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1.
Nature ; 614(7947): 334-342, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36697826

RESUMEN

The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours1-4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+ T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14high myeloid cells in hepatic zone 2. CD14+CD8+ T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+ T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14+CD8+ T cell profile can be recapitulated by the acquisition of membrane proteins-including the lipopolysaccharide receptor complex-from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14+CD8+ T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14+CD8+ T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut-liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+ T cells with immunomodulatory ability.


Asunto(s)
Linfocitos T CD8-positivos , Tolerancia Inmunológica , Receptores de Lipopolisacáridos , Lipopolisacáridos , Hígado , Células Mieloides , Humanos , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , Células Mieloides/inmunología , Células Mieloides/metabolismo , Neoplasias/inmunología , Neoplasias/patología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/inmunología , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/patología , Hígado/virología , Interleucina-2/biosíntesis , Interleucina-2/inmunología , Quimiotaxis de Leucocito , Bacterias/inmunología , Intestinos/inmunología , Intestinos/microbiología
2.
Hepatology ; 66(5): 1570-1584, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28597951

RESUMEN

Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4+ CD127+ CD25high cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH/AISC we noted a substantial increase in peripheral blood-derived CD4+ CD127+ CD25high cells that display a Th1/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL-17) production as well as by high levels of T-bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4+ CD127+ CD25high cells are unresponsive to low-dose IL-2 and in patients have marked proliferative ability, further enhanced by stimulation with IL-7. CD4+ CD127+ CD25high cells obtained from CD4+ cells exposed to Treg polarizing conditions display enhanced IL-10 production; up-regulate CD49b and LAG-3, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH/AISC patients through a mechanism which is dependent on interferon gamma and IL-17. The suppressive function of CD4+ CD127+ CD25high cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH/AISC. CONCLUSION: Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (Hepatology 2017;66:1570-1584).


Asunto(s)
Colangitis Esclerosante/inmunología , Hepatitis Autoinmune/inmunología , Linfocitos T Reguladores/fisiología , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Adulto Joven
3.
J Autoimmun ; 72: 102-12, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27210814

RESUMEN

BACKGROUND & AIMS: T-helper-type 17 (Th17) cells are involved in autoimmune tissue damage. CD39 is an ectonucleotidase that catalyzes extracellular ATP/ADP hydrolysis, culminating in the generation of immunosuppressive adenosine. Functional CD39 expression confers immunosuppressive properties upon immune cells. As the proportion of CD39 lymphocytes is decreased in juvenile autoimmune liver disease (AILD), we have explored whether decreased CD39 expression is present on Th17 cells and whether this phenomenon is associated with heightened effector function and inflammation. METHODS: Thirty-eight patients with juvenile AILD (22 autoimmune hepatitis and 16 autoimmune sclerosing cholangitis), 8 disease controls (DC) and 16 healthy subjects (HS) were studied. Peripheral blood cell phenotype was determined by flow cytometry; ability to suppress by inhibition of cell proliferation/effector cytokine production; ectoenzymatic activity by thin layer chromatography; expression of adenosine receptor, adenosine deaminase (ADA) and phosphodiesterases (PDE) by quantitative real-time PCR or by Western Blot. RESULTS: CD39(+) Th17 (Th17(CD39+)) cells from HS appear activated and contain high frequencies of lymphocytes producing regulatory cytokines. In AILD, however, Th17(CD39+) cells are markedly diminished and fail to generate AMP/adenosine, thereby limiting control of both target cell proliferation and IL-17 production. When compared to HS, Th17 cells from AILD patients also show lower A2A adenosine receptor expression while displaying similar levels of PDE4A, PDE4B and ADA. Only rare Th17(CD39+) cells are observed by liver immunohistochemistry. CONCLUSIONS: Th17(CD39+) cells in juvenile AILD are both quantitatively decreased and qualitatively deficient. Low levels CD39 and A2A expression may contribute to the perpetuation of Th17 cell effector properties and unfettered inflammation in this disease.


