Distinct serum apolipoprotein A-I levels in neuromyelitis optica and acute transverse myelitis
© Zhong et al.; licensee BioMed Central Ltd. 2013
Received: 16 September 2013
Accepted: 18 October 2013
Published: 23 October 2013
NMO and ATM are intertwined both clinically and pathologically. Apolipoprotein (apo) A-I, the main apolipoprotein of HDL, plays an important role in lipid metabolism in the cerebrospinal fluid and is known to suppress pro-inflammatory cytokines generated by activated T cells in some autoimmune diseases as an immune regulator. However, the differences in the levels of serum apoA-I between NMO and ATM patients are unclear.
In the present study, serum apo A-I levels were measured in 53 NMO patients, 45 ATM patients and 49 healthy subjects. We tested serum apoA-I levels in all participants and investigated EDSS scores of patients with NMO and ATM. Statistical analyses were performed by using SPSS statistical software.
We found that serum apoA-I levels in patients with NMO were significantly lower in comparison to those with ATM. We also found that serum levels of apoA-I was lower in male subjects in comparison to the female subjects in all groups although these differences were not statistically significant in patients with NMO or ATM. It is also shown in our study that serum apoA-I levels in patients with NMO were significantly elevated after receiving a high dosage of intravenous corticosteroids over a period of one week. However, we did not find any correlation between the apoA-I levels and disease disability.
From this study, we concluded that serum levels of apoA-I were lower in NMO patients compared to patients with ATM. Serum apoA-I studies might provide some useful clues to differentiate NMO cases from ATM cases.
Neuromyelitis optica (NMO), as a rare autoimmune demyelinateting disorder, arouses inflammatory lesions in the optic nerves and spinal cord and causes some serious clinical symptoms such as blindness and paralysis. In NMO, the inflammatory profile primarily involves eosinophils/neutrophils and autoantibody reaction. At present, an autoantibody (NMO IgG) against aquaporin-4 (AQP4), a water channel expressed on astrocytes, has been incriminated as a causative factor. Similar to other autoimmune diseases, Th17 cells and their effective cytokines (such as interleukin 6) participate in the pathogenesis of NMO [1, 2]. Acute transverse myelitis (ATM) is characterized as a demyelinating, inflammatory, and infectious myelopathy, with a variety of clinical manifestations, including those associated with multiple sclerosis (MS) , NMO , systemic autoimmune disease , infection , as well as cases with no specific origin(idiopathic ATM) . Although acute transverse myelopathy can be presented in a variety of ways and involves pyramidal, sensory, and autonomic dysfunction to varying degrees, the signs and symptoms of myelopathy do not provide an insight into the etiology and the differential diagnosis of the disease. Therefore, there is a requirement for potential-molecular markers to differentiate ATM from other demyelinating and inflammatory myelopathies, including MS, NMO, other systemic inflammatory diseases (SLE), acute disseminated encephalomyelitis, and postvaccinial myelitis . This article emphasizes the differential diagnoses between NMO and ATM. Despite the reported differences, NMO and ATM are still intertwined both clinically and pathologically. In addition, ATM can be the first manifestation of MS and NMO. Thus, it will be very useful if plasma-based biomarkers can be identified to discriminate NMO from ATM.
Apolipoprotein (apo)A-I, as the main component of high density lipoprotein (HDL), plays a vital role in reverse cholesterol transportation by facilitating the binding of HDL and lecithin cholesterol acyltransferase . The central nervous system is the most lipid-rich organ and approximately 25% of the total body’ cholesterol is distributed in the central nervous system . It has previously been shown that apoA-I has been implicated in several antiatherogenic functions, including protection against thrombosis and oxidative stress . Beyond that, apoA-I can protect hippocampal neuronal cultures from amyloid beta-induced neurotoxicity as well . Moreover, apoA-I might play the role of a constitutive anti-inflammatory factor . Therefore, the aim of this study was to evaluate the differences in serum apoA-I levels between patients with NMO and ATM.
Patients and methods
Demographic and clinical characteristics of NMO, ATM patients and healthy control group
NMO (n = 53)
ATM (n = 45)
HC (n = 49)
Range of ages (y)
Means of ages (y)
4.6 ± 2.0
5.0 ± 2.7
All selected patients had never received steroids or statins treatments or disease-modifying immunosuppressive therapy that can affect the serum apoA-I levels two months before admission. The blood was collected to detect serum apoA-I after overnight fasting. Serum apoA-I levels were measured by routine clinical testing. This study was approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-Sen University (200733) and in compliance with the Helsinki Declaration. All subjects gave informed consents to participate in this study.
All statistical analyses were performed using the Statistical Program for Social Sciences (SPSS) statistical software (version 11.0, Chicago, IL, USA). All the data in this study were presented as means ± SD. Statistical significance was set at P < 0.05. The effect of age on serum apoA-I levels of different groups were analyzed by covariance analysis. The comparison of serum apoA-I levels among the NMO, ATM patients and the HC group was performed using covariance analysis with age as the covariant. Since serum apoA-I levels can be moderated by estrogen levels, the patients were divided into two subgroups according to the gender. Covariance analysis was also used to compare serum apoA-I levels of males and females patients with NMO, ATM or in HC group with age as the covariant. Correlations between serum apoA-I and EDSS scores of NMO and ATM patients were analyzed by Spearman correlation analysis.
