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systemic lupus erythematosus ( sle ) is one of the systemic autoimmune diseases characterized by the production of autoantibodies to cellular constituents .
autoantibodies are widely used as biomarkers in many types of autoimmune diseases and other diseases such as cancer .
one of the most important research areas in which autoantibodies are used is diseases diagnosis . besides its use in diagnosis
, the detection of autoantibodies can also provide information about clinical manifestations or prognosis of some autoimmune diseases .
the study on biological functions of autoantibody or its antigens can provide us with a better understanding of the mechanism of pathogenesis of autoimmune diseases and thus may give us new insights into the new strategies in autoimmune diseases treatment .
some autoantibodies are considered to be highly specific to sle , such as anti - sm and antiribosomal p. however , these autoantibodies are present in only about 15% and 10% of sle patients , respectively [ 2 , 3 ] .
though anti - dsdna antibodies are found to be highly presented in sle patients with prevalence of about 70% , its level fluctuates significantly according to disease activity and treatment .
patients with sle are still heterogeneous in clinical manifestations and serological characteristics . more new autoantibodies in sle still need to be identified in order to further classify this disease or to better understand its pathogenesis .
the human homologue of the mouse double minute 2 ( mdm2 ) , also known as e3 ubiquitin - protein ligase , is known to degrade several central cell cycle regulators including p53 and retinoblastoma ( rb ) protein which are involved in important processes such as cell apoptosis .
it was interesting that dna viruses can specifically induce mdm2 expression and then cause b cell lymphoma .
this is a mechanism that might contribute in a similar manner to lymphoproliferation in sle induced by self - dna .
it was further demonstrated that cytosolic dna can trigger the expression and activation of mdm2 . in mrl - fas mice , an animal model of sle
, the expression level of mdm2 was found to be increased and to correlate with disease progression , which provides us with a new molecular target in sle .
since abnormally expressed proteins can induce autoimmune response , overexpression of mdm2 in lupus may trigger the production of autoantibody which may serve as a new serologic marker in sle . in this study , we investigated the presence of autoantibody to mdm2 in sera of sle patients and normal human sera ( nhs ) .
we found that autoantibody to mdm2 was highly presented in sle patients , which may be used as a new serological marker or therapeutic target in sle .
in the current study , 69 normal human sera ( nhs ) and 43 sle patient sera were examined .
these sera were obtained from the serum bank of cancer autoimmunity and epidemiology research laboratory at university of texas at el paso ( utep ) , which were originally provided by our clinical collaborators .
the diagnosis of sle was established according to the american college of rheumatology criteria [ 8 , 9 ] .
mdm2 and p53 cdnas were subcloned into pet28a vector producing fusion proteins with nh - terminal 6x histidine and t7 epitope tags .
recombinant protein was further expressed in e. coli bl21 ( de3 ) and then purified using nickel column chromatography ( qiagen , valencia , usa ) .
reactivities of the purified recombinant protein have been analyzed by electrophoresis on sds - page and determined with polyclonal anti - mdm2 antibody ( genetex , irvine , usa ) .
standard protocol for elisa was conducted as described in our previous study . in brief , a 96-well microtiter plate was coated with recombinant mdm2 or p53 protein overnight at 4c with a final concentration of 0.5  g / ml in phosphate - buffered saline ( pbs ) .
the antigen - coated wells were blocked with gelatin postcoating solution at room temperature for 2  h. human sera were diluted at 1  :  100 and then incubated for 2  h at room temperature in the antigen - coated wells , followed by hrp - conjugated goat anti - human igg .
the substrate 2,2-azino - bis-3-ethylbenzo - thiazoline-6-sulfonic acid ( abts , sigma - aldrich , st .
the average optical density ( od ) value at a wavelength of 405  nm was applied as data analysis .
the cutoff value used to designate a positive sample was the mean od value of 69 nhs + 2sd .
denatured recombinant mdm2 protein was electrophoresed on 10% sds - page and transferred to nitrocellulose membranes . after blocking in pbs with 5% nonfat milk and 0.05% tween-20 for 1  h at room temperature ,
the nitrocellulose membrane was incubated overnight with 1  :  200 dilution of human sera at 4c .
hrp - conjugated goat anti - human igg ( santa cruz , usa ) was then applied as secondary antibody at a 1  :  10,000 dilution .
the immunoreactive bands were detected by ecl kit according to the manufacturer 's instructions ( thermo scientific , waltham , usa ) .
the diluted sle sera ( 1  :  80 ) were incubated with recombinant protein mdm2 ( final concentration of recombinant proteins in the diluted human sera was 0.01  g/l ) overnight at 4c and then centrifuged at 10,000  g for 15  min .
antigen substrate for iifa test system was incubated with diluted sera ( 1  :  80 ) and preabsorbed sera overnight at 4c .
fitc - conjugated goat anti - human igg was then used as secondary antibody at a 1  :  100 dilution .
the frequency of autoantibody to mdm2 in the sera was compared using the  test with fisher 's exact test .
serum level of autoantibody to mdm2 in sle patients and normal human sera was determined by elisa .
the mean titer of autoantibody to mdm2 was significantly higher than that in nhs ( figure 1 ) .
we then used the mean od value plus 2sd of nhs as the cutoff value to determine the frequency of anti - mdm2 autoantibody positive sera in these three groups .