Asunto(s)
Antígenos CD/inmunología , Apirasa/inmunología , Colangitis Esclerosante/inmunología , Hepatitis Autoinmune/inmunología , Células Th17/inmunología , Adenosina Desaminasa/genética , Adenosina Desaminasa/inmunología , Adenosina Desaminasa/metabolismo , Adolescente , Adulto , Antígenos CD/metabolismo , Apirasa/metabolismo , Western Blotting , Proliferación Celular , Niño , Preescolar , Femenino , Citometría de Flujo , Expresión Génica/inmunología , Humanos , Inmunohistoquímica , Lactante , Interleucina-17/inmunología , Interleucina-17/metabolismo , Masculino , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/inmunología , Hidrolasas Diéster Fosfóricas/metabolismo , Receptor de Adenosina A2A/genética , Receptor de Adenosina A2A/inmunología , Receptor de Adenosina A2A/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Th17/metabolismo , Adulto Joven
4.
Hepatology ; 62(3): 863-75, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25953611

RESUMEN

UNLABELLED: Defective immune regulation plays a permissive role enabling effector cells to initiate and perpetuate tissue damage, eventually resulting in autoimmune disease. Numerical and functional regulatory T-cell (Treg) impairment has been previously reported in autoimmune liver disease (AILD; including autoimmune hepatitis and autoimmune sclerosing cholangitis ASC). However, in these early reports, Tregs were phenotypically defined as CD4(+) CD25(+) or CD4(+) CD25(high) cells. In the current study, we reexamined phenotypic and functional properties of Tregs by adopting a more refined definition of these cells that also includes negativity or low level of expression of CD127. We studied 43 AILD patients and 22 healthy subjects (HSs) and found that CD4(+) CD25(+) CD127(-) Tregs were decreased in the former. This decrease was more marked in patients with active disease than in those in remission. In AILD, Treg frequencies correlated inversely with parameters of disease activity and were not affected by immunosuppressive treatment. We also document, for the first time, that, in AILD, bona-fide Tregs produce less interleukin (IL)-10 and are impaired in their ability to suppress CD4(+) CD25(-) target cell proliferation, a feature that in HSs, but not in AILDs, is dependent, at least in part, on IL-10 secretion. Decreased IL-10 production by Tregs in AILD is linked to poor responsiveness to IL-2 and phospho signal transducer and activator of transcription 5 up-regulation. CONCLUSION: Tregs are numerically impaired in AILD, this impairment being more prominent during active disease. Notably, defective IL-10 production, resulting from low Treg responsiveness to IL-2, contributes to Treg functional impairment.


Asunto(s)
Colangitis Esclerosante/inmunología , Hepatitis Autoinmune/inmunología , Interleucina-10/biosíntesis , Interleucina-2/farmacología , Linfocitos T Reguladores/inmunología , Adulto , Análisis de Varianza , Antígenos CD4/inmunología , Estudios de Casos y Controles , Células Cultivadas , Colangitis Esclerosante/tratamiento farmacológico , Colangitis Esclerosante/fisiopatología , Femenino , Citometría de Flujo , Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/fisiopatología , Humanos , Subunidad alfa del Receptor de Interleucina-2/inmunología , Subunidad alfa del Receptor de Interleucina-7/inmunología , Leucocitos Mononucleares/inmunología , Masculino , Análisis Multivariante , Adulto Joven
5.
IUBMB Life ; 67(2): 88-97, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25850692

RESUMEN

There are three classic liver diseases with probable autoimmune etiology: primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. The occurrence of these autoimmune conditions is determined by the breakdown of immune-regulatory mechanisms that in health are responsible for maintaining immunological tolerance against self-antigens. Among the multiple T cell subsets with suppressive function, the regulatory T cells (Tregs), defined by the expression of CD4, the IL-2 receptor α chain (CD25), and the transcription factor FOXP3, have emerged as having a central role in maintaining immune-tolerance to autoantigens. Tregs are equipped with an array of mechanisms of suppression, including the modulation of antigen presenting cell maturation and function, the killing of target cells, the disruption of metabolic pathways, and the production of anti-inflammatory cytokines. In all the three autoimmune liver diseases mentioned above, there is evidence pointing for either a reduced frequency and/or function of Tregs. Here, we review the definition, phenotypic characteristics, and mechanisms of suppression employed by Tregs and then we discuss the evidence available pointing to their impairment in patients with autoimmune liver disease.


