Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus.

An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients' blood cells revealed typical alterations associated with autoimmunity and all patients presented with autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.

Development of clinical and laboratory biomarkers in an international cohort of 428 children with lupus nephritis.

BACKGROUND: Lupus nephritis (LN) is a very severe manifestation of lupus. There is no consensus on which treatment goals should be achieved to protect kidney function in children with LN. METHODS: We retrospectively analyzed trends of commonly used laboratory biomarkers of 428 patients (≤ 18 years old) with biopsy-proven LN class ≥ III. We compared data of patients who developed stable kidney remission from 6 to 24 months with those who did not. RESULTS: Twenty-five percent of patients maintained kidney stable remission while 75% did not. More patients with stable kidney remission showed normal hemoglobin and erythrocyte sedimentation rate from 6 to 24 months compared to the group without stable kidney remission. eGFR ≥ 90 ml/min/1.73m2 at onset predicted the development of stable kidney remission (93.8%) compared to 64.7% in those without stable remission (P < 0.00001). At diagnosis, 5.9% and 20.2% of the patients showed no proteinuria in the group with and without stable kidney remission, respectively (P = 0.0001). dsDNA antibodies decreased from onset of treatment mainly during the first 3 months in all groups, but more than 50% of all patients in both groups never normalized after 6 months. Complement C3 and C4 increased mainly in the first 3 months in all patients without any significant difference. CONCLUSIONS: Normal eGFR and the absence of proteinuria at onset were predictors of stable kidney remission. Significantly more children showed normal levels of Hb and erythrocyte sedimentation rate (ESR) from 6 to 24 months in the group with stable kidney remission.

Attitudes and Behaviors towards Food and Weight in Late Pregnancy: A Comparative Approach between Individuals with and without Previous Bariatric Surgery.

The aims of this study were to compare, between pregnant individuals with and without bariatric surgery: (1) eating behaviors, (2) intuitive eating components and, (3) attitudes towards weight gain. This retrospective study included data collected in healthy pregnant individuals with and without previous bariatric surgery who were recruited at the Centre Hospitalier Universitaire (CHU) de Québec-Université Laval. Pregnant individuals who underwent bariatric surgery (biliopancreatic bypass with duodenal switch [n = 14] or sleeve gastrectomy [n = 5]) were individually matched, for age (±0.4 years) and body mass index (BMI) (±0.3 kg/m2), with pregnant individuals who have not received bariatric surgery. In the second trimester, participants completed the Three Factor Eating Questionnaire (TFEQ) and the Intuitive Eating Scale 2 (IES-2). In the third trimester, participants completed the French version of the Pregnancy Weight Gain Attitude Scale assessing attitudes towards weight gain. Pregnant individuals who have had bariatric surgery had a higher score for flexible restraint and a lower score for situational susceptibility to disinhibition compared to individuals who have not had undergone bariatric surgery (2.89 ± 1.15 vs. 1.95 ± 1.31; p = 0.04 and 1.11 ± 1.29 vs. 2.79 ± 1.44, respectively; p < 0.001). Regarding intuitive eating, pregnant individuals who experienced bariatric surgery had a higher score for reliance on internal hunger and satiety cues and a lower one for unconditional permission to eat compared with those who had not experienced bariatric surgery (3.99 ± 0.81 vs. 3.30 ± 1.03; p = 0.02 and 3.28 ± 0.54 vs. 3.61 ± 0.68, respectively; p = 0.03). No difference in attitudes towards weight gain was observed between groups. Overall, pregnant individuals who had undergone bariatric surgery had different eating behaviors and intuitive eating components compared to pregnant individuals without bariatric surgery. These results need to be confirmed in further studies with larger sample sizes.

Genome-wide comparative methylation analysis reveals the fate of germ stem cells after surrogate production in teleost.

BACKGROUND: Surrogate production by germline stem cell transplantation is a powerful method to produce donor-derived gametes via a host, a practice known as surrogacy. The gametes produced by surrogates are often analysed on the basis of their morphology and species-specific genotyping, which enables conclusion to be drawn about the donor's characteristics. However, in-depth information, such as data on epigenetic changes, is rarely acquired. Germ cells develop in close contact with supporting somatic cells during gametogenesis in vertebrates, and we hypothesize that the recipient's gonadal environment may cause epigenetic changes in produced gametes and progeny. Here, we extensively characterize the DNA methylome of donor-derived sperm and their intergenerational effects in both inter- and intraspecific surrogates. RESULTS: We found more than 3000 differentially methylated regions in both the sperm and progeny derived from inter- and intraspecific surrogates. Hypermethylation in the promoter regions of the protocadherin gamma gene in the intraspecific surrogates was found to be associated with germline transmission. On the contrary, gene expression level and the embryonic development of the offspring remained unaffected. We also discovered MAPK/p53 pathway disruption in interspecific surrogates due to promoter hypermethylation and identified that the inefficient removal of meiotic-arrested endogenous germ cells in hybrid gonads led to the production of infertile spermatozoa. CONCLUSIONS: Donor-derived sperm and progeny from inter- and intraspecific surrogates were more globally hypermethylated than those of the donors. The observed changes in DNA methylation marks in the surrogates had no significant phenotypic effects in the offspring.