Activation-Induced Apoptosis of Autoreactive and Alloreactive T Lymphocytes in the Target Organ as a Major Mechanism of Tolerance

Normal individuals have mature T lymphocytes that are capable of reacting to self-antigens and can be activated by cross-reacting environmental antigens. The mechanism that maintains immune tolerance and prevents these activated autoreactive T cells from causing autoimmune disease is unclear. We have previously hypothesized that activation-induced apoptosis of previously activated autoreactive T cells in the target organ is a major mechanism for maintaining tolerance. Here I review the current evidence to support this hypothesis. It is proposed that when activated autoreactive T cells enter the target organ, they are reactivated mainly by non-professional antigen-presenting cells (APC) and deleted by activation-induced apoptosis through the Fas (CD95) pathway before producing significant target organ damage. This apoptosis occurs because the reactivated T cells do not receive sufficient costimulation from the non-professional APC to up-regulate their expression of Bcl-2-related anti-apoptotic proteins, which inhibit the CD95 pro-apoptotic pathway. This is in contrast to the situation in peripheral lymphoid organs, where reactivation of T cells by professional APC results in sufficient costimulation-induced up-regulation of Bcl-2-related proteins to inhibit the CD95 pathway and allow T cell proliferation and survival as memory T cells. Activation-induced apoptosis of alloreactive T cells in allografts can similarly account for spontaneous allograft acceptance, as occurs after MHC-mismatched liver transplantation

Property-driven Training: All You (N)Ever Wanted to Know About

Neural networks are known for their ability to detect general patterns in noisy data. This makes them a popular tool for perception components in complex AI systems. Paradoxically, they are also known for being vulnerable to adversarial attacks. In response, various methods such as adversarial training, data-augmentation and Lipschitz robustness training have been proposed as means of improving their robustness. However, as this paper explores, these training methods each optimise for a different definition of robustness. We perform an in-depth comparison of these different definitions, including their relationship, assumptions, interpretability and verifiability after training. We also look at constraint-driven training, a general approach designed to encode arbitrary constraints, and show that not all of these definitions are directly encodable. Finally we perform experiments to compare the applicability and efficacy of the training methods at ensuring the network obeys these different definitions. These results highlight that even the encoding of such a simple piece of knowledge such as robustness in neural network training is fraught with difficult choices and pitfalls.Comment: 10 pages, under revie

Avian Pathogenic Escherichia coli (APEC) Infection Alters Bone Marrow Transcriptome in Chickens

Avian pathogenic Escherichia coli (APEC) is a major cause of disease impacting animal health. The bone marrow is the reservoir of immature immune cells; however, it has not been examined to date for gene expression related to developmental changes (cell differentiation, maturation, programming) after APEC infection. Here, we study gene expression in the bone marrow between infected and non-infected animals, and between infected animals with mild (resistant) versus severe (susceptible) pathology, at two times post-infection. We sequenced 24 bone marrow RNA libraries generated from the six different treatment groups with four replicates each, and obtained an average of 22 million single-end, 100-bp reads per library. Genes were detected as differentially expressed (DE) between APEC treatments (mild pathology, severe pathology, and mock-challenged) at a given time point, or DE between 1 and 5 days post-infection (dpi) within the same treatment group. Results demonstrate that many immune cells, genes and related pathways are key contributors to the different responses to APEC infection between susceptible and resistant birds and between susceptible and non-challenged birds, at both times post-infection. In susceptible birds, lymphocyte differentiation, proliferation, and maturation were greatly impaired, while the innate and adaptive immune responses, including dendritic cells, monocytes and killer cell activity, TLR- and NOD-like receptor signaling, as well as T helper cells and many cytokine activities, were markedly enhanced. The resistant birds’ immune system, however, was similar to that of non-challenged birds. The DE genes in the immune cells and identified signaling models are representative of activation and resolution of infection in susceptible birds at both post-infection days. These novel results characterizing transcriptomic response to APEC infection reveal that there is combinatorial activity of multiple genes controlling myeloid cells, and B and T cell lymphopoiesis, as well as immune responses occurring in the bone marrow in these early stages of response to infection

