Tiezheng and I discussed this idea a few months ago. I love this!

Science. 2016 May 26. pii: aaf7907. [Epub ahead of print] Whole organism lineage tracing by combinatorial and cumulative genome editing.
McKenna A1, Findlay GM1, Gagnon JA2, Horwitz MS3, Schier AF4, Shendure J5.
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Abstract
Multicellular systems develop from single cells through distinct lineages. However, current lineage tracing approaches scale poorly to whole, complex organisms. Here, we use genome editing to progressively introduce and accumulate diverse mutations in a DNA barcode over multiple rounds of cell division. The barcode, an array of CRISPR/Cas9 target sites, marks cells and enables the elucidation of lineage relationships via the patterns of mutations shared between cells. In cell culture and zebrafish, we show that rates and patterns of editing are tunable and that thousands of lineage-informative barcode alleles can be generated. By sampling hundreds of thousands of cells from individual zebrafish, we find that most cells in adult organs derive from relatively few embryonic progenitors. In future analyses, genome editing of synthetic target arrays for lineage tracing (GESTALT) can be used to generate large-scale maps of cell lineage in multicellular systems for normal development and disease.
Copyright © 2016, American Association for the Advancement of Science.
PMID: 27229144 [PubMed – as supplied by publisher]

A very special paper as it reveals some interesting facts about mucosal IgA response in babies up to 24 months of age. It is really interesting to find out how breast milk, formula and the transitionary food play a role in the IgA response against gut microbiota, particularly the bacterial population. These people even got replicated results in mice population.

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Development of the gut microbiota and mucosal IgA responses in twins and gnotobiotic mice

Joseph D. Planer, Yangqing Peng, Andrew L. Kau, Laura V. Blanton, I. Malick Ndao, Phillip I. Tarr, Barbara B. Warner & Jeffrey I. Gordon
AffiliationsContributionsCorresponding author
Nature (2016) doi:10.1038/nature17940

Immunoglobulin A (IgA), the major class of antibody secreted by the gut mucosa, is an important contributor to gut barrier function1, 2, 3. The repertoire of IgA bound to gut bacteria reflects both T-cell-dependent and -independent pathways4, 5, plus glycans present on the antibody’s secretory component6. Human gut bacterial taxa targeted by IgA in the setting of barrier dysfunction are capable of producing intestinal pathology when isolated and transferred to gnotobiotic mice7, 8. A complex reorientation of gut immunity occurs as infants transition from passively acquired IgA present in breast milk to host-derived IgA9, 10, 11. How IgA responses co-develop with assembly of the microbiota during this period remains poorly understood. Here, we (1) identify a set of age-discriminatory bacterial taxa whose representations define a program of microbiota assembly and maturation during the first 2 postnatal years that is shared across 40 healthy twin pairs in the USA; (2) describe a pattern of progression of gut mucosal IgA responses to bacterial members of the microbiota that is highly distinctive for family members (twin pairs) during the first several postnatal months then generalizes across pairs in the second year; and (3) assess the effects of zygosity, birth mode, and breast feeding. Age-associated differences in these IgA responses can be recapitulated in young germ-free mice, colonized with faecal microbiota obtained from two twin pairs at 6 and 18 months of age, and fed a sequence of human diets that simulate the transition from milk feeding to complementary foods. Most of these responses were robust to diet, suggesting that ‘intrinsic’ properties of community members play a dominant role in dictating IgA responses. The approach described can be used to define gut mucosal immune development in health and disease states and to help discover ways of repairing or preventing perturbations in this facet of host immunity

Neurology. 2016 May 11. pii: 10.1212/WNL.0000000000002775. [Epub ahead of print] Human neurexin-3α antibodies associate with encephalitis and alter synapse development.
Gresa-Arribas N1, Planagumà J1, Petit-Pedrol M1, Kawachi I1, Katada S1, Glaser CA1, Simabukuro MM1, Armangué T1, Martínez-Hernández E1, Graus F1, Dalmau J2.
Author information
Abstract
OBJECTIVE:
To report a novel autoimmune encephalitis in which the antibodies target neurexin-3α, a cell adhesion molecule involved in the development and function of synapses.