Asunto(s)
Colangitis Esclerosante/inmunología , Hepatitis Autoinmune/inmunología , Cirrosis Hepática Biliar/inmunología , Linfocitos T Reguladores/fisiología , Citocinas/inmunología , Citocinas/metabolismo , Humanos , Linfocitos T Reguladores/inmunología
6.
Hepatology ; 59(3): 1007-15, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23787765

RESUMEN

UNLABELLED: Autoimmune hepatitis (AIH) is an important cause of severe liver disease and is associated with both quantitative and qualitative regulatory T-cell (Treg) impairments. Tregs express CD39, an ectonucleotidase responsible for extracellular nucleotide hydrolysis, culminating in the production of immunosuppressive adenosine. Here, we describe multiple CD39(pos) Treg defects that potentially contribute to the impaired immunoregulation that is characteristic of AIH. We have examined the frequency and phenotype of CD39(pos) Tregs by flow cytometry and measured their ectonucleotidase activity. The capacity of CD4(pos) CD25(high) , CD4(pos) CD25(high) CD39(pos) , and CD4(pos) CD25(high) CD39(neg) subsets to suppress both proliferation of effector T cells and interleukin (IL)-17 production was evaluated. In AIH, CD39(pos) Tregs are decreased in frequency, exhibit limited adenosine triphosphate/adenosine diphosphate hydrolysis activity, and fail to suppress IL-17 production by effector CD4 T cells. Moreover, these CD39(pos) Tregs display a more proinflammatory profile in AIH, which is characterized by elevated CD127 positivity, and a greater propensity to produce interferon-gamma or IL-17 upon challenge with proinflammatory stimuli. CONCLUSIONS: In AIH, CD39(pos) Tregs are decreased in number, fail to adequately hydrolyze proinflammatory nucleotides and do not efficiently suppress IL-17 production by effector CD4 T cells. CD39(pos) Tregs show plasticity and are unstable upon proinflammatory challenge, suggesting that defective immunoregulation in AIH might result not only from reduced Treg number and function, but also from increased conversion of Tregs into effector cells.


Asunto(s)
Antígenos CD/metabolismo , Apirasa/metabolismo , Hepatitis Autoinmune/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Adolescente , Traslado Adoptivo , Adulto , Antígenos CD/inmunología , Apirasa/inmunología , Antígeno CD24/metabolismo , Antígenos CD4/metabolismo , Niño , Femenino , Citometría de Flujo , Humanos , Tolerancia Inmunológica/inmunología , Inmunofenotipificación , Masculino , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo , Adulto Joven
7.
J Autoimmun ; 53: 26-32, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24566085

RESUMEN

Imbalance between effector and regulatory T-cells (Treg) underlies the loss of immune-tolerance to self-antigens in autoimmune disease. In autoimmune hepatitis type 2 (AIH-2), effector CD4 T-cell immune responses to cytochrome P450IID6 (CYP2D6) are permitted by numerically and functionally impaired Treg. Restoration of CYP2D6-specific Treg in AIH-2 would enable control over effectors sharing the same antigen specificity, leading to re-establishment of immune-tolerance. We have previously developed a protocol for generating antigen-specific Treg through co-culture with semi-mature dendritic cells presenting CYP2D6 peptides. In this study, we aimed to explore phenotypic and functional features of patient Treg compared to health, to test Treg stability under pro-inflammatory conditions, and to investigate the potential benefit of supplementation with all-trans-retinoic acid (RA) or rapamycin (RP), agents proven to enhance Treg function. We show that antigen-specific Treg from patients have comparable phenotypic and functional features to those from healthy controls, suppressing both proliferation and pro-inflammatory cytokine production by effector cells. Treg exposure to inflammatory challenge results in decreased suppressive function and up-regulation of Th1/Th2/Th17 transcription factors both in health and AIH-2. The increase of Th1 and Th17 transcription factors is limited by addition of RA in controls and Th1 expression is decreased by RP in patients. Importantly, inflammation-induced decrease in Treg function is also abrogated by RA/RP in health and RA in patients. Our data provide important information for the optimization of protocols aiming at generating antigen-specific Treg for treatment of autoimmune disease and for understanding their biology upon pro-inflammatory challenge and RP/RA supplementation.


