Association between EBV serological patterns and lymphocytic profile of SjS patients support a virally triggered autoimmune epithelitis.

Sjögren's syndrome (SjS) is characterized by lymphocytic infiltration of exocrine glands, i.e. autoimmune epithelitis. Lymphocytes are central in SjS pathogenesis, with B-cell hyperactivity mediated by T-cells. B-cells are main targets of Epstein-Barr virus (EBV) infection, a frequently-suggested trigger for SjS. We aimed to evaluate how the EBV infection modulates B and T-cell subsets in SjS, including as controls Rheumatoid arthritis patients (RA) and healthy participants (HC). SjS patients presented decreased CXCR5+T-cells, although IL21-secreting Tfh and Tfc cells were increased. Tfc were positively correlated with ESSDAI scores, suggesting their relevant role in SjS pathogenesis. As previously described, SjS patients showed expanded circulating naïve B-cell compartments. SjS patients had a higher incidence of EBV-EA-D-IgG+ antibodies, characteristic of recent EBV-infection/reactivation. SjS patients with past infection or recent infection/reactivation showed increased CXCR3+Th1 and CXCR3+Tfh1 cells compared to those without active infection. SjS patients with a recent infection/reactivation profile presented increased transitional B-cells compared to patients with past infection and increased plasmablasts, compared to those without infection. Our results suggest EBV-infection contributes to B and T-cell differentiation towards the effector phenotypes typical of SjS. Local lymphocyte activation at ectopic germinal centres, mediated by Tfh and Tfc, can be EBV-driven, perpetuating autoimmune epithelitis, which leads to gland destruction in SjS.

Updates in Pediatric Congenital Enteropathies: Differential Diagnosis, Testing, and Genetics.

Congenital enteropathies comprise a heterogeneous group of disorders typically resulting in severe diarrhea and intestinal failure. Recent advances in and more widespread application of genetic testing have allowed more accurate diagnosis of these entities as well as identification of new disorders, provided a deeper understanding of intestinal pathophysiology through genotype-phenotype correlations, and permitted the exploration of more specific therapies to diseases that have heretofore been resistant to conventional treatments. The therapeutic armamentarium for these disorders now includes intestinal and hematopoietic stem cell transplantation, specific targeted therapy, such as the use of interleukin-1 receptor antagonists and, in some cases, gene therapy. These considerations are particularly applicable to the group of disorders identified as "very-early onset inflammatory bowel disease" (VEO-IBD), for which a veritable explosion of knowledge has occurred in the last decade. The pathologist plays a crucial role in assisting in the diagnosis of these entities and in ruling out other disorders that enter into the differential diagnosis.

Autoinflammatory Disorders with Perinatal Onset.

Autoinflammatory disorders are rare genetic defects that result in inflammation in the absence of an infectious or autoimmune disease. Although very rare, these disorders can occur in the perinatal period, and recognizing their presentation is important because there are often long-term complications and effective targeted therapies for these disorders. Most of these disorders present with rash, fevers, and laboratory evidence of inflammation. Importantly, these disorders can now be separated into their pathophysiologic mechanisms of action, which can also guide therapies. The article reviews the different mechanisms of autoinflammatory disorders and highlights those disorders that can present in the newborn period.

Complicaciones asociadas a niñas con síndrome de Turner / Complications related to Turner syndrome

No disponible

Blistering diseases in neonates.

PURPOSE OF REVIEW: Neonatal blistering diseases are rare yet potentially fatal. Therefore, it is crucial for clinicians to know its broad range of differential diagnoses. This review discusses the recent literature on the causes and the most appropriate clinical approach to neonatal blistering diseases. RECENT FINDINGS: Neonatal infections are the commonest causes for neonatal blistering. On the other hand, autoimmune blistering diseases are extremely rare with the literature limited to case reports and one systematic review only. Inherited genodermatoses are also rare, with recent developments in epidermolysis bullosa classification. SUMMARY: In conclusion, as neonatal infections are the commonest cause for blistering, any neonate with blistering should have their blister fluid investigated for infection, while an antimicrobial should be initiated early. Autoimmune blistering diseases should be considered in neonates with a maternal history of autoimmune blistering disease. Although pemphigus and bullous pemphigoid have overall good prognoses, linear IgA bullous dermatoses has a poor prognosis and requires aggressive treatment. Inherited genodermatoses should be suspected when there is a family history of genodermatoses or consanguinity. In this case, the clinician should not hesitate to seek dermatology advice, perform a skin biopsy and consider genetic testing.