METHODS:
Five patients with encephalitis and antibodies with a similar pattern of brain reactivity were selected. Antigen precipitation and determination of antibody effects on cultured rat embryonic neurons were performed with reported techniques.

RESULTS:
Immunoprecipitation and cell-based assays identified neurexin-3α as the autoantigen of patients’ antibodies. All 5 patients (median age 44 years, range 23-50; 4 female) presented with prodromal fever, headache, or gastrointestinal symptoms, followed by confusion, seizures, and decreased level of consciousness. Two developed mild orofacial dyskinesias, 3 needed respiratory support, and 4 had findings suggesting propensity to autoimmunity. CSF was abnormal in all patients (4 pleocytosis, 1 elevated immunoglobulin G [IgG] index), and brain MRI was abnormal in 1 (increased fluid-attenuated inversion recovery/T2 in temporal lobes). All received steroids, 1 IV immunoglobulin, and 1 cyclophosphamide; 3 partially recovered, 1 died of sepsis while recovering, and 1 had a rapid progression to death. At autopsy, edema but no inflammatory cells were identified. Cultures of neurons exposed during days in vitro (div) 7-17 to patients’ IgG showed a decrease of neurexin-3α clusters as well as the total number of synapses. No reduction of synapses occurred in mature neurons (div 18) exposed for 48 hours to patients’ IgG. Neuronal survival, dendritic morphology, and spine density were unaffected.

CONCLUSION:
Neurexin-3α autoantibodies associate with a severe but potentially treatable encephalitis in which the antibodies cause a decrease of neurexin-3α and alter synapse development.

© 2016 American Academy of Neurology.

PMID: 27170573 [PubMed – as supplied by publisher]

A tour de force that uncovers a potentially very important new T1D autoantigen:

Discovery of Phosphorylated Peripherin as a Major Humoral Autoantigen in Type 1 Diabetes Mellitus

Todd M. Doran1, Jumpei Morimoto1, Scott Simanski1, Eric J. Koesema1, Lorraine F. Clark1, Kevin Pels1, Sydney L. Stoops1, Alberto Pugliese2, 3, 4, Jay S. Skyler2, 3, Thomas Kodadek1

Summary
A major goal in understanding autoimmune diseases is to define the antigens that elicit a self-destructive immune response, but this is a difficult endeavor. In an effort to discover autoantigens associated with type 1 diabetes (T1D), we used epitope surrogate technology that screens combinatorial libraries of synthetic molecules for compounds that could recognize disease-linked autoantibodies and enrich them from serum. Autoantibodies from one patient revealed a highly phosphorylated form of peripherin, a neuroendocrine filament protein, as a candidate T1D antigen. Peripherin antibodies were detected in 72% of donor patient sera. Further analysis revealed that the T1D-associated antibodies only recognized a dimeric conformation of peripherin. These data explain why peripherin was dismissed as an important T1D antigen previously. The discovery of this novel autoantigen would not have been possible using standard methods, such as hybridizing serum antibodies to recombinant protein arrays, highlighting the power of epitope surrogate technology for probing the mechanism of autoimmune diseases.

Interesting/sort of surprising that booster immunization does not lead to a new dominant clone. Really neat study in that they studied the immune repertoire pre and post vaccination in both identical twins and unrelated individuals.

Sci Transl Med. 2016 Mar 30;8(332):332ra46. doi: 10.1126/scitranslmed.aaf1725.

Diversification of the antigen-specific T cell receptor repertoire after varicella zoster vaccination.

Qi Q1, Cavanagh MM1, Le Saux S1, NamKoong H1, Kim C1, Turgano E2, Liu Y3, Wang C4, Mackey S5, Swan GE6, Dekker CL5, Olshen RA7, Boyd SD4, Weyand CM1, Tian L8, Goronzy JJ9.

