteria could pose the risk of inflammation; immune responses to
mucosal microbiota therefore require a precise regulatory control. The
mucosal immune system has developed specialised regulatory,
anti-inflammatory mechanisms for eliminating or tolerating
non-dangerous, food and airborne antigens and commensal micro-organisms
(oral, mucosal tolerance). However, at the same time the mucosal immune
system must provide local defense mechanisms against environmental
threats (e.g. invading pathogens). This important requirement is
fulfilled by several mechanisms of mucosal immunity: strongly developed
innate defense mechanisms ensuring appropriate function of the mucosal
barrier, existence of unique types of lymphocytes and their products,
transport of polymeric immunoglobulins through epithelial cells into
secretions (sIgA) and migration and homing of cells originating from
the mucosal organised tissues in mucosae and exocrine glands. The
important role of commensal bacteria in development of optimally
functioning mucosal immune system was demonstrated in germ-free animals
(using gnotobiological techniques). Involvement of commensal microflora
and its components with strong immunoactivating properties (e.g. LPS,
peptidoglycans, superantigens, bacterial DNA, Hsp) in etiopathogenetic
mechanism of various complex, multifactorial and multigenic diseases,
including inflammatory bowel diseases, periodontal disease, rheumatoid
arthritis, atherosclerosis, allergy, multiorgan failure, colon cancer
has been recently suggested. Animal models of human diseases reared in
defined gnotobiotic conditions are helping to elucidate the aetiology
of these frequent disorders. An improved understanding of commensal
bacteria-host interactions employing germ-free animal models with
selective colonisation strategies combined with modern molecular
techniques could bring new insights into the mechanisms of mucosal
immunity and also into pathogenetic mechanisms of several infectious,
inflammatory, autoimmune and neoplastic diseases. Regulation of
microflora composition (e.g. by probiotics and prebiotics) offers the
possibility to influence the development of mucosal and systemic
immunity but it can play a role also in prevention and treatment of
some diseases.
PMID: 15158604
Shall we go back to superantigens?
Why not.
http://iai.asm.org/cgi/content/full/69/6/4141
[...]
Streptococcal mitogenic exotoxin Z (SMEZ), a superantigen derived from
Streptococcus pyogenes, provoked expansion of human lymphocytes
expressing the Vbeta 2, 4, 7 and 8 motifs of T-cell receptor. SMEZ was
pyrogenic in rabbits and stimulated the expression of the T-cell
activation markers CD69 and cutaneous lymphocyte-associated antigen. A
variety of cytokines was released by human mononuclear leukocytes
stimulated with SMEZ, which was 10-fold more active than streptococcal
pyrogenic exotoxin A. Th2-derived cytokines were elicited only by
superantigens and not by streptococcal cells.
Group A streptococci (Streptococcus pyogenes) provoke a wide spectrum
of diseases ranging from skin infections and pharyngitis to more severe
diseases such as scarlet fever, deep tissue infections, streptococcal
toxic shock syndrome (STSS), and probably chronic diseases such as
Kawasaki syndrome and guttate psoriasis (1, 2, 22, 23, 31, 33, 44).
Several lines of evidence suggest that these diseases are at least
partially mediated by extracellular mitogens that belong to the family
of the superantigens (SAgs) (2, 33, 47). These effectors trigger
polyclonal expansion of T lymphocytes by simultaneous binding to major
histocompatibility complex class II molecules on antigen-presenting
cells and T-cell receptor via its Vbeta domain (37). The Vbeta motifs
recognized vary from one SAg to another (7). This process leads to the
release of high levels of cytokines by antigen-presenting cells and
lymphocytes as widely investigated for streptococcal SAgs (6, 8, 11,
12, 16, 26-28, 34, 35, 41, 42). Cytokine accumulation in vivo results
in acute shock and other disorders (16, 19, 20, 41, 47). In this
respect, significant levels of SAg (43) and cytokines in the biological
fluids were detected in patients with STSS (6, 11, 20, 32, 36, 43).
S. pyogenes SAgs comprise the classical erythrogenic (pyrogenic)
exotoxins A and C (SPEA and SPEC), encoded by bacteriophage speA and
speC genes (2, 31); other novel SAgs (2, 17, 25, 33, 34, 38, 46); and
the streptococcal mitogenic exotoxin Z (SMEZ) (3, 18, 38), encoded by
the gene smez, which displays 24 allelic forms (39). Four newly
discovered genes speG, speH, speJ, and smez-2, were identified
(reference 38 and genomic database at Oklahoma University
[www.genome.ou.edu/strep.html]).
