The endometrial transcriptome of infertile women with and without implantation failure.

INTRODUCTION: Implantation failure after transferring morphologically "good-quality" embryos in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) may be explained by impaired endometrial receptivity. Analyzing the endometrial transcriptome analysis may reveal the underlying processes and could help in guiding prognosis and using targeted interventions for infertility. This exploratory study investigated whether the endometrial transcriptome profile was associated with short-term or long-term implantation outcomes (ie success or failure). MATERIAL AND METHODS: Mid-luteal phase endometrial biopsies of 107 infertile women with one full failed IVF/ICSI cycle, obtained within an endometrial scratching trial, were subjected to RNA-sequencing and differentially expressed genes analysis with covariate adjustment (age, body mass index, luteinizing hormone [LH]-day). Endometrial transcriptomes were compared between implantation failure and success groups in the short term (after the second fresh IVF/ICSI cycle) and long term (including all fresh and frozen cycles within 12 months). The short-term analysis included 85/107 women (33 ongoing pregnancy vs 52 no pregnancy), excluding 22/107 women. The long-term analysis included 46/107 women (23 'fertile' group, ie infertile women with a live birth after ≤3 embryos transferred vs 23 recurrent implantation failure group, ie no live birth after ≥3 good quality embryos transferred), excluding 61/107 women not fitting these categories. As both analyses drew from the same pool of 107 samples, there was some sample overlap. Additionally, cell type enrichment scores and endometrial receptivity were analyzed, and an endometrial development pseudo-timeline was constructed to estimate transcriptomic deviations from the optimum receptivity day (LH + 7), denoted as ΔWOI (window of implantation). RESULTS: There were no significantly differentially expressed genes between implantation failure and success groups in either the short-term or long-term analyses. Principal component analysis initially showed two clusters in the long-term analysis, unrelated to clinical phenotype and no longer distinct following covariate adjustment. Cell type enrichment scores did not differ significantly between groups in both analyses. However, endometrial receptivity analysis demonstrated a potentially significant displacement of the WOI in the non-pregnant group compared with the ongoing pregnant group in the short-term analysis. CONCLUSIONS: No distinct endometrial transcriptome profile was associated with either implantation failure or success in infertile women. However, there may be differences in the extent to which the WOI is displaced.

Value-based healthcare in fertility care using relevant outcome measures for the full cycle of care leading towards shared decision-making: a retrospective cohort study.

OBJECTIVE: To determine if the introduction of value-based healthcare (VBHC) in fertility care can help to create realistic expectations in patients resulting in increased patient value, by demonstrating the relevance of defining outcome measures that truly matter to subfertile patients. DESIGN: Retrospective cohort study. SETTING: Tertiary fertility centre. RESULTS: Time to pregnancy (TTP) and ongoing pregnancy rate (OPR), as a proxy for the live birth rate, for the full cycle of fertility care, regardless of which and how many treatment cycles performed, were identified as the most relevant medical outcome measures. Outcome measures were incorporated into a digital dashboard by using anonymised and validated patient data from the electronic patient file. We were able to present the TTP and OPR for the population as a whole as well as stratified for age, diagnosis, gravidity and type of gamete source used thereby resulting in a virtual 'patient like me' resembling the individual patient in the consultation room. CONCLUSION: We have shown that, by applying VBHC principles, relevant outcome measures can be generated and stratified for different patient characteristics, in order to develop a virtual 'patient like me'. This virtual 'patient like me' can be used in the consulting room in the form of a digital dashboard, attributing to create realistic patient expectations. This facilitates healthcare providers and patients in shared decision-making.

An integrative analysis of endometrial steroid metabolism and transcriptome in relation to endometrial receptivity in in vitro fertilization patients.

