Adipsic hypernatremia without hypothalamic lesions accompanied by autoantibodies to subfornical organ.

Adipsic (or essential) hypernatremia is a rare hypernatremia caused by a deficiency in thirst regulation and vasopressin release. In 2010, we reported a case in which autoantibodies targeting the sensory circumventricular organs (sCVOs) caused adipsic hypernatremia without hypothalamic structural lesions demonstrable by magnetic resonance imaging (MRI); sCVOs include the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), which are centers for the monitoring of body-fluid conditions and the control of water and salt intakes, and harbor neurons innervating hypothalamic nuclei for vasopressin release. We herein report three newly identified patients (3- to 8-year-old girls on the first visit) with similar symptoms. The common features of the patients were extensive hypernatremia without any sensation of thirst and defects in vasopressin response to serum hypertonicity. Despite these features, we could not detect any hypothalamic structural lesions by MRI. Immunohistochemical analyses using the sera of the three patients revealed that antibodies specifically reactive to the mouse SFO were present in the sera of all cases; in one case, the antibodies also reacted with the mouse OVLT. The immunoglobulin (Ig) fraction of serum obtained from one patient was intravenously injected into wild-type mice to determine whether the mice developed similar symptoms. Mice injected with a patient's Ig showed abnormalities in water/salt intake, vasopressin release, and diuresis, which resultantly developed hypernatremia. Prominent cell death and infiltration of reactive microglia was observed in the SFO of these mice. Thus, autoimmune destruction of the SFO may be the cause of the adipsic hypernatremia. This study provides a possible explanation for the pathogenesis of adipsic hypernatremia without demonstrable hypothalamus-pituitary lesions.

Distribution of beacon immunoreactivity in the rat brain.

Beacon is a novel peptide isolated from the hypothalamus of Israeli sand rat. In the present study, we determined the distribution of beacon in the rat brain using immunohistochemical approach with a polyclonal antiserum directed against the synthetic C-terminal peptide fragment (47-73). The hypothalamus represented the major site of beacon-immunoreactive (IR) cell bodies that were concentrated in the paraventricular nucleus (PVN) and the supraoptic nucleus (SON). Additional immunostained cells were found in the septum, bed nucleus of the stria terminalis, subfornical organ and subcommissural organ. Beacon-IR fibers were seen with high density in the internal layer of the median eminence and low to moderate density in the external layer. Significant beacon-IR fibers were also seen in the nucleus of the solitary tract and lateral reticular formation. The beacon neurons found in the PVN were further characterized by double label immunohistochemistry. Several beacon-IR neurons that resided in the medial PVN were shown to coexpress corticotrophin-releasing hormone (CRH) and most labeled beacon fibers in the external layer of median eminence coexist with CRH. The topographical distribution of beacon-IR in the brain suggests multiple biological activities for beacon in addition to its proposed roles in modulating feeding behaviors and pituitary hormone release.

Differential expression of class I MHC mRNA in the hypothalamus of Lewis and Fischer rats.

The expression of class I major histocompatibility complex (MHC) mRNA was compared in the brains of inflammatory susceptible, hypothalamic-pituitary-adrenal (HPA)-axis blunted Lewis rats and inflammatory resistant, HPA-axis hyperresponsive Fischer rats by quantitative in situ hybridization following lipopolysaccharide (LPS) or vehicle administration. Lewis rats showed lower levels of class I MHC in the hypothalamic paraventricular nucleus (PVN) and retrochiasmatic area (RCA) compared to Fischer rats under both vehicle and LPS conditions. No differences were detected in other brain structures. Differential class I MHC expression in Lewis rats suggests an alteration in mechanisms related to cellular activity of neuroendocrine cells rather than alterations specific to neuroendocrine molecules.

Induction of pro-inflammatory cytokine mRNAs in the brain after peripheral injection of subseptic doses of lipopolysaccharide in the rat.

Although it is generally accepted that pro-inflammatory cytokines produced by cells of the central nervous system play important roles in the communication between the central nervous system and the immune system during sepsis, it is not clear whether these cytokines are produced in the brain under subseptic conditions. In this study, we used in situ hybridization to examine the mRNA expression of the pro-inflammatory cytokines IL-1beta and TNFalpha in the brains of rats 2 and 12 h after they were challenged by peripheral injections of lipopolysaccharide (LPS) ranging from 0.01 to 1000 microg/kg. Unlike septic doses of LPS (> 500 microg/kg), which induce global expression of pro-inflammatory cytokines in the brain, subseptic doses of LPS (0.01-10 microg/kg) induced IL-1beta and TNFalpha mRNA expression only in the choroid plexus, the circumventricular organs, and meninges. The expression of the cytokine-responsive immediate early gene I kappaB alpha was induced in the brain after doses of LPS as low as 0.1 microg/kg. I kappaB alpha mRNA expression was confined to sites where IL-1beta and TNFalpha were expressed. These results indicate that the induction and action of pro-inflammatory cytokines during subseptic infection occur at the blood-brain barrier and at circumventricular organs, which may be sites for elaboration of signal molecules that communicate peripheral immune status to the brain.

Distribution of the endogenous digitalis-like substance (EDLS)-containing neurons labeled by digoxin antibody in hypothalamus and three circumventricular organs of dog and macaque.

Endogenous digitalis-like substance (EDLS) is a newly discovered humoral agent which causes sodium-diuresis. EDLS is well known to have inhibitory activity to Na+,K(+)-ATPase and cross-immunoreactivity to digoxin antibody; however, its precise chemical structure has not yet been determined. We had previously developed a histochemical technique for EDLS, i.e., digoxin-immunohistochemistry, and demonstrated that EDLS was produced in the hypothalamic neurons. In the present study, the distribution of EDLS-containing neurons in the hypothalamus of dog and macaque was investigated using this technique, because anti-EDLS antibody cannot be obtained yet. In both species, EDLS neuronal somata were mainly localized in the paraventricular nucleus and the supraoptic nucleus and its accessory nuclei. A number of somata were also scattered in the other hypothalamic areas. The processes of these neurons ran from the area where the somata were located, through the lateral and basal area of the hypothalamus, to the infundibulum. These nerve fibers with varicosities were associated with the primary capillaries of hypophysial portal veins. A few immunopositive nerve fibers were also seen in the pituitary posterior lobe of both species. Intensive immunoreactivities were observed in the subfornical organ and organum vasculosum laminae terminalis. There were no differences between dog and macaque.