<sniP>
**************************************
Back to Mikhail and his Group B streP? Sure,
http://www.psora.df.ru/referats.html
Lots to consider there. Whew..
Lets pubmed instead,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20peptidoglycan*+superantigen*+psor*
&
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20peptidoglycan*+psor*
&
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20superantigen*+psor*
&
Using keyword antigen really opens it uP,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20antigen*+psor*
And going back to the P ng,
http://groups.google.com/groups/search?q=superantigens+psoriasis&qt_s=Search
&
http://groups.google.com/groups/search?q=antigens+psoriasis&qt_s=Search
&
http://groups.google.com/groups/search?q=peptidoglycan+psoriasis&qt_s=Search
or
http://groups.google.com/groups/search?q=peptidoglycans+psoriasis&qt_s=Search
And or,
http://groups.google.com/groups/search?q=randall+lps+spea+tsst+sea+seb&qt_s=Search
Comes down to having the right biota in the gut,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12675685
But who knows if there is a B-5 link?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14966568
randall.. suPer, antigen, bug, viral or all of the above?
Pete
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7718088&dopt=Abstract
Immunol Today. 1995 Mar;16(3):145-9.
Comment in:
Immunol Today. 1996 Jan;17(1):46-7.
Psoriasis: a T-cell-mediated autoimmune disease induced by streptococcal
superantigens?
Valdimarsson H, Baker BS, Jonsdottir I, Powles A, Fry L.
Dept of Immunology, National University Hospital, Reykjavik, Iceland.
Psoriasis is a T-cell-mediated disease that can be triggered by
infection with group A beta-haemolytic streptococci. It is proposed that
psoriatic skin lesions are initiated by exotoxin-activated T cells, and
persist because of specific T cells that react both with streptococcal M
protein and a skin determinant, possibly a variant of keratin. As
discussed here by Helgi Valdimarsson and colleagues, cytokines released
by the superantigen (SAg)-stimulated T cells could induce or enhance the
expression of the crossreactive autoantigen, leading to the rescue and
activation of autoreactive T cells. In this way, the SAg-determined
T-cell receptor V beta phenotype would be maintained by T cells in
psoriatic lesions.
PMID: 7718088 [PubMed - indexed for MEDLINE]
--
All the best,
Pete
------------------------------------------------
Home Page: http://users.bigpond.com/lansma
Location: 42°53'S; 147°19'E
"randall" <ranh...@aol.com> wrote in message
news:1145691096.7...@z34g2000cwc.googlegroups.com...
Pete
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9020931&dopt=Abstract
Clin Exp Immunol. 1997 Jan;107 Suppl 1:21-4.
Is psoriasis induced by streptococcal superantigens and maintained by
M-protein-specific T cells that cross-react with keratin?
Valdimarsson H, Sigmundsdottir H, Jonsdottir I.
Department of Immunology, National University Hospital, Reykjavik,
Iceland.
The evidence that T lymphocytes play a key role in the pathogenesis of
psoriasis is now compelling. Eruption of psoriatic skin lesions
coincides with epidermal infiltration and activation of T cells, and
spontaneous or treatment-induced resolution of the lesions is preceded
by the reduction or disappearance of epidermal T cells. An upregulation
has also been demonstrated for various molecules associated with T-cell
mediated inflammation, and treatments selectively directed against T
cells have proved very effective. Infections with group A
beta-haemolytic streptococci have been associated with onset of acute
psoriasis and exacerbation of chronic psoriasis. Such infections are
also frequently accompanied by erythematous skin rashes. Also, recent
reports indicate that streptococcal superantigens can induce expression
of cutaneous lymphocyte antigens (CLA), believed to play a major role in
enabling T cells to migrate to the skin. Furthermore, T-cell lines
isolated from psoriatic lesions may show strong reactivity to
streptococcal antigens. We have postulated that psoriasis is an
autoimmune disease mediated by T cells reacting to epitopes that are
common to streptococcal M-proteins and keratins. To investigate this
possibility, circulating T cells from 12 patients with active psoriasis,
paired controls, and six patients with atopic dermatitis were challenged
in vitro with five synthetic 20aa (amino acid) M-peptides: production of
IFN-gamma and IL-4 was analysed by ELISPOT and RT-PCR techniques. Four
of these peptides shared five to six aa sequences with several type I
keratins and one did not. In 10 of the 12 psoriasis patients, measurable
IFN-gamma production could be induced by one or more of the four
peptides that share sequences with keratins. A borderline response was
observed in only four of the 18 controls: the dermatitis patients were
all negative. The only peptide that shared 6aa with keratins was the one
that induced a response in the psoriatic patients most frequently, and
four of them showed the strongest response to this peptide while none of
the controls reacted to it. In all instances negligible responses were
observed to the control peptide that did not share sequences with
keratins. Except for PHA-stimulated controls, IL-4 responses could not
be detected by either ELISPOT or RT-PCR and there was generally good
agreement between the two techniques. A marked reduction in the
M-peptide-induced IFN-gamma responses was observed in the psoriasis
patients during remission induced by UVB treatment, while their
responses to streptokinase-streptodornase were not affected. Thus,
active psoriasis is associated with a Th1 type response to short
peptides with epitopes shared by streptococcal M-protein and keratin.
