B cell-intrinsic MyD88 signaling controls IFN-γ-mediated early IgG2c class switching in mice in response to a particulate adjuvant.

Adjuvants improve the potency of vaccines, but the modes of action (MOAs) of most adjuvants are largely unknown. TLR-dependent and -independent innate immune signaling through the adaptor molecule MyD88 has been shown to be pivotal to the effects of most adjuvants; however, MyD88's involvement in the TLR-independent MOAs of adjuvants is poorly understood. Here, using the T-dependent antigen NIPOVA and a unique particulate adjuvant called synthetic hemozoin (sHZ), we show that MyD88 is required for early GC formation and enhanced antibody class-switch recombination (CSR) in mice. Using cell-type-specific MyD88 KO mice, we found that IgG2c class switching, but not IgG1 class switching, was controlled by B cell-intrinsic MyD88 signaling. Notably, IFN-γ produced by various cells including T cells, NK cells, and dendritic cells was the primary cytokine for IgG2c CSR and B-cell intrinsic MyD88 is required for IFN-γ production. Moreover, IFN-γ receptor (IFNγR) deficiency abolished sHZ-induced IgG2c production, while recombinant IFN-γ administration successfully rescued IgG2c CSR impairment in mice lacking B-cell intrinsic MyD88. Together, our results show that B cell-intrinsic MyD88 signaling is involved in the MOA of certain particulate adjuvants and this may enhance our specific understanding of how adjuvants and vaccines work.

Raman spectroscopic analysis of malaria disease progression via blood and plasma samples.

In this study Raman spectroscopy has been used to monitor the changes in erythrocytes and plasma during Plasmodium infection in mice, following malaria disease progression over the course of 7 days. The Raman spectra of both samples are dominated by the spectra of hemoglobin and hemozoin, due to their resonant enhancement. In plasma samples, due to the inherently low heme background, heme-based changes in the Raman spectra could be detected in the very early stages of infection, as little as one day after Plasmodium infection, where parasitemia levels were low, on the order of 0.2%, and typically difficult to detect by existing methods. Further principal component analysis also indicates concurrent erythrocyte membrane changes at around day 4, where parasitemia levels reached 3%. These results show that plasma analysis has significant potential for early, quantitative and automated detection of malaria, and to quantify heme levels in serum which modulate malarial effects on the immune system.

Plasmodium products persist in the bone marrow and promote chronic bone loss.

Although malaria is a life-threatening disease with severe complications, most people develop partial immunity and suffer from mild symptoms. However, incomplete recovery from infection causes chronic illness, and little is known of the potential outcomes of this chronicity. We found that malaria causes bone loss and growth retardation as a result of chronic bone inflammation induced by Plasmodium products. Acute malaria infection severely suppresses bone homeostasis, but sustained accumulation of Plasmodium products in the bone marrow niche induces MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, leading to increased RANKL expression and overstimulation of osteoclastogenesis, favoring bone resorption. Infection with a mutant parasite with impaired hemoglobin digestion that produces little hemozoin, a major Plasmodium by-product, did not cause bone loss. Supplementation of alfacalcidol, a vitamin D3 analog, could prevent the bone loss. These results highlight the risk of bone loss in malaria-infected patients and the potential benefits of coupling bone therapy with antimalarial treatment.

Effects of alcohol on thermoregulation during mild heat exposure in humans.

We investigated the effects of alcohol on thermoregulatory responses and thermal sensations during mild heat exposure in humans. Eight healthy men participated in this study. Experiments were conducted twice for each subject at a room temperature of 33 degrees C. After a 30-min resting period, the subject drank either 15% alcohol (alcohol session) at a dose of 0.36 g/kg body weight or equal volume of water (control session). Skin blood flow and chest sweat rate in the alcohol session significantly increased over those in controls 10 min after drinking. Deep body temperature in the alcohol session started to decrease 20 min after the onset of sweating and eventually fell 0.3 degrees C lower than in the controls. Whole body hot sensation transiently increased after alcohol drinking, whereas it changed little after water drinking. The increased "hot" sensation would presumably cause cool-seeking behavior, if permitted. Thus, alcohol influences thermoregulation so that body core temperature is lowered not only by automatic mechanisms (sweating and skin vasodilation) but also behaviorally. These results suggest that decreases in body temperature after alcohol drinking are not secondary to skin vasodilation, a well-known effect of alcohol, but rather result from a decrease in the regulated body temperature evidenced by the coordinated modulation of various effectors of thermoregulation and sensation.

