체액 면역에서 Egr1과 Roquin의 역할

Abstract

B세포는 항원 자극에 의해 형질세포로 분화하여 항체를 생성한다. 항체는 미생물에 대한 보호작용을 하는 한편 루푸스, 쇼그렌 증후군(sjogren’s syndrome)과 같은 염증 과민 반응을 매개한다. 이런 중요성에도 불구하고 형질세포의 분화과정과 형질세포 매개 질환의 발병기전에 대한 연구는 미흡한 실정이다. 이 논문에서는 첫째로 Early growth response (Egr) 1이 형질세포분화에 어떤 역할을 하는지를 조사하였다. Egr1은 Cys2-His2 형 아연 집게 전사인자로 미성숙 B세포에서 세포자멸을 유도하고, 성숙 B세포에서 성장을 촉진한다고 알려져 있다. 그러나, Egr1이 B세포가 형질세포로 분화하는데 어떤 역할을 하는지 아직 알려지지 않았다. Egr1 유전자 결손(KO) 생쥐, 도는 정상대조군(WT)생쥐에서 얻은 미감작 B세포를 LPS와 IL-4로 자극 한 후 FACS로 분석하였다. KO세포는 WT세포에 비해 생존과 증식반응에 차이가 없었지만 CD138+ 형질세포로의 분화가 덜 일어났다. 이를 생체 내에서 확인하기 위해, WT과 KO생쥐에 항원을 주사한 뒤 항체생성과 항체분비세포를 측정하였다. KO 생쥐에서 대조군에 비해 항원 특이 IgG 항체 역가와 IgG 항체분비세포 수가 감소되었다. 그러므로 Egr1은 B세포의 증식과 생존에는 무관하고 형질세포로의 분화를 촉진하는 인자로 생각된다. 이 논문의 두번째 목표는 쇼그렌 증후군 발병기전을 규명하는 것이다. 쇼그렌 증후군은 침샘과 눈물샘이 파괴되는 만성 자가면역질환이다. 우리는 Roquin 유전자 변이에 의해 follicular helper T세포가 과다 발생하는 sanroque생쥐에서 쇼그렌 증후군이 발병하는지를 조사하였다. 24주령 암컷 sanroque생쥐는 C57BL/6 생쥐에 비해 항-이중가닥 DNA 항체의 역가가 높고 신장염이 발생하지만, 침샘의 기능에 결함이 나타나지 않는다. 그러나 48주령 sanroque생쥐에서 침 분비량이 감소하고 침샘에 장수형질세포를 포함하는 염증세포의 침윤이 관찰되었다. 그러므로, 늙은 sanroque생쥐에서 쇼그렌 증후군 병증이 자연발생함을 알 수 있다. 이상의 결과는 Egr1이 형질세포 분화에 중요함을 시사하고, sanroque생쥐가 쇼그렌 증후군의 동물모델로서 사용할 수 있다는 것을 제안한다.|B cells differentiate into plasma cells to generate antibodies upon antigen stimulation. Antibodies elicit protective responses to microbes and/or hypersensitivity response to hosts. However, mechanisms of plasma cell differentiation and pathogenesis of plasma cell-mediated diseases remains unclear. In the present study, first, we examined whether early growth response (Egr)-1 plays a role in plasma cell differentiation. Egr1 is a Cys2-His2 type zinc-finger transcription factor. Egr-1 has been known to induce apoptosis and growth in immature and mature B cells, respectively, but its role in the differentiation of B cells to plasma cells remains obscure. Here we examined whether Egr-1 is important for B cells to commit to plasma cell fates using Egr-1 knockout (KO) mice. Naive B cells from Egr-1 wild-type (WT) or KO mice were stimulated with LPS and IL-4, and the resulting cells were assayed by FACS. Cell viability and apoptosis were not different between WT and KO cells, but the differentiation profile was different: fewer Egr-1 KO B cells gave rise to CD138+ plasma cells than WT B cells. To confirm this result in vivo, we measured aspects of antibody production and antibodies secreting cell after immunization. Antigen specific IgG antibody titer and cell numbers IgG secreting antibodies was lower in the serum from KO mice than that from WT mice. Second, we sought association of plasma cells with sjogren’s syndrome. Sjogren syndrome is a chronic autoimmune disorder that affects mainly salivary and lacrimal glands. Along with the deficiency of animal models for sjogren’s syndrome, its etiopathogenesis largely remains to be explored. Here we examined whether Sanroque mice have a potential to act as a model for sjogren’s syndrome. Sanroque mice mutate of Roquin which function as an ICOS repressor. Sanroque females at the age of 24 weeks develop anti-dsDNA antibodies at the higher levels than C57BL/6 mice, but sjogren’s syndrome symptoms were not accompanied at this age. However, the mice at the age of 48 weeks spontaneously developed signs of sjogren’s syndrome. Saliva flow was significantly reduced, and salivary glands were severely infiltrated by lymphoid cells including long-lived plasma cells. Thus, our results demonstrate that Egr-1 is non-redundantly crucial for B cells to commit toward plasma cell fates and propose sanroque mice as a model of sjogren’s syndrome.; B cells differentiate into plasma cells to generate antibodies upon antigen stimulation. Antibodies elicit protective responses to microbes and/or hypersensitivity response to hosts. However, mechanisms of plasma cell differentiation and pathogenesis of plasma cell-mediated diseases remains unclear. In the present study, first, we examined whether early growth response (Egr)-1 plays a role in plasma cell differentiation. Egr1 is a Cys2-His2 type zinc-finger transcription factor. Egr-1 has been known to induce apoptosis and growth in immature and mature B cells, respectively, but its role in the differentiation of B cells to plasma cells remains obscure. Here we examined whether Egr-1 is important for B cells to commit to plasma cell fates using Egr-1 knockout (KO) mice. Naive B cells from Egr-1 wild-type (WT) or KO mice were stimulated with LPS and IL-4, and the resulting cells were assayed by FACS. Cell viability and apoptosis were not different between WT and KO cells, but the differentiation profile was different: fewer Egr-1 KO B cells gave rise to CD138+ plasma cells than WT B cells. To confirm this result in vivo, we measured aspects of antibody production and antibodies secreting cell after immunization. Antigen specific IgG antibody titer and cell numbers IgG secreting antibodies was lower in the serum from KO mice than that from WT mice. Second, we sought association of plasma cells with sjogren’s syndrome. Sjogren syndrome is a chronic autoimmune disorder that affects mainly salivary and lacrimal glands. Along with the deficiency of animal models for sjogren’s syndrome, its etiopathogenesis largely remains to be explored. Here we examined whether Sanroque mice have a potential to act as a model for sjogren’s syndrome. Sanroque mice mutate of Roquin which function as an ICOS repressor. Sanroque females at the age of 24 weeks develop anti-dsDNA antibodies at the higher levels than C57BL/6 mice, but sjogren’s syndrome symptoms were not accompanied at this age. However, the mice at the age of 48 weeks spontaneously developed signs of sjogren’s syndrome. Saliva flow was significantly reduced, and salivary glands were severely infiltrated by lymphoid cells including long-lived plasma cells. Thus, our results demonstrate that Egr-1 is non-redundantly crucial for B cells to commit toward plasma cell fates and propose sanroque mice as a model of sjogren’s syndrome.