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fredag 22 maj 2020

Suollsto ja interferonit Tyyppi I ja III

Type I and III Interferon in the Gut: Tight Balance between Host Protection and Immunopathology

Johanna Pott and Silvia Stockinger


Importance of Type I/III IFN Signaling Under Inflammatory Conditions..


Type I IFN and IBD

The IBD, comprising Crohn’s disease (CD), and ulcerative colitis (UC) are chronic debilitating inflammatory disorders of the gastrointestinal tract. IBD affects about 0.2% of Western populations and there is no current cure, typically requiring long-term treatment with immune suppressive agents and, in many cases, surgical intervention. Although the etiology remains unclear, IBD is thought to arise due to aberrant immune responses to components of the commensal bacterial microbiota (117). Recent genome-wide association studies have identified more than 160 genetic susceptibility loci for IBD, with affected genes involved in immunity and in barrier function (118). Many of those single-nucleotide polymorphisms (SNPs) are found in genes associated with pathogenic cytokine circuits, such as the Th17/IL23 circuit, IL-10, and type I IFN-I signaling (119). The majority of signaling mediators are shared between different cytokine signaling cascades and therefore exact determination of the relevant pathways is impossible from the genetic data only. Interestingly, several of the IBD-associated genes are also involved in the type I IFN signaling pathway. The rs2284553 SNP is commonly associated with the IFNGR2 gene but could also affect the IFNAR1 gene (118). JAK2, TYK2, STAT1, and STAT3 genes harbor identified SNPs and are signaling mediators in many cytokine pathways such as IL-22, IL-10, and also type I/III IFN. Furthermore, polymorphisms in the MDA5 or IRF5 gene might alter the production of type I/III IFN (118). Although the type I IFN signaling network is not one of the major players in IBD pathology, slight alterations may contribute to the imbalanced immune response at the lamina propria, as suggested by mouse studies.
Indeed, Giles and colleagues analyzed the responsiveness of T cells from healthy controls and IBD patients to IFN-β and found that IFN-β signaling modulates colonic T cell responses in a context-dependent manner. Human colonic T cells were responsive to exogenous IFN-β and endogenous IFN-β influenced the cytokine profile of ex vivo cultured T cells. T cells from healthy controls produced decreased levels of IL-10 in the absence of IFN-β signaling whereas T cells from IBD patients produced elevated levels of proinflammatory cytokines (120).
Interferons-β has been approved for the treatment of multiple sclerosis (MS); however, a subset of patients does not respond to the treatment. Axtell and colleagues analyzed the effect of IFN-β on different Th subsets and found that IFN-β treatment in a mouse model of EAE attenuates disease development in a Th1-driven pathology, but had no effect or even exacerbates pathology in Th17-driven disease. Furthermore, they could correlate high IL-17-F serum levels in MS patients to non-responsiveness toward IFN-β treatment. These findings confirm the immunomodulatory role of IFN-β but also demonstrate the diverse consequences it has in different context with opposing effects within a Th1 and Th17 setting (121).
Despite the varying results from mouse studies on the role of type I IFN in colitis and the discrepancy between type I IFN effects on suppressing acute colitis and delaying recovery (74, 75), type I IFN have been suggested for the treatment of IBD. Several small studies have evaluated the consequences of IFN-β1a in IBD patients with varying results (122128). Although small pilot studies suggested a beneficial outcome of type I IFN treatment of IBD patients (123, 124), a placebo-controlled, double-blind study on Crohn’s patients in remission did not find any improvement by IFN-β1a treatment on the maintenance of remission (127). Also two randomized placebo-controlled studies in UC patients with active disease could not show a beneficial effect of IFN-α or IFN-β1 treatment on disease remission (125, 126). A small study analyzing cytokine levels before and after treatment with IFN-β1a found a correlation between responsiveness and reduction of IL-13 levels in UC patients. The unresponsiveness to IFN-β1 treatment correlated with elevated levels of IL-17 in accordance with the findings in MS patients (121, 128).
Taken together, these studies do not support a beneficial outcome of type I IFN treatment during IBD. This conclusion was also drawn in a recent intervention review analyzing all trial data published on the effectiveness of type I IFN treatment on remission in UC patients (129). However, considering the analysis of IFN-β non-responsiveness of patients with MS (121), context-specific responsiveness of T cells toward type I IFN (120), and controversial findings in mouse studies (23, 74, 75), the effect of the treatment might vary between Th profiles of patients and a careful pre-selection of patients would be required. Further studies with sufficient patient numbers and thorough analysis of immunological and disease parameters are required.

