REVIEW
Autoimmunity related to anti-Nax and anti-ZSCAN1 autoantibodies in adipsic hypernatremia
2024 Volume 71 Issue 11 Pages 1023-1029
Details
2024 Volume 71 Issue 11 Pages 1023-1029
“Adipsic hypernatremia” is clinically characterized by chronic elevation of plasma [Na+] with an inappropriate lack of thirst and upward resetting of the osmotic set point for arginine vasopressin (AVP) secretion, combined with a relative deficiency of AVP, thereby resulting in persistent hypernatremia. Many cases are accompanied by structural lesions in the hypothalamus, pituitary gland, and circumventricular organs (CVOs). On the other hand, cases without structural lesions have been reported since the 1970s, but the pathophysiology was unknown for a long time. In 2010, Hiyama et al. reported that an anti-Nax antibody response caused adipsic hypernatremia in a pediatric case with ganglioblastoma. In recent years, advances in clinical research have led researchers to recognize that an autoimmunological pathogenic mechanism might be associated with periventricular organs such as the subfornical organ (SFO). In addition, in pediatric cases diagnosed as ROHHAD (rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation) syndrome, it has been reported that half of the cases have abnormal serum Na levels, and some research findings indicated an autoimmune mechanism acting on the organs of the hypothalamus and CVOs. Then, anti-ZSCAN1 antibody response was detected in cases diagnosed as ROHHAD-NET in 2022. In this review, by summarizing a series of studies on Nax and ZSCAN1, which are expressed in the hypothalamus, pituitary gland, and SFO, I would like to describe the current findings of the autoimmune pathogenesis of adipsic hypernatremia.
Sodium (Na) homeostasis is crucial for life, and the Na+ level of body fluids is strictly maintained at a range of 135–145 mEq/L [1]. Serum Na level is reflected by water metabolism which is controlled by the sensation of thirst; arginine vasopressin secreted from the gland; and, renal collecting ducts and renal tubules [2, 3]. Hypernatremia results from either water deficiency or increased Na solutes in body fluids [4]. While chronic hypernatremia develops due to various disorders in those regulation factors, such as genetic factors, tumors, and inflammatory diseases, determining its etiology is important for precise management not only in correcting serum Na level but also in preventing the other severe complications [5].
Among those, cases diagnosed as adipsic hypernatremia have been reported since the 1970’s [6, 7]. Normally, a thirst is perceived when the plasma osmolality exceeds a level of 295 mOsm/L level, however it has been reported that the threshold for AVP is reset to the upper limit in adipsic hypernatremia. Therefore, usual thirst is not perceived at normal osmolarity and Na level. Adipsia is known to be caused by damage to the CVOs of the anterior hypothalamus where the osmoreceptors and Na+ sensors are sited. Patients with adipsic hypernatremia could not react appropriately to hypertonic dehydration, and as a result they do not respond with appropriate increase in fluid intake and are thus vulnerable to the developing hypernatremia [5]. In 2010, Hiyama et al. reported a pediatrics case with adipsic hypernatremia associated with ganglioblastoma exhibiting an autoimmune mechanism in which immunological response associated with the anti-Nax antibody leads to inflammation and apoptosis in cells of SFO [8] (Fig. 1). As Nax was also expressed on the surface of the ganglioblastoma in that case, this pathology was speculated to be similar to paraneoplastic neurological syndrome [8]. Following this, autoimmunological mechanisms related to SFO without Nax antibody were reported in cases diagnosed as adipsic hypernatremia and ROHHAD (rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation) syndrome in 2017 [9]. In that global epidemiological study, cases with anti-SFO antibody response consisted of both pediatric and adult cases and in spite of association of tumors [10]. In addition, it has been described that anti-SFO antibody response cases tend to be associated with hypothalamic dysfunction such as thermal dysfunction and central apnea, and laboratory findings of hyperprolactinemia [11]. On the other hand, a specific antigen reaction to SFO antibody was not detected at that time. In 2022, Mandel-Brehm et al. reported that anti-ZSCAN1 autoantibodies were associated with seven pediatric cases diagnosed as a paraneoplastic ROHHAD-so-called ROHHAD-NET [12]. Moreover, more than 85% of cases diagnosed as ROHHAD syndrome without tumor showed a positive response to anti-ZSCAN1 antibody [13]. In this review, I give an overview of an autoimmune etiology and pathology related to Nax and ZSCAN1 antibody response.
As previously described, serum Na levels are recognized clinically as a marker of water metabolism [3]. There are three factors that influence water metabolism: central thirst nuclei, AVP secreted from the pituitary gland, and renal collect tube and renal tubules [2]. The circumventricular organs (CVOs) are responsible for the sensation of thirst as a sensor of Na and osmolarity [1]. As one of CVOs that forms a sensory interface between blood and the brain, the SFO is the principal site for the control of salt intake behavior-generating physiological responses to dehydration and hypernatremia when Nax populates the cellular processes of astrocytes and ependymal cells enveloping neurons [1, 11]. The SFO is a unique nucleus in that its afferent and efferent projections are well placed to respond to blood-borne signals and integrate them with neuronal signals [11]. The SFO is the part that operates this neural network by sensing molecules such as angiotensin II in the blood [11].