Abstract
Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood can escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-reactive CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. Although all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly. A genetic influence was seen for the sharing of individual TCR sequences from antigen-reactive cells but not for repertoire richness or the selection of dominant clones. VZV vaccination favored the expansion of infrequent VZV antigen-reactive TCRs, including those from naïve T cells with lesser boosting of dominant T cell clones. Thus, vaccination does not reinforce the in vivo selection that occurred during chronic infection but leads to a diversification of the VZV-reactive T cell repertoire. However, a single-booster immunization seems insufficient to establish new clonal dominance. Our results suggest that repertoire analysis of antigen-specific TCRs can be an important readout to assess whether a vaccination was able to generate memory cells in clonal sizes that are necessary for immune protection.

PMID: 27030598 [PubMed – in process]

This is a great paper! It talks about using the dual-RNA-seq of both the pathogen and the host at various time points, simultaneously in a Salmonella infection. They have used this technique to illustrate the role of some sRNA in virulence and pathogenesis. The idea itself is unique! The authors used Ilumina Sequencing, FACS, micro-array and various other techniques to reveal the molecular impact of bacterial riboregulators. It was a joyful journey to go through this paper!

Dual RNA-seq unveils noncoding RNA functions in host–pathogen interactions
Alexander J. Westermann1, Konrad U. Förstner1,2, Fabian Amman3,4, Lars Barquist1, Yanjie Chao1, Leon N. Schulte1, Lydia Müller3, Richard Reinhardt5, Peter F. Stadler3,4,6,7 & Jörg Vogel1,8

doi:10.1038/nature16547

Bacteria express many small RNAs for which the regulatory roles in pathogenesis have remained poorly understood due to a paucity of robust phenotypes in standard virulence assays. Here we use a generic ‘dual RNA-seq’ approach to profile RNA expression simultaneously in pathogen and host during Salmonella enterica serovar Typhimurium infection and reveal the molecular impact of bacterial riboregulators. We identify a PhoP-activated small RNA, PinT, which upon bacterial internalization temporally controls the expression of both invasion-associated effectors and virulence genes required for intracellular survival. This riboregulatory activity causes pervasive changes in coding and noncoding transcripts of the host. Interspecies correlation analysis links PinT to host cell JAK–STAT signalling, and we identify infection- specific alterations in multiple long noncoding RNAs. Our study provides a paradigm for a sensitive RNA-based analysis of intracellular bacterial pathogens and their hosts without physical separation, as well as a new discovery route for hidden functions of pathogen genes.

I thought this was a great article.

http://www.nytimes.com/2016/02/28/magazine/what-google-learned-from-its-quest-to-build-the-perfect-team.html

Tissue is the issue!

Sci Transl Med. 2016 Feb 24;8(327):327ra26. doi: 10.1126/scitranslmed.aad6352.
The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis.
Mlecnik B1, Bindea G1, Kirilovsky A1, Angell HK2, Obenauf AC3, Tosolini M1, Church SE1, Maby P1, Vasaturo A1, Angelova M1, Fredriksen T1, Mauger S1, Waldner M4, Berger A5, Speicher MR3, Pagès F6, Valge-Archer V7, Galon J1.
Author information
Abstract
Although distant metastases account for most of the deaths in cancer patients, fundamental questions regarding mechanisms that promote or inhibit metastasis remain unanswered. We show the impact of mutations, genomic instability, lymphatic and blood vascularization, and the immune contexture of the tumor microenvironment on synchronous metastases in large cohorts of colorectal cancer patients. We observed large genetic heterogeneity among primary tumors, but no major differences in chromosomal instability or key cancer-associated mutations. Similar patterns of cancer-related gene expression levels were observed between patients. No cancer-associated genes or pathways were associated with M stage. Instead, mutations of FBXW7 were associated with the absence of metastasis and correlated with increased expression of T cell proliferation and antigen presentation functions. Analyzing the tumor microenvironment, we observed two hallmarks of the metastatic process: decreased presence of lymphatic vessels and reduced immune cytotoxicity. These events could be the initiating factors driving both synchronous and metachronous metastases. Our data demonstrate the protective impact of the Immunoscore, a cytotoxic immune signature, and increased marginal lymphatic vessels, against the generation of distant metastases, regardless of genomic instability.

Copyright © 2016, American Association for the Advancement of Science.