Type I IFN and Celiac Disease

Celiac disease is a small-intestinal enteropathy characterized by an aberrant T cell-mediated immune response of susceptible individuals to dietary gluten. The pathogenic adaptive immune response is initiated by the interplay between gluten and the MHC class II molecules HLA-DQ2 and DQ8 and is characterized by a potent Th1 response. The excessive tissue destruction is further driven by a severe IEL hyperplasia targeting IECs. Histologically, celiac disease is characterized by villous flattening, crypt hyperplasia, and IEL infiltration. Affected individuals can present with very variable symptoms ranging from asymptomatic to severe symptoms ascribed to impaired absorption of nutrients (130).
The strongest genetic factor for the disease is HLA-DQ2 and DQ8; however, it is now recognized that further immune-regulatory or activating factors are required for disease establishment. Several celiac disease susceptibility loci in genes associated with innate immune responses have been identified, suggesting a role for innate immunity in the development of the disease (131).
An influence of type I IFN on the development of celiac disease has been widely discussed. Indeed, a number of case studies reported on the development of diarrhea and the onset of celiac disease during treatment with IFN-α for chronic hepatitis C patients (132137). A retrospective study of 534 hepatitis C patients with or without symptoms of celiac disease showed an activation of silent celiac disease in the majority of patients positive for transglutaminase antibodies while on IFN therapy (138). The immunomodulatory properties of type I IFN might worsen underlying autoimmune disorders and monitoring of hepatitis C patients for celiac disease before starting an IFN therapy has been suggested.

A potential role of cotreatment with ribavirin, which promotes a Th1-mediated immune response while suppressing Th2 responses, has also been discussed (133).
The high prevalence of celiac disease in HCV patients treated with IFN-α was investigated in a study including 210 chronic hepatitis C patients. This study failed to detect a significant association of celiac disease and HCV infection and in addition came to the conclusion that IFN-α therapy per se does not trigger celiac disease in patients negative for endomysium (EMA) and tissue transglutaminase (139). It does not however rule out that IFN-α treatment might trigger the development of celiac disease in susceptible individuals.
To investigate the underlying mechanisms, explant cultures of human fetal gut were analyzed after activation of T cells with anti-CD3 and IFN-α. While single treatment with either anti-CD3 or IFN-α alone did not trigger any profound changes, the combination of both resulted in enhanced Th1 responses and crypt cell hyperplasia associated with enhanced STAT1, STAT3, and FYN phosphorylation. IFN-α treatment might thus facilitate activation of Th1-reactive cells and trigger immunopathology (135, 140).
Onset of celiac disease-like symptoms have also been observed in a case of chronic myeloid leukemia treated with IFN-α again suggesting a role of type I IFN in promoting Th1 responses to gluten (135). Also, IFN-α protein was detected in duodenal tissue of celiac disease patients but not in control samples (135).
Further studies are required to determine whether a direct link exists between type I IFN signaling and celiac disease.

Concluding Remarks

Although important progress has been made in recent years, additional studies are required to deepen our understanding of the role of type I IFN and type III IFN in the gut. Type I IFN signaling in enteric viral infections is mostly protective, whereas it can be detrimental in certain enteric bacterial infections. The clinical data using type I IFN for colitis treatment are partly contradictory and a larger number of patients are required to obtain conclusive results.
With the exception of some viral infection and colitis models, where type III IFN signaling is mostly protective, the data on illuminating the role of type III IFN signaling in the gut are generally scarce. It is now well established that epithelial cells are especially responsive to type III IFN, which enforces the mucosal barrier and prevents viral entry and infection. Less clear is the non-responsiveness of the epithelium to type I IFN observed under several conditions (Figure 1). What benefit do epithelial cells gain from the decreased responsiveness? Can receptor expression levels and localization fully explain reduced type I IFN responsiveness in the epithelium?
The narrow range of cells responding to type III IFN makes it an attractive target for future clinical studies with increased specificity and fewer side effects than type I IFN.


