Tumor necrosis factor α (TNF-α) is a key regulator of inflammation and rheumatoid arthritis (RA). TNF-α blocker therapies can be very effective for a substantial number of patients, but fail to work in one third of patients who show no or minimal response. It is therefore necessary to discover new molecular intervention points involved in TNF-α blocker treatment of rheumatoid arthritis patients. We describe a data analysis strategy for predicting gene expression measures that are critical for rheumatoid arthritis using a combination of comprehensive genotyping, whole blood gene expression profiles and the component clinical measures of the arthritis Disease Activity Score 28 (DAS28) score. Two separate network ensembles, each comprised of 1024 networks, were built from molecular measures from subjects before and 14 weeks after treatment with TNF-α blocker. The network ensemble built from pre-treated data captures TNF-α dependent mechanistic information, while the ensemble built from data collected under TNF-α blocker treatment captures TNF-α independent mechanisms. In silico simulations of targeted, personalized perturbations of gene expression measures from both network ensembles identify transcripts in three broad categories. Firstly, 22 transcripts are identified to have new roles in modulating the DAS28 score; secondly, there are 6 transcripts that could be alternative targets to TNF-α blocker therapies, including CD86 - a component of the signaling axis targeted by Abatacept (CTLA4-Ig), and finally, 59 transcripts that are predicted to modulate the count of tender or swollen joints but not sufficiently enough to have a significant impact on DAS28.

/pdf/causal-modeling-using-network-ensemble-simulations-of-4lc8eg4gj1.pdf

Causal Modeling Using Network Ensemble Simulations of Genetic and Gene Expression Data Predicts Genes Involved in Rheumatoid Arthritis

A conserved interaction that is essential for the biogenesis of histone locus bodies.

https://www.jbc.org/content/286/20/18311.full.pdf

The Developmental Regulator Protein Gon4l Associates with Protein YY1, Co-repressor Sin3a, and Histone Deacetylase 1 and Mediates Transcriptional Repression

B-cell-biased lymphoid progenitors (BLPs) and Pre-pro B cells lie at a critical juncture between B cell specification and commitment. However, both of these populations are heterogenous, which hampers investigation into the molecular changes that occur as lymphoid progenitors commit to the B cell lineage. Here, we demonstrate that there are PDCA-1+Siglec H+ plasmacytoid dendritic cells (pDCs) that co-purify with BLPs and Pre-pro B cells, which express little or no CD11c or Ly6C. Removal of PDCA-1+ pDCs separates B cell progenitors that express high levels of a Rag1-GFP reporter from Rag1-GFPlow/neg pDCs within the BLP and Pre-pro B populations. Analysis of Flt3-ligand knockout and IL-7Rα knockout mice revealed that there is a block in B cell development at the all-lymphoid progenitor (ALP) stage, as the majority of cells within the BLP or Pre-pro B gates were PDCA-1+ pDCs. Thus, removal of PDCA-1+ pDCs is critical for analysis of BLP and Pre-pro B cell populations. Analysis of B cell potential within the B220+CD19− fraction demonstrated that AA4.1+Ly6D+PDCA-1− Pre-pro B cells gave rise to CD19+ B cells at high frequency, while PDCA-1+ pDCs in this fraction did not. Interestingly, the presence of PDCA-1+ pDCs within CLPs may help to explain the conflicting results regarding the origin of these cells.

/pdf/separation-of-plasmacytoid-dendritic-cells-from-b-cell-56l7wr5rn1.pdf

Separation of plasmacytoid dendritic cells from B-cell-biased lymphoid progenitor (BLP) and Pre-pro B cells using PDCA-1.

Although mutation and natural selection have given rise to our immune system, a well-placed mutation can also cripple it, and within an expanding population we are recognizing more and more cases of single-gene mutations that compromise immunity. These mutations are an ideal tool for understanding human immunology, and there are more ways than ever to measure their physiological effects. There are also more ways to create mutations in the laboratory, and to use these resources to systematically define the function of every gene in our genome. This review focuses on the discovery and creation of mutations in the context of mammalian immunity, with an emphasis on the use of genome-wide chemical and CRISPR/Cas9 mutagenesis to reveal gene function.

https://onlinelibrary.wiley.com/doi/pdf/10.1038/icb.2014.8

Dissecting mammalian immunity through mutation

A recessive mutation named Justy was found that abolishes B lymphopoiesis but does not impair other major aspects of hematopoiesis. Transplantation experiments showed that homozygosity for Justy prevented hematopoietic progenitors from generating B cells but did not affect the ability of bone marrow stroma to support B lymphopoiesis. In bone marrow from mutant mice, common lymphoid progenitors and pre-pro-B cells appeared normal, but cells at subsequent stages of B lymphopoiesis were dramatically reduced in number. Under culture conditions that promoted B lymphopoiesis, mutant pre-pro-B cells remained alive and began expressing the B cell marker CD19 but failed to proliferate. In contrast, these cells were able to generate myeloid or T/NK precursors. Genetic and molecular analysis demonstrated that Justy is a point mutation within the Gon4-like (Gon4l) gene, which encodes a protein with homology to transcriptional regulators. This mutation was found to disrupt Gon4l pre-mRNA splicing and dramatically reduce expression of wild-type Gon4l RNA and protein. Consistent with a role for Gon4l in transcriptional regulation, the levels of RNA encoding C/EBPalpha and PU.1 were abnormally high in mutant B cell progenitors. Our findings indicate that the Gon4l protein is required for B lymphopoiesis and may function to regulate gene expression during this process.

https://rupress.org/jem/article-pdf/207/7/1359/1204835/jem_20100147.pdf

The Justy mutation identifies Gon4-like as a gene that is essential for B lymphopoiesis

Disclosed are (1) a nucleic acid sequence encoding a novel mutant PLCϜ-2 protein which, when expressed in a mammal is capable of enhancing the inflammation response and suppressing male fertility; (2) the mutant PLCϜ-2 protein which includes at least one amino acid residue substitution corresponding to residue 993 of the normal PLCϜ-2 protein; (3) a cell line or strain transfected with said nucleic acid sequence; (4) compositions comprising said nucleic acid or said protein and (5) a transgenic non-human comprising said DNA and protein.

Modified phospholipase c-gamma-2, expression products, and non-human animal models comprising said genes, and therapeutic uses

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The Justy mutation identifies Gon4-like as a gene that is essential for B lymphopoiesis

Modified phospholipase c-gamma-2, expression products, and non-human animal models comprising said genes, and therapeutic uses