Asunto(s)
Antineoplásicos/farmacología , Hepatitis Autoinmune , Linfocitos T Reguladores/inmunología , Tretinoina/farmacología , Adolescente , Adulto , Niño , Citocromo P-450 CYP2D6/inmunología , Femenino , Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/patología , Humanos , Inmunosupresores/farmacología , Masculino , Sirolimus/farmacología , Linfocitos T Reguladores/patología , Células Th17/inmunología , Células Th17/patología
8.
J Autoimmun ; 41: 126-39, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23218932

RESUMEN

Autoimmune hepatitis (AIH) is an immune-mediated liver disorder characterised by female preponderance, elevated transaminase and immunoglobulin G levels, seropositivity for autoantibodies and interface hepatitis. Presentation is highly variable, therefore AIH should be considered during the diagnostic workup of any increase in liver enzyme levels. Overlap/variant forms of the disease, presenting with concomitant features of primary biliary cirrhosis or primary sclerosing cholangitis are increasingly recognised. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival. Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil or, failing that, calcineurin inhibitors. Persistent failure to respond or lack of adherence to treatment result in end-stage liver disease. These patients, and those with fulminant liver failure (encephalopathy grade II-IV) at diagnosis, will require liver transplantation. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4(pos) T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. Animal models faithfully representing the human condition are needed to unravel the contribution of innate and adaptive, effector and regulatory immune responses. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigen-specific regulatory T-cells, which ultimately aim to restore tolerance to liver-derived antigens.


Asunto(s)
Autoanticuerpos/inmunología , Cadenas HLA-DRB1/inmunología , Hepatitis Autoinmune/inmunología , Hígado/inmunología , Femenino , Cadenas HLA-DRB1/genética , Hepatitis Autoinmune/genética , Hepatitis Autoinmune/terapia , Humanos , Hígado/metabolismo , Hígado/patología , Modelos Inmunológicos
9.
J Autoimmun ; 41: 146-51, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23287048

RESUMEN

Autoimmune hepatitis (AIH), a severe hepatopathy characterized by hypergammaglobulinaemia, autoantibodies and interface hepatitis, is occasionally associated with systemic autoimmune manifestations [systemic lupus erythematosus (SLE); mixed connective tissue disease (MCTD)]. In both AIH and SLE/MCTD numerical and/or functional impairment of regulatory T-cells (T-regs) is believed to favour autoimmunity. To investigate whether immune-tolerance breakdown profiles differ in patients with AIH and SLE/MCTD, isolated AIH or systemic autoimmunity, we studied phenotypic and functional features of T-regs in 10 patients with AIH-SLE/MCTD, 22 with AIH, 12 with SLE and 20 healthy subjects. Compared to health, CD4(pos)CD25(pos) cells were decreased in number and expressed high levels of the CD127 activation marker in all three disease groups; in AIH-SLE/MCTD and in SLE they displayed low levels of FOXP3. In AIH-SLE/MCTD, they also contained a high proportion of IFNγ positive cells, indicating a Th1 profile. Similarly, in AIH-SLE/MCTD, CD4(pos)CD25(pos)CD25(high) T-regs were reduced in number and contained an increased proportion of activated CD127(pos) and IFNγ(pos) cells. Such skewing towards a Th1 profile was also present at effector level, as a high frequency of IFNγ-producing cells was observed within AIH-SLE/MCTD CD4(pos)CD25(neg) responder cells. Impairment in suppressor function both of CD4(pos)CD25(pos) cells and CD4(pos)CD25(pos)CD127(neg) T-regs was observed in all three autoimmune conditions, but while addition of CD4(pos)CD25(pos)CD127(neg) T-regs decreased CD4(pos)CD25(neg) responder cell proliferation in healthy subjects and partially in AIH patients, it had no effect in AIH-SLE/MCTD and SLE patients. In conclusion, in AIH-SLE/MCTD T-regs display a distinctive phenotypic and functional signature, characterized by marked activation, elevated IFNγ production and by a profound impairment of suppressive function, suggesting that multiple autoimmune manifestations may derive from a complex defect of immune-regulation.


