Duodenal mucosa FOXP3 expression in different etiologies of lymphocytic duodenosis.

BACKGROUND/AIMS: In celiac disease there is an increase of lymphocytes expressing FOXP3 in the intestinal mucosa associated with varying degrees of villous atrophy. Our aim was to evaluate FOXP3 expression in duodenal mucosa with lymphocytic enteritis according to aetiology and correlation with lymphocytes T-γδ. METHODS: We compared three adult patient groups suffering lymphocytic enteritis: celiacs following a gluten-free diet (n=12), first-degree relatives of celiac patients with genetic risks (n=14) and patients with functional dyspepsia (n=14), along with a control group not suffering from duodenal enteritis (n=16). The population of duodenal lymphocytes was analysed by immunohistochemistry assays for CD3+ characterisation and FOXP3 expression. Quantification of lymphocytes T-γδ in duodenal mucosa was performed by flow cytometry in fresh tissue samples. RESULTS: Presence of lymphocytes T-γδ was significantly higher in the group of celiac individuals compared to the group of relatives of these individuals (37.44 vs 5,52: p<0.0001) and the group with functional dyspepsia (37.44 vs 11.76: p=0.008). FOXP3 expression was also significantly higher in the celiac group than in the groups of relatives (18.85 vs 6.31; p=0.001) and functional dyspepsia patients (18.85 vs 7.61; p=0.023). The proportion of lymphocytes T-γδ and FOXP3- expressing lymphocytes was similar in the control group to that in the relatives or functional dyspepsia groups. CONCLUSIONS: Lymphocytic enteritis associated to celiac disease shows an increase of FOXP3 expression and lymphocytes T-γδ that is not detected in other etiologies of enteritis.

Golimumab as rescue therapy for refractory immune-mediated uveitis: a three-center experience.

OBJECTIVE: To evaluate, in three Spanish tertiary referral centres, the short-term safety and efficacy of golimumab (GLM) for treatment of immune-mediated uveitis resistant to previous immunosuppressive therapy. METHODS: Nonrandomized retrospective interventional case series. Thirteen patients with different types of uveitis that were resistant to treatment with at least 2 previous immunosuppressors were included in this study. All included patients were treated with GLM (50 mg every four weeks) during at least 6 months. Clinical evaluation and treatment-related side effects were assessed at least four times in all included patients. RESULTS: Eight men and 5 women (22 affected eyes) with a median age of 30 years (range 20-38) and active immune-mediated uveitides were studied. GLM was used in combination with conventional immunosuppressors in 7 patients (53.8%). GLM therapy achieved complete control of inflammation in 12/13 patients (92.3%) after six months of treatment. There was a statistically significant improvement in mean BCVA (0.60 versus 0.68, P = 0.009) and mean 1 mm central retinal thickness (317 versus 261.2 µ, P = 0.05) at the six-month endpoint when compared to basal values. No major systemic adverse effects associated with GLM therapy were observed. CONCLUSIONS: GLM is a new and promising therapeutic option for patients with severe and refractory uveitis.

Predominance of CXCR4 tropism in HIV-1 CRF14_BG strains from newly diagnosed infections.

OBJECTIVES: R5-tropic viruses are associated with HIV-1 transmission and predominate during the early stages of infection. X4-tropic populations have been detected in ~50% of patients with late-stage disease infected with subtype B viruses. In this study, we compared the frequency of X4 tropism in individuals infected with HIV-1 CRF14_BG viruses, which have a V3 loop of subtype B, with a control group of individuals infected with subtype B viruses. METHODS: Sixty-three individuals infected with HIV-1 CRF14_BG (n = 31) or subtype B (n = 32) were studied. Similar proportions of newly diagnosed and chronically infected individuals were included in the subtype B and CRF14_BG groups. V3 sequences were obtained and coreceptor tropism was predicted using the Geno2pheno[coreceptor] algorithm. V3 net charge and 11/25 rules were also used for coreceptor prediction. RESULTS: Overall, X4 tropism was more frequent among individuals infected with CRF14_BG viruses (87.1%) than subtype B viruses (34.3%), a difference that was statistically highly significant (P = 0.00001). Importantly, the frequencies among newly diagnosed individuals were 90% and 13.3%, respectively (P = 0.0007). Characteristic amino acids in the V3 loop (T13, M14, V19 and W20) were identified at higher frequencies in CRF14_BG viruses (54%) than subtype B viruses (0%; P < 0.000001). CONCLUSIONS: CRF14_BG is the genetic form with the highest proportion of X4-tropic viruses reported to date in newly diagnosed and chronic infections. This suggests high pathogenicity for CRF14_BG viruses, potentially leading to rapid disease progression. CCR5 antagonists will be ineffective in most CRF14_BG-infected patients, even at early stages of infection.