OBJECTIVE: To study the relationship between the steroid concentration in the endometrium, in serum, and the gene expression level of steroid-metabolizing enzymes in the context of endometrial receptivity in in vitro fertilization (IVF) patients. DESIGN: Case-control study of 40 IVF patients recruited in the SCRaTCH study (NTR5342), a randomized controlled trial investigating pregnancy outcome after "endometrial scratching." Endometrial biopsies and serum were obtained from patients with a first failed IVF cycle randomized to the endometrial scratch in the midluteal phase of the natural cycle before the next fresh embryo transfer during the second IVF cycle. SETTING: University hopsital. PATIENTS: Twenty women with clinical pregnancy were compared with 20 women who did not conceive after fresh embryo transfer. Cases and controls were matched for primary vs. secondary infertility, embryo quality, and age. INTERVENTION: None. MAIN OUTCOME MEASURE(S): Steroid concentrations in endometrial tissue homogenates and serum were measured with liquid chromatography-mass spectrometry. The endometrial transcriptome was profiled by RNA-sequencing, followed by principal component analysis and differential expression analysis. False discovery rate-adjusted and log-fold change >|0.5| were selected as the threshold for differentially expressed genes. RESULT(S): Estrogen levels were comparable in both serum (n = 16) and endometrium (n = 40). Androgens and 17-hydroxyprogesterone were higher in serum than that in endometrium. Although steroid levels did not vary between pregnant and nonpregnant groups, subgroup analysis of primary women with infertility showed a significantly lower estrone concentration and estrone:androstenedione ratio in serum of the pregnant group (n = 5) compared with the nonpregnant group (n = 2). Expression of 34 out of 46 genes encoding the enzymes controlling the local steroid metabolism was detected, and estrogen receptor ß gene was differentially expressed between pregnant and nonpregnant women. When only the primary infertile group was considered, 28 genes were differentially expressed between pregnant and nonpregnant women, including HSD11B2, that catalyzes the conversion of cortisol into cortisone. CONCLUSION(S): Steroidomic and transcriptomic analyses show that steroid concentrations are regulated by the local metabolism in the endometrium. Although no differences were found in endometrial steroid concentration in the pregnant and nonpregnant IVF patients, primary women with infertility showed deviations in steroid levels and gene expression, indicating that a more homogeneous patient group is required to uncover the exact role of steroid metabolism in endometrial receptivity. CLINICAL TRIAL REGISTRATION NUMBER: The study was registered in the Dutch trial registry (www.trialregister.nl), registration number NL5193/NTR5342, available at https://trialsearch.who.int/Trial2.aspx?TrialID=NTR6687. The date of registration is July 31, 2015. The first enrollment is on January 1, 2016.

The endometrial microbiota of women with or without a live birth within 12 months after a first failed IVF/ICSI cycle.

The endometrial microbiota composition may be associated with implantation success. However, a 'core' composition has not yet been defined. This exploratory study analysed the endometrial microbiota by 16S rRNA sequencing (V1-V2 region) of 141 infertile women whose first IVF/ICSI cycle failed and compared the microbiota profiles of women with and without a live birth within 12 months of follow-up, and by infertility cause and type. Lactobacillus was the most abundant genus in the majority of samples. Women with a live birth compared to those without had significantly higher Lactobacillus crispatus relative abundance (RA) (p = 0.029), and a smaller proportion of them had ≤ 10% L. crispatus RA (42.1% and 70.4%, respectively; p = 0.015). A smaller proportion of women in the male factor infertility group had ≤ 10% L. crispatus RA compared to women in the unexplained and other infertility causes groups combined (p = 0.030). Women with primary infertility compared to secondary infertility had significantly higher L. crispatus RA (p = 0.004); lower proportions of them had ≤ 10% L. crispatus RA (p = 0.009) and > 10% Gardnerella vaginalis RA (p = 0.019). In conclusion, IVF/ICSI success may be associated with L. crispatus RA and secondary infertility with endometrial dysbiosis, more often than primary infertility. These hypotheses should be tested in rigorous well-powered longitudinal studies.