Asunto(s)
Citocinas/inmunología , Hepatitis Autoinmune/inmunología , Lupus Eritematoso Sistémico/inmunología , Enfermedad Mixta del Tejido Conjuntivo/inmunología , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Adolescente , Adulto , Autoanticuerpos/inmunología , Niño , Citocinas/metabolismo , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Hepatitis Autoinmune/metabolismo , Humanos , Inmunofenotipificación , Interferón gamma/inmunología , Interferón gamma/metabolismo , Subunidad alfa del Receptor de Interleucina-2/inmunología , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-7/inmunología , Subunidad alfa del Receptor de Interleucina-7/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Enfermedad Mixta del Tejido Conjuntivo/metabolismo , Síndrome , Linfocitos T Reguladores/metabolismo , Células TH1/metabolismo , Adulto Joven
10.
Hepatology ; 56(2): 677-86, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22371007

RESUMEN

UNLABELLED: In autoimmune hepatitis (AIH), liver-damaging CD4 T cell responses are associated with defective CD4(pos) CD25(pos) regulatory T cells (T-regs). Galectin-9 (Gal9), a ß-galactosidase-binding protein expressed by T-regs, is key to their function, inhibiting T helper 1 immune responses by binding T cell immunoglobulin and mucin domain 3 (Tim-3) on CD4 effector cells. We investigated whether impaired immunoregulation in AIH results from reduced expression of Gal9 in T-regs and/or Tim-3 on CD4 effector cells. Circulating Gal9(pos) CD4(pos) CD25(pos) and Tim-3(pos) CD4(pos) CD25(neg) T cell phenotype was assessed by flow cytometry in 75 AIH patients. To evaluate whether Tim-3 expression renders CD4(pos) CD25(neg) T cells amenable to T-reg control, purified CD4(pos) CD25(neg) Tim-3(pos) (Tim-3(pos)) and CD4(pos) CD25(neg) Tim-3(neg) (Tim-3(neg)) cells were cocultured with T-regs. To determine whether Gal9 expression is essential to function, T-regs were treated with small interfering RNA (siRNA) to repress Gal-9 translation; T-reg suppressor function was assessed by proliferation. In AIH, Tim-3(pos) cells within CD4(pos) CD25(neg) cells and their T-bet(pos) and RORC(pos) subsets were fewer and contained higher numbers of interferon-γ (IFNγ)(pos) and interleukin (IL)-17(pos) cells than healthy subjects (HS). In AIH and HS, Tim-3(pos) cells proliferated less vigorously and were more susceptible to T-reg control than Tim-3(neg) cells. In AIH, Gal9(pos) T-regs were fewer and contained less FOXP3(pos), IL-10(pos), and transforming growth factor ß(pos) and more IFNγ(pos) and IL-17(pos) cells than HS. siRNA treatment of Gal-9(pos) T-regs drastically reduced T-reg ability to suppress CD4(pos) CD25(neg) and Tim-3(pos) cell proliferation in AIH and HS. Tim-3(pos) cell percentage correlated inversely with aminotransferase and CD25(neg) T-bet(pos) cell values. CONCLUSION: Reduced levels of Tim-3 on CD4(pos) CD25(neg) effector cells and of Gal9 in T-regs contribute to impaired immunoregulation in AIH by rendering effector cells less prone to T-reg control and T-regs less capable of suppressing.


Asunto(s)
Galectinas/metabolismo , Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/metabolismo , Proteínas de la Membrana/metabolismo , Transducción de Señal/inmunología , Adolescente , Niño , Femenino , Galectinas/genética , Galectinas/inmunología , Receptor 2 Celular del Virus de la Hepatitis A , Humanos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Hígado/inmunología , Hígado/metabolismo , Masculino , Proteínas de la Membrana/inmunología , ARN Interferente Pequeño/genética , Recurrencia , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Adulto Joven
11.
Clin Gastroenterol Hepatol ; 10(4): 346-53, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22056300

RESUMEN

Liver transplantation is an effective treatment for patients with end-stage acute and chronic autoimmune hepatitis. However, despite the good outcomes reported, disease recurrence is relatively common in the allograft. In addition, autoimmunity and autoimmune liver disease can arise de novo after transplantation for non-autoimmune liver disorders. Little is known about the mechanisms by which autoimmune diseases develop after liver transplantation, but genetic factors, molecular mimicry, impaired regulatory T-cell responses, and exposures to new alloantigens might be involved. Regardless of the pathogenic mechanisms, it is important to remain aware of the existence of recurrent and de novo autoimmune hepatitis after liver transplantation; these disorders are similar to classic autoimmune hepatitis and are therefore not treated with standard antirejection strategies.


