梅尼爾氏症的病毒假說與免疫理論

梅尼爾氏症的病毒假說與免疫理論

翻譯自
http://www.sciencedirect.com/science/article/pii/S1568997212000092

Endolymphatic hydrops of the membranous labyrinth has been recognised as the pathological correlate of Meniere's disease for over 70 years
迷路薄膜的內耳水腫已經被公認為與MD致病機轉超過70年了

Significant questions to this proposed pathophysiological mechanism persist.
但這個提出的致病機轉仍然有許多重要問題存在

First, although endolymphatic hydrops is readily produced by surgical obliteration of the endolymphatic sac in lower organisms
首先，在低等動物的實驗中可以輕易藉由手術閉合內淋巴囊使內淋巴產生水腫，但是在高等哺乳類動物卻沒以這個反應。

Second, imbalance (vertigo) has not been observed in these animal models. Third, the temporal bones of animal models with experimentally induced endolymphatic hydrops do not contain fibrous tissue adjacent to the stapes footplate with attachment to the saccular wall.
其次，平衡問題與眩暈在這些動物實驗上並沒有發生。第三，這些被刻意產生內淋巴水腫的動物顱骨在緊貼球囊壁的鐙骨足板鄰近並沒有產生組織纖維化的現象

Viral infection has been advocated as a possible cause of Meniere's disease by many authors
許多作者提出MD的可能原因是病毒感染

It has also been postulated that certain viruses have more affinity than others for affecting the inner ear. 
猜測特定病毒相較於其他病毒更容易感染內耳

For this reason, many studies have been carried out to verify whether viruses such as the neurotropic viruses, herpes simplex virus (HSV) types 1 and 2 [32], varicella zoster virus (VZV), and cytomegalovirus (CMV) [33], can cause Meniere's disease by invading the endolymphatic sac. 
因此，須多研究提出驗證到底是哪些病毒入侵內淋巴囊造成MD，例如嗜神經病毒，人類簡單泡疹病毒 HSV I & II型, 水痘泡疹病毒VZV，巨型細胞病毒CMV

The endolymphatic sac is known to be the site of immune reaction due to the existence of lymphocytes and immunoglobulins in addition to the resorption of endolymphatic fluid
內淋巴囊被認為是免疫反應站因其具有淋巴球與免疫球蛋白，除此之外還可以吸收內淋巴液

有研究發現MD病人的外淋巴內存有高IgG抗體。這個結果支持了HSV病毒在MD致病機轉中扮演重要角色的假說。且有研究發現相對於對照組病人，在MD病人的血清中發現有對腺病毒與VZV病毒的高IgG(?)。這些發現支持了腺病毒與VZV病毒可能在MD發病過程也很重要

各種病毒感染造成MD的機制不同，這是因為病毒與宿主抗原之間存在的變化性。首先病毒必須要是容易感染內爾的結構。其次在一般正常狀況下，病毒的入侵球囊會被免疫機制給阻擋。抗原可能會長時間存在但躲在宿主的免疫系統中直到有活化病毒感染。在病毒感染的期間，病毒的釋放或暴露會以造成細胞損壞的方式出現。如此一來先前休眠的抗原會被宿主認為是外來物，並且使得免疫反映去產生抗體且可能透過自體免疫進入組織破壞的下一個循環

一個可能在迷路上的化學性損害源頭是從前庭神經端釋放的傳染性核酸連帶著前庭神經節上的病毒再次活化。不像其他病毒的核酸，這種核酸有某程度的感染力是被血液成分中的核酸脢釋放來中和。比較MD患者與正常人的顱骨，前者前庭神經細胞有明顯損失，這支持了病毒造成MD的這個假說。病毒的再度活化與病毒量有關，當病毒量達到某個臨界水準，病毒的活性會克服宿主免疫反應並且是放病毒核酸。這些有毒物質在迷路的釋放會早成迷路炎，其為中會造成前庭槽纖維化與內淋巴水腫。

近來，MD的病毒神經病理學的直接證據已經被提出(經由電子顯微鏡觀察MD病人的前庭神經節細胞病毒結構)。抗病毒藥物的臨床反應指出MD的眩暈可以有85~90%的舒緩率。沒有超過九成的這個結果並不令人驚訝，因為HSV的突變株會對 acyclovir的抗病毒藥物產生抗藥性。在更新的抗病毒藥物發展出來前，有將近10%的MD患者的眩暈將沒辦法被控制。相較之下，抗病毒藥物對聽力症狀的改善則較無效，原因是毛細胞的損失是不可逆的。

