Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice

Mice that lack the p85alpha regulatory subunit of phosphatidylinositol-3 kinase (PI3K) are deficient in gastrointestinal and peritoneal mast cells but have dermal mast cells. Accordingly, these mice show impaired bacterial clearance in response to acute septic peritonitis and are highly susceptible to infection by the intestinal nematode Strongyloides venezuelensis. Systemic anaphylactic shock responses, however, are intact. We found that although reconstitution of PI3Kminus sign/minus sign mice with bone marrow--derived mast cells (BMMCs) restored anti-bacterial immunity, only T helper type 2 (TH2)-conditioned BMMCs, not "standard" BMMCs, were able to restore anti-nematode immunity. This finding highlights the importance of the TH2 response in the control of nematode infection. Thus, PI3K likely plays an essential role in host immune responses by regulating both the development and induction of mast cells.     

Multi-center study of seasonal affective disorders in Japan. A preliminary report

A multi-center study on seasonal affective disorder (SAD) was conducted from the autumn of 1988 to the spring of 1989 with the cooperation of 16 facilities in Japan. Forty-six SAD patients were identified among 1104 respondents to our advertisements in mass media, or patients seen at the outpatient clinics. Essentially similar findings to other previous reports were obtained in terms of onset age of the first episode, duration of episode, high proportion of depression in first-degree relatives and atypical vegetative symptoms. However, a nearly equal sex ratio, together with a high proportion of unipolar depression, is characteristic of the present study. Increased appetite and carbohydrate craving were predominant only in female patients, whereas hypersomnia was prominent in both sexes. Effective response to light therapy was found in 17 SAD patients. However, a controlled study on a large number of patients is required to allow final conclusions on the efficacy of light therapy in Japanese SAD patients.     

B Lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse

Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell signaling contribute to specific autoantibody production.     

Live varicella vaccine polarizes the mucosal adjuvant action of cholera toxin or its B subunit on specific Th1-type helper T cells with a single nasal coadministration in mice

This study was undertaken to determine whether the specific Th1- or Th2-cell response to varicella-zoster virus was induced predominantly by a mucosal adjuvant, cholera toxin, in mice. A commercially available live varicella vaccine (Oka strain) and cholera toxin or its B subunit were administered simultaneously via the nasal route. Delayed-type hypersensitivity to the Oka vaccine was induced, but the systemic neutralizing antibody response was low. The delayed-type hypersensitivity evoked after a single administration was relatively higher than that on administration three times. When spleen cells from mice immunized once with the vaccine and cholera toxin or its B subunit were restimulated with the live vaccine in vitro, there was greater thymidine uptake and production of interleukin- 2 (IL-2) than controls, but only a low level of IL-4 production. The production of IL-2 induced by the B subunit of cholera toxin was less than that by cholera toxin and a mutant of Escherichia coli enterotoxin on co-immunization with the vaccine in mice. Cholera toxin and its B subunit have been reported to induce predominantly a specific Th2-type T-cell response to various antigens. However, the Oka vaccine is an antigen that polarizes the activation of specific Th1/Th2-type T cells by cholera toxin or its B subunit to the Th1-type side. Cholera toxin and its B subunit are thus useful mucosal adjuvants for inducing cellular immunity to the Oka vaccine similar to Escherichia coli enterotoxin.     

Heat-shock induced nuclear retention and recycling inhibition of importin alpha

Heat-shock induces a strong stress response and modifies all aspects of cellular physiology, which involves dynamic changes in the nucleocytoplasmic distributions of a variety of proteins. Many distinct nucleocytoplasmic transport pathways exist in eukaryotic cells, but how a particular transport pathway is regulated under different cellular conditions remains elusive. The finding of this study indicate that conventional nuclear import, which is mediated by importin alpha/beta, is down-regulated, while the nuclear import of 70 kD heat-shock cognate protein is up-regulated in heat-shock cells. Among the factors involved in the mediation of the conventional nuclear import, significant levels of importin alpha accumulate in the nucleus in response to heat-shock. An analysis of the behaviour of importin alpha with fluorescence recovery after photobleaching and fluorescence loss in photobleaching studies show that nuclear importin alpha becomes less mobile and its nucleocytoplasmic recycling is impaired in heat-shock cells. These data coincided well with biochemical and cytological studies. Our present data show that heat-shock induces the nuclear accumulation, nuclear retention, and recycling inhibition of importin alpha, resulting in the suppression of conventional nuclear import. This suggests a new regulatory mechanism for the adaptation of cells to environmental changes, such as heat-shock.     