Analysis of serum apoA-I among the patients with NMO and ATM and healthy control
Gender ratio (female: male)
Means age ± SD (years)
38.2 ± 14.4
1.20 ± 0.21
39.0 ± 16.1
1.32 ± 0.22
41.0 ± 17.7
1.59 ± 0.13
Serum apoA-I levels in male and female NMO, ATM patients and healthy controls
38.1 ± 13.2
1.21 ± 0.23
38.5 ± 17.3
1.17 ± 0.17
39.8 ± 16.1
1.43 ± 0.22
38.6 ± 16.4
1.34 ± 0.19
39.3 ± 18.7
1.67 ± 0.21
42.5 ± 16.8
1.52 ± 0.16
Our research showed that the serum apoA-I levels in NMO and ATM were significantly lower than those in healthy group. Although the exact reason for these differences remained unknown, the following evidences may explain this phenomenon. It is well-known that multiple factors are involved in the development of their pathological process, such as genetic susceptibility, gender and environment. The autoimmune-inflammation reaction was believed to play a critical role in such process. The immune-inflammation reaction was characterized by the infiltration of immune-inflammatory cells and plasma factors into the lesion site to eradicate infection and to repair damaged tissues . Contact-mediated activation of monocytes by stimulated T lymphocytes acted as a major stimulus, triggering the production of large amounts of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1 β) which played an important role in chronic inflammation . ApoA-I, as a specific inhibitor of cytokine production in monocyte-macrophages upon contact with stimulated T cells, exerted most of its inhibitory activity by specifically binding the activating factor on stimulated T cells, consequently blocking the interaction between T-lymphocytes and monocytes . Therefore, apoA-I was known as a negative acute-phase protein and might diffuse into the extra-vascular compartment and interfere with the cross-talk between cells in acute or chronic inflammation , resulting in a decrease of serum apoA-I levels. In addition, the maintenance of inflammation in a particular target tissue would in turn keep up a low concentration of apoA-I at the systemic level and thus be beneficial to the production of inflammatory cytokines . This could account for a significantly lower serum apoA-I levels in NMO and ATM patients in comparison to the corresponding serum apoA-I levels in the healthy group. This also implied that apoA-I may be a sign of the possible development of inflammation. ApoA-I level was decreased in the plasma of rheumatoid arthritis (RA) patients. However, it was enhanced in synovial fluid of RA patients. It has been reported that ApoA-I also exists in human cerebrospinal fluid . Therefore, we need to explore the changes of CSF apoA-I levels in NMO and ATM in the future.
In this study, another notable finding was the significantly lower serum apoA-I levels in patients with NMO in comparison to those with ATM. Although the reason is still unclear, it may be associated with the following factors. Several reports indicated that humoral immunity participated in the pathogenesis of NMO . The discovery of NMO IgG, which is directed against aquaporin-4 (AQP4), is the strong evidence. A subset of B-cells in the peripheral tissues is stimulated to produce anti-AQP4 IgG antibody, which results in an extensive loss of astrocytes in specific regions of the CNS via complement mediated cytotoxicity . It had been previously confirmed that astrocytes could generate apoA-I in rat , and the extensive loss of astrocytes resulted in significantly decreased productions of apoA-I. Moreover, some studies indicated that apoA-I plasma concentrations was diminished in SLE and this decrease was associated with the presence of anti-apoA-I antibodies in 32% of patients . Such specific anti-apoA-I antibodies are likely to exist in NMO patients because humoral immunity involved in the pathological process. In addition, based on a survey of serum cytokine levels , the study indicated that increased inflammation existed in patients with NMO compared to patients with MS. Therefore, we cannot excludethe possibility that patients with NMO have an increased inflammatory response in comparison to patients with ATM, resulting in the increased utilization of apoA-I. Based on the above mentioned reasons, it is reasonable that patients with NMO might have significantly lower serum apoA-I levels than the patients with ATM as shown in our results. Our results also suggest that the serum apoA-I levels in NMO might provide some useful clues for the differential diagnosis against ATM.
Finally, we found that the serum levels of apoA-I were lower in males than in females in all the analyzed groups, though the differences were not statistically significant in patients with NMO or ATM. It could be explained by that apoA-I levels are moderated by estrogen levels . However, a correlation between apoA-I and EDSS score in NMO and ATM patients showed no statistical differences. This suggested that apoA-I level was not correlated with disease disability. However, further researches are needed to verify this finding with a larger patient population. Interestingly, the serum ApoA-I levels were significantly increased after NMO patients received corticosteroid treatment for one week. Corticosteroids have anti-inflammatory properties and immunosuppressive effects that could result in decrease of the productions of cytokines and stimulated T lymphocytes , resulting in increased levels of apoA-I after corticosteroid administration.
In the future, we plan to measure the apoA-I levels in cerebrospinal fluid of the patients suffered from NMO and ATM and discuss the relationship between CSF apoA-I and clinical presentations of NMO and ATM patients. We also intend to collect more study subjects to seek out more clues to help differentiate these two diseases at outset.
The study was supported by National Science Foundation (No. 81271327) and Technology Project of Guangdong Province (No. 2011B031800015).
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