A small portion of SFO neurons in the periphery extend collateral projections to both the MnPO and the paraventricular nucleus of the hypothalamus (PVN), likely affecting the AVP system [11]. Central thirst nuclei are known to be the anterior cingulate cortex, the central nucleus of the amygdala, the insular cortex [14]. Among them, the BNST (bed nucleus of the stria terminalis) is connected by efferent neurons from the SFO [11]. These findings show that the SFO plays a critical and principal role in thirst by monitoring serum Na and osmolarity and creating neuron network.
Nax was originally cloned by several independent groups from rat astrocytes [15], the human heart [16], a mouse atrial tumor cell line [17], and the rat dorsal root ganglia (DRG) [18]. Noda et al. have long studied the functional roles of an atypical Na channel: Nax, which was initially classified as a subfamily of voltage-gated Na channels and called Nav2 [2]. In 2000, Noda et al. revealed that Nax expressed in some limited loci in the brain, including the SFO and OVLT [19]. Nax expression in these loci was confirmed by immunohistochemistry [2]. Under electron microscopy, Nax channels are specifically expressed in perineuronal processes of astrocytes and ependymal cells enveloping particular neural populations, including GABAergic neurons in the SFO [2]. Based on a battery of studies on Nax-knockout (Nax-KO) mice, they have reported that Nax channel is the Na-level sensor of body fluids in the brain [20]. Cells in the SFO, which lacks a blood-brain barrier, may be exposed to circulating hormones, including Endothelin. Hiyama et al. reported that ET-3 locally produced in the SFO probably stimulates Nax-positive glial cells through ETBR in an autocrine or paracrine fashion [21].
| Nax | ZSCAN1 | |
|---|---|---|
| Gene name | SCN7A | ZSCAN1 |
| Protein name | Sodium voltage-gated channel alpha subunit 7 | Zinc finger and SCAN domain containing 1 |
| Expression | ||
| Subcellular locations | Localized to the plasma membrane | Localized to the nucleoli |
| Tissue expressions | Heart, skeletal, smooth muscle and ovary, etc. | Brain, pituitary gland, testis |
| Brain expressions | Hypothalamus Midbrain, and pons, etc. |
Hypothalamus Midbrain, and pons, etc. |
| Function | ||
| For proper functioning of neurons and muscles during action potentials, voltage-gated sodium channels direct sodium ion diffusion for membrane depolarization. | Maybe involved in transcriptional regulation. Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. |
|
| Information related to antibody | ||
| First report | Hiyama TY et al. in 2010 | Mandel-Brehm C et al. in 2022 |
| Associated tumors | Ganglioneuroma | Ganglioneuroblastoma Ganglioneuroma Neuroblastoma |
| Characteristics of clinical findings | High PRL (47.5 ± 26.0 ng/mL) and PRA (29.4 ± 35.7 ng/mL/h) | High PRL (58.9 ± 33.5 ng/mL), and hypothalamic dysfunction (thermal dysfunction, obesity, and central apnea) |
It has been reported that a pediatric case with ganglioneuroma and adipsic hypernatremia had an anti-Nax antibody response in 2010 [8]. According to that report, the ganglioneuroma was markedly positive for both Nax and S-100. It has been reported that the Nax signal colocalized with the S-100 signal at the cellular level, indicating that Schwann-like cells in the tumor express Nax [8]. Moreover, these findings were not detected in three cases with adrenal ganglioblastoma without hypernatremia. In an in vivo experiment, they then examined deposition of the complement component C3 and apoptosis findings by TUNEL staining in the brains of mice injected with the patient’s IgG [8]. Their findings suggested that the Nax antibody response in the SFO and OVLT leads to inflammation and apoptosis, and hypernatremia and Nax antibody might be produced as an effect of the Nax-positive ganglioblastoma.
Another etiological study showed that the clinical characteristics of positive cases with anti-Nax antibody included a high level of serum prolactin (47.5 ± 26.0 ng/mL) and plasma renin activity level (29.4 ± 35.7 ng/mL/h) (Table 1) [11]. Therefore, patients associated with such high PRL and PRA level should be considered the autoimmunological response with anti-Nax antibody as their pathophysiology. It has been reported that the dysfunction of the Nax channel, which is a sodium sensor, might lead to a compensatory increase in plasma renin activity [10, 11]. Clinical findings such as AVP and plasma osmolarity in cases with anti-Nax and anti-ZSCAN1 antibody indicated the partial central diabetes insipidus (Fig. 2)
Mandel-Brehm et al. have reported that ZSCAN1 autoantibodies were detected in the serum of pediatric cases with diagnosed as ROHHAD-NET or ROHHAD for the first time [12]. ROHHAD syndrome was proposed by Ize-Ludlow et al. in 2007 [22].
