JP7366428B2 - Skin sample analysis method and system for determining psoriasis - Google Patents

Description

The present invention relates to a skin sample analysis method for determining psoriasis using the amount of D-serine as an indicator from a skin sample, a psoriasis testing method, and a sample analysis system that outputs pathological information regarding psoriasis. Psoriasis can be determined using not only the amount of D-serine but also parameters calculated from the amount of D-serine.

Psoriasis is an inflammatory skin disease accompanied by skin hyperkeratosis due to abnormal proliferation of keratinocytes, and is characterized by an erythematous rash mainly covered with scales. Although the cause of psoriasis has not yet been identified, genetic factors and multiple factors are thought to contribute. External therapy, phototherapy, internal therapy, surgical therapy, etc. are used to treat psoriasis. In particular, immunosuppressive drugs such as cyclosporine and TNF-α antibodies such as infliximab and adalimumab have high therapeutic effects, but their high drug prices place a heavy burden on patients, and these treatment methods must be applied after accurately diagnosing psoriasis. That is what is needed.

Diagnosis of psoriasis is based on the appearance and distribution of lesions, but in addition to psoriasis, diseases characterized by erythema covered with scales include psoriasis, pityriasis rosea, and pityriasis pilaris. Different skin diseases are also known, such as rash, pityriasis licheniformis, lichen planus, and lichen sclerosus. In addition, the diagnosis of psoriasis includes atopic dermatitis, seborrheic dermatitis, dermatophytosis, cutaneous lupus erythematosus, eczema, lichen planus, pityriasis rosea, intraepidermal squamous cell carcinoma, and lichen simplex chronicus. A differential diagnosis with diseases such as syphilis and secondary syphilis is required, and the judgment of an experienced physician is required. Until now, inflammatory markers such as TNF-α, IFN-γ, IL-6, IL-8, IL-10, and IL-12 have been used as psoriasis markers (Patent Document 1), but other There has been no marker that has been put to practical use that can specifically diagnose psoriasis, which can be distinguished from other inflammatory diseases.

With the development of detection technology (Patent Document 2), it has been revealed that D-amino acids, which were previously thought not to exist in mammalian bodies, exist in various tissues and may play some physiological functions. It was expected that he would play the role. D-amino acids are broadly divided into bound types that exist as amino acid residues in proteins, and free types that dissolve in tissue fluids and cells. Some free D-amino acids in body fluids are independent of L-amino acids. It is known that the content varies depending on the type of disease, and it has also been shown that it varies depending on the type of disease (Patent Document 3). In addition, it has been shown that D-serine, D-alanine, D-glutamic acid, and D-aspartic acid exist in free form in the skin (Non-Patent Document 1: Biotechnology (2014), Vol. 92, No. 12, pp. 653-656; Non-Patent Document 2: Fragrance Journal (2016), vol. 4, pages 14-18).

International Publication No. 2009/093288 Patent No. 4291628 International Publication No. 2013/140785

Biotechnology (2014), Volume 92, No. 12, pp. 653-656 Fragrance Journal (2016), vol. 4, pages 14-18

Instead of the conventional diagnosis of psoriasis based on external appearance and inflammatory markers by skilled specialists, it is desired to develop diagnostic markers that are more characteristic of psoriasis, and to develop techniques to accurately determine, test, or diagnose psoriasis using these markers. ing.

The present inventors analyzed chiral amino acids in skin samples from patients with various skin diseases, and found that the amount of D-serine decreased specifically in psoriasis, leading to the present invention.

Therefore, the present invention relates to a skin sample analysis method for determining psoriasis using the amount of D-serine as an indicator. According to the present invention, a decrease in the amount of D-serine can be associated with psoriasis. Psoriasis can be determined using not only the amount of D-serine but also parameters calculated from the amount of D-serine.

Yet another aspect relates to a sample analysis system capable of implementing the analysis method of the present invention. Such a sample analysis system includes a storage section, an input section, a data processing section, and an output section, in which skin sample analysis results are inputted from the input section, and psoriasis pathology information is outputted to the output section. can do.

In yet another aspect, the present invention also relates to a program that can be installed in the sample analysis system of the present invention and a storage medium that stores the program. Furthermore, another aspect relates to a method of operating the sample analysis system of the present invention.

In yet another aspect, the invention also relates to a kit for determining psoriasis comprising an anti-D-serine antibody.