fredag 1 maj 2020

Pandemian aikana ei erityisempiä muutoksia keliakiadieetissä

Kuitenkin pitää muistaa käsien huolellinen pesu ja myös kannattaa välttää kovin bakteeripitoisia ruokia, siis sormin syömistä, esimerksi pähkinöitä ym   voi kyllä syödä lusikan avulla. Hedelmät kannattaa pestä hyvin kotona ennen kuin niitä nauttii.  On tietysti hedelmiä, jotka voi ottaa välipalaksi  kuten banaanin. Siinä ei tarvitse  varsinaista hedelmää koskea käsin, jos  pitää mielessä  asian merkityksen. sormibakteerien  syönnin välttämisen. 
Kannattaa olla tarkempi myös elintrvikkeiden laadusta, ettei tule syötyä homeisia ja  vanhettuneita ruokia.  Pakasteesta otetut  elintarvikkeet kannattaa valmistaa  huolella kuumentaen. 
Kuten muutakin väkeä kehoitetaan viihtymään kotona,  sitä sopii  pyrkiä  tekemään kotona  ruokansa tavalliseen tapaan riskeeraamatta poikkeuksellisia   ruokailutilanteita tai ulkona aterioimista. Omat eväät  mukaan,  jos  on matkalla. välipalat  joita ostaa kaupasta,  voi syödä niin että sormenpäät eivät koske  kuorittuun  elintarvikkeeseen, suklaapalaan  yms.

onsdag 29 januari 2020

Kaura (Out, Havre, Avena sativa) ja kaura ja iho Pustulosis palmoplantaris

Internetmedicin , viimeinen, oli otanut vain yhden artikkelin kirjeeseensä ja se oli Pustulosis palmo- plantaris.
Joka muuten on sellaisen vaivan joskus kokenut, tietää mitä on  inhottava kutina  siinä kohtaa kehoa, josa on eniten hermoääteitä, kämmenissä ja jalanpohjissa.
nimittäin- itselläni oli nuoruudessa tuollainen vaihe, kun sitä ihottumaa oli  vuosi vuodelta aikamoinen kirjonsa, vaihteleva , ja  kuten sanottu , olihan sitä naftalan pastaa.

Ei ollut käsitystä mistään  dieetin merkityksestä iholle.
 kun sittemmin tuli  anergiaa  huonomman kunnon ja ehkä röntgentyönkin jälkeen  varsinainen lyhyt pustuloosivaihe ohittui - välillä oli sormien ja  varpaiden ihovälit vetiset , punoitavat ja kutiavat. Sen vaiheen ohittumisen jälkeen  tuli suolisto-oireita eniten, jasitten lopulta 30 vuoden iässä  oli pääoire.

 Jossain vaiheessa huomasin että varsinkin kaura aiheutti  ihon kutinan.  Nuorena  söin usein kaurapuroa aamulla aivan 18 vuotiaaksi asti, jolloin muutin  kotoa opiskelemaan ja  lopetin kauran jokapäiväisen käytön. Kauraleivät olivat helppoja paistaa  ( kaurahiutaleta, sokerissa ja voita taikinaksi, rautaisessa lättypannussa uuniin)  Niitä teimme silloin tällöin iltaisin. ne olivat herkullisia.

Nyt ajattelin katsoa yhteyttä Pustulosis palmoplantaris , kaura.(oat).
Löytyy erikoisia asioita, missä kauralla on jokin ominaisuus jota voi ihoon hyödyntää, mutta ei varmastikaan  olisi minun hoitoaineitani.jos vanha allergisuus kauralle on vielä solumuistissa olemassa.

(1)  Saattaa  olla,  että kaura jotenkin assosioituu ihoon enemmän kuin muut viljat. Mitähän asia koskee?
 Mikä molekyylikaurassa on niin ihovetoinen?