Genetic sharing and heritability of paediatric age of onset autoimmune diseases.

Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.

Descripción de las enfermedades autoinmunes acompañantes de la diabetes mellitus tipo 1 en un área sanitaria / Description of disease type 1 diabetes mellitus associated autoimmune disease in a health area

FUNDAMENTO Y OBJETIVO: Describir la patología autoinmune al inicio y en el seguimiento asociadas a la diabetes mellitus tipo 1 (DM1), así como exponer la importancia del cribado al comienzo y en el seguimiento de la DM1 en nuestro entorno de trabajo. PACIENTES Y MÉTODOS: Estudio observacional descriptivo transversal del periodo 2001-2011 de pacientes con inicio de DM1 menores de 19 años, correspondientes al Área de Salud Oeste de Valladolid. A todos los pacientes de nuestra muestra durante el período estudiado se realizaron estudios para las enfermedades comórbiles de la DM1 (síndromes autoinmunes poliendocrinos, enfermedad de Addison, anemia perniciosa, vitíligo, enfermedad tiroidea, enfermedad celíaca). RESULTADOS: Se realizaron anticuerpos antitiroideos al ingreso (anticuerpos antiperoxidasa, anti-TPO) en el 85,9% de los pacientes (67 casos), siendo positivos en el 23,9% (16 casos) tanto al inicio como en el seguimiento. La patología tiroidea más común fue la tiroiditis linfocitaria crónica. Se realizó al inicio de la DM1 el cribado de la enfermedad celíaca en el 75,6% (59 casos) de los pacientes, siendo positivos el 3,4% de los pacientes (2 casos), y el 1,7% (un caso) en el seguimiento. Ningún paciente de nuestra población presentó síndromes autoinmunes poliendocrinos, enfermedad de Addison, anemia perniciosa, ni vitíligo. CONCLUSIONES: Quizá con las recomendaciones internacionales actuales y el consenso médico se pueda realizar el cribado rutinario de las enfermedades autoinmunes comórbiles con DM1 de manera estandarizada. Es conveniente realizar el cribado de enfermedades autoinmunes relacionadas con la DM1, tanto en el momento del diagnóstico de la enfermedad como periódicamente en el seguimiento posterior

BACKGROUND AND OBJECTIVE: To describe the onset of autoimmune disease and monitoring associated with type 1 diabetes mellitus (T1DM) in a sample of patients under 19 years, and to explain the importance of the onset and monitoring screening of T1DM in this health area. PATIENTS AND METHODS: An observational descriptive study was conducted on patients under 19 years-old with onset of type 1 diabetes mellitus in the health district of West Valladolid (Spain) during the period from 2001 to 2011. The results of the diagnostic tests for diseases associated with T1DM (autoimmune polyendocrine syndromes, Addison's disease, pernicious anemia, vitiligo, thyroid disease, celiac disease) were recorded). RESULTS: Antithyroid antibodies were performed (peroxidase antibodies, anti-TPO) in 85.9% of patients (67 cases), being positive in 23.9% (16 cases) at onset and during follow-up. The most common thyroid disease was chronic lymphocytic thyroiditis. Screening for celiac disease was performed in 75.6% (59 cases) of patients, being positive in 3.4% of patients at onset, and 1.7% (1 case) in the follow-up. None of the patients in our population sample presented with autoimmune polyendocrine syndromes, Addison's disease, pernicious anemia, or vitiligo. CONCLUSIONS: The results suggest that it may be worthwhile screening for autoimmune diseases associated with T1DM, both at the time of diagnosis of disease and periodically during the follow-up of T1DM. Perhaps, with current international recommendations and medical consensus, screening for autoimmune diseases associated with T1DM could become routine

Neonatal liver cirrhosis without iron overload caused by gestational alloimmune liver disease.

Gestational alloimmune liver disease has emerged as the major cause of antenatal liver injury and failure. It usually manifests as neonatal liver failure with hepatic and extrahepatic iron overload, a clinical presentation called neonatal hemochromatosis. We report on a newborn in whom fetal hepatomegaly was detected during pregnancy and who presented at birth with liver cirrhosis and mild liver dysfunction. Liver biopsy showed the absence of iron overload but strong immunostaining of hepatocytes for the C5b-9 complex, the terminal complement cascade neoantigen occurring specifically during complement activation by the immunoglobulin G-mediated classic pathway, which established the alloimmune nature of the hepatocyte injury. The infant survived with no specific therapy, and follow-up until 36 months showed progressive normalization of all liver parameters. This case report expands the recognized clinical spectrum of congenital alloimmune liver disease to include neonatal liver disease and cirrhosis, even in the absence of siderosis. Such a diagnosis is of utmost importance regarding the necessity for immunotherapy in further pregnancies to avoid recurrence of alloimmune injury.