A psoriasis marker different from previously known inflammatory markers can be provided.

FIG. 1 is a graph showing the proportion of D-serine in skin samples obtained from eruption areas and non-eruption areas of psoriasis patients, atopic patients, and xeroderma patients. FIG. 2 is an example of a configuration diagram of the analysis system of the present invention. FIG. 3 is a flowchart illustrating an example of operations for determining psoriasis.

The present invention relates to a skin sample analysis method for determining psoriasis using the amount of D-serine in the skin sample as an index. "Using the amount of D-serine as an index" refers to any embodiment in which the amount of D-serine is used as an index for determination. Therefore, it is not intended to use only the amount of D-serine, but includes the use of parameters calculated from the amount of D-serine. Specifically, the analysis method of the present invention relates to an analysis method that includes a step of measuring the amount of D-serine in a skin sample, and a step of correlating a decrease in the amount of D-serine with psoriasis. Since psoriasis can be determined by the analysis method of the present invention, in another aspect, the present invention can also be called a diagnostic method.

In the present invention, all diseases classified as psoriasis, such as plaque psoriasis, psoriatic arthritis, pustular psoriasis, and guttate psoriasis, can be determined. This example shows that the analysis method of the present invention can distinguish psoriasis from atopic dermatitis, which is an inflammatory skin disease, and xeroderma. Psoriasis can also be specifically distinguished and determined based on the disease.

In the present invention, the subject may be any subject; for example, the analysis method of the present invention may be performed on a patient suffering from a skin disease of unknown etiology, or the analysis method may be performed on a patient clinically diagnosed with psoriasis. For diagnosis, the analytical method of the invention may be performed.

In the step of measuring the amount of D-serine, only the chiral amino acid of interest may be measured, or it may be measured together with other chiral amino acids. Chiral amino acids can also serve as diagnostic markers for other diseases. Therefore, from the viewpoint of analyzing multiple diseases at once, it is preferable to simultaneously measure the D-form and L-form of amino acids that serve as diagnostic markers for other diseases, for example, 20 types of protein-constituting amino acids. In particular, it has been shown that D-amino acids such as D-serine, D-alanine, D-glutamic acid, and D-aspartic acid exist in the skin, so these D-amino acids and the corresponding L-amino acids It is more preferable to measure them all at once.

Before the step of measuring the amount of D-serine, a step of obtaining a skin sample and a step of processing the obtained skin sample may be performed. Examples of skin samples include skin sections and stratum corneum samples obtained using tape strips. The skin sample may be obtained from an eruption area or from an eruption-free area, but is preferably obtained from an eruption area in order to increase the accuracy of psoriasis determination. Since psoriasis eruptions are covered with scales, a sample of the stratum corneum may be obtained after performing tape stripping multiple times to remove scales. A stratum corneum sample obtained using a tape strip can be treated with a solvent such as methanol to extract the amino acids contained in the sample. The amount of each chiral amino acid can be measured by subjecting the extracted chiral amino acids to HPLC using a chiral column or an immunological method using an antibody capable of detecting chiral amino acids. When using HPLC to measure the amount of D-serine, a multi-step HPLC can be performed using another column before the chiral column. Multi-stage HPLC is performed, for example, by holding the separated fractions in a multi-loop unit after separation on a column and sequentially introducing them into the next column.

Determination of the amount of D-serine in a sample may be performed using any method well known to those skilled in the art. For example, D- and L-amino acids are previously stereoisomerically derivatized with o-phthalaldehyde (OPA), N-tert-butyloxycarbonyl-L-cysteine (Boc-L-Cys), or other modifying reagents, and then It is possible to simultaneously measure the D- and L-forms of amino acids by using an analytical column such as ODS-80TsQA and separating them by gradient elution of a mixture of 100 mM acetate buffer (pH 6.0) and acetonitrile. Can be used. Additionally, D- and L-amino acids were derivatized in advance with a fluorescent reagent such as 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), and then ODS-80TsQA, Mightysil RP A method of separating each amino acid non-sterically isomerically using an analytical column such as -18GP, and then optically resolving it using a Pirkle-type chiral stationary phase column (for example, Sumichiral OA-2500S or R) is a method that separates proteins. It can be used for trace measurement of the constituent amino acids (Kenji Hamase and Kiyoshi Zaitsu, Analytical Chemistry, Vol. 53, 677-690 (2004)). The optical resolution column system in this specification refers to a separation and analysis system that uses at least an optical resolution column, and may include separation and analysis using an analysis column other than the optical resolution column. More specifically, passing a sample containing components having optical isomers through a first column packing material as a stationary phase together with a first liquid as a mobile phase to separate the components of the sample; holding each of the components of the sample separately in a multi-loop unit, each of the components of the sample held individually in the multi-loop unit as a stationary phase, with a second liquid as a mobile phase; supplying the optical isomer contained in each of the components of the sample through a flow path to a second column packing material having an optically active center of The concentration of D-/L-amino acids in a sample can be measured by using an optical isomer analysis method characterized by including a step of detecting amino acids (Japanese Patent No. 4291628).