Näyttää olevan kaurassa  paljon hyviä antioksidatiivisiä ja antikutinaaineita jotka varmasti suurimmalle osalle ihmiskuntaa sopivat

 Saattaa olla enttä entinen  kauralaari , joka  meidän  isonkeittiön vehnälaarin vieressä  sijaitsi, saattoi sisältää vehnäpölyn tuomia  immunologisia hitusia gliadiinia ja gliadiini taas  antigeeninä massiivisen kauran sisällä  saattoi antaa iho-oireita suolioireiden sijasta.


Mechanism of action and clinical benefits of colloidal oatmeal for dermatologic practice.Cerio R1, Dohil M, Jeanine D, Magina S, Mahé E, Stratigos AJ.  Abstract

Colloidal oatmeal has a long history of beneficial use in dermatology. It is a natural product that has an excellent safety record and has demonstrated efficacy for the treatment of atopic dermatitis, psoriasis, drug-induced rash and other conditions. In recent years, in vitro and in vivo studies have begun to elucidate the multiple mechanisms of action of naturally derived colloidal oatmeal. Evidence now describes its molecular mechanisms of anti-inflammatory and antihistaminic activity. The avenanthramides, a recently described component of whole oat grain, are responsible for many of these effects. Studies have demonstrated that avenanthramides can inhibit the activity of nuclear factor kappaB and the release of proinflammatory cytokines and histamine, well known key mechanisms in the pathophysiology of inflammatory dermatoses. Topical formulations of natural colloidal oatmeal should be considered an important component of therapy for atopic dermatitis and other conditions and may allow for reduced use of corticosteroids and calcineurin inhibitors.
[Indexed for MEDLINE]
(2)  Kaurassa näyttää olevan keramideja, jotka voivat painua ihon läpi:
(3) Miten kauran todella hyvät  edut voidaan saada esiin ja välttää haitat? Edulliset  osat otetaan käyttöön ja mahdollinen haittaava proteiiniosa ( kauran aveniinit ja gluteliinit) jätetään pois, koska niille joku allergisoituu kuitenkin.

2018 Apr;32 Suppl 1:1-15. doi: 10.1111/jdv.14846.
Effects of a protein-free oat plantlet extract on microinflammation and skin barrier function in atopic dermatitis patients.
Atopic dermatitis (AD) is a common, highly pruritic, chronic inflammatory skin disease. Dysfunction of the epidermal barrier is witnessed by an increased transepidermal water loss in lesional and non-lesional AD skin. The inflammation in lesional AD skin is well characterized. Non-lesional skin of AD patients shows histological signs of a subclinical inflammation and a pro-inflammatory cytokine milieu. This microinflammation is present even in seemingly healed skin and must be taken into account regarding treatment of AD. Emollients provide a safe and effective method of skin barrier improvement, because they provide the skin with a source of exogenous lipids, thus improving its barrier function. The use of emollients is recommended for all AD patients irrespective of overall disease severity. Patients with moderate to severe AD should combine the emollients with a proactive therapy regimen of topical calcineurin inhibitors or topical corticosteroids. Skin areas affected by active eczema in flare should receive daily anti-inflammatory therapy first before introducing emollients, to induce rapid relief of skin lesions and pruritus. The microinflammation persisting in seemingly healed AD lesions should be addressed by a proactive treatment approach, consisting of minimal anti-inflammatory therapy and liberal, daily use of emollients. An emollient containing an extract of Rhealba oat plantlet has shown anti-inflammatory and barrier repairing properties, and was clinically tested in studies targeting the microinflammation in AD. All emollients based on Rhealba oat plantlet extract are free of oat protein, as the Rhealba extract is derived from the aerial parts of the oat plantlet and is unrelated to oatmeal proteins. The Rhealba oat plantlet extract is produced in a specific process, allowing the extraction of high levels of active principles such as flavonoids and saponins, whilst being virtually free of oat proteins to minimize the risk for allergic reactions.
(4) Mayo klinikan tutkimuksen mukaan Pustulosis palmoplantaris- etiologiassa oli odotettua vähemmän keliakiaa  aiheuttajana.
To further characterize clinical characteristics, etiologic factors, associated disorders, and treatment of palmoplantar pustulosis (PPP). PATIENTS AND METHODS:
We conducted a retrospective review of patients with PPP at Mayo Clinic between January 1, 1996, and December 31, 2013. RESULTS:
Of 215 patients with PPP identified, 179 (83%) were female, and the mean age at onset was 45.3 years. Most patients (n=165, 77%) were current or former smokers. At diagnosis, 15 patients (7%) had an anxiety diagnosis and 9 (4%) had an infection. Nineteen cases (9%) were drug induced. Comorbid conditions included thyroid disease in 18 patients (8%), gluten sensitivity in 3 (1%), and type 2 diabetes mellitus in 21 (10%). In all, 194 patients (90%) received topical corticosteroids, 55 (26%) received phototherapy, and 54 (25%) received systemic agents. CONCLUSION:
More than three-fourths of the patients in this study had a history of smoking, which is considered a triggering or aggravating factor for PPP. Regarding comorbid conditions, gluten sensitivity and thyroid disease were found less frequently than previously reported in the literature. Treatment regimens and responses in this cohort varied considerably.