Asunto(s)
Hepatitis Autoinmune/epidemiología , Hepatitis Autoinmune/cirugía , Trasplante de Hígado/métodos , Humanos , Recurrencia
12.
Cureus ; 14(9): e28743, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36211098

RESUMEN

Enterolith formation is a rare condition precipitated by decreased bowel motility. It may cause obstruction or other complications and the diagnosis usually is confirmed after surgery and analysis of the stones or fragments. It is often seen in association with intestinal abnormalities such as diverticula and inflammation or in biliary tract fistulas where stones migrate to the duodenum and small bowel. We report an unusual case of a primary true enterolith formation in a patient without any underlying bowel condition or any previous surgery.

13.
Immunology ; 132(1): 111-22, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20880379

RESUMEN

Relatively little is known about regulatory T (Treg) cells and their functional responses in dogs. We have used the cross-reactive anti-mouse/rat Foxp3 antibody clone FJK-16s to identify a population of canine CD4(+) FOXP3(high) T cells in both the peripheral blood (PB) and popliteal lymph node (LN). FOXP3(+) cells in both PB and LN yielded positive staining with the newly developed anti-murine/human Helios antibody clone 22F6, consistent with the notion that they were naturally occurring Treg cells. Stimulation of mononuclear cells of LN origin with concanavalin A (Con A) in vitro yielded increased proportions and median fluorescence intensity of FOXP3 expression by both CD4(+) and CD8(+) T cells. Removal of the Con A and continued culture disclosed a CD4(+) FOXP3(high) population, distinct from the CD4(+) FOXP3(intermediate) T cells; very few CD8(+) FOXP3(high) T cells were observed, though CD8(+) FOXP3(intermediate) cells were present in equal abundance to CD4(+) FOXP3(intermediate) cells. The CD4(+) FOXP3(high) T cells were thought to represent activated Treg cells, in contrast to the FOXP3(intermediate) cells, which were thought to be a more heterogeneous population comprising predominantly activated conventional T cells. Co-staining with interferon-γ (IFN-γ) supported this notion, because the FOXP3(high) T cells were almost exclusively IFN-γ(-) , whereas the FOXP3(intermediate) cells expressed a more heterogeneous IFN-γ phenotype. Following activation of mononuclear cells with Con A and interleukin-2, the 5% of CD4(+) T cells showing the highest CD25 expression (CD4(+) CD25(high) ) were enriched in cells expressing FOXP3. These cells were anergic in vitro, in contrast to the 20% of CD4(+) T cells with the lowest CD25 expression (CD4(+) CD25(-) ), which proliferated readily. The CD4(+) CD25(high) FOXP3(high) T cells were able to suppress the proliferation of responder CD4(+) T cells in vitro, in contrast to the CD4(+) CD25(-) cells, which showed no regulatory properties.


Asunto(s)
Antígenos CD4/inmunología , Factores de Transcripción Forkhead/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Células Cultivadas , Perros , Fenotipo , Linfocitos T Reguladores/citología
15.
Clin Rev Allergy Immunol ; 60(2): 271-292, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33405100

RESUMEN

Calcium is the most abundant mineral in the human body and is central to many physiological processes, including immune system activation and maintenance. Studies continue to reveal the intricacies of calcium signalling within the immune system. Perhaps the most well-understood mechanism of calcium influx into cells is store-operated calcium entry (SOCE), which occurs via calcium release-activated channels (CRACs). SOCE is central to the activation of immune system cells; however, more recent studies have demonstrated the crucial role of other calcium channels, including transient receptor potential (TRP) channels. In this review, we describe the expression and function of TRP channels within the immune system and outline associations with murine models of disease and human conditions. Therefore, highlighting the importance of TRP channels in disease and reviewing potential. The TRP channel family is significant, and its members have a continually growing number of cellular processes. Within the immune system, TRP channels are involved in a diverse range of functions including T and B cell receptor signalling and activation, antigen presentation by dendritic cells, neutrophil and macrophage bactericidal activity, and mast cell degranulation. Not surprisingly, these channels have been linked to many pathological conditions such as inflammatory bowel disease, chronic fatigue syndrome and myalgic encephalomyelitis, atherosclerosis, hypertension and atopy.