Marabou 2.0: A Versatile Formal Analyzer of Neural Networks

This paper serves as a comprehensive system description of version 2.0 of the Marabou framework for formal analysis of neural networks. We discuss the tool's architectural design and highlight the major features and components introduced since its initial release.Comment: Condensed version accepted at CAV'2

IRF4 Is a Suppressor of c-Myc Induced B Cell Leukemia

Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B cell development and function. We have previously shown that IRF4, together with IRF8, orchestrates pre-B cell development by limiting pre-B cell expansion and by promoting pre-B cell differentiation. Here, we report that IRF4 suppresses c-Myc induced leukemia in EμMyc mice. Our results show that c-Myc induced leukemia was greatly accelerated in the IRF4 heterozygous mice (IRF4+/−Myc); the average age of mortality in the IRF4+/−Myc mice was only 7 to 8 weeks but was 20 weeks in the control mice. Our results show that IRF4+/−Myc leukemic cells were derived from large pre-B cells and were hyperproliferative and resistant to apoptosis. Further analysis revealed that the majority of IRF4+/−Myc leukemic cells inactivated the wild-type IRF4 allele and contained defects in Arf-p53 tumor suppressor pathway. p27kip is part of the molecular circuitry that controls pre-B cell expansion. Our results show that expression of p27kip was lost in the IRF4+/−Myc leukemic cells and reconstitution of IRF4 expression in those cells induced p27kip and inhibited their expansion. Thus, IRF4 functions as a classical tumor suppressor to inhibit c-Myc induced B cell leukemia in EμMyc mice

The transition to adulthood from care as a struggle for recognition

Introduction In this article we focus on young people transitioning to adulthood from child welfare services, and how the concept of recognition can be useful for understanding the complexity of young people’s needs in this transition. We draw upon Honneth’s (1996) theory of intersubjective recognition as a way of understanding young people’s experiences of their contact with child welfare services. We ask how recognition theory can help us to understand young people’s experiences and needs in their transition to adulthood from child welfare services, and what are the practical implications. We focus on relationships, participation and social support as the three components highlighted by the young people who participated in interviews. Previous research also indicates that young people leaving care often face challenges related to creating and maintaining good relationships (Marion et al., 2017; Rutman & Hubberstey, 2016), participating effectively in decisions (Authors reference 1) and receiving good quality social support (Barry, 2010; Höjer & Sjöblom, 2010; Authors reference 2; Authors reference 3; Thomas, 2005). We argue that Honneth’s theory is potentially useful, in that these three elements appear to depend on, and imply, the kinds of recognition that he identifies. This theoretical framework provides us with an analytical tool that enables us to understand the young people’s negative stories as experiences of misrecognition, and to show the complexity of the dynamics that shape recognition and misrecognition for this group (Warming, 2015)

Idd Loci Synergize to Prolong Islet Allograft Survival Induced by Costimulation Blockade in NOD Mice

OBJECTIVE—NOD mice model human type 1 diabetes and are used to investigate tolerance induction protocols for islet transplantation in a setting of autoimmunity. However, costimulation blockade–based tolerance protocols have failed in prolonging islet allograft survival in NOD mice

Lag Time Between Onset of First Symptom and Treatment of Retinoblastoma: Outcomes at Three Years from Recruitment

Purpose: To evaluate the effect of lag time between diagnosis of retinoblastoma (RB) and treatment in patients from 10 countries. Methods: Prospective study of 692 treatment-naïve RB patients from 10 countries followed up for 3 years from recruitment. Results: The mean lag time from the onset of the first symptom to visit to the RB treatment center was 150 days. The mean follow-up duration was 26 months (median, 32 months; range, 12 months. Conclusion: A lower socioeconomic status and greater AJCC stage were associated with an increased risk of enucleation. Increased lag time from the onset of the first symptom to visit the RB treatment center and AJCC T4 stage were associated with an increased risk of death from RB