Selective drop-out in successive in-vitro fertilization attempts: the pendulum danger.

Success rates from in-vitro fertilization (IVF) in the long term are dependent on selection procedures with regard to continuation into further IVF episodes. Publications on success rates in successive episodes will give incentives to adapt selection criteria, but if these publications do not deal explicitly with patient selection, the adaptations might change their direction every time: the pendulum danger.     

Analysis of B cell receptor production and rearrangement. Part I. Light chain rearrangement

A probabilistic model of allelic exclusion fails to explain the status of receptor genes and the receptor phenotype of most B cells. A large proportion of B cells have incompletely rearranged H and/or L chain genes (e.g. kappa0/kappa+) and most B cells express only one receptor. These properties seem to require deterministic features of B cell development such as special mechanisms that stop rearrangement. However, receptor editing has revealed that rearrangement-stop is not stable and that multi-receptor lymphocytes make up a significant fraction of certain B and T cell populations. Consequently we have revived the purely probabilistic approach in a model that now includes receptor editing and allows for some multi-receptor B cells. We find that this model can explain the observed properties of B cells when the frequency of self-reactive B cells is high. Indeed, as we illustrate for anti-DNA, this is the case. Hence the probabilistic model has life and assiduous use of the model suggests unexpected but not unrealistic features of lymphocyte development.     

Analysis of B cell subsets following pancreatic islet cell transplantation in a patient with type 1 diabetes by cytometric fingerprinting

Manual gating of bivariate plots remains the most frequently used data analysis method in flow cytometry. However, gating is operator-dependent and cumbersome, particularly with the increasing complexity of modern multicolor immunophenotyping data. A method that can remove operator bias, enable systematic and thorough analysis of complex high-dimensional data, correlate temporal changes in different subsets and lead to biomarker discovery is needed. Here we apply such a method, called cytometric fingerprinting (CF), to data obtained on peripheral blood B cells from an adult patient with type-1 diabetes who underwent pancreatic islet transplantation. We establish that CF can be used to analyze longitudinal trends in immunophenotypic data, and show that results from CF are comparable to those obtained with traditional gating methods. Both methods reveal the appearance of transitional B cells and subsequent accumulation of more mature B cells following immunosuppression and transplantation. This pattern is consistent with a temporally ordered process of B cell auto-reconstitution. We also show the comparative efficiency of fingerprinting in recognizing relative changes in B cell subsets with respect to time, its ability to couple the data with statistical methods (agglomerative clustering) and its potential to define novel subsets.     

Results of IVF from a prospective multicentre study.

Part of a cost-effectiveness study of in-vitro fertilization was the evaluation of the medical results of this fertility treatment. Data were prospectively collected from greater than 3000 IVF treatments in five Dutch hospitals during a 2-year period. The average 'take-at-least-one-healthy-baby-home-rate' per started treatment was 10% (the average clinical pregnancy rate per embryo transfer was 20%). After more IVF treatments, about one in three to four couples were successful. Differences in results were mainly caused by patient characteristics, the treatment episode and the treating hospital. These differences remained in a multivariate logistic regression analysis.     

The results of in-vitro fertilization in a Dutch multicenter study

Part of a cost-effectiveness study on in-vitro fertilisation was the evaluation of the medical results of this fertility treatment. Data were prospectively collected from more than 3000 IVF treatments in the five Dutch hospitals during a two-year period. The average take-at-least-one-healthy-baby-home rate per started treatment was 10% (the average clinical pregnancy rate per embryo transfer was 20%). After several IVF treatments about one in three or four couples were successful. Ranges in results were mainly caused by patient characteristics, the individual treatment number and the treating hospital. Male subfertility and long-lasting and primary infertility result in a bad prognosis. Success rates differed substantially between hospitals, even after correction for patient mix.     

Restoring balance to B cells in ADA deficiency

It is paradoxical that immunodeficiency disorders are associated with autoimmunity. Adenosine deaminase (ADA) deficiency, a cause of X-linked severe combined immunodeficiency (SCID), is a case in point. In this issue of the JCI, Sauer and colleagues investigate the B cell defects in ADA-deficient patients. They demonstrate that ADA patients receiving enzyme replacement therapy had B cell tolerance checkpoint defects. Remarkably, gene therapy with a retrovirus that expresses ADA resulted in the apparent correction of these defects, with normalization of peripheral B cell autoantibody frequencies. In vitro, agents that either block ADA or overexpress adenosine resulted in altered B cell receptor and TLR signaling. Collectively, these data implicate a B cell-intrinsic mechanism for alterations in B cell tolerance in the setting of partial ADA deficiency that is corrected by gene therapy.     

Somatic mutation and light chain rearrangement generate autoimmunity in anti-single-stranded DNA transgenic MRL/lpr mice.

Antibodies to single-stranded (ss)DNA are expressed in patients with systemic lupus erythematosus and in lupus-prone mouse models such as the MRL/Mp-lpr/lpr (MRL/lpr) strain. In nonautoimmune mice, B cells bearing immunoglobulin site-directed transgenes (sd-tgs) that code for anti-ssDNA are functionally silenced. In MRL/lpr autoimmune mice, the same sd-tgs are expressed in peripheral B cells and these autoantibodies gain the ability to bind other autoantigens such as double-stranded DNA and cell nuclei. These new specificities arise by somatic mutation of the anti-ssDNA sd-tgs and by secondary light chain rearrangement. Thus, B cells that in normal mice are anergic can be activated in MRL/lpr mice, which can lead to the generation of pathologic autoantibodies. In this paper, we provide the first direct evidence for peripheral rearrangement in vivo.