[Isolated fallopian tubal torsion; rare or overlooked?] / Geïsoleerde tubatorsie: zeldzaam of miskend?

Isolated fallopian tubal torsion (IFTT) is a rare cause of lower abdominal pain. It's difficult to diagnose preoperatively due to non-specific clinical symptoms. Furthermore, IFTT is often not considered in the differential diagnosis. Prompt diagnosis is critical, to prevent progression of symptoms and to maintain fertility; therefore, this article discusses diagnostic pitfalls and reports on key imaging features of IFTT that may facilitate preoperative diagnosis. IFTT should be suspected in a female patient with acute lower abdominal pain and a unilateral pelvic mass close to a normal ipsilateral ovary; there may be a history of prior tubal ligation. Specific imaging findings include the sonographic 'whirlpool sign' and absent flow during colour Doppler ultrasound. CT is often performed when the diagnosis remains unclear, but has no clinical consequences. IFTT requires emergency surgical treatment; detorsion without resection can be considered in women who would like to retain potential future fertility, but salpingectomy is often inevitable due to necrosis.

Uterine selection of human embryos at implantation.

Human embryos frequently harbor large-scale complex chromosomal errors that impede normal development. Affected embryos may fail to implant although many first breach the endometrial epithelium and embed in the decidualizing stroma before being rejected via mechanisms that are poorly understood. Here we show that developmentally impaired human embryos elicit an endoplasmic stress response in human decidual cells. A stress response was also evident upon in vivo exposure of mouse uteri to culture medium conditioned by low-quality human embryos. By contrast, signals emanating from developmentally competent embryos activated a focused gene network enriched in metabolic enzymes and implantation factors. We further show that trypsin, a serine protease released by pre-implantation embryos, elicits Ca(2+) signaling in endometrial epithelial cells. Competent human embryos triggered short-lived oscillatory Ca(2+) fluxes whereas low-quality embryos caused a heightened and prolonged Ca(2+) response. Thus, distinct positive and negative mechanisms contribute to active selection of human embryos at implantation.

Reprint of: In-vitro model systems for the study of human embryo-endometrium interactions.

Implantation requires highly orchestrated interactions between the developing embryo and maternal endometrium. The association between abnormal implantation and reproductive failure is evident, both in normal pregnancy and in assisted reproduction patients. Failure of implantation is the pregnancy rate-limiting step in assisted reproduction, but, as yet, empirical interventions have largely failed to address this problem. Better understanding of the mechanisms underlying human embryo-endometrium signalling is a prerequisite for the further improvement of assisted reproduction outcomes and the development of effective interventions to prevent early pregnancy loss. Studying human embryo implantation is challenging since in-vivo experiments are impractical and unethical, and studies in animal models do not always translate well to humans. However, in recent years in-vitro models have been shown to provide a promising way forward. This review discusses the principal models used to study early human embryo development and initial stages of implantation in vitro. While each model has limitations, exploiting these models will improve understanding of the molecular mechanisms and embryo-endometrium cross-talk at the early implantation site. They provide valuable tools to study early embryo development and pathophysiology of reproductive disorders and have revealed novel disease mechanisms such as the role of epigenetic modifications in recurrent miscarriage.

In-vitro model systems for the study of human embryo-endometrium interactions.

Implantation requires highly orchestrated interactions between the developing embryo and maternal endometrium. The association between abnormal implantation and reproductive failure is evident, both in normal pregnancy and in assisted reproduction patients. Failure of implantation is the pregnancy rate-limiting step in assisted reproduction, but, as yet, empirical interventions have largely failed to address this problem. Better understanding of the mechanisms underlying human embryo-endometrium signalling is a prerequisite for the further improvement of assisted reproduction outcomes and the development of effective interventions to prevent early pregnancy loss. Studying human embryo implantation is challenging since in-vivo experiments are impractical and unethical, and studies in animal models do not always translate well to humans. However, in recent years in-vitro models have been shown to provide a promising way forward. This review discusses the principal models used to study early human embryo development and initial stages of implantation in vitro. While each model has limitations, exploiting these models will improve understanding of the molecular mechanisms and embryo-endometrium cross-talk at the early implantation site. They provide valuable tools to study early embryo development and pathophysiology of reproductive disorders and have revealed novel disease mechanisms such as the role of epigenetic modifications in recurrent miscarriage.