the frequency of anti - mdm2 positive sera was significantly higher in sle patients group ( 23.30% ) than nhs group ( 4.30% ) ( table 1 ) . in order to confirm the presence of anti - mdm2 in sle patients , anti - mdm2 autoantibody positive sera
these sera also had strong reactivity with mdm2 recombinant protein in western blotting analysis ( figure 2 ) . to further confirm the reactivity of autoantibodies against mdm2 in sle sera and the intracellular localization of mdm2
, commercially available hep-2 cell slides were used in indirect immunofluorescence assay to examine anti - mdm2 autoantibody positive sle sera . as shown in figure 3 ,
the anti - mdm2 positive sera had the nuclear staining patterns , while the normal human serum had very weak staining .
the fluorescent staining was significantly reduced when the same serum was preabsorbed with recombinant anti - mdm2 protein . since mdm2 has been demonstrated as an important negative regulator of p53 and anti - p53
was also been reported to be found in sle patients , whether there was an association between anti - mdm2 and anti - p53 is still unknown .
we further investigated the presence of anti - p53 in these sle patients by elisa .
we used the mean od value + 2sd of nhs as the cutoff value to determine the frequency of anti - p53 autoantibody positive sera .
consistent with results reported in other studies , the frequency of anti - p53 positive sera was significantly higher in sle patients group ( 39.50% ) than nhs group ( 5.90% ) ( figure 4 ) , and the titer of anti - mdm2 was positively correlated with anti - p53 ( figure 5 ) .
the present study showed that anti - mdm2 autoantibody was presented in 23.30% sle patients , significantly higher than normal heathy humans .
this suggests that the anti - mdm2 autoantibody might be used as a new serologic marker for sle . the mdm2 protein ( also known in humans as hdm2 )
was first identified as the product of a gene amplified over 50-fold on acentromeric extrachromosomal bodies ( called  double minutes  ) found in a 3t3 dm spontaneously transformed mouse cell line [ 13 , 14 ] .
besides its regulation on p53 , it was found that mdm2 also interacted with many proteins in addition to p53 such as nf-b [ 15 , 16 ] .
it was described as one of the tumor associated antigens ( taa ) as mdm2 was overexpressed in several kinds of tumors .
it has also been reported that autoantibody to mdm2 can be found in patients with esophageal squamous cell carcinoma .
the role of mdm2 in immune regulation can be speculated by its regulation on p53 . in recent years , p53 has been found to be important in both innate and acquired immune regulation [ 20 , 21 ] , and it was necessary in the inhibition of autoimmune inflammation .
several studies have found that the presence of anti - p53 in sle patient , with a prevalence of about 26%59% , showed that anti - p53 was related to anti - dna antibodies and can be used as a marker for detecting the disease activity of sle [ 12 , 23 , 24 ] .
our study showed that anti - p53 was presented in 39.50% of sle patients , and the titer of anti - p53 was positively correlated with anti - mdm2 .
. showed that mdm2 can modulate dendritic cell - induced t cell proliferation   and mulay et al .
proved that mdm2 was required to induce mrna expression and secretion of nf-b - dependent cytokines upon toll - like receptor stimulation , which were important processes in sle pathogenesis .
another study showed that mdm2 can promote sle and inhibition of mdm2 can suppress the abnormal expansion of all t cell subsets , without causing myelosuppression effect on splenic regulatory t cells , neutrophils , dendritic cells , or monocytes .
our study further confirmed the importance of mdm2 in the pathogenesis of sle and provided a new serological marker for sle .
an increased risk of cancer in sle patients has been observed [ 27 , 28 ] .
whether the high prevalence of autoantibodies to mdm2 and p53 was related to the high risk of cancer in sle patients still needs to be clarified .
our study is the first one to demonstrate the presence of anti - mdm2 antibody in sle patients .
however , an obvious limitation of the present study is the limited clinical information of sle patients included in this study .
analysis regarding the association of anti - mdm2 autoantibody and the clinical manifestations was hard to conduct due to the limited clinical information .
studies on anti - mdm2 in more sle patients with detailed clinical information are needed to further ensure the role of anti - mdm2 in sle diagnosis , disease activity evaluation , or prognosis prediction .
the presence of anti - mdm2 still needs to be investigated in other autoimmune diseases such as rheumatoid arthritis , systemic sclerosis , sjgren 's syndrome , and dermatomyositis .
in conclusion , the present study reported a high prevalence of anti - mdm2 in sle patients , which suggests the role of mdm2 in the pathogenesis of sle .
the detection of anti - mdm2 autoantibody may provide a new serological marker in sle diagnosis .
introduction . systemic lupus erythematosus ( sle ) is one of the systemic autoimmune diseases characterized by the polyclonal autoantibody production . 
 the human homologue of the mouse double minute 2 ( mdm2 ) is well known as the negative regulator of p53 . 
 mdm2 has been reported to be overexpressed in sle animal model and to promote sle . 
 since abnormally expressed proteins can induce autoimmune response , anti - mdm2 autoantibody was examined in sle patients . 
 methods . 
 anti - mdm2 antibody in sera from 43 sle patients and 69 healthy persons was investigated by elisa . 
 positive samples were further confirmed by western blotting . 
 the immunological feathers of anti - mdm2 positive sera were analyzed by indirect immunofluorescence assay . 
 anti - p53 was also investigated in sle patients by elisa , and the correlation of anti - mdm2 and anti - p53 was analyzed . 
 results . 
 the presence of anti - mdm2 in sle patients was 23.30% , much higher than normal healthy persons ( 4.30% ) . 
 these anti - mdm2 positive sera present a nuclear staining pattern . 
 the presence of anti - p53 in sle patients was 39.50% , and the titer of anti - mdm2 was positively correlated with anti - p53 in sle patients . conclusions . 
 anti - mdm2 autoantibody was detected at high prevalence in sle patients . 
 the detection of anti - mdm2 in sle patients should be clinically useful .