[Congenital diarrhoea]. / Biegunka wrodzona.

Congenital diarrhoea of heterogenic etiology is a rare cause of chronic diarrhoea. Characteristic features are: onset in the first weeks of life, life-threatening severe dehydratation and electrolyte disorders leading to a necessity of long-term parenteral nutrition. The clinical onset may be delayed and the degree of diarrhoea may be modest, making the diagnosis difficult. The main causes of congenital diarrhoea such as intestine electrolytes, carbohydrates, lipid and protein transport disorders and congenital enzymatic deficiencies, enterocyte polarization disorders, hormonal, immunological, metabolic, genetic and congenital anatomic disorders are presented in the paper. Some of them, such as: microvillus inclusion disease, tufting enteropathy, intestinal anedocrynosis, IPEX syndrome (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome) have been described recently. One of the basic investigations, when congenital diarrhea is suspected, is general examination of the stool, its electrolyte concentration and serum electrolytes and blood gas analysis. Often, small bowel biopsy with histological examination (with the use of electronic microscopy and PAS staining) is indicated. In some cases molecular examination is possible and indicated. In differential diagnosis other, more frequent causes of chronic diarrhea of infancy, have to be excluded. In most of the cases of congenital diarrhoea there is no casual treatment available - usually long-term parenteral nutrition is necessary.

Autoimmune associated congenital heart block: integration of clinical and research clues in the management of the maternal / foetal dyad at risk.

One of the strongest associations with autoantibodies directed to components of the SSA/Ro-SSB/La ribonucleoprotein complex is the development of congenital heart block (CHB) in an offspring, an alarming prospect facing 2% of primigravid mothers with these reactivities. This risk is 10-fold higher in women who have had a previously affected child with CHB. Anti-Ro/La antibodies are necessary but insufficient to cause disease. In vitro and in vivo experiments suggest that the pathogenesis involves exaggerated apoptosis, macrophage/myfibroblast crosstalk, TGFbeta expression and extensive fibrosis in the conducting system and in some cases surrounding myocardium. A disturbing observation is the rapidity of disease progression, with advanced heart block and life-threatening cardiomyopathy observed <2 weeks from normal sinus rhythm. Once 3rd degree (complete) block is identified, reversal has never been achieved, despite dexamethasone. Current strategies include the evaluation of an early echocardiographic marker of injury, such as a prolonged PR interval and the use of IVIG as a preventative measure for pregnancies of mothers with previously affected children.

[From Ipex to foxp3: a new contribution of pediatrics to the understanding of the immune system]. / De l'Ipex à foxp3: une nouvelle contribution de la pédiatrie à la compréhension du système immunitaire.

In 10 years, the neonatal autoimmune enteropathy has been individualized from other causes of neonatal severe protracted diarrheas as a syndrome called Ipex for Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked. Thanks to linkage analyses in affected families, this rare paediatric syndrome with fatal outcome has been correlated to mutations of the foxp3 gene. Homozygous loss of function of foxp3 gene results in the absence of development of a crucial subpopulation of lymphocytes with CD4+CD25+ phenotype, called regulatory T-cells. The study of these lymphocytes allows a better understanding of the immune system homeostasis and of the physiopathology of Ipex syndrome, which is a prerequisite for treatment. Achieving ex vivo manipulation of such lymphocytes will end up on promising applications of cell therapy.

Autoantibody-mediated cardiac arrhythmias: mechanisms and clinical implications.

Cardiac arrhythmias, including conduction defects and tach- yarrhythmias, represent an important source of morbidity and mortality in industrialized countries. Among the different pathophysiological mechanisms involved in the arrhythmogenesis, an inappropriate activation of the immune system represents a field of recent increasing interest. In fact, a large amount of studies suggest that specific autoantibody may be significantly involved in the pathogenesis of cardiac arrhythmias not only in the course of systemic autoimmune disease, but also in a number of rhythm disorders currently classified as "idiopathic." Although the strongest evidence concerns the relationship between anti-Ro/SSA antibodies and the development of congenital heart block in foetus and newborn, other specific autoantibodies demonstrated the aptitude to affect directly the myocardial tissue, thus producing interference in its bioelectric activity thereby leading to rhythm disorders, also life-threatening. The identification of an immunological autoantibody-mediated mechanism opens new perspectives in the treatment and prevention of cardiac arrhythmias in such patients, including the use of immunosuppressive agents and/or the removal of autoantibodies by immuno-adsorption technique.