服用acyclovir的副作用很小，通常是消化道機能亢進，在停藥後可以舒緩。其他的副作用有皮膚癢、頭痛、顫抖。這些狀況發生後，病人需要其他方式來控制眩暈，像是中耳鼓室注射抗病毒藥物Ganciclovir，一些研究指出長期(超過十年)服用acyclovir並不會讓負作用增加或是產生抗藥性。


免疫理論
將近有1/3的MD患者有其他的自體免疫疾病，雖然牽涉的免疫機制還不清楚，但有許多理論提出AIED如何引起的

交叉反應: 抗體或是T細胞造成意外的內耳受損，原因是內耳與一些具有潛在有害物(例如細菌病毒)共用共同的抗原，這是目前最受歡迎的AIED理論 (免疫系統經由辨識抗原去攻擊外來物時會誤傷到內耳)

旁觀者損害: 內耳的損傷會造成細胞激素釋放，這會在一段時間以後刺激一些額外的免疫反應，這個理論可以解釋MD的週期性反覆發作

無容忍性: 人體不能辨認人體所有的內耳抗原，當抗原釋放的時候(也許是在手術或是感染後)，人體可能會錯誤的對"外來"抗原發出攻擊，在一耳受影響的狀況下，另一耳也可能會受影響，此現象在動物實驗中可以複製出來。

基因因素: 看不懂

自體免疫似乎在單耳MD病人中造成6%的影響，在雙耳MD中大約有16%的影響，

TNF-alpha is a cytokine that induces the infiltration of immunocompetent cells into the tissues and amplifies the immune response.

TNF-alpha 是一種可以造成免疫功能正常細胞浸潤到組織且加劇免疫反應的一種細胞激素

 the TNF-alpha blocker, Etanercept, was shown to reduce the amount of inflammation in guinea pigs 
在天竺鼠動物實驗上，TNF-alpha blocker, Etanercept (腫瘤壞死因子抑制劑)可以減緩發炎

Encouraging results in a clinical study have shown that the administration of Etanercept to patients with immune-mediated inner ear diseases, including MD patients, improved or stabilised symptoms in 50% of treated patients
投入Etanercept 給予自我免疫內耳疾病(包含MD患者)在臨床上顯示有50%的症狀改善率 (眩暈耳鳴耳悶改善)

A statistically significant elevation in the levels of antiphospholipid antibodies has been demonstrated in patients with Meniere's disease
有研究提出數據顯示MD患者體內抗磷脂質抗體有顯著的統計上的提升

These data support the hypothesis that antiphospholipid antibodies are involved in the pathogenesis of some forms of inner ear dysfunction, presumably by causing microthrombus formation in the labyrinthine vasculature. 
這些數據支持抗磷脂質抗體與部分內耳功能失調患者的致病原因有關，可能是造成迷路血管微血栓的形成

Clinical studies to evaluate the efficacy of anticoagulation in Meniere's disease patients are also required
需要臨床研究來評估抗凝血藥物對MD患者的效用

On the contrary, antibodies to ubiquitous antigens, which are commonly recognised by systemic autoimmune disease sera, are not present in Meniere's disease patients. At the same time, signs and symptoms of autoimmune disorders are not present in these patients, and significant associations with connective tissue disorders have not been found. 
在自體免疫疾病中扮演重要角色的抗體在MD患者中並沒有被發現，且這些病人也沒有出現自我免疫失調也沒有發現跟結締組織失調有明顯相關

The results obtained in many studies suggest that the immune response in Meniere's disease is focused on inner ear antigens.
許多研究的結果將MD的免疫反應聚焦在內耳抗原上

It remains unclear whether the antibodies to these antigens play a role in the pathogenesis of Meniere's disease or if they represent the result of inflammation and tissue destruction. 
還不能釐清的是 對這些抗體的抗原是MD的致病因素還是組織遭到破壞發炎的結果

While specific tests for autoimmunity to the inner ear would be desirable, there are currently none that are both commercially available and proven to be useful. 
目前還沒有商業化且被證明有效的測試以供內耳自體免疫檢測用

 At the same time, steroid responsiveness is high, and with prompt treatment, inner ear damage may be reversible. Currently, the diagnosis of autoimmune inner ear disease is based either on clinical criteria or on a positive response to steroids.
如果對類固醇反應為陽性，如果接受適當治療，內耳損傷可能是可逆的。目前AIED的診斷在臨床上是基於對類固醇的臨床反應為陽性。

 Conclusion

The treatment of Meniere's disease is still based on incomplete knowledge about the underlying pathophysiology.
MD的治療方式仍然是基於不完整的基礎病理學的知識而來


The fact that so many patients with recurrent vertigo are referred because of the ineffectiveness of diuretics, low salt diets, and vestibular suppressants (Meclizine, Diazepam) indicates that the currently employed medical management of recurrent dizziness needs to be changed.

