A群鏈球菌會引起感染後併發症，例如急性腎絲球腎炎與風濕性心臟病。而引發這種後遺症的原因被認為是A群鏈球菌的分子與宿主的抗原有分子上相似的現象，稱為molecular mimicry。鏈球菌熱原性外毒素B(SPE B)是一種cysteine protease，是A群鏈球菌主要的細胞外蛋白質，先前的研究顯示在A群鏈球菌中腎炎型菌株(nephritic strain)與其他型非腎炎型菌株比較，會分泌較大量的SPE B，因此SPE B也被認為是腎原性抗原(nephritogenic antigen)，可能參與急性腎絲球腎炎的致病機轉。在本論文中，我們利用動物模式以主動免疫小鼠SPE B與被動免疫給予anti-SPE B抗體兩種方式，證實anti-SPE B抗體在急性腎絲球腎炎致病機轉的角色，實驗結果顯示主動免疫小鼠SPE B其腎臟會有病變與蛋白尿的情形。而在主動免疫SPE A或小牛血清蛋白(BSA)的小鼠腎臟則沒有明顯的組織病變。主動免疫SPE B小鼠的腎臟絲球體發現有免疫球蛋白沉積、補體活化與白血球浸潤。Anti-SPE B單株抗體10G與腎臟的內皮細胞有交叉反應(cross-reactivity)，並且造成小鼠腎臟損傷與蛋白尿的發生。除此之外，單株抗體10G也會與心臟的內皮細胞有交叉作用，包括人類的瓣膜內皮細胞與小鼠的心臟內皮細胞。先前的研究報導指出，風濕性心臟病的初期是由自體抗體造成瓣膜的內皮細胞發炎，進而吸引T細胞浸潤最終導致心臟組織的損傷。因此我們利用peptide array與合成片段胜肽的ELISA確定單株抗體10G所辨識SPE B的抗原決定位(antigenic epitope)。結果顯示單株抗體10G辨識的主要抗原決定位為SPE B胺基酸296-310的位置，並且單株抗體10G與內皮細胞株HMEC-1的交叉反應會被SPE B胺基酸 296-310的合成胜肽所抑制。在風溼性心臟病病人血清的研究發現，anti-SPE B抗體IgG的量較高，並且與病人血清交叉反應到內皮細胞株HMEC-1的程度呈現顯著的正相關，病人血清與內皮細胞的交叉反應亦可以被SPE B胺基酸 296-310的合成胜肽所抑制。總結而言，本篇論文發現(1)主動免疫小鼠SPE B與直接被動免疫給予anti-SPE B抗體都會造成小鼠腎臟病變，(2)anti-SPE B抗體可能藉由與腎臟絲球體的內皮細胞有交叉反應而參與了急性腎絲球腎炎的致病機轉，(3)anti-SPE B抗體亦可能參與了風濕性心臟病的致病機轉，而主要的SPE B抗原決定位為SPE B胺基酸296-310。

Group A streptococcal infection may cause post-infectious sequelae, such as acute post-streptococcal glomerulonephritis (APSGN) and rheumatic heart disease (RHD). Molecular mimicry between group A streptococcus and host antigens is thought to play roles in the development of post-streptococcal sequelae. Streptococcal pyrogenic exotoxin B (SPE B), a cysteine protease, is a predominant extracellular protein. Previous studies showed that nephritis-associated strains preferentially secreted SPE B compared to non-nephritis-associated strains. Zymogen/SPE B was proposed as the major nephritogenic antigen involved in the pathogenesis of APSGN. Using a mouse model, we demonstrated the pathologic role of anti-SPE B antibody in the pathogenesis of glomerulonephritis. Mice were actively immunized with recombinant SPE B or passively immunized with anti-SPE B antibody. Mice immunized with SPE B showed pathologic changes in kidney and proteinuria. None of the mice given bovine serum albumin or SPE A showed any marked change in renal tissue. Immunoglobulin deposition, complement activation, and cell infiltration occurred only in the glomeruli of SPE B-hyperimmunized mice. One monoclonal anti-SPE B antibody clone, 10G, was cross-reactive with kidney endothelial cells. Furthermore, monoclonal antibody 10G caused kidney injury and proteinuria in mice. Besides the binding with glomerular endothelial cells, monoclonal antibody 10G could also cross-react with human heart valve and mouse heart endothelial cells. Previous studies have reported that autoantibodies caused valve endothelial inflammation, followed by T cell infiltration and heart tissue damage in RHD. Therefore, we conducted peptide array and ELISA using synthetic peptides to identify SPE B antigenic epitopes recognized by 10G. Results showed that the major epitope of monoclonal antibody 10G is localized in amino acid 296-310 residues of SPE B. The cross-reactivity of 10G with endothelial cells was inhibited by pre-absorption with SPE B amino acids 296-310 peptides. Studies with patient sera indicated that the levels of anti-SPE B immunoglobulin G (IgG) and the endothelial cell binding activity of RHD patient sera were significantly higher than control sera. The levels of anti-SPE B IgG in RHD patient sera were positively correlated with the endothelial cell binding activity. Furthermore, the binding activities to SPE B and to endothelial cells of RHD patient sera were reduced by pre-absorption with SPE B amino acids 296-310 peptides. In conclusion, we found that (1) both SPE B hyperimmunization and passive immunization with anti-SPE B antibody caused pathologic changes in mouse kidneys, (2) anti-SPE B antibodies cross-reacted with glomerular endothelial cells, which may be involved in the pathogenesis of APSGN after group A streptococcal infection, (3) anti-SPE B antibodies, at least in part, play roles in the pathogenesis of RHD, and the amino acid residues 296-310 of SPE B possess a dominant epitope.

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