Vitamin D and its role in immunology: multiple
sclerosis, and inflammatory bowel disease.
譯自：http://www.ncbi.nlm.nih.gov/pubmed/16563470
摘要Abstract：維生素D預防自體免疫疾病
自體免疫疾病如多發性硬化症，發炎性腸道疾病，都因不適當的自體免疫調解導致攻擊自己的組織細胞。Autoimmune
diseases like multiple sclerosis (MS) and
inflammatory bowel disease (IBD) occur because
of an inappropriate immune-mediated attack
against self-tissue.分析基因完全相同的雙胞胎顯示，除了遺傳外，重要的環境因素誘發多發性硬化症和發炎性腸道疾病的病程。Analyses
of genetically identical twins shows that
besides genetics there are important
environmental factors that contribute to MS and
IBD development. 維生素D可從日晒或飲食獲得，可能在多發性硬化症和發炎性腸道疾病的病程扮演一定的角色。Vitamin
D availability due to sunshine exposure or diet
may play a role in the development of MS and
IBD. 在小鼠的多發性硬化症，發炎性腸道疾病實驗中，維生素D透過維生素D受體的信息傳遞實驗結果顯現令人信服的數據。Compelling
data in mice show that vitamin D and signaling
through the vitamin D receptor dictate the
outcome of experimental MS and IBD.
此外，實驗證據指向維生素D直接和間接調控T細胞發育和功能。Furthermore,
the evidence points to the direct and indirect
regulation of T cell development and function by
vitamin D. 在缺乏維生素D，及透過維生素D受體的信號傳遞，會自動誘發T細胞的發育，在活性維生素D
(1,25(OH)2D3 )和具功能性維生素D受體出現存在下，會還原T細胞的反應平衡和避免自體免疫。In
the absence of vitamin D and signals delivered
through the vitamin D receptor, auto reactive T
cells develop and in the presence of active
vitamin D (1,25(OH)2D3 ) and a functional
vitamin D receptor the balance in the T cell
response is restored and autoimmunity avoided.
1.
自體免疫Autoimmunity
免疫系統已進化到保護我們免受致病微生物攻擊。The
immune system has evolved to protect us from
disease causing microorganisms.
為了做到這一點，免疫系統必須能區別屬於（自己）的東西，或不屬於自己（外來）之間的東西。
In order to do this the immune system must
differentiate between things that belong (self)
and things that do not belong (non-self).
在一些個體存在的基因缺陷過程中，由於對自己做出不恰當的反應的結果造成發生自體免疫性疾病。In
some individuals there is a flaw in the process
and autoimmune disease occurs as a consequence
of the inappropriate reactivity to self.
在自體免疫患者中，T細胞在周邊標靶組織如中樞神經系統（多發性硬化症），腸道（發炎症性腸疾病），關節（關節炎）和胰腺（第1型糖尿病）上發育成長。In
autoimmune patients, T cells develop in the
periphery that target tissues such as the
central nervous system (multiple sclerosis), the
gut (inflammatory bowel diseases), the joints
(arthritis) and the pancreas (type-1 diabetes).
這些疾病之間的共通性是T細胞，及特別是T幫助細胞1（Th1）驅動病變的病理。The
commonality between these diseases are that
T-cells and in particular Th1 cells drive
disease pathology.
T幫助細胞1（Th1）媒介的自體免疫疾病的特徵是T幫助細胞1（Th1）分泌腫瘤壞死因子（TNF）-α和干擾素（IFN）-γ在自己組織和患部誘發炎症（在腸道發生-發炎性腸疾病（IBD），在中樞神經系統發生-多發性硬化症（MS））。Th1-mediated
autoimmune diseases are characterized by Th
cells that secrete tumor necrosis factor
(TNF)-a, and interferon (IFN)-g that home to
self-tissues and induce inflammation at those
sites (inflammatory bowel disease (IBD)-gut,
multiple sclerosis (MS)—central nervous system).
在一般情況下，如治療Th1媒介的自體免疫疾病原理是，抑制產生Th1細胞和/或細胞激素（尤其是腫瘤壞死因子-α(TNF-α）)的數量。In
general, if a treatment for Th1-mediated
autoimmunity works it suppresses the number of
Th1 cells and/or the cytokines (TNF-a in
particular) that they produce.
