B cells in the aging immune system: time to consider B-1 cells

The investigation of immune senescence has uncovered many changes in B cell development, maintenance, and function with increasing age. However, most of these studies have focused on conventional B cell subsets in the spleen. The B-1 cell subset is an essential arm of the innate immune system, which in general has been understudied in terms of immune senescence. Here, we review what is currently known about B cells during aging and go on to describe why B-1 cell biology is an important component of the aging immune system in the context of diseases that most affect the aged population

Splenic B-1a Cells Expressing CD138 Spontaneously Secrete Large Amounts of Immunoglobulin in Naive Mice

B-1a cells constitutively secrete natural antibody that provides immediate protection against microbial pathogens and functions homeostatically to speed removal of apoptotic cell debris. Although B-1a cells are especially prominent in the peritoneal and pleural cavities, some B-1a cells reside in the spleen. A small subset of splenic B-1a cells in naive, unimmunized mice express CD138, a recognized plasma cell antigen, whereas the bulk of splenic B-1a cells are CD138 negative. Splenic B-1a cells in toto have been shown to generate much more antibody per cell than peritoneal B-1a cells; however, specific functional information regarding CD138(+) splenic B-1a cells has been lacking. Here, we find a higher proportion of CD138(+) splenic B-1a cells spontaneously secrete more IgM as compared to CD138(-) B-1a cells. Moreover, IgM secreted by CD138(+) splenic B-1a cells is skewed with respect to N-region addition, and some aspects of VH and JH utilization, as compared to CD138(-) splenic B-1a cells and peritoneal B-1a cells. The small population of CD138(+) splenic B-1a cells is likely responsible for a substantial portion of natural IgM and differs from IgM produced by other B-1a cell subsets

The role of B-1 cells in inflammation

B-1 lymphocytes exhibit unique phenotypic, ontogenic, and functional characteristics that differ from the conventional B-2 cells. B-1 cells spontaneously secrete germline-like, repertoire-skewed polyreactive natural antibody, which acts as a first line of defense by neutralizing a wide range of pathogens before launching of the adaptive immune response. Immunomodulatory molecules such as interleukin-10, adenosine, granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-35 are also produced by B-1 cells in the presence or absence of stimulation, which regulate acute and chronic inflammatory diseases. Considerable progress has been made during the past three decades since the discovery of B-1 cells, which has improved not only our understanding of their phenotypic and ontogenic uniqueness but also their role in various inflammatory diseases including influenza, pneumonia, sepsis, atherosclerosis, inflammatory bowel disease, autoimmunity, obesity and diabetes mellitus. Recent identification of human B-1 cells widens the scope of this field, leading to novel innovations that can be implemented from bench to bedside. Among the vast number of studies on B-1 cells, we have carried out a literature review highlighting current trends in the study of B-1 cell involvement during inflammation, which may result in a paradigm shift toward sustainable therapeutics in various inflammatory diseases

A Novel Mechanism of B Cell-Mediated Immune Suppression through CD73 Expression and Adenosine Production

Immune suppression by regulatory T cells and regulatory B cells is a critical mechanism to limit excess inflammation and autoimmunity. IL-10 is considered the major mediator of B cell induced immune suppression. We report a novel mechanism for immune suppression through adenosine generation by B cells. We identified a novel population of B cells that expresses CD73 as well as CD39, two ectoenzymes that together catalyze the extracellular dephosphorylation of adenine nucleotides to adenosine. Whereas CD39 expression is common among B cells, CD73 expression is not. Approximately 30-50% of B-1 cells (B220(+)CD23(-)) and IL-10 producing B (B10) cells (B220(+)CD5(+)CD1d(hi)) are CD73111, depending on mouse strain, whereas few conventional B-2 cells (B220+CD23+AA4.1) express CD73. In keeping with expression of both CD73 and CD39, we found that CD73(+) B cells produce adenosine in the presence of substrate, whereas B-2 cells do not. CD73(-/-) mice were more susceptible to dextran sulfate sodium salt (DSS)-induced colitis than wild type (WT) mice were, and transfer of CD73+ B cells ameliorated the severity of colitis, suggesting that B cell CD73/CD39/adenosine can modulate DSS-induced colitis. IL-10 production by B cells is not affected by CD73 deficiency. Interestingly, adenosine generation by IL-10(-/-) B cells is impaired because of reduced expression of CD73, indicating an unexpected connection between IL-10 and adenosine and suggesting caution in interpreting the results of studies with IL-10(-/-) cells. Our findings demonstrate a novel regulatory role of B cells on colitis through adenosine generation in an IL10 independent manner

Matched Asymptotic Expansion for Caged Black Holes - Regularization of the Post-Newtonian Order