Alternatively, for measuring the amount of D-serine, D-amino acid can be quantified by an immunological method using a monoclonal antibody that discriminates between optical isomers of D-serine (Japanese Patent Laid-Open No. 2009-184981). Specifically, as an example, detection can be performed by ELISA using a monoclonal antibody that binds to D-serine and a secondary antibody that binds to the antibody and has a label.

The step of associating a decrease in the amount of D-serine with psoriasis may be performed using a parameter calculated from the amount of D-serine. As the parameter calculated from the amount of D-serine, for example, a parameter obtained by normalizing the amount of D-serine using the amount of D-serine and an internal standard contained in the skin sample can be used. As such a parameter, a ratio or ratio between D-serine and the internal standard may be calculated, or an arbitrary constant may be added, subtracted, multiplied, or divided. The amount of skin samples, especially the stratum corneum samples obtained by tape strips, that can be obtained varies depending on the condition of the skin. In particular, the eruption area is covered with scales, so it is difficult to obtain a constant amount no matter what technique is used. Therefore, by normalizing using an internal standard in the skin sample, stable results can be obtained regardless of the technique used to obtain the skin sample.

Internal standards that can be used include protein content, gene content, total amino acid content, total D-amino acid content, total L-amino acid content, arbitrary L-amino acid content, stratum corneum weight, etc. Any substance can be used as long as it is contained in a certain proportion. In the present invention, it is particularly preferable to use the total amount of L-amino acids or the amount of individual L-amino acids as an internal standard. More preferably, L-serine can be used as an internal standard. As an example, when L-serine amount is used as an internal standard, D-serine amount/L-serine amount or D-serine% (=100 x D-serine amount/D-serine amount + L-serine amount) is used. be able to.

In the process of associating a decrease in the amount of D-serine with psoriasis, it is possible to determine whether or not a person is suffering from psoriasis by comparing the cut-off value of the parameter calculated from the amount of D-serine derived as described above. . Therefore, the determination may be made by a medical assistant who is not a doctor, or by an analytical institution. Therefore, the analysis method of the present invention can also be called a preliminary method or an auxiliary method for diagnosis.

In another aspect of the present invention, the analysis method of the present invention may include a step of calculating it as a parameter for determining psoriasis, instead of associating a decrease in the amount of D-serine with psoriasis. Psoriasis can be determined by comparing the parameters calculated by this analysis method with a predetermined cutoff value.

A cutoff value for determining psoriasis can be arbitrarily determined by analyzing a cohort and performing statistical processing. Statistical processing methods that are well known to those skilled in the art may be used; for example, ROC analysis, t-test, etc. may be used, and the mean value, median value, You can also use Here, any numerical value can be selected for X, and 3, 5, 10, 15, 20, 30, 40, 60, 70, 80, 85, 90, 95, and 97 can be used as appropriate. There may be one cutoff value, or the pathological condition may be classified according to the severity of the disease. Further, the cutoff value can be determined by comparison with a patient group having skin diseases other than psoriasis.

When psoriasis is determined using the analysis method of the present invention, a treatment suitable for psoriasis is selected and performed. At least one psoriasis treatment step selected from the group consisting of, but not limited to, external therapy, phototherapy, internal therapy, injection therapy, surgical therapy, and lifestyle improvement is further performed. External treatments include topical steroid preparations, topical immunosuppressant preparations, and external preparations of vitamin D3 and its derivatives. Phototherapy includes ultraviolet irradiation, such as medium wavelength ultraviolet (UVB) and long wavelength ultraviolet (UVA) irradiation. As for internal therapy, vitamin A derivatives such as retinoids, steroids, immunosuppressants such as cyclosporine, and PDE4 inhibitors are administered. As injection therapy, antibody drugs such as antibodies against inflammatory cytokines are administered. The treatment steps for psoriasis are not intended to be limited to those described above, and new therapies and agents may be used as medical advances develop.