Preoperative cataract surgery use of an intravitreal dexamethasone implant (Ozurdex) in a patient with juvenile idiopathic arthritis and chronic anterior uveitis.

We report a 6-year-old boy with anterior uveitis associated with juvenile idiopathic arthritis (JIA) who underwent cataract extraction in his right eye. One month before surgery he received an intravitreal sustained-release dexamethasone implant. During 10 months' follow-up, his uveitis remained quiet. To our knowledge this is the first report using an intravitreal sustained-release dexamethasone implant as a perioperative anti-inflammatory medication.

Serum cytokine profile in adalimumab-treated refractory uveitis patients: decreased IL-22 correlates with clinical responses.

PURPOSE: To report the effect of adalimumab on serum cytokines in chronic refractory uveitis. METHODS: Prospective study on the effects of adalimumab on serum cytokine levels at different time points in a cohort of 12 refractory chronic uveitis patients. Results were analyzed according to clinical outcomes and compared with systemic steroid-treated recurrent uveitis patients. RESULTS: Before treatment, patients exhibited significantly increased IL-1ß, IL-6, TNFα, IL-12 p70, IL-10, and IL-22. Adalimumab significantly decreased IL-6, and IL-12p70 at early time points (after 1 month of treatment). Adalimumab effects on IL-10 and IL-22 appeared later (after 6 months of treatment). IL-1ß, IL-17A, and TNFα were not modified at any time point. Only decreased IL-22 serum levels correlated with disease activity (p = 0.011). These effects were not observed in steroid-treated patients. CONCLUSIONS: Adalimumab induced drug-specific and time-dependent declines in serum levels of particular cytokines, although only IL-22 correlated with disease activity in 10 out 12 patients.

Refractory pyoderma gangrenosum of the orbit and the lacrimal sac.

Pyoderma gangrenosum (PG) is a rare, idiopathic, necrotizing, and non-infectious ulcerating skin disease included among the neutrophilic dermatoses. It rarely affects the eye, orbit, and/or ocular adnexa. We describe one case of PG affecting both orbits and the lacrimal sac in a patient with Crohn's disease.

Linfoma intestinal de células T asociado a enteropatía y sin relación con enfermedad celíaca / Enteropathy-associated intestinal t-cell lymphoma without celiac disease

La enteropatía asociada a linfoma de células T tipo II es un linfoma intestinal infrequente. Presentamos el caso un varón de 73 años con diarrea y pérdida de peso. La biopsia duodenal presentaba atrofia e infiltrado de linfocitos irregulares. La inmunohistoquímica detectó positividad para CD3, CD8, CD56 con reordenamiento monoclonal del TCR. El genotipifación de HLA-DQ era DQ5/DQ9. El test para EBVRNA fue negativo. Antes del tratamiento específico quimioterápico ingresó por infección respiratoria, y falleció por causa independiente del linfoma. El diagnóstico diferencial de los procesos linfoproliferativos CD56-positivo incluye EATL tipo II, linfoma intestinal primario de células T/NK y linfoma de células T hepatoesplénico.El paciente presentaba CD8 y CD56+ marcadores que permiten descartar EALT tipo I. la genotipificación HLA-DQ no corresponde a enfermedad celíaca, y la biopsia presentaba proliferación de linfocitos con atipias. El linfoma intestinal primario de células T/NK se caracteriza principalmente por ausencia de CD8 y del reordenamiento monoclonal del TCR presentes en este caso(AU)

Type II enteropathy-associated T-cell lymphoma (EATL) is an uncommon intestinal lymphoma. We report the case of a 73-year-old man with diarrhea and weight loss. Duodenal biopsy showed atrophy and infiltration of irregular lymphocytes. Immunohistochemistry was positive for CD3, CD8, and CD56 with monoclonal TCR rearrangement. The HLA-DQ genotype was DQ5/DQ9. The Epstein-Barr virus RNA test was negative. Before specific chemotherapy could be administered, the patient was admitted to hospital for a respiratory infection and died from a cause unrelated to his lymphoma. The differential diagnosis of CD56-positive lymphoproliferative processes include type II EATL, primary T-cell/natural killer-cell intestinal lymphoma and hepatosplenic T-cell lymphoma. The patient had CD8 y CD56+ markers that allowed type I EATL to be excluded. The HLA-DQ genotype did not correspond to celiac disease and the biopsy showed proliferation of lymphocytes with atypia. The primary intestinal T-cell/natural killer-cell lymphoma was characterized mainly by the absence of CD8 and monoclonal reassortment of the TCR present in this case (AU)

[Enteropathy-associated intestinal t-cell lymphoma without celiac disease]. / Linfoma intestinal de células T asociado a enteropatía y sin relación con enfermedad celíaca.