Autoimmune lymphoproliferative syndrome (ALPS): a case with congenital onset.

We describe a case of autoimmune lymphoproliferative syndrome (ALPS), which is very unusual with regard to a clinical onset soon after birth, and a clinical picture dominated by splenomegaly, jaundice, and consumptive peripheral blood cytopenias, with minimal lymphadenopathy. Our documented close follow up demonstrated initial involvement of the spleen, followed by involvement of the bone marrow and the peripheral blood. The patient underwent bone marrow transplant and is alive and well 20 months after diagnosis.

Transforming growth factor beta1 in the pathogenesis of autoimmune congenital complete heart block: lesson from twins and triplets discordant for the disease.

OBJECTIVE: Clinical evidence and experimental evidence suggest that anti-Ro/La autoantibodies are necessary but not sufficient for the development of congenital complete heart block (CCHB). Maternal, fetal, and environmental factors may also contribute to heart damage in CCHB. The aim of our study was to investigate polymorphisms of transforming growth factor beta1 (TGFbeta1) and tumor necrosis factor alpha (TNFalpha) genes in twins and triplets discordant for CCHB whose mothers are anti-Ro/La positive. METHODS: We studied 2 families in which 1 of the mothers gave birth to triplets and the other gave birth to twins. Only 1 child in each family was affected by CCHB, although 1 of the triplets had incomplete heart block. We analyzed TNFalpha and TGFbeta1 polymorphisms in the 2 babies with CCHB and their siblings. TNFalpha polymorphisms at the promoter region and TGFbeta1 polymorphisms at codons 10 and 25 were determined using polymerase chain reaction-restriction fragment length polymorphism analysis. In addition, the production of TGFbeta1 and TNFalpha by resting or mitogen-stimulated peripheral blood mononuclear cells in cell culture supernatants was evaluated by enzyme-linked immunosorbent assay. RESULTS: The profibrotic TGFbeta1 genotype was detected in the twin with CCHB but not in the healthy twin, while all of the triplets displayed the same TGFbeta1 genotype at codon 10. Peripheral blood mononuclear cells from the children with CCHB displayed higher spontaneous and mitogen-stimulated TGFbeta1 secretion than was observed in their siblings. No differences regarding TNFalpha polymorphisms and secretion of TNFalpha were observed. CONCLUSION: The results of this study suggest that, besides anti-Ro/La autoantibodies, a fetal profibrotic response might contribute to the development of CCHB, but additional pathogenic mechanism(s) are also likely to play a role.

Autoantibodies against the serotoninergic 5-HT4 receptor and congenital heart block: a reassessment.

The specificity of autoantibodies against the serotoninergic 5-HT4 receptor in congenital heart block has led to conflicting observations. In order to clarify the situation, a collaborative effort was undertaken to discover the reasons for these discrepancies and to reassess the importance of such autoantibodies by making use of the Research Registry for Neonatal Lupus. Sera from 128 patients (101 anti-SSA/Ro52 positive mothers among which 74 have children with congenital heart block (CHB), 9 anti-SSA/Ro52 negative patients of which 1 had a child with heart block and 18 healthy donors) were assessed in a single blind test using an ELISA coated with a 5-HT4 receptor-derived peptide. Discrepancies between previous observations in our two groups could be ascribed to small differences in the set up of the assay. Of the 75 sera from mothers of children with CHB, 12 were reactive with the 5-HT4 peptide. Four sera among which three were from 35 Ro52 negative mothers without affected children as well as 2 in the 18 controls were positive. Interestingly, in 1 mother with an isolated child with CHB but who had no detectable anti-SSA/Ro52 antibodies and 1 mother with a child with a structural heart block and no detectable antibodies to any component of SSA/Ro, reactivity with the 5-HT4 receptor was noted. While 5-HT4 receptor autoantibodies do not have the predictive value of anti-Ro52 autoantibodies, the presence of these antibodies in a minor subset of mothers whose children have CHB suggests an additional risk factor which may contribute to the pathogenesis of disease.