In recent years, psoriasis has come to be considered as a Th17 cell-mediated chronic disease that produces interleukin-17, and drugs that suppress the activity of Th17 cells are used for its treatment. Specifically, anti-TNF-α monoclonal antibodies adalimumab and infliximab, anti-human IL-12/23p40 monoclonal antibody ustekinumab, anti-IL-23p19 monoclonal antibody guselkumab, anti-IL-17A monoclonal antibody secukinumab and ixekizumab, anti-IL -17A receptor A monoclonal antibody brodalumab and other drugs have been effective. On the other hand, these antibody drugs are very expensive and often have low or no effect on skin diseases that can be misdiagnosed as psoriasis, so it is important to accurately determine or treat psoriasis after diagnosis. . Therefore, the method of the present invention may include a treatment step that includes administering these antibody drugs after determination or diagnosis.

The sample analysis system of the present invention is configured to carry out the method of the present invention. FIG. 2 is a configuration diagram of the sample analysis system of the present invention. Such a sample analysis system 10 includes a storage section 11, an input section 12, a data processing section 14, and an output section 15, and can analyze a target skin sample and output pathological information. More specifically, in the sample analysis system 10 of the present invention,
The storage unit 11 stores the cutoff value of D-serine amount and psoriasis pathological information for determining psoriasis input from the input unit 12,
A measured value of the amount of D-serine in the target skin sample is input from the input unit 12 and stored in the storage unit,
The data processing unit 14 determines the pathology information of the target psoriasis by comparing the measured value of the amount of D-serine with the cutoff value stored in the storage unit 11,
The output unit 15 can output pathological information regarding the target psoriasis.

A further aspect of the present invention may relate to a program for operating such a sample analysis system, and also to a medium on which such a program is recorded. FIG. 3 is a flowchart illustrating an example of operations for determining psoriasis according to the program of the present invention. Such programs include:
A command to cause the storage unit 11 to store the relationship between the cutoff value of D-serine amount and psoriasis pathological information;
A command to read the measured value of the amount of D-serine in the target skin sample from the input unit 12 and store it in the storage unit 11;
A command to operate the data processing unit 14 to compare the measured value of the amount of D-serine stored in the storage unit with the cutoff value, to determine the pathology information of psoriasis as a control, and to store it in the storage unit 11; and a command for activating the output unit 15 to output the stored pathology information regarding psoriasis. Such a program may be stored in a storage medium, or may be provided via a telecommunications line such as the Internet or a LAN.

The storage unit 11 includes a memory device such as a RAM, ROM, or flash memory, a fixed disk device such as a hard disk drive, or a portable storage device such as a flexible disk or an optical disk. The storage unit 11 stores data measured by the analysis and measurement unit, data and instructions input from the input unit 12, results of arithmetic processing performed by the data processing unit 14, and computer programs used for various processes of the information processing device. Store databases, etc. The computer program may be installed on a computer-readable recording medium such as a CD-ROM or DVD-ROM, or via the Internet. The computer program is installed in the storage unit using a known setup program or the like.

The input unit 12 is an interface or the like, and includes operation units such as a keyboard and a mouse. Furthermore, when the analysis and measurement section 13 is located externally, measured data and the like can be input directly or via a network or storage medium through the interface of the input section. Thereby, the input section can input data measured by the analysis and measurement section 13, instructions for arithmetic processing to be performed by the data processing section 14, and the like.

The analysis system of the present invention may be provided with the analysis and measurement section 13 via an input section, or may be provided with the analysis and measurement section 13 without an input section. When the analysis system of the present invention includes the analysis and measurement unit 13, the measurement value of the amount of D-serine in the target skin sample is input from the input unit 12, and instead of storing it in the storage unit, the analysis and measurement unit Step 13 includes the step of measuring the amount of chiral amino acids in the skin sample and storing it in the storage unit. In that case, the program includes a command to operate the analysis and measurement section 13 to determine the measured value of the amount of D-serine and to store it in the storage section.