Cell lineage specific distribution of H3K27 trimethylation accumulation in an in vitro model for human implantation.

Female mammals inactivate one of their two X-chromosomes to compensate for the difference in gene-dosage with males that have just one X-chromosome. X-chromosome inactivation is initiated by the expression of the non-coding RNA Xist, which coats the X-chromosome in cis and triggers gene silencing. In early mouse development the paternal X-chromosome is initially inactivated in all cells of cleavage stage embryos (imprinted X-inactivation) followed by reactivation of the inactivated paternal X-chromosome exclusively in the epiblast precursors of blastocysts, resulting temporarily in the presence of two active X-chromosomes in this specific lineage. Shortly thereafter, epiblast cells randomly inactivate either the maternal or the paternal X-chromosome. XCI is accompanied by the accumulation of histone 3 lysine 27 trimethylation (H3K27me3) marks on the condensed X-chromosome. It is still poorly understood how XCI is regulated during early human development. Here we have investigated lineage development and the distribution of H3K27me3 foci in human embryos derived from an in-vitro model for human implantation. In this system, embryos are co-cultured on decidualized endometrial stromal cells up to day 8, which allows the culture period to be extended for an additional two days. We demonstrate that after the co-culture period, the inner cell masses have relatively high cell numbers and that the GATA4-positive hypoblast lineage and OCT4-positive epiblast cell lineage in these embryos have segregated. H3K27me3 foci were observed in ∼25% of the trophectoderm cells and in ∼7.5% of the hypoblast cells, but not in epiblast cells. In contrast with day 8 embryos derived from the co-cultures, foci of H3K27me3 were not observed in embryos at day 5 of development derived from regular IVF-cultures. These findings indicate that the dynamics of H3K27me3 accumulation on the X-chromosome in human development is regulated in a lineage specific fashion.

The fate of the mosaic embryo: chromosomal constitution and development of Day 4, 5 and 8 human embryos.

BACKGROUND: Post-zygotic chromosome segregation errors are very common in human embryos after in vitro fertilization, resulting in mosaic embryos. However, the significance of mosaicism for the developmental potential of early embryos is unknown. We assessed chromosomal constitution and development of embryos from compaction to the peri-implantation stage. METHODS: From 112 cryopreserved Day 4 human embryos donated for research, 21 were immediately fixed and all cells were analysed by fluorescent in situ hybridization (FISH) for chromosomes 1, 7, 13, 15, 16, 18, 21, 22, X and Y. The remaining 91 embryos were thawed, with 54 embryos undergoing biopsy of one or two cells which were fixed and analysed by FISH. Biopsied embryos were kept in standard culture conditions for 24 h. Embryos arrested before cavitation (n = 24) were fixed whereas developing Day 5 blastocysts (n = 24) were co-cultured for a further 72 h on an endometrial monolayer followed by fixation. Cell numbers were counted and all nuclei were analysed by FISH. Data from a previous FISH analysis on cryopreserved good-quality Day 5 blastocysts (n = 36) were also included in the present study. RESULTS: FISH analysis was successful for 18 Day 4 fixed embryos and, according to our definition, 83% were mosaic and 11% showed a chaotic chromosomal constitution. FISH analysis of two blastomeres from Day 4 developing embryos showed that 54% were mosaic, 40% were normal and 6% were abnormal. Analysis of Day 4, 5 and 8 whole embryos showed a decrease in incidence of mosaicism over time, from 83% on Day 4 to 42% on Day 8. A significant positive correlation was observed between the total cell number and the percentage of normal cells in developing Day 5 and Day 8 embryos but not in developing Day 4 or embryos arrested before cavitation. CONCLUSIONS: These data suggest that both the developmental arrest of a significant proportion of mosaic embryos on Day 4, and the cell death or reduced proliferation of aneuploid cells within an embryo may be responsible for the observed decrease of aneuploid blastomeres from compaction to the peri-implantation stage.

