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PRRS의 모든 지식

[PRRS의 모든 지식(8)] PRRS의 면역 반응에 대한 심도 깊은 질문

한국히프라 Swine Technical Service 노현동 수의사(hyun.noh@hipra.com)

 

모두가 양돈 현장에서 PRRS를 여러 차례 겪어 봤지만, 아직도 PRRS 컨트롤에 대한 '정답'은 없습니다. 오랜 기간 양돈농가를 괴롭혀온 만큼 PRRS에 대한 오해와 편견이 많이 쌓여있는 현실입니다. 'PRRS의 모든 지식'(총 15화)을 통해 우리 농장에 맞는 PRRS 컨트롤의 '해답'을 발견할 수 있길 기대합니다. 본 기고글은 HIPRA 본사에서 출간한 'The book for PRRS Knowledge"' 내용을 번역·정리한 것입니다.

 

 

 

1. PRRS 바이러스에 대한 중화항체(NA)가 '비(非)중화항체(중화능력이 없는 항체, non-NA)'보다 약하고 늦게 유도되는 이유는 무엇일까?

 

이 현상의 원인을 살펴보기 전에 더 중요하게 기억해야 될 부분은 실험실에서 쉽게 ELISA 검사로 확인 가능한 PRRS 항체는 바이러스 방어와 무관하다는 점입니다. 실제 PRRS 바이러스 방어에 관여하는 항체는 이러한 비중화항체의 검출 시기보다 늦게 생성됩니다. 그 원인을 따져보는 것은 농장에 따라 다양한 양상으로 발생하는 PRRS를 컨트롤하는데 유용한 힌트가 될 수 있습니다. 이 현상의 원인은 명확히 규명되진 않았지만, 이론적으로 다양한 가설들이 제시되었습니다. 각 가설들이 제시하는 가능성들은 합당한 근거를 가지고 있으며, 여러 가능성들이 복합적으로 작용하여 일어나는 현상으로 보기도 합니다.

 

1) 면역세포 표면 분자들의 발현 및 사이토카인 자극을 억제

지난 원고들에서 살펴보았듯 PRRS 바이러스는 항원제시세포(APC)의 기능을 억제하고 Th1 및 Th2 세포의 면역 반응을 방해합니다. 이것이 후천성 면역세포들의 작동 및 이에 따른 중화항체 생성을 지연시킨다는 가설입니다.

 

2) 면역 반응성이 높은 미끼 항원결정기(decoy epitope)

 

 

'항원결정기(epitope)'란 면역세포(B세포, T세포)에 인식되는 항원의 특정 부위를 의미합니다. 이 가설에 따르면 바이러스 중화능력이 없는 항체를 많이 형성시키는 '미끼 항원결정기'가 있으며, 이러한 미끼들이 중화항체 형성에 관여하는 주요 항원결정기 근처에 위치하여 방어에 필요한 면역 반응을 억제할 수 있습니다. 이러한 원리에 따라 미끼 항원결정기가 감염 초기에 ‘방어와 관련 없는’ 항체를 형성하는 체액성 면역반응을 강하게 형성하고, 이로 인해 정작 방어에 필요한 중화항체 형성 면역결정기에 대한 반응은 훨씬 뒤로 늦춰집니다.

 

3) 중화항체 형성 항원결정기의 글리코실화(glycosylation化, 당화)

바이러스의 막단백질에는 보통 '글리칸(glycan)'이라고 하는 당 사슬이 결합되어 있습니다. PRRS 바이러스의 경우 N-글리칸이 결합되어 있습니다. 이 N-글리칸은 중화항체 형성 항원결정기의 내부 혹은 측면에서 방패 역할을 하며 PRRS에 대한 중화항체 형성 및 항체의 특이적 결합을 방해합니다.