此外，針對T幫助細胞1（Th1）驅動的疾病的治療原理是，抑制其他T幫助細胞1（Th1）驅動的自身免疫性疾病。
In addition, treatments that work for one Th1
driven disease are likely to suppress other Th1
driven autoimmune diseases. 自體免疫性疾病的病因不明。Autoimmune
diseases are of unknown etiology.
多重基因和環境之間的複雜交互作用，決定哪些個案將發生那一種自體免疫性疾病。Complicated
interactions between multiple genes and the
environment dictate which individuals will
develop any given autoimmune disease. 維生素D可能是有助於自體免疫疾病發展的環境因素。Vitamin
D may be an environmental factor that
contributes to autoimmune disease development.
環境維生素D的來源包括飲食和紫外線照射皮膚上的前驅物7
- 脫氫膽固醇（seven-dehydrocholesterol）產生的維生素D3
(DeLuca, 1993).。Environmental
sources of vitamin D include the diet and the
production of vitamin D3
in the skin following UV exposure
of the skin precursor seven-dehydrocholesterol
(DeLuca, 1993).
維生素D3的合成在夏天的陽光下做10分鐘的皮膚曝曬，相對有效的過程，就可產生對人體建議的每日攝入量（400國際單位，DeLuca，1993）。Vitamin
D3 synthesis is a relatively efficient process
in which 10 min of summer sun will produce the
recommended daily intake for humans (400 IU,
DeLuca, 1993).
暗黑和老人的皮膚是對維生素D的合成效率較低（Holick等人，1981）。
Dark skin, and the skin of the elderly are less
efficient producers of vitamin D (Holick et al.,
1981). 此外，使用防曬產品會阻斷合成維生素D3所需的的紫外線波長。Furthermore,
sunscreen application blocks the UV wavelengths
required for vitamin D3 synthesis.
此外，食物中攝取的維生素D是有問題的，因為很少食物含有自然豐富的維生素D。In
addition, dietary intake of vitamin D is
problematic since there are few foods, which are
naturally rich in vitamin D.
這裡的證據將對多發性硬化症(MS)和發炎性腸道疾病(IBD)提供了建議，在環境中可取用的維生素D有兩種途徑，透過紫外線曝曬皮膚或飲食攝取維生素D，有助於多發性硬化症(MS)和發炎性腸道疾病(IBD)病情發展的一個因素。Here
evidence will be provided in MS and IBD that
suggests that vitamin D status available in the
environment either following UV release of
vitamin D in the skin or ingestion of vitamin D
in the diet is a factor that contributes to both
MS and IBD development.
2.
發炎性腸道疾病Inflammatory
bowel disease
發炎性腸道疾病(IBD)是影響胃腸道（GI）的免疫相關的疾病，病因不明。IBD
are immune-mediated diseases of unknown etiology
affecting the gastrointestinal (GI) tract.
發炎性腸道疾病(IBD)
至少以兩種不同形式的結腸炎存在，分別為潰瘍性結腸炎和克隆氏症結腸炎。There
are at least two distinct forms of IBD,
ulcerative colitis and Crohn’s disease.
發炎性腸道疾病(IBD)是最常見於迴腸和結腸末端相關慢性復發炎症的疾病，IBD
are chronic recurring illnesses most commonly
involving inflammation of the terminal ileum and
colon,
發炎性腸道疾病也可能在整個消化道很多位置發病。although
these diseases can also affect many sites
throughout the alimentary tract.
在北美和歐洲，大約有1/1000人患有發炎性腸道疾病(IBD)（Podolsky,1991a ，b）。In
North America and Europe
about
1 in 1000 people are affected
with IBD (Podolsky,
1991a , b).
顯示於基因對疾病的生物學發展影響：帶有發炎性腸道疾病(IBD)家族史的親屬和兄弟姐妹對發生發炎性腸道疾病(IBD)的風險分別為高於常人的10
和40倍高。The
effect of genes on disease develop is shown in
biological relatives and siblings of IBD
patients who are at an increased (10- and
40-fold higher, respectively) risk of developing
IBD. 然而，患有克隆氏症（Crohn's
disease）或潰瘍性結腸炎患者的同卵雙胞胎發生克隆氏症（Crohn's
disease）有50％或發生潰瘍性結腸炎有18％的一致率。However,
monozygotic twins only have concordance rates of
50% (Crohn’s) or less (18%, ulcerative colitis).
因此，更多基因完全相同的同卵雙胞胎個案中有50％的人不會兩者同時發生發炎性腸道疾病(IBD)。Therefore
50% of the time or more genetically identical
individuals do not both develop IBD.