Natural selection of human embryos: decidualizing endometrial stromal cells serve as sensors of embryo quality upon implantation.

BACKGROUND: Pregnancy is widely viewed as dependent upon an intimate dialogue, mediated by locally secreted factors between a developmentally competent embryo and a receptive endometrium. Reproductive success in humans is however limited, largely because of the high prevalence of chromosomally abnormal preimplantation embryos. Moreover, the transient period of endometrial receptivity in humans uniquely coincides with differentiation of endometrial stromal cells (ESCs) into highly specialized decidual cells, which in the absence of pregnancy invariably triggers menstruation. The role of cyclic decidualization of the endometrium in the implantation process and the nature of the decidual cytokines and growth factors that mediate the crosstalk with the embryo are unknown. METHODOLOGY/PRINCIPAL FINDINGS: We employed a human co-culture model, consisting of decidualizing ESCs and single hatched blastocysts, to identify the soluble factors involved in implantation. Over the 3-day co-culture period, approximately 75% of embryos arrested whereas the remainder showed normal development. The levels of 14 implantation factors secreted by the stromal cells were determined by multiplex immunoassay. Surprisingly, the presence of a developing embryo had no significant effect on decidual secretions, apart from a modest reduction in IL-5 levels. In contrast, arresting embryos triggered a strong response, characterized by selective inhibition of IL-1beta, -6, -10, -17, -18, eotaxin, and HB-EGF secretion. Co-cultures were repeated with undifferentiated ESCs but none of the secreted cytokines were affected by the presence of a developing or arresting embryo. CONCLUSIONS: Human ESCs become biosensors of embryo quality upon differentiation into decidual cells. In view of the high incidence of gross chromosomal errors in human preimplantation embryos, cyclic decidualization followed by menstrual shedding may represent a mechanism of natural embryo selection that limits maternal investment in developmentally impaired pregnancies.

Natural selection of human embryos: impaired decidualization of endometrium disables embryo-maternal interactions and causes recurrent pregnancy loss.

BACKGROUND: Recurrent pregnancy loss (RPL), defined as 3 or more consecutive miscarriages, is widely attributed either to repeated chromosomal instability in the conceptus or to uterine factors that are poorly defined. We tested the hypothesis that abnormal cyclic differentiation of endometrial stromal cells (ESCs) into specialized decidual cells predisposes to RPL, based on the observation that this process may not only be indispensable for placenta formation in pregnancy but also for embryo recognition and selection at time of implantation. METHODOLOGY/PRINCIPAL FINDINGS: Analysis of mid-secretory endometrial biopsies demonstrated that RPL is associated with decreased expression of the decidual marker prolactin (PRL) but increased levels of prokineticin-1 (PROK1), a cytokine that promotes implantation. These in vivo findings were entirely recapitulated when ESCs were purified from patients with and without a history of RPL and decidualized in culture. In addition to attenuated PRL production and prolonged and enhanced PROK1 expression, RPL was further associated with a complete dysregulation of both markers upon treatment of ESC cultures with human chorionic gonadotropin, a glycoprotein hormone abundantly expressed by the implanting embryo. We postulated that impaired embryo recognition and selection would clinically be associated with increased fecundity, defined by short time-to-pregnancy (TTP) intervals. Woman-based analysis of the mean and mode TTP in a cohort of 560 RPL patients showed that 40% can be considered "superfertile", defined by a mean TTP of 3 months or less. CONCLUSIONS: Impaired cyclic decidualization of the endometrium facilitates implantation yet predisposes to subsequent pregnancy failure by disabling natural embryo selection and by disrupting the maternal responses to embryonic signals. These findings suggest a novel pathological pathway that unifies maternal and embryonic causes of RPL.