Asunto(s)
Linfocitos B/inmunología , Mastocitos/inmunología , Neutrófilos/inmunología , Linfocitos T/inmunología , Canales de Potencial de Receptor Transitorio/metabolismo , Animales , Autoinmunidad , Degranulación de la Célula , Humanos , Activación de Linfocitos , Ratones , Transducción de Señal , Canales de Potencial de Receptor Transitorio/genética
16.
Clin Res Hepatol Gastroenterol ; 41(1): 6-16, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27526967

RESUMEN

There are several examples of liver tolerance: the relative ease by which liver allografts are accepted and the exploitation of the hepatic microenvironment by the malarial parasite and hepatotrophic viruses are notable examples. The vasculature of the liver supports a unique population of antigen presenting cells specialised to maintain immunological tolerance despite continuous exposure to gut-derived antigens. Liver sinusoidal endothelial cells and Kupffer cells appear to be key to the maintenance of immune tolerance, by promoting T cell anergy or deletion and the generation of regulatory cell subsets. Despite this, there are three liver diseases with likely autoimmune involvement: primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. How can we reconcile this with the inherent tolerogenicity of the liver? Genetic studies have uncovered several associations with genes involved in the activation of the innate and adaptive immune systems. There is also evidence pointing to pathogenic and xenobiotic triggers of autoimmune liver disease. Coupled to this, impaired immunoregulatory mechanisms potentially play a permissive role, allowing the autoimmune response to proceed.


Asunto(s)
Autoinmunidad , Colangitis Esclerosante/inmunología , Hepatitis Autoinmune/inmunología , Cirrosis Hepática Biliar/inmunología , Hepatocitos/inmunología , Humanos , Tolerancia Inmunológica , Hepatopatías/inmunología , Linfocitos T Reguladores/inmunología
17.
World J Hepatol ; 8(28): 1157-1168, 2016 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-27729952

RESUMEN

Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) constitute the classic autoimmune liver diseases (AILDs). While AIH target the hepatocytes, in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells. Persistent liver injury, associated with chronic AILD, leads to un-resolving inflammation, cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts. Liver cirrhosis, and the resultant loss of normal liver function, inevitably ensues. Patients with cirrhosis have higher risks or morbidity and mortality, and that in the decompensated phase, complications of portal hypertension and/or liver dysfunction lead to rapid deterioration. Accurate diagnosis and monitoring of cirrhosis is, therefore of upmost importance. Liver biopsy is currently the gold standard technique, but highly promising non-invasive methodology is under development. Liver transplantation (LT) is an effective therapeutic option for the management of end-stage liver disease secondary to AIH, PBC and PSC. LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy; in addition, LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.

18.
Clin Res Hepatol Gastroenterol ; 39(2): 157-67, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25659878

RESUMEN

Porto-pulmonary hypertension (PoPH) is a rare but threatening vasculopathy, defined by the presence of pulmonary arterial hypertension (PAH) in the setting of portal hypertension. Although most commonly observed in cirrhotic patients, those with non-cirrhotic portal hypertension are also at risk of developing it. Little is known about the mechanisms by which PAH develop in patients with portal hypertension, but genetic factors, pulmonary vascular wall shear stress, and a dysregulation of vasoactive, proliferative and inflammatory mediators might be involved. PoPH is estimated to occur in 3 to 10% of patients with end-stage liver disease, although its frequency is not related to the severity of liver dysfunction or the degree of portal hypertension. Moderate-to-severe PoPH portends an extremely poor prognosis. Presentation is highly variable, therefore a high index of suspicion is required to establish the diagnosis. PoPH should be screened by transthoracic echocardiography (TTE) in cirrhotic patients presenting with dyspnoea as well as in all patients being evaluated for liver transplantation (LT) regardless of their symptoms. If TTE shows elevated pulmonary pressures, patients should undergo right heart catheterisation, which is required for the definitive diagnosis of PoPH. Without LT, the overall 5-year mortality in PoPH patients is 70%, but it should not be considered an indication for LT. Moderate-to-severe PoPH contraindicates LT, since it is associated with a prohibitively increased intra and postoperative mortality. However, there is now evidence supporting the use of PAH-specific therapies pre-LT in order to improve pulmonary haemodynamic measurements, so the procedure can then be performed with significantly lower risks.