維生素D在陽光照射不足地區，如北美和北歐地區的北方氣候，最常見發生發炎性腸道疾病(IBD)
(Podolsky,
1991a , b; Sonnenberg et al.,
1991)。
Vitamin D from sunlight
exposure is less in areas where IBD occurs most
often, as IBD is most prevalent in northern
climates, such as North America and
Northern Europe (Podolsky,
1991a , b; Sonnenberg et al.,
1991). 患有發炎性腸道疾病(IBD)
即使病情處於緩解期的患者，常見維生素D缺乏症。
Vitamin D deficiency is
common in patients with IBD even when the
disease is in remission (Andreassen et al.,
1997, 1998). 目前還不清楚為什麼維生素D缺乏症經常發生在發炎性腸道疾病(IBD)患者身上。It
is unclear why vitamin D deficiency occurs more
frequently in IBD. 這大概是由於低量的維生素D攝取，結合許多營養物質包括維生素D的吸收不良，並處在不適合在皮膚合成維生素D的氣候下減少戶外運動。It
is probably due to the combined effects of low
vitamin D intake, malabsorption of many
nutrients including vitamin D, and decreased
outdoor activities in climates that are not
optimal for vitamin D synthesis in the skin.
3.
多發性硬化症Multiple
sclerosis
在美國，有35萬人患多發性硬化症。Multiple
sclerosis afflicts 350,000 people in the
US
4.
維生素D與實驗性的自身免疫Vitamin
D and experimental autoimmunity
典型的維生素D是調節鈣的體內平衡和維護造骨及骨吸收的功能。
The classical function of vitamin D is in the
regulation of calcium homeostasis and thus bone
formation and resorption.確認存在周邊血液的單核細胞中的維生素D受體（VDR）引發早期認為維生素D是免疫系統的調節劑的研究興趣。(Bhalla
et al., 1983; Provvedini et al., 1983)。
The identification of vitamin D receptors (VDR)
in peripheral blood mononuclear cells sparked
the early interest in vitamin D as an immune
system regulator (Bhalla et al., 1983;
Provvedini et al., 1983).
維生素D是類固醇甲狀腺超級家族核接受體的成員。Vitamin
D is a member of the steroid thyroid super
family of nuclear receptors.
維生素D和維生素D受體（VDR）結合產生活性維生素D（1,25（OH）2D3）的功能。Active
vitamin D (1,25(OH)2D3) functions by binding to
the VDR.
連同一些其它轉錄因子，1,25（OH）2D3和維生素D受體（VDR）的複合物調控含有維生素D反應元素的轉錄基因。Together
with a number of other transcription factors the
1,25(OH)2D3/VDR complex regulates the
transcription of genes which contain vitamin D
response elements.
所有類固醇激素超級家族的成員已被證明是具調控基因轉錄。All
the members of the steroid hormone super family
have been shown to regulate gene transcription.
在體內的維生素D的免疫目標，是定義主要在T幫助細胞1（Th1）驅動的自體免疫性疾病。
In vivo the immune targets of vitamin D have
been defined primarily in Th1 driven autoimmune
diseases.
在實驗，維生素D缺乏會加速多發性硬化症(MS)，第1型糖尿病的病程而發病(Cantorna
et al.,1996, 1998, 2000; Zella and DeLuca,
2003).。
Vitamin D deficiency accelerates the development
of experimental MS, and type-1 diabetes
(Cantorna et al.,1996, 1998, 2000; Zella and
DeLuca, 2003).
相對的，以1,25（OH）2D3治療可抑制這些T幫助細胞1（Th1）誘發的自體免疫疾病的發生(Cantorna
et al., 1996, 1998, 2000; Zella and DeLuca,
2003)。
Conversely, 1,25(OH)2D3 treatment suppressed the
development of these Th1-mediated autoimmune
diseases (Cantorna et al., 1996, 1998, 2000;
Zella and DeLuca, 2003).
此外，以1,25（OH）2D3治療多發性硬化症(MS)症狀發病中的的小鼠，中止這些老鼠的多發性硬化症(MS)病徵的發生，顯示，甚至在多發性硬化症(MS)確診發病後，維生素D仍能改變自體免疫反應(Cantorna
et al., 1996)。
In addition, 1,25(OH)2D3 treatment of mice with
ongoing MS symptoms halted the progression of
the disease in these mice, showing that vitamin
D altered the immune response even after the
disease had been established (Cantorna et al.,
1996).