The analysis and measurement section 13 has a configuration that enables separation and measurement of chiral amino acids. Amino acids may be analyzed one by one, but some or all types of amino acids can be analyzed all at once. The analysis measurement section 13 may be, for example, a high performance liquid chromatography system (HPLC) equipped with a sample introduction section, an optical separation column, and a detection section, although it is not intended to be limited to the following. Such HPLC is preferably two-dimensional HPLC that includes a column for separating amino acids in addition to the optical resolution column. The analysis measurement unit 13 may be included in the sample analysis system 10. Further, it may be configured separately from the sample analysis system 10, and measured data and the like may be inputted via the input unit 12 using a network or a storage medium.

The data processing unit 14 is configured to determine psoriasis by comparing the measured amount of chiral amino acids with the cutoff value stored in the storage unit 11. The data processing section 14 performs various calculation processes on the data measured by the analysis measurement section 13 and stored in the storage section 11 according to the program stored in the storage section 11 . Arithmetic processing is performed by the CPU included in the data processing section 14. This CPU includes functional modules that control the analysis and measurement section 13, the input section 12, the storage section 11, and the output section 15, and can perform various types of control. Each of these units may be configured with an independent integrated circuit, microprocessor, firmware, or the like.

The output unit 15 is configured to output pathological condition index values and/or pathological condition information that are the results of the arithmetic processing performed by the data processing unit 14. The arithmetic processing results in the data processing section 14 may be directly output to the output section 15, or may be temporarily stored in the storage section 11 and then output to the output section 15 as necessary. The output unit 15 may be a display device such as a liquid crystal display that directly displays the results of arithmetic processing, an output means such as a printer, or an interface unit for outputting to an external storage device or via a network. There may be.

A further aspect of the invention may relate to a kit for determining psoriasis. Such a kit contains an antibody for detecting D-serine and is capable of detecting D-serine in a sample. Examples of antibodies for detecting D-serine include anti-D-serine antibodies, and as an example, the antibody described in JP-A-2009-184981 can be used. In samples obtained from psoriasis patients, the amount of D-serine is extremely low or absent, so psoriasis can be determined by detecting the presence of D-serine. In a more preferred embodiment, it further comprises a control antibody that allows detection of a substance present in a certain amount in the skin sample. Thereby, even if D-serine is not detected, it can be determined whether sample preparation has failed.

A kit for determining psoriasis may further include, in addition to the antibody, a tape for tape strips and a solvent for amino acid extraction. Such a kit may further include a base material having a detection part, on which an antibody that captures D-serine is immobilized. In this case, the stratum corneum sample obtained by the tape strip is treated with a solvent for amino acid extraction, and this solution is spread on the substrate, and D-serine is captured by the antibody in the detection part. Thereafter, the captured D-serine can be detected by developing a label that can detect the captured D-serine. Examples of such labels include antibodies labeled with colloidal gold or the like.

All documents mentioned herein are incorporated by reference in their entirety.

The embodiments of the invention described below are for illustrative purposes only and are not intended to limit the scope of the invention. The technical scope of the present invention is limited only by the claims. Changes in the present invention, such as additions, deletions, and substitutions of constituent elements of the present invention, may be made without departing from the spirit of the present invention.

Population and sample analysis Stratum corneum samples were obtained from the eruption and non-eruption areas of 21 plaque psoriasis patients, 31 atopic dermatitis patients, and 8 xeroderma patients using the tape strip method. . Similarly, samples of the stratum corneum were obtained from the skin of 42 healthy subjects as a control. The severity of psoriasis patients was mild in 8 patients, moderate in 7 patients, severe in 3 patients, and unknown in 3 patients. For the stratum corneum sample, a stratum corneum tape with a sampling area of 5.6 cm ² was used, tape stripping was performed three times at the same location, and the third sample was used. The stratum corneum sample adhered to the stratum corneum tape was treated with 1,500 μl of 95% methanol, subjected to ultrasonication, and centrifuged at 15,000 rpm for 10 minutes. 250 μl of the supernatant was collected and dried under reduced pressure. A 200 mM aqueous sodium borate solution (pH 8.0: 30 μl) was added to the dried product to dissolve it. To the obtained solution, a 40mM NBD-F acetonitrile solution (5μl) was added, the reaction was carried out at 60°C for 2 minutes, and a 2% (v/v) trifluoroacetic acid aqueous solution (90μl) was added to create a two-dimensional It was subjected to HPLC analysis.