An Autopsy Case Combined With So-called Masson Bodies of Lung, Necrotizing Angitis of Gall Bladder and Subacute Glomerulonephritis—Pathologic and Histochemical Studies on the'Bourgexons Conjonctifs' (Masson,—

The Masson body termed by Masson, Riopelle and Martin in 1937, and periarteritis nodosa termed by Kusmaul and Maier in 1866 are both diseases recongnized as representing an allergic reaction.
I have studied an autopsy case of subacute glomerulonephritis, which also represents an allergic reaction, associated with Masson body and periarteritis nodosa.     

IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response

IL-1 is a pro-inflammatory cytokine consisted of two molecular species, IL-1alpha and IL-1beta, and the IL-1 receptor antagonist (IL-1Ra) is a natural inhibitor of both molecules. Although it is suggested that IL-1 potentiates immune responses mediated by T(h)2 cells, the role of IL-1 in asthma still remains unclear. In this study, we demonstrate that the ovalbumin (OVA)-induced airway hypersensitivity response (AHR) in IL-1alpha/beta-deficient (IL-1alpha/beta(-/-)) mice was significantly reduced from the levels seen in wild-type mice, whereas the responses seen in IL-1Ra(-/-) mice were profoundly exacerbated, suggesting that IL-1 is required for T(h)2 cell activation during AHR. OVA-specific T cell proliferation, IL-4 and IL-5 production by T cells, and IgG1 and IgE production by B cells in IL-1alpha/beta(-/-) mice were markedly reduced compared with these responses in wild-type mice; such responses were enhanced in IL-1Ra(-/-) mice. Using IL-1alpha(-/-) and IL-1beta(-/-) mice, we determined that both IL-1alpha and IL-1beta are involved in this reaction. Both IgG1 and IgE levels were reduced in IL-1beta(-/-) mice, while only IgE levels were affected in IL-1alpha(-/-) mice, indicating a functional difference between IL-1alpha and IL-1beta. These observations indicate that IL-1 plays important roles in the development of AHR.     

Endogenous gamma interferon, tumor necrosis factor, and interleukin-6 in Staphylococcus aureus infection in mice.

The production and roles of endogenous gamma interferon (IFN-gamma), tumor necrosis factor (TNF), and interleukin-6 (IL-6) in both lethal and nonlethal infections of Staphylococcus aureus were investigated in mice. In the case of nonlethal infection, although no bacteria were detected in the bloodstreams, bacteria that colonized and proliferated persistently for 3 weeks were found in the kidneys. All mice given lethal injections died within 7 days, and large numbers of bacteria were detected in the bloodstreams, spleens, and kidneys. The first peaks of IFN-gamma, TNF, and IL-6 were observed in the bloodstreams and spleens of the mice with nonlethal and lethal infections within 24 h. Thereafter, in the nonlethal cases, IFN-gamma, TNF, and IL-6 peaked again in the spleens and kidneys during the period of maximum growth of bacteria in the kidneys, although only IL-6 was detected in the sera. In contrast, in the case of lethal infection, the titers of IFN-gamma and IL-6 in the sera and TNF in the kidneys peaked before death. Effects of in vivo administration of monoclonal antibodies (MAbs) against IFN-gamma and TNF on the fates of S. aureus-infected mice were studied. In the nonlethal infections, anti-TNF alpha (anti-TNF-alpha) MAb-treated mice, but not anti-IFN-gamma MAb-treated mice, died as a result of worsening infection, suggesting that endogenous TNF plays a protective role in host resistance to S. aureus infection. In the mice that received lethal doses, injection of anti-TNF-alpha MAb accelerated death. However, although injection of anti-IFN-gamma MAb inhibited host resistance of the infected mice early in infection, most of the animals survived the lethal infection by injection of anti-IFN-gamma MAb, suggesting that endogenous IFN-gamma plays a detrimental role in S. aureus infection. Thus, this study demonstrated that IFN-gamma and TNF play different roles in S. aureus infection.