Type II enteropathy-associated T-cell lymphoma (EATL) is an uncommon intestinal lymphoma. We report the case of a 73-year-old man with diarrhea and weight loss. Duodenal biopsy showed atrophy and infiltration of irregular lymphocytes. Immunohistochemistry was positive for CD3, CD8, and CD56 with monoclonal TCR rearrangement. The HLA-DQ genotype was DQ5/DQ9. The Epstein-Barr virus RNA test was negative. Before specific chemotherapy could be administered, the patient was admitted to hospital for a respiratory infection and died from a cause unrelated to his lymphoma. The differential diagnosis of CD56-positive lymphoproliferative processes include type II EATL, primary T-cell/natural killer-cell intestinal lymphoma and hepatosplenic T-cell lymphoma. The patient had CD8 y CD56+ markers that allowed type I EATL to be excluded. The HLA-DQ genotype did not correspond to celiac disease and the biopsy showed proliferation of lymphocytes with atypia. The primary intestinal T-cell/natural killer-cell lymphoma was characterized mainly by the absence of CD8 and monoclonal reassortment of the TCR present in this case.

Differences of small intestinal bacteria populations in adults and children with/without celiac disease: effect of age, gluten diet, and disease.

BACKGROUND: Scientific evidence has revealed microecological changes in the intestinal tract of celiac infants. The objective of this work is the study of bacterial differences in the upper small intestine in both adults (healthy, untreated celiac disease [CD], and CD treated with a gluten-free diet) and children (healthy and untreated CD). METHODS: Intestinal bacterial communities were identified by 16S rRNA gene sequencing of DNA extracted from duodenal biopsies. RESULTS: Analysis of the sequences from adults and children showed that this niche was colonized by bacteria affiliated mainly with three phyla: Firmicutes, Proteobacteria, and Bacteroidetes. In total, 89 different genera were identified in adults and 46 in children. Bacterial richness was significantly lower in the children than in the adults. A global principal component analysis of the bacterial communities of both healthy and untreated CD patient groups (including both children and adults) revealed a strong effect of age in principal component 1--clustering all adults and children separately--and a possible effect of the disease in adults with untreated patients clustering separately. CONCLUSIONS: There are bacterial differences in the upper small intestine between untreated children CD patients and untreated CD adults due to age. There are bacterial differences in the upper small bacteria microbiota between treated and untreated CD adults due to treatment with a gluten-free diet.

Dynamics of non-conventional intraepithelial lymphocytes-NK, NKT, and γδ T-in celiac disease: relationship with age, diet, and histopathology.

BACKGROUND: Intraepithelial lymphocytes (IEL) are a heterogeneous population of lymphocytes raised in celiac disease (CD), whose role in CD pathogenesis remains to be defined. AIMS: To investigate how the age of diagnosis, diet, and the severity of the histological lesions are related to the changes observed in unconventional IEL populations. METHODS: Prospective analysis of 101 confirmed celiac patients from a single center, including 66 at diagnosis (45 children, 21 adults) and 112 non-celiac controls (12 children, 100 adults). IEL from duodenal biopsies were studied by six-color flow cytometry. The results were analyzed in relationship with age, diet (gluten intake), and histopathology (Marsh type). RESULTS: In comparison with respective age controls, both children and adult patients showed duodenal intraepithelial lymphocytosis with significant differences in every single non-conventional IEL population: CD3+ TCR γδ, NK (CD3-, CD16+, CD56+), NKT (CD3+, CD161+, CD56+), and iNKT (CD3+ Vα24) (P < 0.001 for all). Gluten intake was not only directly associated with severe atrophy, but also with decreased percentages of NK (P = 0.02), NKT (P = 0.003), and iNKT (P = 0.03). Changes in iNKT and γδ IEL were more marked in celiac children compared with celiac adults (P = 0.02 and 0.01, respectively). In contrast, increased CD3+ TCR γδ were diet- and Marsh grade-independent. CONCLUSIONS: The typical phenotypical profile of intraepithelial lymphocytosis in untreated pediatric and adult celiacs consists of increased CD3+ TCR γδ populations with decreased NK, NKT, and iNKT cells. NK, NKT, and iNKT IEL, but not γδ IEL, are dynamic populations associated with diet, age, and histopathology.