Heat shock protein-derived T-cell epitopes contribute to autoimmune inflammation in pediatric Crohn's disease.

Pediatric Crohn's disease is a chronic auto inflammatory bowel disorder affecting children under the age of 17 years. A putative etiopathogenesis of Crohn's disease (CD) is associated with disregulation of immune response to antigens commonly present in the gut microenvironment. Heat shock proteins (HSP) have been identified as ubiquitous antigens with the ability to modulate inflammatory responses associated with several autoimmune diseases. The present study tested the contribution of immune responses to HSP in the amplification of autoimmune inflammation in chronically inflamed mucosa of pediatric CD patients. Colonic biopsies obtained from normal and CD mucosa were stimulated with pairs of Pan HLA-DR binder HSP60-derived peptides (human/bacterial homologues). The modulation of RNA and protein levels of induced proinflammatory cytokines were measured. We identified two epitopes capable of sustaining proinflammatory responses, specifically TNF< and IFN induction, in the inflamed intestinal mucosa in CD patients. The responses correlated positively with clinical and histological measurements of disease activity, thus suggesting a contribution of immune responses to HSP in pediatric CD site-specific mucosal inflammation.

Review: in vitro models for the study of early human embryo-endometrium interactions.

The molecular interactions at the embryo-endometrial interface during the period of blastocyst adhesion and subsequent invasion into the endometrial stroma are not fully understood. Current knowledge is primarily based on evidence from implantation studies in the mouse. The degree to which data derived from animal studies mirror human implantation is limited. The ethical and technical challenges studying implantation in the human can partly be overcome by designing in vitro models of embryo-endometrium interactions. In this review, the principal models in current use are described. Basic models using tissue explants and monolayers are distinguished from complex models using multilayer isolated cells, and embryo-endometrium coculture systems used therapeutically. Although there are limitations to current approaches, a number of research questions that could be addressed using these techniques are identified.

The androgen and progesterone receptors regulate distinct gene networks and cellular functions in decidualizing endometrium.

Progesterone is indispensable for differentiation of human endometrial stromal cells (HESCs) into decidual cells, a process that critically controls embryo implantation. We now show an important role for androgen receptor (AR) signaling in this differentiation process. Decreased posttranslational modification of the AR by small ubiquitin-like modifier (SUMO)-1 in decidualizing cells accounted for increased responsiveness to androgen. By combining small interfering RNA technology with genome-wide expression profiling, we found that AR and progesterone receptor (PR) regulate the expression of distinct decidual gene networks. Ingenuity pathway analysis implicated a preponderance of AR-induced genes in cytoskeletal organization and cell motility, whereas analysis of AR-repressed genes suggested involvement in cell cycle regulation. Functionally, AR depletion prevented differentiation-dependent stress fiber formation and promoted motility and proliferation of decidualizing cells. In comparison, PR depletion perturbed the expression of many more genes, underscoring the importance of this nuclear receptor in diverse cellular functions. However, several PR-dependent genes encode for signaling intermediates, and knockdown of PR, but not AR, compromised activation of WNT/beta-catenin, TGFbeta/SMAD, and signal transducer and activator of transcription (STAT) pathways in decidualizing cells. Thus, the nonredundant function of the AR in decidualizing HESCs, centered on cytoskeletal organization and cell cycle regulation, implies an important role for androgens in modulating fetal-maternal interactions. Moreover, we show that PR regulates HESC differentiation, at least in part, by reprogramming growth factor and cytokine signal transduction.

Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network.