Measurement of amino acid enantiomers by 2D-HPLC Amino acid enantiomers were measured as described in J Chromatogr A 1217, 1056-1062 (2010) and Journal of chromatography. Quantification was performed using a micro 2D-HPLC platform as described above. Briefly, NBD-derivatives of amino acids were collected using a reverse phase column (monolithic ODS column, 0.53 mmi.d. Gradient elution was performed using an aqueous mobile phase containing: In order to separate and measure the D-form and L-form, a fraction of the target amino acid was automatically collected using a multi-loop valve, and then added to an optical resolution column (OA2500S-15250, 1.5 mmi.e. × 250 mm). Distributor: Daicel Industries). The mobile phase was a mixed solution of MeOH-MeCN with citric acid or formic acid, and the fluorescence of NBD-amino acids was excited at 470 nm and detected at 530 nm. All quantitative data were obtained by fluorescence detection. HPLC-MS/MS was used to confirm the presence of D-amino acids in real biological matrices.

に基づいて、Ｄ－セリンの含有率を測定した。各疾患における測定結果を、図１に示した。The concentration of D-serine and L-serine in the sample was measured and calculated using the following formula:

The content of D-serine was measured based on the following. The measurement results for each disease are shown in Figure 1.

Statistical processing The %D-Ser in each group was divided into healthy subjects, eruption areas of each disease, and no eruption areas, and intergroup comparisons were performed using Student's t-test (equal variance assumption) to verify significant differences. (Table 1). These results not only show that %D(Ser) can be used to distinguish between healthy subjects and psoriasis, but also clearly demonstrate that it is also useful for differentiating other skin diseases because it is a parameter variation characteristic of psoriasis. It is shown in

Differentiation between healthy individuals and psoriasis can also be made using another index that includes the amount of D-Ser in the calculation formula. For example, a parameter obtained by multiplying and dividing the amount of D-Ser by the amount of another amino acid (here, D-Ser/D-Ala as an example) showed a significant difference between healthy subjects and psoriatic eruptions. In addition, the parameter (D-Ser/cm ² ), which normalizes the amount of D-Ser to the amount per stratum corneum area, is also useful for diagnosis and differentiation, as a significant difference was observed between healthy subjects and psoriatic eruptions. I understand that there is something.

Claims (11)

A skin sample analysis method for determining psoriasis in a subject, the analysis method using the amount of D-serine as an index. below:
measuring the amount of D-serine in the skin sample;
The analysis method according to claim 1, comprising the step of associating a decrease in the amount of D-serine with psoriasis. The analysis method according to claim 1 or 2, further comprising the step of quantifying the amount of the internal standard in the skin sample and normalizing the amount of D-serine using the amount of the internal standard. The internal standard is at least one selected from the group consisting of protein amount, gene amount, total amino acid amount, total D-amino acid amount, total L-amino acid amount, amount of any L-amino acid, and stratum corneum weight. The analysis method according to claim 3. The analysis method according to claim 4, wherein the internal standard is an amount of L-serine or an amount of D,L-serine. The analysis method according to any one of claims 2 to 5, wherein the decrease in the amount of D-serine is determined by comparing with a predetermined cutoff value. A skin sample analysis system for determining psoriasis in a target, including a storage unit, an input unit, a data processing unit, and an output unit,
A cutoff value for the amount of D-serine in a skin sample for determining psoriasis and psoriasis pathological information are input from the input unit and stored in the storage unit,
A measured value of the amount of D-serine in the target skin sample is input from the input unit and stored in the storage unit,
the data processing unit compares the stored measured value of the amount of D-serine with the stored cutoff value to determine pathological information of psoriasis of the subject;
Output psoriasis pathology information to the output section
The skin sample analysis system. 7. The method further comprises an analysis and measurement section, wherein the analysis and measurement section determines a measurement value by quantifying D-serine from the target skin sample, and inputs the measurement value instead of or via the input section. Analysis system described in. The analysis system according to claim 7 or 8 , wherein the amount of the internal standard is input from the input section , and the data processing section further normalizes the amount of D-serine based on the amount of the internal standard. The internal standard is at least one selected from the group consisting of protein amount, gene amount, total amino acid amount, total D-amino acid amount, total L-amino acid amount, amount of any L-amino acid, and stratum corneum weight. The analysis system according to claim 9. The analysis system according to claim 10, wherein the internal standard is an amount of L-serine or an amount of D,L-serine.

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