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Background Dendritic cells (DC) induce adaptive responses against foreign antigens, and play an essential role in maintaining peripheral tolerance to self-antigens. Therefore they are involved in preventing fatal autoimmunity. Selective delivery of antigens to immature DC via the endocytic DEC-205 receptor on their surface promotes antigen-specific T cell tolerance, both by recessive and dominant mechanisms. We provide evidence that the induction of antigen-specific T cell tolerance is not a unique property of CD11c+CD8+DEC-205+ DCs. Methods We employed a fusion between αDCIR2 antibodies and the highly encephalitogenic peptide 139–151 of myelin-derived proteolipid protein (PLP139–151), to target CD11c +CD8- DCs with a DEC-205−DCIR2+ phenotype in vivo, and to substantially improve clinical symptoms in the PLP139–151-induced model of experimental autoimmune encephalomyelitis (EAE). Results Consistent with previous studies targeting other cell surface receptors, EAE protection mediated by αDCIR2-PLP139–151 fusion antibody (Ab) depended on an immature state of targeted DCIR2+ DCs. The mechanism of αDCIR2-PLP139–151 mAb function included the deletion of IL-17- and IFN-γ-producing pathogenic T cells, as well as the enhancement of regulatory T (Treg) cell activity. In contrast to the effect of αDEC-205+ fusion antibodies, which involves extrathymic induction of a Foxp3+ Treg cell phenotype in naïve CD4+Foxp3- T cells, treatment of animals with DCIR2+ fusion antibodies resulted in antigen-specific activation and proliferative expansion of natural Foxp3+ Treg cells. Conclusions These results suggest that multiple mechanisms can lead to the expansion of the Treg population, depending on the DC subset and receptor targeted. Electronic supplementary material The online version of this article (10.1186/s10020-018-0017-6) contains supplementary material, which is available to authorized users.

Samara B Ginzburg, Susan Deutsch, Jaclyn Bellissimo, David E Elkowitz, Joel NH Stern, Robert Lucito Department of Science Education, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA Purpose: The evolution of health care systems in response to societal and financial pressures has changed care delivery models, which presents new challenges for physicians. Leadership training is increasingly being recognized as an essential component of medical education training to prepare physicians to meet these needs. Unfortunately, most medical schools do not include leadership training. It has been suggested that a longitudinal and integrated approach to leadership training should be sought. We hypothesized that integration of leadership training into our hybrid problem-based learning (PBL)/case-based learning (CBL) program, Patient-Centered Explorations in Active Reasoning, Learning and Synthesis (PEARLS), would be an effective way for medical students to develop leadership skills without the addition of curricular time. Methods: We designed a unique leadership program in PEARLS in which 98 medical students participated during each of their six courses throughout the first 2years of school. A program director and trained faculty facilitators educated students and coached them on leadership development throughout this time. Students were assessed by their facilitator at the end of every course on development of leadership skills related to teamwork, meaningful self-assessment, process improvement, and thinking outside the box. Results: Students consistently improved their performance from the first to the final course in all four leadership parameters evaluated. The skills that demonstrated the greatest change were those pertaining to thinking outside the box and process improvement. Conclusion: Incorporation of a longitudinal and integrated approach to leadership training into an existing PBL/CBL program is an effective way for medical students to improve their leadership skills without the addition of curricular time. These results offer a new, time-efficient option for leadership development in schools with existing PBL/CBL programs. Keywords: student-centered, learner-centered, self-directed learning, curricular innovation, higher-order thinking

Here we propose a new approach to defining nerve ‘cell types’ in reaction to recent advances in single cell analysis. Among cells previously thought to be equivalent, considerable differences in global gene expression and biased tendencies among differing developmental fates have been demonstrated within multiple lineages. The model of classifying cells into distinct types thus has to be revised to account for this intrinsic variability. A ‘cell type’ could be a group of cells that possess similar, but not necessarily identical properties, variable within a spectrum of epigenetic adjustments that permit its developmental path toward a specific function to be achieved. Thus, the definition of a cell type is becoming more similar to the definition of a species: sharing essential properties with other members of its group, but permitting a certain amount of deviation in aspects that do not seriously impact function. This approach accommodates, even embraces the spectrum of natural variation found in various cell populations and consequently avoids the fallacy of false equivalence. For example, developing neurons will react to their microenvironments with epigenetic changes resulting in slight changes in gene expression and morphology. Addressing the new questions implied here will have significant implications for developmental neurobiology.

The benefits of exercise at reducing cardiovascular and all-cause mortality have been well described, but certain cohorts of individuals exist in which the safety of exercise has not been studied and its benefits and harms are thus far unknown. During participation in sports or other forms of exercise, patients with transposition of the great arteries (TGA) with systemic right ventricles (SRVs) may have a higher risk of adverse events, including sudden cardiac death. There is little evidence regarding the exercise tolerance and safety in this cohort of patients and it is unknown if exercise will increase the stress on the SRV and result in diminished function.

