Functional, Non-Clonal IgMa-Restricted B Cell Receptor Interactions with the HIV-1 Envelope gp41 Membrane Proximal External Region

The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E10 is due to structural constraints with the gp41 MPER, or alternatively, if gp41 MPER epitope-specific B cells are lost to immunological tolerance. An equally important question is how B cells interact with, and respond to, the gp41 MPER epitope, including whether they engage this epitope in a non-canonical manner i.e., by non-paratopic recognition via B cell receptors (BCR). To begin understanding how B cells engage the gp41 MPER, we characterized B cell-gp41 MPER interactions in BALB/c and C57BL/6 mice. Surprisingly, we found that a significant (∼7%) fraction of splenic B cells from BALB/c, but not C57BL/6 mice, bound the gp41 MPER via their BCRs. This strain-specific binding was concentrated in IgMhi subsets, including marginal zone and peritoneal B1 B cells, and correlated with enriched fractions (∼15%) of gp41 MPER-specific IgM secreted by in vitro-activated splenic B cells. Analysis of Igha (BALB/c) and Ighb (C57BL/6) congenic mice demonstrated that gp41 MPER binding was controlled by determinants of the Igha locus. Mapping of MPER gp41 interactions with IgMa identified MPER residues distinct from those to which mAb 2F5 binds and demonstrated the requirement of Fc CH regions. Importantly, gp41 MPER ligation produced detectable BCR-proximal signaling events, suggesting that interactions between gp41 MPER and IgMa determinants may elicit partial B cell activation. These data suggest that low avidity, non-paratopic interactions between the gp41 MPER and membrane Ig on naïve B cells may interfere with or divert bnAb responses

Mixing, hypersalinity and gradients in Hervey Bay, Australia

Hervey Bay, a large coastal embayment situated off the central eastern coast of Australia, is a shallow tidal area (average depth = 15 m), close to the continental shelf. It shows features of an inverse estuary, due to the high evaporation rate (approx. 2 m/year), low precipitation (less than 1 m/year) and on average almost no freshwater input from rivers that drain into the bay. The hydro- and thermodynamical structure of Hervey Bay and their variability are presented here for the first time, using a combination of four-dimensional modelling and observations from field studies. The numerical studies are performed with the Coupled Hydrodynamical Ecological model for RegioNal Shelf seas (COHERENS). Due to the high tidal range (> 3.5 m) the bay is considered as a vertically well-mixed system and therefore only horizontal fronts a likely. Recent field measurements, but also the numerical simulations indicate characteristic features of an inverse/hypersaline estuary with low salinities (35.5 psu) in the open ocean and peak values (> 39.0 psu) in the head water of the bay. The model further predicts a nearly persistent mean salinity gradient of 0.5 psu across the bay (with higher salinities close to the shore)

Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen

B lymphocyte development occurs in the bone marrow, while final differentiation and maturation can occur in both the bone marrow and the spleen. Here we provide evidence that signal regulatory protein α (SIRPα), an Ig-superfamily ITIM-receptor expressed by myeloid but not by lymphoid cells, is involved in regulating B cell maturation. Lack of SIRPα signaling in adult SIRPα-mutant mice resulted in a reduced maturation of B cells in the bone marrow, evident by reduced numbers of semi-mature IgD+IgMhi follicular type-II (F-II) and mature IgD+IgMlofollicular type-I (F-I) B cells, as well as reduced blood B cell numbers. In addition, lack of SIRPα signaling also impaired follicular B cell maturation in the spleen. Maturing BM or splenic B cells of SIRPα-mutant mice were found to express higher levels of the pro-apoptotic protein BIM and apoptosis was increased among these B cells. Bone marrow reconstitution experiments revealed that the B cell maturation defect in bone marrow and blood was due to lack of SIRPα signaling in non-hematopoietic cells, while hematopoietic SIRPα signaling was important for follicular B cell maturation in the spleen. Adding on to our previous findings of a stromal cell defect in SIRPα-mutant mice was the finding that gene expression of receptor activator of nuclear factor-ĸB ligand (RANKL) was significantly lower in cultured bone marrow stromal cells of SIRPα mutant mice. These data suggest a novel and opposite contribution of SIRPα signaling within non-hematopoietic and hematopoietic cells, respectively, to maintain B cell maturation and to prevent apoptosis in the bone marrow and spleen of adult mice

The impact of childhood obesity on musculoskeletal form

Despite the greater prevalence of musculoskeletal disorders in obese adults, the consequences of childhood obesity on the development and function of the musculoskeletal system have received comparatively little attention within the literature. Of the limited number of studies performed to date, the majority have focused on the impact of childhood obesity on skeletal structure and alignment, and to a lesser extent its influence on clinical tests of motor performance including muscular strength, balance and locomotion. Although collectively these studies imply that the functional and structural limitations imposed by obesity may result in aberrant lower limb mechanics and the potential for musculoskeletal injury, empirical verification is currently lacking. The delineation of the effects of childhood obesity on musculoskeletal structure in terms of mass, adiposity, anthropometry, metabolic effects and physical inactivity, or their combination, has not been established. More specifically, there is a lack of research regarding the effect of childhood obesity on the properties of connective tissue structures, such as tendons and ligaments. Given the global increase in childhood obesity, there is a need to ascertain the consequences of persistent obesity on musculoskeletal structure and function. A better understanding of the implications of childhood obesity on the development and function of the musculoskeletal system would assist in the provision of more meaningful support in the prevention, treatment and management of the musculoskeletal consequences of the condition