在許多不同的模式的實驗，1,25（OH）2D3已被證明能抑制T幫助細胞1（Th1）引發的自體免疫反應。1,25(OH)2D3
has been shown to inhibit Th1 driven responses
in a number of different models.
對細胞介素（IL）-1
0基因擊倒(KO)的小鼠做發炎性腸道疾病(IBD)的實驗，是小鼠的一種自發性疾病，部分是由於在小鼠的小腸和大腸內正常菌落不適當免疫反應引起的病徵。
Experimental IBD in the
interleukin (IL)-10 KO mouse is a spontaneous
disease, which develops in part due to an
inappropriate response to the normal bacterial
flora in the small intestine and large intestine
of the mice. 發炎性腸道疾病(IBD)的實驗是由腫瘤壞死因子（TNF）-α和干擾素（IFN）-γ誘發分泌T幫助細胞1（Th1）。T幫助細胞2（Th2）或調節性T細胞會抑制T幫助細胞1（Th1）的發育和功能（分泌細胞激素）。Experimental
IBD is induced by TNF-α
and IFN-γ secreting
Th1 cells. Th2 or T regulatory cells inhibit
both the development and function (cytokine
secretion) of Th1 cells. 以充足的維生素D飼料餵養12週齡細胞介素（IL）-1
0基因擊倒(KO)
已發生發炎性腸道疾病(IBD)的小鼠。Vitamin
D sufficient chow fed IL-10 KO mice develop IBD
beginning at 12 weeks of age.，在細胞介素（IL）-1
0基因擊倒(KO)的小鼠，缺乏維生素D，會加速發炎性腸道疾病(IBD)病程(Cantorna
et al., 2000)。Vitamin
D deficiency accelerated the development of
symptoms in the IL-10 KO mice (Cantorna et al.,
2000)。細胞介素（IL）-1
0基因擊倒(KO)的小鼠，缺乏維生素D，
100％會有發炎性腸道疾病(IBD)的症狀（腹瀉，直腸出血）和60％細胞介素（IL）-1
0基因擊倒(KO)的小鼠由於發炎性腸道疾病(IBD)重症死於9週齡前（Cantorna等，2000;。Froicu等，2003）。such
that 100% of the vitamin D deficient IL-10 KO
mice had symptoms (diarrhea, rectal bleeding) of
IBD and 60% died due to a severe form of IBD
before 9 weeks of age（Cantorna等，2000;。Froicu等，2003）.
相較維生素D供應充足的細胞介素（IL）-1
0基因擊倒(KO)的小鼠在同一時間框架未表現出發炎性腸道疾病(IBD)外在症狀（Cantorna等，2000;。Froicu等，2003）。In
contrast vitamin D sufficient mice showed no
outward symptoms of IBD in the same time frame (Cantorna
et al., 2000; Froicu et al., 2003).
維生素D缺乏的實驗數據的證實，以維生素D受體（VDR）＋細胞介素（IL）-1
0雙基因擊倒(KO)的小鼠（雙VDR/IL-10
KO）做發炎性腸道疾病(IBD)
暴發形式的發展實驗，導致在受測小鼠7週齡時有100％的死亡率（Froicu等，2003年）。
Confirming the vitamin D deficiency data, mice
that are both IL-10 and VDR deficient (double
VDR/IL-10 KO) develop a fulminating form of
experimental IBD that leads to 100% mortality by
7 weeks of age (Froicu et al., 2003).
有趣的是，不管致病性微生物菌落是否存在維生素D受體（VDR）＋細胞介素（IL）-1
0雙基因擊倒(KO)的小鼠腸道，發炎性腸道疾病(IBD)的嚴重程度是一樣的，。Interestingly
the severity of IBD in the VDR/IL-10 KO mice is
the same regardless of whether or not disease
causing microorganisms are present in the
colony.
這兩種維生素D缺乏和維生素D受體缺乏（基因缺陷）的小鼠實驗，會使發炎性腸道疾病(IBD)病情更嚴重。
Both vitamin D deficiency and VDR deficiency
render experimental IBD more severe.
5.
維生素D的目標是T細胞T
cells are vitamin D targets
維生素D受體（VDR）是存在於免疫系統的多種細胞中，及已經在這些免疫系統的多種細胞中開始探索1,25（OH）2D3的目標細胞。The
VDR is present in multiple cells of the immune
system and the targets of 1,25(OH)2D3
in these cells has begun to be
explored.