Despite a rapidly accumulating clinical experience with autologous stem cell transplantation (ASCT) as a treatment for severe refractory autoimmune disease, data on the mechanisms by which ASCT induces immune tolerance are still very scarce. In this study it is shown that ASCT restores immunologic self-tolerance in juvenile idiopathic arthritis (JIA) via 2 mechanisms. First, ASCT induces a restoration of the frequency of FoxP3 expressing CD4+CD25bright regulatory T cells (Tregs) from severely reduced numbers before ASCT to normal levels after ASCT. This recovery is due to a preferential homeostatic expansion of CD4+CD25+ Tregs during the lymphopenic phase of immunereconstitution, as measured by Ki67 and CD44 expression, and to a renewed thymopoiesis of naive mRNA FoxP3 expressing CD4+CD25+ Tregs after ASCT. Second, using artificial antigen-presenting cells to specifically isolate self-reactive T cells, we demonstrate that ASCT induces autoimmune cells to deviate from a proinflammatory phenotype (mRNA interferon-gamma [IFN-gamma] and T-bet high) to a tolerant phenotype (mRNA interleukin-10 [IL-10] and GATA-3 high). These data are the first to demonstrate the qualitative immunologic changes that are responsible for the induction of immune tolerance by ASCT for JIA: the restoration of the CD4+CD25+ immune regulatory network and reprogramming of autoreactive T cells.

Tolerogenic immune responses to novel T-cell epitopes from heat-shock protein 60 in juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis is a heterogeneous autoimmune disease characterised by chronic inflammation of one or more joints. In patients with this disease, T-cell reactivity to autologous heat-shock protein 60 (HSP60) is associated with a favourable prognosis. We sought to identify HSP60 T-cell epitopes to find potential targets for HSP60 immunotherapy and to assess whether immune responses to these epitopes contribute to the distinct clinical outcome of this disease. METHODS: We identified eight potential epitopes using a computer algorithm from both self and microbial HSP60 binding to many HLA-DR molecules. We analysed the pattern of T-cell responses induced by these HSP60 peptides in peripheral-blood mononuclear cells (PBMC) of 57 patients with juvenile idiopathic arthritis, 27 healthy controls, and 20 disease controls. We undertook in-vitro MHC binding studies with the identified peptides, and HLA class II typing of a subset of patients with juvenile idiopathic arthritis. FINDINGS: Five of the eight peptides identified yielded proliferative T-cell responses in 50-70% of PBMC from patients with juvenile idiopathic arthritis irrespective of MHC genotype, but not in PBMC from healthy or disease controls. Although PBMC from both patients with juvenile idiopathic arthritis and healthy controls produced interferon gamma in response to these peptides, only PBMC from patients with the disease produced interleukin 10. INTERPRETATION: The recorded T-cell-induction in juvenile idiopathic arthritis is tolerogenic. In patients with oligoarticular disease, the immune responses to the HSP60 epitopes identified could contribute to disease remission. RELEVANCE TO PRACTICE: The broad recognition of these HSP60 epitopes in a population of patients with polymorphic MHC genotypes opens the way for HSP60-peptide immunotherapy, representing a novel treatment option to specifically modulate the immune system in patients with juvenile idiopathic arthritis.

The role of immune tolerance in preventing and treating arthritis.

It has become increasingly clear that the innate and adaptive arms of the immune response cooperate in generating autoimmune damage in the pathogenesis of rheumatoid arthritis and juvenile idiopathic arthritis. Treatment targets the immunologic pathophysiology of the disease and is based on regaining immune tolerance. Recently introduced biological agents neutralize or simply block cytokines and their proinflammatory pathways, with favorable clinical outcome. However, major downsides are their lack of specificity and the need of continuous administration to be effective. Possibly, more can be gained from a specific approach. Indeed, recent findings suggest that targeting antigen-specific T cells can reinstate regulatory mechanisms and thus induce immune tolerization. This improved understanding has paved the way to novel immunotherapeutic approaches, some of which will be discussed here.