Almost half of all cases of hypernatremia are associated with this syndrome, and various hypothalamic dysfunction progress gradually. Previous study reported the ROHHAD (-NET) syndrome with immunological response to mouse SFO and ZSCAN1 exhibited more frequently hypothalamic dysfunction such as thermal dysfunction, obesity, and central apnea [11]. Similar to Nax antibody, ZSCAN1 was also expressed on the surfaces of tumors such as ganglioneuroma and neuroblastoma (Fig. 3) [12]. Therefore, pathophysiology related to anti-ZSCAN1 autoantibodies were speculated to indicate paraneoplastic syndrome (Fig. 4) [12].
ZSCAN1 is a 408-amino-acid-long protein whose functions remain mostly unknown [23]. The ZSCAN1 protein is a putative zinc finger transcription factor (znTF) that contains a single SCAN domain and three Cysteine2-Histidine2 (C2H2) zinc finger domains [23]. Although several studies have reported the association of ZSCAN family members with lipid metabolism, cell growth, and differentiation [23-25], the function of most members in this group has remained elusive. According to a protein database [26], ZSCAN1 is known to be a transcription factor and located in nucleus in testis and CNS including the hypothalamus and pituitary gland at a protein level [26].
It has been reported that it is a molecule that exhibits a tumor suppressive effect in breast cancer, and that DNA methylation is a prognostic marker in cervical cancer [27-29]. Therefore, it is speculated that ZSCAN1 is a molecule related to tumor immunity. On the other hand, the ZSCAN1 gene lacks a genetic ortholog in rodents, including mice and rats, with evolutionary divergence towards primate-specificity in the C2H2 region [29-31]. These observations suggest the putative epitope within ZSCAN1 has a high likelihood of being exclusive to primates. A primate-specific epitope in autoimmune disease has not yet been described [12]. In addition, anti-ZSCAN1 antibody positivity has been observed even in cases of ROHHAD syndrome without tumor complications, and the co-existence of ZSCAN1 and patient’s IgG in mouse subfornical organ (Fig. 1). The molecular mechanism of antibody production is unknown [13]. Certain inflammation might be related to a triggering of anti-ZSCAN1 antibody production, but further research and case accumulation are needed.
As shown in the current literature, the antibody level of antigen molecules is expected to be used as a diagnostic marker [13]. It is expected to enable early diagnosis in a group of diseases where structural lesions in the hypothalamus and pituitary gland are absent. In fact, an analysis method using ELISA has been developed [11, 13], and it is suggested that it may be more versatile and can be used for clinical diagnosis in the future.
There have been some cases in the U.S. and Europe where rituximab and intravenous immunoglobulin treatments have been used in severe cases [32]. It is expected that early diagnosis will lead to early and appropriate treatment. It has been reported that the antibody titer may be more strongly positive in cases with tumor complications than in cases without complications [33], and it is suggested that adaptation, including immunosuppressive treatment, will be considered for cases with tumor complications and severe cases.
On the other hand, it is presumed that there are cases in which the disease has not been properly diagnosed at present. In the future, it will be necessary to collect accurate information on the accurate number of patients, their natural history, and long-term complications through a wide-ranging patient registration system.
From the perspective of pathological research, some cases without tumor complications have been observed, however the cause of antibody production in these cases has not been completely elucidated. It is generally known that antibody production is triggered by inflammation within the body, so it is thought that some kind of prior infection may have had an effect. Case reports have also confirmed that patients developed symptoms similar to ROHHAD syndrome after being infected with COVID-19 [34].
In ROHHAD syndrome, exome analysis is being carried out with the aim of identifying the responsible gene, but the responsible gene has not yet been definitely identified [35]. Since this syndrome is associated with a high rate of tumor production, it is possible that there is some underlying genetic predisposition. It has been previously reported that identical twins with ROHHAD syndrome have different clinical symptoms and course [36], and therefore it is expected that future analyses will accumulate regarding the imprinting abnormalities.
Nax antibody and ZSCAN1 antibody were found to be associated with the pathology of adipsic hypernatremia. All of these symptoms result from pathological conditions in which periventricular organs, such as the subfornical organs, are affected by an autoimmune mechanism. On the other hand, although it is thought that tumors are the cause of antibody production, there are some cases in which no tumor complications are found, so it is hoped that research will progress further in the pathological analysis and that more cases will be accumulated.
I thank Prof. N. Goshima and Mr. K. Yamaguchi and Mr. R. Kumagai for their collaboration. I also thank Prof. K. Kosaki for the suggestions about this study. I thank Dr. Tocan Vlad for offering the radiological images of patient. I am really grateful all patients and their doctors, and all collaborators.
This work was supported by MEXT/JSPS KAKENHI (grant number 21K15894 to A.N.-U) and MHLW Program Grant Number JPMH 23FC1052.
There is no conflict of interest.