This is consistent with the hypothesis that psoriasis may be induced and
exacerbated in susceptible individuals by M-protein-specific Th1-like
cells that cross-react with human epidermal keratin.
PMID: 9020931 [PubMed - indexed for MEDLINE]
--
All the best,
Pete
------------------------------------------------
Home Page: http://users.bigpond.com/lansma
Location: 42°53'S; 147°19'E
"randall" <ranh...@aol.com> wrote in message
news:1145691096.7...@z34g2000cwc.googlegroups.com...
JXStern
>From 1997...
>
>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9020931&dopt=Abstract
...
>This is consistent with the hypothesis that psoriasis may be induced and
>exacerbated in susceptible individuals by M-protein-specific Th1-like
>cells that cross-react with human epidermal keratin.
Excellent! So, how do we turn it OFF?
J.
randall
Pete wrote:
> Another going back a few years...
>
1995 i see. From the blue lagoon country,
http://www.art-iceland.com/blue-lagoon-iceland.html
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7718088&dopt=Abstract
>
Yet are we not on the trail of group B?
>
>
> "randall" <ranh...@aol.com> wrote in message
> news:1145691096.7...@z34g2000cwc.googlegroups.com...
> Pete wrote:
> > An interesting read with some relevance to Psoriasis
> >
> > http://www.ijmm.org/article.asp?issn=0255-0857;year=2004;volume=22;issue=4;spage=204;epage=211;aulast=Hemalatha
> >
> > Superantigens - Concepts, clinical disease and therapy
>
> <sniP>
>
> Like your Pantothenic acid synthesized by intestinal microflora, we
> have
> more then a few gut hunches here.
>
> If it all doesn't connect at one time or another in the gut then what
> does?
>
> Don't the scientist guys need to connect Jun proteins and ap1 with some
> uPstream suspects?
Yes, it would be nice. Guess i'll go look some more. lol
So? What?
Are you waiting for?
You mean me? Yes stupid... stat.. i mean strat now.
I hate these infernal dialogues. Ok i'll do it. ;-0
>
> What if it's downstream hiding under our nostrils?
Then they should test for this pathway.
Isn't it what Mikhails group B strep is working up to?
Yes. I guess so..
Email him. OK... already
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15158604
> Commensal bacteria (normal microflora), mucosal immunity and chronic
> inflammatory and autoimmune diseases.
<sniP>.
>
>
> http://iai.asm.org/cgi/content/full/69/6/4141
<sniP>
> [www.genome.ou.edu/strep.html]).
> <sniP>
>
> **************************************
>
> Back to Mikhail and his Group B streP? Sure,
> http://www.psora.df.ru/referats.html
>
> Lots to consider there. Whew..
Look at the time line and recall what i sent to Mikhail only
a few weeks back.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16493599
Peptidoglycan and peptidoglycan-specific Th1 cells in psoriatic skin
lesions.
Baker B, Laman J, Powles A, van der Fits L, Voerman J, Melief MJ, Fry
L.
Department of Dermatology, Faculty of Medicine, St Mary's campus,
Imperial College, London, UK.