Manifestaciones gastrointestinales en pacientes con inmunodeficiencias primarias que cursan con déficit de anticuerpos / Gastrointestinal manifestations in patients with primary immunodeficiencies causing antibody deficiency

Introducción. Las inmunodeficiencias primarias pueden presentar manifestaciones digestivas aún no bien definidas. Objetivo. Analizar la patología digestiva que se asocia a las inmunodeficiencias primarias. Material y métodos. Estudio retrospectivo que incluyó a los pacientes diagnosticados de deficiencias primarias de anticuerpos en un hospital de tercer nivel. Fueron divididos en 2 grupos: déficit aislado de IgA (Def-IgA) y síndrome de inmunodeficiencia común variable (SICV). Se analizaron el momento de presentación y tipo de sintomatología digestiva. Resultados. Se recogieron 57 pacientes: 20 con SICV (35%) y 37 con Def-IgA (65%). El diagnóstico fue realizado en edad pediátrica en 17 casos, de los cuales 13 cursaban con Def-IgA. El diagnóstico de inmunodeficiencia fue previo a las manifestaciones digestivas en el 84% de los casos. La clínica digestiva se presentaba en un 74% de los pacientes, la diarrea fue el síntoma más frecuente. La patología se confirmó en el 46% de los casos principalmente mediante endoscopia. La enfermedad celiaca-like, gastritis crónica atrófica, colitis ulcerosa-like y enfermedad de Crohn fueron más comunes en el SICV. Mientras que en el Def-IgA predominaron la gastritis crónica con Helicobacter positivo. La edad media fue significativamente mayor (36 vs. 24 años, p=0,02) y el título de IgA menor (17 vs. 34UI/ml; p=0,008) en los pacientes que presentaban patología digestiva asociada. Conclusiones. Los síntomas digestivos son frecuentes y se llega al diagnóstico en la mitad de los pacientes con inmunodeficiencias primarias mediante estudio endoscópico. La colitis ulcerosa, Crohn y celiaca-like son entidades atípicas y propias del SICV (AU)

ObjectiveTo analyze gastrointestinal manifestations associated with primary immunodeficiencies. Material and methods. We performed a retrospective study that included patients diagnosed with primary antibody deficiencies in a third-level hospital. The patients were divided into two groups: isolated IgA deficiency and common variable immunodeficiency syndrome (CVIS). The timing of presentation and type of gastrointestinal symptoms were analyzed. Results. There were 57 patients: 20 with CVIS (35%) and 37 with isolated IgA deficiency (65%). Diagnosis was made in the pediatric age in 17 patients, of whom 13 had isolated IgA deficiency. In 84% of the patients, diagnosis of immunodeficiency was made before the development of gastrointestinal manifestations. Digestive symptoms were found in 74% of the patients, the most frequent being diarrhea. In 46% of the patients, digestive disease was confirmed, mainly through endoscopy. Celiac-like lesions, chronic atrophic gastritis, ulcerative colitis-like disease and Crohn's disease were more common in CVIS. In isolated IgA deficiency, Helicobacter pylori-positive chronic gastritis predominated. Mean age was significantly higher (36 vs. 24 years, p=0.02) and IgA titer significantly lower (17 vs. 34UI/ml; p=0.008) in patients with associated gastrointestinal disease. Conclusions. Gastrointestinal symptoms are frequent and lead to endoscopic diagnosis in half of patients with primary immunodeficiencies. Ulcerative colitis, and celiac- and Crohn's-like disease are atypical entities that occur in CVIS (AU)

[Gastrointestinal manifestations in patients with primary immunodeficiencies causing antibody deficiency]. / Manifestaciones gastrointestinales en pacientes con inmunodeficiencias primarias que cursan con déficit de anticuerpos.