Asunto(s)
Hipertensión Portal/complicaciones , Hipertensión Pulmonar/complicaciones , Humanos , Hipertensión Portal/diagnóstico , Hipertensión Portal/epidemiología , Hipertensión Portal/cirugía , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/cirugía , Trasplante de Hígado
19.
Autoimmun Rev ; 14(2): 105-16, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25449680

RESUMEN

Regulatory T cells (Tregs) are central to the maintenance of self-tolerance and tissue homeostasis. Markers commonly used to define human Tregs in the research setting include high expression of CD25, FOXP3 positivity and low expression/negativity for CD127. Many other markers have been proposed, but none unequivocally identifies bona fide Tregs. Tregs are equipped with an array of mechanisms of suppression, including the modulation of antigen presenting cell maturation and function, the killing of target cells, the disruption of metabolic pathways and the production of anti-inflammatory cytokines. Treg impairment has been reported in a number of human autoimmune conditions and includes Treg numerical and functional defects and conversion into effector cells in response to inflammation. In addition to intrinsic Treg impairment, resistance of effector T cells to Treg control has been described. Discrepancies in the literature are common, reflecting differences in the choice of study participants and the technical challenges associated with investigating this cell population. Studies differ in terms of the methodology used to define and isolate putative regulatory cells and to assess their suppressive function. In this review we outline studies describing Treg frequency and suppressive function in systemic and organ specific autoimmune diseases, with a specific focus on the challenges faced when investigating Tregs in these conditions.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Linfocitos T Reguladores/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Biomarcadores/análisis , Citocinas/inmunología , Humanos , Inflamación/inmunología
20.
Autoimmun Rev ; 13(4-5): 435-40, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24418295

RESUMEN

Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disorder characterised by female preponderance, elevated transaminase and immunoglobulin G levels, seropositivity for autoantibodies and interface hepatitis. Presentation is highly variable, therefore AIH should be considered during the diagnostic workup of any increase in liver enzyme levels. A set of inclusion and exclusion criteria for the diagnosis of AIH have been established by the International Autoimmune Hepatitis Group (IAIHG). There are two main types of AIH: type 1, positive for anti-nuclear (ANA) and/or anti-smooth muscle antibodies (SMAs) and type 2, defined by the presence of anti-liver kidney microsomal antibody type 1 (LKM-1) and/or anti-liver cytosol type 1 (LC-1) autoantibodies. The central role of autoantibodies in the diagnosis of AIH has led the IAIHG to produce a consensus statement detailing appropriate and effective methods for their detection. Autoantibodies should be tested by indirect immunofluorescence at an initial dilution of 1/40 in adults and 1/10 in children on a freshly prepared rodent substrate that includes kidney, liver and stomach sections to allow for the simultaneous detection of all reactivities relevant to AIH. Anti-LKM-1 is often confused with anti-mitochondrial antibody (AMA) if rodent kidney is used as the sole immunofluorescence substrate. The identification of the molecular targets of anti-LKM-1 and AMA has led to the establishment of immuno-assays based on the use of the recombinant or purified autoantigens. Perinuclear anti-nuclear neutrophil antibody (p-ANNA) is an additional marker of AIH-1; anti soluble liver antigen (SLA) antibodies are specific for autoimmune liver disease, can be present in AIH-1 and AIH-2 and are associated with a more severe clinical course. Anti-SLA are detectable by ELISA or radio-immuno-assays, but not by immunofluorescence. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival.


Asunto(s)
Hepatitis Autoinmune/diagnóstico , Anticuerpos Antinucleares/inmunología , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Biomarcadores , Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/terapia , Humanos
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