We have previously demonstrated, in psoriatic skin lesions, the
presence of a subset of dermal CD4(+) T cells that produce
interferon-gamma (IFN-gamma) in response to a mixture of cell wall
proteins extracted from group A streptococci. However, the identity of
the antigen(s) involved is unknown. To investigate the hypothesis that
peptidoglycan (PG), the major constituent of the streptococcal cell
wall, acts as a T cell activator in psoriasis, we performed in situ
analysis to detect antigen-presenting cells containing PG in lesional
versus non-lesional skin, and determined proliferation and IFN-gamma
responses of lesional skin T cells. Increased numbers of PG-containing
cells were detected in the dermal papillae and cellular infiltrates of
guttate and chronic plaque skin lesions compared with normal and
non-lesional psoriatic skin. A varying proportion of these were CD68(+)
macrophages, but the remaining cells did not double stain for either
Langerhans' or dendritic cell markers. Psoriatic dermal
streptococcal-specific CD4(+) T cell lines proliferated and produced
IFN-gamma in a self HLA-DR allele-restricted manner in response to
streptococcal PG, excluding mitogenic or superantigenic stimulation,
but were unresponsive to staphylococcal PG. Similarly, psoriatic
staphylococcus-specific T cell lines recognized staphylococcal, but not
streptococcal, PG by IFN-gamma production. The presence of
PG-containing macrophages in close association with PG-specific CD4(+)
T cells in lesional skin suggests that PG may be responsible, at least
in part, for T cell activation in psoriasis. Copyright (c) 2006
Pathological Society of Great Britain and Ireland. Published by John
Wiley & Sons, Ltd.
PMID: 16493599
If you may also recall I tried to get the authors of this abstract to
send him the study.
I'm sure he has it by now.
I'll check back to see how it fits into their hypothesis soon.
Don't talk about it. Do it...
OK
>
> Lets pubmed instead,
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20peptidoglycan*+superantigen*+psor*
And we can see the first hit is what I just posted above.
Science, we hope anyway, stands on the shoulders of those that come
before us/
http://www.aerospaceweb.org/question/history/q0162b.shtml
Nowadays we have only to google a vision of things to come. lol
Google vision is head and shoulders above the rest... i'm hired?
No fired stuPidO!
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20peptidoglycan*+psor*
> &
This one expanded the above search a little deeper.
But look, their looking at antigens. The first hit excludes sags for
all but atopic
dermatitis, the th2 side of screwed up skin. NOT us as we are Th1.
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20superantigen*+psor*
And this further expands the search. But don't we have enough from all
the
giant shoulders to make some very good guesses at these pathways?
Sure...
The rest of this will call smoke for now. Lets work on the fire at
hand.
Or toPically if you will..;-)
Help my Ps on fire... can't get that guy out of my mind. The
one who went out for a nip of the fag and caught fire and died. sheesh
what
a way to go...
> &
> Using keyword antigen really opens it uP,
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20antigen*+psor*
>
> And going back to the P ng,
> http://groups.google.com/groups/search?q=superantigens+psoriasis&qt_s=Search
> &
> http://groups.google.com/groups/search?q=antigens+psoriasis&qt_s=Search
> &
> http://groups.google.com/groups/search?q=peptidoglycan+psoriasis&qt_s=Search
> or
> http://groups.google.com/groups/search?q=peptidoglycans+psoriasis&qt_s=Search
>
> And or,
> http://groups.google.com/groups/search?q=randall+lps+spea+tsst+sea+seb&qt_s=Search
>
> Comes down to having the right biota in the gut,
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12675685
>
>
> But who knows if there is a B-5 link?
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14966568
>
> randall.. suPer, antigen, bug, viral or all of the above?
This much is bugging me. If we go back to the first abstract posted
today.
We want to find what turns on CD68+ (acitvated macrophage).
http://ard.bmjjournals.com/cgi/content/full/64/suppl_2/ii30/F1
& a larger version for you blind folks,
http://ard.bmjjournals.com/content/vol64/suppl_2/images/large/ar31120.f1.jpeg
the rest of this runs amuck,
http://ard.bmjjournals.com/content/vol64/suppl_2/images/large/ar31120.f2.jpeg
Notice that 65 genes are involved for IFN activations alone.
Once again we can depend on Bowcock and Krueger,
http://ard.bmjjournals.com/cgi/content/full/64/suppl_2/ii30
Or the folks looking at jak/stats,
http://groups.google.com/groups/search?q=jak+stat+psoriasis&qt_s=Search
Or Ap1 and JUN,
http://groups.google.com/groups/search?q=jun+psoriasis+ap1&qt_s=Search
Am i forgetting anything?
Oh a few thousand genes or so.... But once they get their hapmaps
figured out. So will we be figured out.
http://groups.google.com/groups/search?hl=en&lr=&q=psoriasis+haplotype&qt_s=Search
or hapmap, (short for haplotype)
http://groups.google.com/groups/search?hl=en&lr=&q=psoriasis+hapmap&qt_s=Search
Is it getting time for a cure?
Sure hoPe so!
randall... and a sunbath regardless? Why not!