維生素D受體（VDR）是存在胸腺和週邊血液T細胞，顯示維生素D在胸腺和週邊血液T細胞的發育和功能的扮相角色。維生素D調控T細胞是透過直接和間接兩者間來調控T細胞(Adorini,
2002; Mahon et al., 2003).。
The presence of the VDR in both the thymus and
the peripheral T cells suggests a role for
vitamin D in both development and function of T
cells. The regulation of T cells is a result of
both direct and indirect actions of vitamin D (Adorini,
2002; Mahon et al., 2003).
如果維生素D或透過維生素D受體（VDR）的信號傳遞受到限制，導致調節性T細胞和T幫助細胞2（Th2）銷耗並圖利T幫助細胞1（Th1）引發自體免疫反應.。
If vitamin D or signals through the VDR are
limiting Th1 cells are favored at the expense of
regulatory T cells and Th2 cells (Fig. 1,
Cantorna and
Mahon
生理上維生素D受體（VDR）需要保持T細胞反應平衡及此外在沒有維生素D受體（VDR）T幫助細胞2（Th2）被削弱的情況下也要維持T細胞反應平衡。
Physiologically the VDR is required to maintain
a balance in the T cell response and furthermore
in the absence of the VDR Th2 cells are
diminished (Fig. 1, Froicu et al., 2003).
更多最近尚未公佈的數據顯示，在基因剔除鼠（KO
mouse）維生素D受體（VDR）的T細胞調控功能可能會受到影響(Cantorna
unpublished).。
More recent unpublished data suggests that T
regulatory function may be compromised in the
VDR KO mouse (Cantorna unpublished).
正常T細胞的功能和自體免疫疾病的預防需要維生素D和透過1,25（OH）2D3信號傳遞到維生素D受體（VDR）。Normal
T cell function and the prevention of autoimmune
disease require vitamin D and signaling via
1,25(OH)2D3 and the VDR.
6.
結論Conclusions：
因此免疫系統的T細胞發育和功能的建議模型，是個體經由環境中攝取足量的維生素D（透過食品維生素D和陽光照射產生的維生素D3）調控T細胞的發育和功能。
因此免疫系統的T細胞發育和功能的建議模型，是個體經由環境中攝取足量的維生素D（透過食品維生素D和陽光照射產生的維生素D3）調控T細胞的發育和功能。
A model is proposed whereby the amount of
vitamin D in the environment (food and sunlight
exposure) affects both the development and
function of T cells and therefore the immune
system.
實驗證據顯示，自體免疫疾病，如發炎性腸道疾病(IBD)，多發性硬化症(MS)都受維生素D和維生素D受體的信息傳遞變化所影響。The
experimental evidence suggests that autoimmune
diseases like IBD and MS are acutely affected by
changes in vitamin D status and VDR signaling.
基因傾向的個案的含義是，保持足夠的維生素D濃度或者具有維生素D重要代謝、分解代謝和功能的多樣性基因，與發炎性腸道疾病(IBD)，多發性硬化症(MS)
相關病情發展的可能性增加。The
implications are that genetically predisposed
individuals that either do not maintain adequate
vitamin D levels or perhaps have polymorphisms
in genes important for vitamin D metabolism,
catabolism or function have an increased
likelihood of developing MS/IBD.
維生素D介入治療應該會增加1,25(OH)2D3供應量和T細胞正常化反應，結果會抑制T幫助細胞1（Th1）功能和增加調控及T幫助細胞2（Th2）間隔。Vitamin
D interventions should result in the increased
availability of 1,25(OH)2D3 and a normalization
of the T cell response which comes as a result
of decreased Th1 cell function and increased
regulatory and Th2 cell compartments.
有更多的工作要做，以確定維生素D是以何種機轉調節自體免疫性疾病？維生素D用來調節免疫的最適合量是多少？以及是否有遺傳因素的機制，為什麼無論是由維生素D生產1,25（OH）2D3或透過維生素D受體（VDR）信息傳遞機轉在患者身上做改變，而發生自體免疫性疾病？More
needs to be done to determine the mechanisms by
which vitamin D regulates autoimmune disease,
what the optimal amount of vitamin D is for
immune-regulation and whether there are genetic
reasons why either production of 1,25(OH)2D3
from vitamin D or signaling through the VDR is
altered in patients with autoimmune diseases.
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