狼疮自身抗体的新线索

翻译：runa

校对：nichang

来源:宾夕法尼亚州立大学米尔顿好时医疗中心

摘要:
这个称为γ干扰素的信号分子对于了解狼疮患者所产生的自身抗体的危害性起到关键作用。研究人员称，这一发现能为自身免疫慢性疾病提供新的治疗方向。

系统性红斑狼疮(SLE)是最为常见的红斑狼疮类型。系统性红斑狼疮的患者，免疫系统会产生攻击自身细胞并导致炎症发生、造成组织损伤的自身抗体，而这些奇特的抗体是如何形成的正是狼疮研究者关注的一个非常重要的领域。

当如病毒一样的病原体侵入人体,体内将大量产生B淋巴细胞的免疫细胞来对抗入侵。这些淋巴细胞会有针对性的产生相应抗体对抗病原体的入侵，或者转变为抗体分泌细胞和记忆B细胞，而记忆B细胞能起到长期保护并预防相同病原体再次侵袭的作用。

但患有红斑狼疮的人类和小鼠在没有病原体的侵袭的情况下，机体也会自发产生一系列的B淋巴细胞(B细胞)。这些B细胞并产生对抗感染病毒的抗体，相反，它们产生的一些特定的侵袭人体组织健康的自身抗体。这些针对人体自身细胞的侵袭正是自身免疫性疾病如红斑狼疮的标志。

与此同时，能持续产生自身抗体的自身抗体分泌B细胞和记忆B细胞也会增加，它使机体时刻处于被攻击的状态下，会引发长期感染，长此以往便会造成器官损伤。


但是什么原因促使这系列产生自身抗体的B细胞——自身反应性B细胞在狼疮患者体内形成呢？

微生物学和免疫学副教授齐亚·克里拉赫曼医生正致力于研究在没有病原体的情况下，这一系列B淋巴细胞是如何形成的。

宾夕法尼亚州立大学医学院的研究人员着力研究一种特定细胞活素在免疫系统中的作用，即一种信号蛋白——γ干扰素，并将他们的研究结果发表在《实验医学》杂志上。

系统性红斑狼疮患者往往会产生多于常人的γ干扰素,而狼疮小鼠会因为缺乏γ干扰素使自身抗体产生数量减少，同时降低红斑狼疮主要并发症严重肾脏疾病的发病率。

为了确定γ干扰素是否参与了这系列B淋巴细胞的自发形成，研究人员对B细胞干扰素γ受体被移除的狼疮小鼠进行了观察。

被观察的小鼠并没有产生这系列B淋巴细胞,有完整的干扰素γ受体的小鼠却产生了。与正常小鼠相比，这些狼疮小鼠自身抗体的数量也较低。


“这表明, B细胞中能发出信号的γ干扰素，对机体产生这系列自发形成的 B淋巴细胞，以及自身免疫的自主发生有着关键作用。”拉赫曼说，“如果能追踪γ干扰素在B细胞中的信号路径,就有可能治疗狼疮。”

另外,研究人员还发现,真正产生抗体对抗感染的B淋巴细胞群体的形成,并不会依赖于γ干扰素信号。

“目前，可供系统性红斑狼疮的治疗选择仍然很有限，所使用的免疫抑制药物,也使患者很容易受感染。追踪γ干扰素信号，可以消除这系列能自发产生自身抗体且成熟的B细胞，并使正常B细胞对病原体侵入做出完整的反应，这种新型的干预治疗方式或许能缓解狼疮患者的病情。”拉赫曼说。

New clue in lupus autoantibody production found

Source:

Penn State Milton S. Hershey Medical Center

Summary:

A signaling molecule called interferon gamma could hold the key to understanding how harmful autoantibodies form in lupus patients. The finding could lead to new treatments for the chronic autoimmune disease, said researchers at Penn State College of Medicine.

Systemic lupus erythematosus (SLE) is the most common form of lupus. In patients with SLE, the immune system forms autoantibodies that attack the body's own cells, causing inflammation and tissue damage. How these rogue antibodies form is an important area of interest for lupus researchers.

When a pathogen like a virus invades the body, immune cells called B lymphocytes multiply to fight the foreigner. These groups of B lymphocytes produce antibodies specially designed to fight the specific invader or turn into antibody-secreting cells and memory B cells that give long-term protection and help protect the next time the same pathogen is encountered.

In both humans and mice with lupus, groups of B lymphocytes (B cells) spontaneously arise in the absence of a pathogenic infection. Instead of producing antibodies to fight an infection, these groups pump out specialized autoantibodies that efficiently attack healthy tissue. These attacks on the body's own cells are the hallmark of autoimmune disorders like lupus.

Autoantibody-secreting B cells and memory B cells that continuously generate autoantibodies are also created, setting the body up for ongoing attacks, chronic inflammation and -- over time -- organ damage.

But what factors drive the development of groups of B cells, called autoreactive B cells, that produce autoantibodies in lupus?

Dr. Ziaur S.M. Rahman, assistant professor of microbiology and immunology, is working to answer what factors drive the development of B lymphocyte groups without the presence of a pathogen.

Penn State College of Medicine researchers homed in on the role of a particular cytokine -- a cell-signaling protein -- called interferon gamma, that is involved in the immune system. Researchers published their results in theJournal of Experimental Medicine.

People with SLE tend to have higher levels of interferon gamma production, and lupus mice that are deficient in it have reduced autoantibody production and less severe renal disease, a major lupus complication.

To find out if interferon gamma is behind the formation of spontaneously developed B lymphocyte groups, the researchers looked at lupus mice whose interferon gamma receptors in B cells had been removed.

These mice did not form the groups, while mice that had intact interferon gamma receptors did. These mice also had lower levels of autoantibodies involved in lupus compared to the normal mice.

"This suggests that interferon gamma signaling in B cells is critical for the formation of spontaneously-developed B lymphocyte groups and autoimmunity," Rahman said. "If you could target this interferon gamma signaling pathway in B cells, you could potentially treat lupus."

Moreover, the researchers also discovered that the formation of normal B lymphocyte groups that produce antibodies to fight real infections is not dependent on interferon gamma signaling.

The current treatment options for SLE are limited to the use of immunosuppressive agents that make patients susceptible to infection. This novel intervention could be an improvement for lupus patients, as targeting interferon gamma signaling would eliminate spontaneously developed groups of B cells that produce autoantibodies and keep normal B cell responses intact to fight against infection, Rahman said.