PMID: 26912905 [PubMed – in process]

A really interesting article about how siblings may have an immune modulatory effect in neonates…

Allergy. 2016 Jan 25. doi: 10.1111/all.12847. [Epub ahead of print]

Siblings Promote a Type 1/Type 17-oriented immune response in the airways of asymptomatic neonates.

Wolsk HM1, L Chawes B1, Følsgaard NV1, Rasmussen MA2, Brix S3, Bisgaard H1.

BACKGROUND:
Siblings have been shown to reduce the risk of later asthma and allergy, but the mechanism driving this association is unknown. The objective was to study whether siblings affect the airway immune response in healthy neonates. We hypothesized that siblings exert immune modulatory effects on neonates mirrored in the airway mucosa.

METHODS:
We measured 20 immune-mediators related to the Type 1, Type 2, Type 17 or regulatory immune pathways in the airway mucosa of 571 one-month-old asymptomatic neonates from the Copenhagen Prospective Studies on Asthma in Childhood2010 birth-cohort (COPSAC2010 ). The association between airway mediator levels and presence of siblings was investigated using conventional statistics and principle component analyses (PCA).

RESULTS:
Neonates with siblings had an up-regulated level of airway immune-mediators, with predominance of Type 1- and Type 17-related mediators. This was supported by the PCA showing a highly significant difference between children with vs. without siblings: p<10-10 , which persisted after adjustment for potential confounders including pathogenic airway bacteria and viruses: p<0.0001. The immune priming effect was inversely associated with time since last childbirth: p=0.0015.

CONCLUSIONS:
Siblings mediate a Type 1/Type 17-related immune-stimulatory effect in the airways of asymptomatic neonates, also after adjustment for pathogenic bacteria and viruses, indicating that siblings exert a transferable early immune modulatory effect. These findings may represent an in-utero immune priming effect of the fetal immune system caused by previous pregnancies as the effect was attenuated with time since last childbirth or presence of unidentified microbes, but further studies are needed to confirm our findings. This article is protected by copyright. All rights reserved.

PMID: 26808998 [PubMed – as supplied by publisher] Share on FacebookShare on TwitterShare on Google+

Zhang et al. report altered immunity at birth (based on analyzing cord blood immune cell components and cytokine secretion) in kids that later develop food allergies., and skewing towards a Th2 phenotype. These findings are surprising to me- I would guess that these changes would be more related to postnatal exposures and microbiome makeup… I’d also be curious to know correlation with mom’s allergy and/or medication history.

Sci Transl Med. 2016 Jan 13;8(321):321ra8. doi: 10.1126/scitranslmed.aad4322.

Cord blood monocyte-derived inflammatory cytokines suppress IL-2 and induce nonclassic “TH2-type” immunity associated with development of food allergy.

Zhang Y1, Collier F2, Naselli G3, Saffery R4, Tang ML4, Allen KJ4, Ponsonby AL4, Harrison LC5, Vuillermin P6; BIS Investigator Group.

Abstract
Food allergy is a major health burden in early childhood. Infants who develop food allergy display a proinflammatory immune profile in cord blood, but how this is related to interleukin-4 (IL-4)/T helper 2 (TH2)-type immunity characteristic of allergy is unknown. In a general population-derived birth cohort, we found that in infants who developed food allergy, cord blood displayed a higher monocyte to CD4(+) T cell ratio and a lower proportion of natural regulatory T cell (nTreg) in relation to duration of labor. CD14(+) monocytes of food-allergic infants secreted higher amounts of inflammatory cytokines (IL-1β, IL-6, and tumor necrosis factor-α) in response to lipopolysaccharide. In the presence of the mucosal cytokine transforming growth factor-β, these inflammatory cytokines suppressed IL-2 expression by CD4(+) T cells. In the absence of IL-2, inflammatory cytokines decreased the number of activated nTreg and diverted the differentiation of both nTreg and naïve CD4(+) T cells toward an IL-4-expressing nonclassical TH2 phenotype. These findings provide a mechanistic explanation for susceptibility to food allergy in infants and suggest anti-inflammatory approaches to its prevention.

PMID: 26764159 [PubMed – in process]