Optical projection tomography reveals dynamics of HEV growth after immunization with protein plus CFA and features shared with HEVs in acute autoinflammatory lymphadenopathy

The vascular-stromal compartment of lymph nodes is important for lymph node function, and high endothelial venules (HEVs) play a critical role in controlling the entry of recirculating lymphocytes. In autoimmune and autoinflammatory diseases, lymph node swelling is often accompanied by apparent HEV expansion and, potentially, targeting HEV expansion could be used therapeutically to limit autoimmunity. In previous studies using mostly flow cytometry analysis, we defined three differentially regulated phases of lymph node vascular-stromal growth: initiation, expansion, and the re-establishment of vascular quiescence and stabilization. In this study, we use optical projection tomography to better understand the morphologic aspects of HEV growth upon immunization with ovalbumin/CFA (OVA/CFA). We find HEV elongation as well as modest arborization during the initiation phase, increased arborization during the expansion phase, and, finally, vessel narrowing during the re-establishment of vascular quiescence and stabilization. We also examine acutely enlarged autoinflammatory lymph nodes induced by regulatory T cell depletion and show that HEVs are expanded and morphologically similar to the expanded HEVs in OVA/CFA-stimulated lymph nodes. These results reinforce the idea of differentially regulated, distinct phases of vascular-stromal growth after immunization and suggest that insights gained from studying immunization-induced lymph node vascular growth may help to understand how the lymph node vascular-stromal compartment could be therapeutically targeted in autoimmune and autoinflammatory diseases.

The antinociceptive triterpene β-amyrin inhibits 2-arachidonoylglycerol (2-AG) hydrolysis without directly targeting cannabinoid receptors

Pharmacological activation of cannabinoid CB(1) and CB(2) receptors is a therapeutic strategy to treat chronic and inflammatory pain. It was recently reported that a mixture of natural triterpenes α- and β-amyrin bound selectively to CB(1) receptors with a subnanomolar K(i) value (133 pM). Orally administered α/β-amyrin inhibited inflammatory and persistent neuropathic pain in mice through both CB(1) and CB(2) receptors. Here, we investigated effects of amyrins on the major components of the endocannabinoid system.

Xenomelia: a social neuroscience view of altered bodily self-consciousness

Xenomelia, the "foreign limb syndrome," is characterized by the non-acceptance of one or more of one's own extremities and the resulting desire for elective limb amputation or paralysis. Formerly labeled "body integrity identity disorder" (BIID), the condition was originally considered a psychological or psychiatric disorder, but a brain-centered Zeitgeist and a rapidly growing interest in the neural underpinnings of bodily self-consciousness has shifted the focus toward dysfunctional central nervous system circuits. The present article outlays both mind-based and brain-based views highlighting their shortcomings. We propose that full insight into what should be conceived a "xenomelia spectrum disorder" will require interpretation of individual symptomatology in a social context. A proper social neuroscience of xenomelia respects the functional neuroanatomy of corporeal awareness, but also acknowledges the brain's plasticity in response to an individual's history, which is lived against a cultural background. This integrated view of xenomelia will promote the subfield of consciousness research concerned with the unity of body and self.

Functional flexibility of intestinal IgA - broadening the fine line

Intestinal bacteria outnumber our own human cells in conditions of both health and disease. It has long been recognized that secretory antibody, particularly IgA, is produced in response to these microbes and hypothesized that this must play an important role in defining the relationship between a host and its intestinal microbes. However, the exact role of IgA and the mechanisms by which IgA can act are only beginning to be understood. In this review we attempt to unravel the complex interaction between so-called "natural," "primitive" (T-cell-independent), and "classical" IgA responses, the nature of the intestinal microbiota/intestinal pathogens and the highly flexible dynamic homeostasis of the mucosal immune system. Such an analysis reveals that low-affinity IgA is sufficient to protect the host from excess mucosal immune activation induced by harmless commensal microbes. However, affinity-maturation of "classical" IgA is essential to provide protection from more invasive commensal species such as segmented filamentous bacteria and from true pathogens such as Salmonellatyphimurium. Thus a correlation is revealed between "sophistication" of the IgA response and aggressiveness of the challenge. A second emerging theme is that more-invasive species take advantage of host inflammatory mechanisms to more successfully compete with the resident microbiota. In many cases, the function of IgA may be to limit such inflammatory responses, either directly by coagulating or inhibiting virulence of bacteria before they can interact with the host or by modulating immune signaling induced by host recognition. Therefore IgA appears to provide an added layer of robustness in the intestinal ecosystem, promoting "commensal-like" behavior of its residents.

Antimicrobial activities of chemokines: not just a side-effect?

The large family of chemoattractant cytokines (chemokines) embraces multiple, in part unrelated functions that go well beyond chemotaxis. Undoubtedly, the control of immune cell migration (chemotaxis) is the single, unifying response mediated by all chemokines, which involves the sequential engagement of chemokine receptors on migrating target cells. However, numerous additional cellular responses are mediated by some (but not all) chemokines, including angiogenesis, tumor cell growth, T-cell co-stimulation, and control of HIV-1 infection. The recently described antimicrobial activity of several chemokines is of particular interest because antimicrobial peptides are thought to provide an essential first-line defense against invading microbes at the extremely large body surfaces of the skin, lungs, and gastrointestinal-urinary tract. Here we summarize the current knowledge about chemokines with antimicrobial activity and discuss their potential contribution to the control of bacterial infections that may take place at the earliest stage of antimicrobial immunity. In the case of homeostatic chemokines with antimicrobial function, such as CXCL14, we propose an immune surveillance function in healthy epithelial tissues characterized by low-level exposure to environmental microbes. Inflammatory chemokines, i.e., chemokines that are produced in tissue cells in response to microbial antigens (such as pathogen-associated molecular patterns) may be more important in orchestrating the cellular arm in antimicrobial immunity.