 

 

각 PRRS 바이러스에 따라 이러한 글리코실화의 패턴이나 수는 다양합니다. PRRS 바이러스에서 글리코실화가 가능한 부위는 GP3에 6개, GP4에 4개, GP5에 4개(PRRSV1에서 3개, PRRSV2에서 4개)까지 발견되었습니다. PRRS 야외주 바이러스 및 이들의 탈글리코실화 변이주(deglycosylated mutant) 비교 실험은 흥미로운 결과를 보여주며 이 가설을 뒷받침합니다. 탈글리코실화 변이주를 주입한 돼지에서 더 높은 역가의 중화항체가 유도되었을 뿐 아니라, 생성된 중화항체에 대한 감수성 역시 해당 변이주들에서 더 높았습니다.

 

4) 비정상적인 B세포 증식

PRRS 바이러스는 다중클론성 B세포 활성화(polyclonal B cell activation, 항원과 관계없는 다수의 B세포클론 분열)를 유도하여 림프선이 비대해지는 병증을 일으킵니다(원칙적으로 항원특이적 면역세포는 1종류의 항원수용체를 발현하는 단일 특이성을 가짐). PRRS 바이러스에 감염된 돼지에서는 항원에 감작된 B 세포군(CD2-CD21-)이 두드러지게 감소하며 성숙 및 기억 세포 형성이 억제됩니다.

 

5) 유전적 다양성

PRRS 바이러스의 유전적 다양성이 매우 높다는 것도 원인일 수 있습니다. 감염이 진행되는 동안 변이주 바이러스의 지속적인 면역 회피가 중화항체의 형성을 방해할 수 있습니다. PRRS 감염 초기에 바이러스의 ORF2-4, ORF5-6 유전자 부위의 다양성에 따라 중화항체에 대한 저항성이 증가하는 것이 확인되기도 했습니다.

 

2. PRRS 바이러스에 대한 세포매개성 면역반응은 왜 느리고 약하게 일어날까?

해당 현상을 설명하기 위해 역시 다양한 가설들이 제안되었습니다.

 

1) 특정 사이토카인의 결여 또는 분비 강화

IFN-α 또는 TNF- α와 같은 사이토카인의 분비 억제는 효과적인 Th1 면역 반응 발달에 영향을 미칩니다. 반대로 IL-10의 경우 PRRS 감염에 의해 촉진되며 세포성 면역을 억제하는 작용을 합니다.

 

2) 적절한 항원 제시 작용 및 T 림프구의 활성 방해

PRRS 바이러스는 항원제시과정 중 면역세포의 표면 분자 발현 맟 T세포의 활성에 관여하는 사이토카인 작용을 방해하여 효과적인 세포성 면역 반응을 억제합니다.

 

3) T regulatory(Treg) 세포의 작용

 

 

Treg 세포의 주요 기능은 과도한 면역 반응이 일어나지 않도록 예방하는 것입니다. 일부 바이러스들은 이 Treg의 작용을 촉진하거나, IL-10, TGF-β 등과 같은 면역억제성 사이토카인 분비를 촉진하는 방법으로 숙주의 면역 반응을 회피한다는 것이 밝혀졌습니다. PRRSV2에 감염된 경우 Treg 세포들이 TGF-β 생성에 관여하는 림프 조직에서 지속적으로 관찰됩니다. 하지만, Treg 세포와 바이러스 혈증 기간의 관계성은 명확하게 보이지 않습니다. PRRS 바이러스의 N단백질(바이러스 RNA와 작용하여 뉴클레오캡시드를 형성하는 구조단백질)이 Treg의 작용을 조절하는 것으로 보입니다. 한편, PRRS 바이러스가 Treg 세포를 유도하는 능력은 바이러스 분리주에 따라 다르게 나타납니다.

 

4) 유전적 다양성

중화항체 부분에서 다룬 내용과 유사하게, 변이주의 지속적인 면역 회피 과정은 적절한 세포 매개성 면역의 발달을 방해합니다.

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