söndag 6 oktober 2019

Steatorrhea-ongelmisto ja gluteeni-intoleranssi

Jo 1957 oli  todettu , että idiopaattisen steatorrhean takana voi piillä gluteeni-intoleranssi.  Jatkuva steatorrhea aiheuttaa ajanmitatan ADEK-vitamiinien vajautta.


Effect of a Gluten-free Diet in Idiopathic Steatorrhoea

Br Med J 1957; 2 doi: https://doi.org/10.1136/bmj.2.5040.337 (Published 10 August 1957) Cite this as: Br Med J 1957;2:337

tisdag 1 oktober 2019

Rehumaissi ja sokerimaissi

Ihmisille viljellään sokerimaissia. Löysin tiedon rehumaissista, jota viljellään nautakarjalle.
Artikklein lopussa mainitaan, että ihminenkin voi syödä tätä laatua maissia. olisi mmukava saada vertailu näiden maissilaatujen soveltuvuudesta esim  keliakia-diabeteskompbinaatiota poteville. Ja sitäpaitsi keliakiravinto on muutenkin liian glykemistä, joten  olisi hyvä löytää vähemmän glykemisiä  elintarvikelaatuja. 

Grillattu sokerimaissi

onsdag 17 juli 2019

Tarkka gluteenittoman dieetin pitäminen vähentää malignisoitumisen riskejä.


Association of celiac disease and intestinal lymphomas and other cancers

Celiac disease (CD) is associated with intestinal lymphoma and other forms of cancer, especially adenocarcinoma of the small intestine, of the pharynx, and of the esophagus. Enteropathy-associated T-cell lymphoma (EATL) is a rare form of high-grade, T-cell non-Hodgkin lymphoma (NHL) of the upper small intestine that is specifically associated with CD. This NHL subtype arises in patients with either previously or concomitantly diagnosed CD. In a subgroup of patients, there is progressive deterioration of a refractory form of CD. EATL derives from a clonal proliferation of intraepithelial lymphocyte s(IEL) and is often disseminated at diagnosis. Extraintestinal presentations are not uncommon in the liver/spleen, thyroid, skin, nasal sinus, and brain. The outlook of EATL is poor. Recent studies indicated that
(1) CD is associated with a significantly increased risk for NHL, especially of the T-cell type and primarily localized in the gut (EATL);
(2) the CD-lymphoma association is less common than previously thought, with a relative risk close to 3;
 (3) CD screening is not required in patients with NHL of any primary site at the onset, unless suggested by specific findings (T-cell origin and/or primary gut localization). The risk of NHL associated with clinically milder (or silent) forms could be lower than in typical cases of CD. Several follow-up studies suggest that the GFD protects from cancer development, especially if started during the first years of life. Strict adherence to the GFD seems to be the only possibility of preventing a subset of rare but very aggressive forms of cancer.


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