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腸内細菌叢が制御するパイエル板依存的な母子移行IgA抗体産生経路の特定

宇佐美 克紀 東北大学

2021.03.25

概要

1-1 感染症に対する予防治療法開発の重要性
 家畜生産現場において、母体乳腺で発症する乳房炎や、新生仔の腸管で頻繁に発症する下痢症などの感染症は、出荷の停止や多くの治療費などから日本では800億円以上、アメリカでも20億円以上と世界的に見ても莫大な経済損失を引き起こし大きな問題となっている1,2。加えて、ヒトの新生児の下痢症も発展途上国で特に発症率が高く問題となっており、年間50万人以上の乳幼児が死亡している3。さらにこのような感染症の治療に対し最も主要に用いられる抗菌剤は、世界的な問題となっている薬剤耐性菌出現の原因となり更なる問題へとつながっている。薬剤耐性菌の問題はG7伊勢志摩サミットでも優先課題として議論が行われており、特に畜産動物に使われる抗菌剤は全体の抗菌剤使用例の中で最も多くの割合を占める4ことから、獣医学、農学領域における重点的な研究を求めている。このようにヒトの感染症に留まらず、家畜などの感染症は世界共通の大きな問題となっており、特に抗菌剤に頼らない感染症予防、治療法の開発は急務となっている。このことから、生体本来が備える防御機構の向上を目指すことで感染予防を抑えることが重要であると考えられるが、未だ効果的な方法は確立されていない。

1-2 感染防御の観点から母乳の重要性
 感染症発症の要因を考える上で、近年、将来の健康や特定の病気へのかかりやすさは、胎生期や生後早期の環境の影響を強く受けて決定されるというDOHaDという概念が注目されている5。母乳による育児は、新生児に栄養素や微生物、免疫成分などの有益な成分を子に送り届け、子の健全育成に深く関わる6ことから、DOHaDの概念の中で重要なファクターとなる。実際、WHOのグループでは一定期間以上の哺育が、新生児の感染症に対する死亡率と罹患率を著しく下げることを報告しており、結果として母乳は発展途上国における823000人の新生児の死亡を防ぐことが出来ると予測している7。このことからWHOは一定期間以上の哺育を行うことで新生児の健康を維持することを推奨している。さらに家畜生産現場においても、母乳中成分の違いや哺育の期間によって、子の感染症発症リスクが異なるという報告がなされている8,9。特に母乳中に含まれる免疫成分は、ヒトや家畜動物の次世代の感染症防御に深くかかわっていることが多くの研究から示されている10,11,12。さらに母乳中免疫成分は、母体乳腺の感染防御機構の役割も同時に担う13ことから、母乳中免疫成分の向上は、家畜生産現場で問題となっている母体の乳房炎および新生仔の下痢症の双方に対し有効であると考えられる。しかしながら、母乳中に含まれるどのような免疫成分が重要なのか、また、乳腺の免疫環境がどのようにして発達しているのかはこれまでに明らかになっていない。

1-3 母乳中免疫成分の一つであるIgA抗体の一般的な機能と産生機序
 母乳中に含まれる免疫成分の中で、IgA抗体(以下IgA)を主とする移行抗体は量的に多くの割合を占めている14。IgAは、粘膜組織で豊富に分泌される免疫成分であり、腸管におけるIgAの分泌メカニズムや機能は広く研究されている。IgAは成熟B細胞から分化するIgA産生細胞から分泌されるが、腸内に共生するBacteroidesなどの常在菌や腸内に侵入した病原微生物を主とする抗原からの刺激を成熟B細胞が受けることで、認識した抗原情報を持つIgA産生細胞が腸管粘膜固有層に送り込まれ、抗原特異的なIgAが分泌される15。腸管管腔に分泌されるIgAは、例えば、細菌に特異的に結合することで、病原菌の排除16や、有用な細菌を定着させ17,18、腸内細菌叢を形成に重要な役割を有することが分かっており、IgAは腸内の環境維持に深く関わっていることが唱えられてきた。母乳中にも、多量のIgA抗体が含まれており、新生児の腸内に移行することで、子の腸管内の環境維持に関わるとされている14。実際、乳汁中IgAは直接的に病原菌や寄生虫に結合し、下痢症などの感染症を予防する19,20ことや、腸内微生物環境を制御することで免疫機能に影響を及ぼし、アレルギーなどの疾患にも関与することが報告されている21。このことから、乳汁中IgA産生の制御を行うことは、子の健全育成を促すような技術開発に向けて、非常に重要となると考えられる。しかしながら、乳汁中IgAを分泌するIgA産生細胞がどこでどのように抗原情報を受け取っているのか明らかにされておらず、このことは、病原菌排除を目指した乳汁中IgA産生を誘導するような粘膜ワクチンや、乳汁中IgAによる子の健全育成を促すような技術開発に対して、大きな障壁となっている。

1-4 本研究の目的
 一般的に粘膜組織には粘膜関連リンパ組織(MALT)が存在し、これが粘膜組織内に集積するIgA産生細胞の供給源となっている15。MALT内では、多量に存在する成熟B細胞への抗原刺激が行われており、その後、抗原特異的なIgA産生細胞に分化することで免疫を実効する粘膜組織実質部に送り込まれる15。さらにこの時、IgA産生細胞ごとに数種のケモカイン受容体を獲得する15。それぞれの粘膜実質部では異なるケモカインが分泌されており、このケモカインと受容体の相互作用によりIgA産生細胞は決まった粘膜組織へと遊走される15。これまでの研究から、授乳期の乳腺実質部には、乳腺上皮細胞から分泌されるケモカインCCL28に引き付けられたIgA産生細胞が乳腺組織内に集積することで、母乳中にIgAが分泌されることが示されている22,23。しかしながら、乳腺組織内にはMALT様のリンパ集積は確認できておらず、どこからCCL28の受容体を持ったIgA産生細胞が遊走しているのか明らかになっていない。乳腺にIgA産生細胞を送り込むMALTを特定し、そのリンパ組織内の免疫刺激システムを解明することが、乳汁中IgA産生の産生システムの全貌を解明することにつながり、母体乳腺IgA産生を誘導し母子免疫移行強化を目指した技術開発につながると考えられる。よって本研究ではまず初めに、乳腺に集積するIgA産生細胞の追跡を行うために、①乳腺のIgA産生細胞の性状解析を行うための技術確立を目的として実験を行った。さらにその後、②乳腺IgA産生細胞の供給源の特定、また③その供給を制御する免疫刺激機構を解明することで、乳腺におけるIgA産生経路を特定することを目的とし、乳汁中IgA産生の質的、量的な向上を目指した技術開発に迫る。

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参考文献

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