因為利尿劑、低鈉飲食、前庭抑制劑使用無效，許多有反覆眩暈的病人指出現有針對反覆眩暈的治療方式必須要改變

The antiviral approach to the very common disabling balance symptoms experienced by patients with Meniere's disease has virtually eliminated the use of various surgical methods used in the past. 
使用抗病毒藥物在MD患者常見的平衡症狀上已經實質上的消除了使用過去使用各種破壞性手術的必要

These include labyrinthectomy, endolymphatic sac decompression and vestibular nerve transection. The high (90%) rate of vertigo control with orally administered antivirals should be considered as a frontline treatment for vertigo.
這些手術包含迷路切除術，內耳淋巴囊減壓術，前庭神經切除術。以口服的抗病毒藥物有近九成的眩暈控制率，應該要被考慮當作眩暈的前線治療藥物

TNF-alpha blockers (Etanercept) could play a role in the treatment of Meniere's disease in the future 

TNF-alpha blockers將來也許會伴也MD治療的重要角色

 At the same time, steroid responsiveness is high, and with prompt treatment, inner ear damage may be reversible.
如果對類固醇反應為陽性，如果接受適當治療，內耳損傷可能是可逆的。

 If patients do not respond to the oral steroids, intratympanic injection can be given.
如果病人對口服類固醇沒有反應，則可給予中耳鼓室類固醇注射

Diagnosis of autoimmune inner ear disorders is still based on the response to steroid therapy. 
目前AIED的診斷在臨床上仍然是基於對類固醇的臨床反應為陽性

The cure for this disease is yet to be discovered, but it could lie in genetic re-engineering that might require a functioning labyrinth for an effective outcome.
MD的治療還需要再探索，但它可能要依靠基因重建工程，而基因工程可能需要完整功能的迷路以產生有意義的治療結果。

Therefore, destructive procedures like transtympanic perfusion of Gentamicin, which might preclude a possible cure for patients in the future, should be avoided. 
因此，破壞性的手段例如ITG，可能會排除未來痊癒的可能性，應該盡量避免

Gene therapy has been characterised over the last decade and can be used to transfer genetic material into inner ear cells using viral vectors.
基因治療在過去這十年已經提及可以運用病毒載具將基因物質送到內耳

Theoretically, and now experimentally, gene therapy can be used to alter the cellular microenvironment of the inner ear as well as change the cellular phenotype to protect, preserve, rescue, and even regenerate hair cells
理論上(且目前正在進行實驗)，基因治療可以刺激內耳的細胞微環境也可以改變細胞表型來保護、保存、拯救、甚至重建內耳毛細胞

Take-home messages

•

Meniere's disease is an autoimmune disorder. Its etiopathogenesis includes viral infection. The histopathological correlate of Meniere's disease is endolymphatic hydrops and vestibular endorgans demonstrates variable degrees of neuroepithelial degeneration

MD是一種自體免疫失調，其致病機轉包含病毒感染。與MD相關的組織病理表現為內淋巴水腫，且前庭感覺器官顯示不同程度的神經上皮退化

•

Due to the possible autoimmune pathogenesis of the disease, pharmacotherapy for Meniere's disease may include corticosteroids, etanercept and warfarin. The use of antiviral agents corresponds to the viral hypothesis and has eliminated the various surgical methods of the past.

根據可能的自體免疫致病機轉，MD的藥物治療可能包含類固醇 etanercept (TNF抑制劑) and warfarin (口服抗凝血藥物)。對應病毒感染的假設加以使用抗病毒藥物，已經可以免除過去各種破壞性手術的實施。

•

Gene therapy could be used in the future to transfer genetic material into inner ear cells using viral vectors and to protect, rescue, and even regenerate hair cells of the inner ear

在未來基因治療可以用來藉由病毒載體轉移基因物質到內耳細胞內並且保護、拯救、甚至重建內耳毛細胞