The "dialogue of multipoles" matched asymptotic expansion for small black holes in the presence of compact dimensions is extended to the Post-Newtonian order for arbitrary dimensions. Divergences are identified and are regularized through the matching constants, a method valid to all orders and known as Hadamard's partie finie. It is closely related to "subtraction of self-interaction" and shows similarities with the regularization of quantum field theories. The black hole's mass and tension (and the "black hole Archimedes effect") are obtained explicitly at this order, and a Newtonian derivation for the leading term in the tension is demonstrated. Implications for the phase diagram are analyzed, finding agreement with numerical results and extrapolation shows hints for Sorkin's critical dimension - a dimension where the transition turns second order.Comment: 28 pages, 5 figures. v2:published versio

A nonlinear scalar model of extreme mass ratio inspirals in effective field theory I. Self force through third order

The motion of a small compact object in a background spacetime is investigated in the context of a model nonlinear scalar field theory. This model is constructed to have a perturbative structure analogous to the General Relativistic description of extreme mass ratio inspirals (EMRIs). We apply the effective field theory approach to this model and calculate the finite part of the self force on the small compact object through third order in the ratio of the size of the compact object to the curvature scale of the background (e.g., black hole) spacetime. We use well-known renormalization methods and demonstrate the consistency of the formalism in rendering the self force finite at higher orders within a point particle prescription for the small compact object. This nonlinear scalar model should be useful for studying various aspects of higher-order self force effects in EMRIs but within a comparatively simpler context than the full gravitational case. These aspects include developing practical schemes for higher order self force numerical computations, quantifying the effects of transient resonances on EMRI waveforms and accurately modeling the small compact object's motion for precise determinations of the parameters of detected EMRI sources.Comment: 30 pages, 8 figure

The k-Point Random Matrix Kernels Obtained from One-Point Supermatrix Models

The k-point correlation functions of the Gaussian Random Matrix Ensembles are certain determinants of functions which depend on only two arguments. They are referred to as kernels, since they are the building blocks of all correlations. We show that the kernels are obtained, for arbitrary level number, directly from supermatrix models for one-point functions. More precisely, the generating functions of the one-point functions are equivalent to the kernels. This is surprising, because it implies that already the one-point generating function holds essential information about the k-point correlations. This also establishes a link to the averaged ratios of spectral determinants, i.e. of characteristic polynomials

Genomic analysis of human and mouse TCL1 loci reveals a complex of tightly clustered genes

TCL1 and TCL1b genes on human chromosome 14q23.1 are activated in T cell leukemias by translocations and inversions at 14q32.1, juxtaposing them to regulatory elements of T cell receptor genes. In this report we present the cloning, mapping, and expression analysis of the human and murine TCL1/Tcl1 locus. In addition to TCL1 and TCL1b, the human locus contains two additional genes, TCL1-neighboring genes (TNG) 1 and 2, encoding proteins of 141 and 110 aa, respectively. Both genes show no homology to any known genes, but their expression profiles are very similar to those of TCL1 and TCL1b. TNG1 and TNG2 also are activated in T cell leukemias with rearrangements at 14q32.1. To aid in the development of a mouse model we also have characterized the murine Tcl1 locus and found five genes homologous to human TCL1b. Tcl1b1- Tcl1b5 proteins range from 117 to 123 aa and are 65-80% similar, but they show only a 30-40% similarity to human TCL1b. All five mouse Tcl1b and murine Tcl1 mRNAs are abundant in mouse oocytes and two-cell embryos but rare in various adult tissues and lymphoid cell lines. These data suggest a similar or complementary function of these proteins in early embryogenesis

Experimental Observation of ABCB Stacked Tetralayer Graphene

In tetralayer graphene, three inequivalent layer stackings should exist; however, only rhombohedral (ABCA) and Bernal (ABAB) stacking have so far been observed. The three stacking sequences differ in their electronic structure, with the elusive third stacking (ABCB) being unique as it is predicted to exhibit an intrinsic bandgap as well as locally flat bands around the K points. Here, we use scattering-type scanning near-field optical microscopy and confocal Raman microscopy to identify and characterize domains of ABCB stacked tetralayer graphene. We differentiate between the three stacking sequences by addressing characteristic interband contributions in the optical conductivity between 0.28 and 0.56 eV with amplitude and phase-resolved near-field nanospectroscopy. By normalizing adjacent flakes to each other, we achieve good agreement between theory and experiment, allowing for the unambiguous assignment of ABCB domains in tetralayer graphene. These results establish near-field spectroscopy at the interband transitions as a semiquantitative tool, enabling the recognition of ABCB domains in tetralayer graphene flakes and, therefore, providing a basis to study correlation physics of this exciting phase