Olfactory plays a key role in spatiotemporal pathogenesis of cerebral malaria.

Cerebral malaria is a complication of Plasmodium falciparum infection characterized by sudden coma, death, or neurodisability. Studies using a mouse model of experimental cerebral malaria (ECM) have indicated that blood-brain barrier disruption and CD8 T cell recruitment contribute to disease, but the spatiotemporal mechanisms are poorly understood. We show by ultra-high-field MRI and multiphoton microscopy that the olfactory bulb is physically and functionally damaged (loss of smell) by Plasmodium parasites during ECM. The trabecular small capillaries comprising the olfactory bulb show parasite accumulation and cell occlusion followed by microbleeding, events associated with high fever and cytokine storm. Specifically, the olfactory upregulates chemokine CCL21, and loss or functional blockade of its receptors CCR7 and CXCR3 results in decreased CD8 T cell activation and recruitment, respectively, as well as prolonged survival. Thus, early detection of olfaction loss and blockade of pathological cell recruitment may offer potential therapeutic strategies for ECM.

Lipocalin 2 bolsters innate and adaptive immune responses to blood-stage malaria infection by reinforcing host iron metabolism.

Plasmodium parasites multiply within host erythrocytes, which contain high levels of iron, and parasite egress from these cells results in iron release and host anemia. Although Plasmodium requires host iron for replication, how host iron homeostasis and responses to these fluxes affect Plasmodium infection are incompletely understood. We determined that Lipocalin 2 (Lcn2), a host protein that sequesters iron, is abundantly secreted during human (P. vivax) and mouse (P. yoeliiNL) blood-stage malaria infections and is essential to control P. yoeliiNL parasitemia, anemia, and host survival. During infection, Lcn2 bolsters both host macrophage function and granulocyte recruitment and limits reticulocytosis, or the expansion of immature erythrocytes, which are the preferred target cell of P. yoeliiNL. Additionally, a chronic iron imbalance due to Lcn2 deficiency results in impaired adaptive immune responses against Plasmodium parasites. Thus, Lcn2 exerts antiparasitic effects by maintaining iron homeostasis and promoting innate and adaptive immune responses.

A new system for the analysis of thermal judgments: multipoint measurements of skin temperatures and temperature-related sensations and their joint visualization.

We report a new system for monitoring sensations of many body parts as well as comprehensively showing the distribution of overall skin temperature (T(sk)) and temperature-related sensations. The system consists of a console with 52 levers to report temperature-related sensations and software that facilitates the visualization of the distribution of T(sk) and temperature-related sensations by displaying them on a model of the human body. The system's utility was demonstrated with a physiological experiment involving three males and three females. They were exposed to step changes of ambient temperature from 23 degrees C to 33 degrees C. We measured T(sk) at 50 points, and the subjects concurrently provided estimates of local temperature sensation and thermal comfort/discomfort at 25 loci. This system greatly facilitates the perception and analysis of spatial relationships and differences in temperature and sensation in various areas of the body.

A case report of unilateral hypoglossal neuroparalysis resulting from horizontal subluxation in the atlanto-occipital joint due to rheumatoid arthritis.

We experienced a case of unilateral hypoglossal neuroparalysis, in which the right hypoglossal nerve was compressed by horizontal subluxation in the atlanto-occipital joint, due to rheumatoid arthritis. This report represents a very rare case of unilateral hypoglossal neuroparalysis, in which diagnostic imaging of CT with multiple cross-sectional images (three-dimensional CT) was quite useful for the identification of compression by horizontal subluxation.