INTRODUCTION: Primary immunodeficiencies can lead to gastrointestinal manifestations that are still not well defined. OBJECTIVE: To analyze gastrointestinal manifestations associated with primary immunodeficiencies. MATERIAL AND METHODS: We performed a retrospective study that included patients diagnosed with primary antibody deficiencies in a third-level hospital. The patients were divided into two groups: isolated IgA deficiency and common variable immunodeficiency syndrome (CVIS). The timing of presentation and type of gastrointestinal symptoms were analyzed. RESULTS: There were 57 patients: 20 with CVIS (35%) and 37 with isolated IgA deficiency (65%). Diagnosis was made in the pediatric age in 17 patients, of whom 13 had isolated IgA deficiency. In 84% of the patients, diagnosis of immunodeficiency was made before the development of gastrointestinal manifestations. Digestive symptoms were found in 74% of the patients, the most frequent being diarrhea. In 46% of the patients, digestive disease was confirmed, mainly through endoscopy. Celiac-like lesions, chronic atrophic gastritis, ulcerative colitis-like disease and Crohn's disease were more common in CVIS. In isolated IgA deficiency, Helicobacter pylori-positive chronic gastritis predominated. Mean age was significantly higher (36 vs. 24 years, p=0.02) and IgA titer significantly lower (17 vs. 34UI/ml; p=0.008) in patients with associated gastrointestinal disease. CONCLUSIONS: Gastrointestinal symptoms are frequent and lead to endoscopic diagnosis in half of patients with primary immunodeficiencies. Ulcerative colitis, and celiac- and Crohn's-like disease are atypical entities that occur in CVIS.

Duodenal biopsy may be avoided when high transglutaminase antibody titers are present.

AIM: To evaluate the predictive value of tissue transglutaminase (tTG) antibodies for villous atrophy in adult and pediatric populations to determine if duodenal biopsy can be avoided. METHODS: A total of 324 patients with celiac disease (CD; 97 children and 227 adults) were recruited prospectively at two tertiary centers. Human IgA class anti-tTG antibody measurement and upper gastrointestinal endoscopy were performed at diagnosis. A second biopsy was performed in 40 asymptomatic adults on a gluten-free diet (GFD) and with normal tTG levels. RESULTS: Adults showed less severe histopathology (26% vs 63%, P < 0.0001) and lower tTG antibody titers than children. Levels of tTG antibody correlated with Marsh type in both populations (r = 0.661, P < 0.0001). Multiple logistic regression revealed that only tTG antibody was an independent predictor for Marsh type 3 lesions, but clinical presentation type and age were not. A cut-off point of 30 U tTG antibody yielded the highest area under the receiver operating characteristic curve (0.854). Based on the predictive value of this cut-off point, up to 95% of children and 53% of adults would be correctly diagnosed without biopsy. Despite GFDs and decreased tTG antibody levels, 25% of the adults did not recover from villous atrophy during the second year after diagnosis. CONCLUSION: Strongly positive tTG antibody titers might be sufficient for CD diagnosis in children. However, duodenal biopsy cannot be avoided in adults because disease presentation and monitoring are different.

A novel RMRP mutation in a Spanish patient with cartilage-hair hypoplasia.

Cartilage-hair hypoplasia (CHH), or McKusick type metaphyseal chondrodysplasia, was first recognized as a distinct entity in the Old Order Amish in the USA, but was later identified in other groups, and found to be unusually frequent among Finns. CHH is highly pleiotropic with manifestations that include short stature, defective cellular immunity and predisposition to several cancers. CHH is caused by mutations in the RNA component of RNase MRP (RMRP, ribonuclease mitochondrial RNA processing) and is transmitted as an autosomal recessive trait. In the present work, a Spanish CHH patient was extensively characterized at the immunological and molecular DNA level. Several parameters of cellular and humoral immunity were analyzed in this patient: lymphocyte subpopulation, proliferative responsiveness in mitogen stimulation and quantification of serum immunoglobulins. Sequencing of the RMRP gene allowed identification of two mutations in the patient: a +4 C>T substitution previously described on one allele, and a duplication of 15 nucleotides at position -11 on the other allele. This mutation has not previously been described.

A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphoproliferation and autoimmune clinical manifestations and is generally caused by defective Fas-mediated apoptosis. This report describes the first homozygous FASL gene mutation in a woman with clinical and immunologic features of ALPS. T-cell blasts from the patient did not induce FasL-mediated apoptosis on Fas-transfected murine L1210 or on Jurkat cells, and activation-induced cell death was impaired. Furthermore, Fas-dependent cytotoxicity was drastically reduced in COS cells transfected with the mutant FasL. In addition, FasL expression on T-cell blasts from the patient was similar to that observed in a healthy control, despite its bearing the high-producer genotype -844C/C in the FASL promoter. Sequencing of the patient's FASL gene revealed a new mutation in exon 4 (A247E). The location of A247E in the FasL extracellular domain and the conservation of the protein sequence of that region recorded in 8 species different from humans support the essential role of FasL COOH terminal domain in Fas/FasL binding. These findings provide evidence that inherited nonlethal FASL abnormalities cause an uncommon apoptosis defect producing lymphoproliferative disease, and they highlight the need for a review of the current ALPS classification to include a new ALPS type Ic subgroup.