Analyses of somatic hypermutation (SHM) patterns in B cell immunoglobulin (Ig) sequences contribute to our basic understanding of adaptive immunity, and have broad applications not only for understanding the immune response to pathogens, but also to determining the role of SHM in autoimmunity and B cell cancers. Although stochastic, SHM displays intrinsic biases that can confound statistical analysis, especially when combined with the particular codon usage and base composition in Ig sequences. Analysis of B cell clonal expansion, diversification, and selection processes thus critically depends on an accurate background model for SHM micro-sequence targeting (i.e., hot/cold-spots) and nucleotide substitution. Existing models are based on small numbers of sequences/mutations, in part because they depend on data from non-coding regions or non-functional sequences to remove the confounding influences of selection. Here, we combine high-throughput Ig sequencing with new computational analysis methods to produce improved models of SHM targeting and substitution that are based only on synonymous mutations, and are thus independent of selection. The resulting "S5F" models are based on 806,860 Synonymous mutations in 5-mer motifs from 1,145,182 Functional sequences and account for dependencies on the adjacent four nucleotides (two bases upstream and downstream of the mutation). The estimated profiles can explain almost half of the variance in observed mutation patterns, and clearly show that both mutation targeting and substitution are significantly influenced by neighboring bases. While mutability and substitution profiles were highly conserved across individuals, the variability across motifs was found to be much larger than previously estimated. The model and method source code are made available at http://clip.med.yale.edu/SHM.

IL-10-secreting regulatory T cell lines specific to glatiramer acetate [poly(Y,E,A,K)n] or poly(Y,F,A,K)n have been established from the enlarged spleen and lymph nodes that result from copolymer treatment of SJL mice in which experimental autoimmune encephalomyelitis was induced by PLP139-151. These CD4+CD25+T cell lines secrete high levels of IL-10 and IL-13 but only small amounts of IL-4 and virtually no TGF-β, IL-17, IL-6, IFN-γ, or TNF-α. Their phenotypes are particularly characterized by the absence of Foxp3 and the presence of two TNFR family members, CD30 and GITR. The lines proliferated specifically to the immunizing copolymers but were autoantigen-nonspecific, in that the same T cell line could suppress autoimmunity induced by three different autoantigens in SJL mice, i.e., PLP139-151(EAE), MBP85-99 (EAE), and bovine peripheral nerve myelin (experimental autoimmune neuritis), indicating they function by bystander suppression.

Interaction of the activating receptor NKG2D with its ligands is a major stimulatory pathway for cytotoxicity of natural killer (NK) cells. Here, the signaling pathway involved after NKG2D ligation is examined. Either incubation of the NKG2D-bearing human NKL tumor cell line with K562 target cells or cross-linking with NKG2D mAb induced strong activation of the mitogen-activated protein (MAP) kinases. Selective inhibition of JNK MAP kinase with four different means of inhibition greatly reduced NKG2D-mediated cytotoxicity toward target cells and furthermore, blocked the movement of the microtubule organizing center (MTOC), granzyme B (a component of cytotoxic granules), and paxillin (a scaffold protein) to the immune synapse. NKG2D-induced activation of JNK kinase was also blocked by inhibitors of Src protein tyrosine kinases and phospholipase PLCγ, upstream of JNK. Similarly, a second MAP kinase pathway through ERK was previously shown to be required for NK cell cytotoxicity. Thus, activation of two MAP kinase pathways is required for cytotoxic granule and MTOC polarization and for cytotoxicity of human NK cells when NKG2D is ligated.

Myelin basic protein (MBP) is a major candidate autoantigen in multiple sclerosis (MS). Its immunodominant epitope, MBP 85–99, forms a complex with human leukocyte antigen (HLA)-DR2 with which multiple sclerosis is genetically associated. Copolymer 1 (Copaxone), a random amino acid copolymer [poly (Y,E,A,K)n] as well as two modified synthetic copolymers [poly (F,Y,A,K)n and poly (V,W,A,K)n] also form complexes with HLA-DR2 (DRA/DRB1*1501) and compete with MBP 85–99 for binding. Moreover, two high-affinity synthetic peptide 15-mers that could inhibit binding even more effectively were previously designed. Here, we show that further-modified peptide 15-mers inhibited even more strongly (in order J5 > J3 > J2) both the binding of MBP 85–99 to HLA-DR2 and IL-2 production by two MBP 85–99-specific HLA-DR2-restricted T cells. J5, J3, and J2 also suppressed both MBP 85–99-induced experimental autoimmune encephalomyelitis (EAE) in humanized mice and proteolipid protein 139–151-induced EAE in SJL/J mice. Moreover, none of these previously uncharacterized peptide inhibitors crossreacted with MBP 85–99- or proteolipid protein 139–151-specific T cells. In both cases, spleen and lymph node cultures stimulated with these peptides produced large amounts of Th2 cytokines (IL-4 and IL-10), and adoptive transfer of established T cell lines suppressed disease induction. These peptide 15-mers provide specific, nonrandom sequences that appear to be at least as effective as random copolymers in suppressing EAE in several models.

Summary Objectives To determine the effect of anti-tuberculin antibodies in the T-cell proliferation in response to tuberculin and Candida antigens in individuals with different levels of tuberculosis (TB) risk. Methods Sixteen high-risk TB individuals, 30 with an intermediate TB risk (group A), and 45 with a low TB risk (group B), as well as 49 control individuals, were studied. Tuberculin skin test (TST) results were analyzed and serum levels of antibodies (IgG and IgM) against purified protein derivative (PPD) were measured by ELISA. Tuberculin and Candida antigens were used to stimulate T-cell proliferation in the presence of human AB serum or autologous serum. Results High levels of anti-tuberculin IgG antibodies were found to be significantly associated with the blocking of T-cell proliferation responses in cultures stimulated with tuberculin but not with Candida antigens in the presence of autologous serum. This phenomenon was particularly frequent in high-risk individuals with high levels of anti-tuberculin IgG antibodies in the autologous serum when compared to the other risk groups, which exhibited lower levels of anti-tuberculin antibodies. Conclusions Although cellular immunity plays a central role in the protection against TB, humoral immunity is critical in the control of Mycobacterium tuberculosis infection in high-risk individuals with latent TB infection.