The plasma cell: Culprit and therapeutic target in antibody-mediated diseases

Autoantibodies crucially contribute to the pathogenesis of multiple human diseases including autoimmune haemolytic anaemia, myasthenia gravis and systemic lupus erythematosus (SLE). Refractory disease courses are frequent and may be caused by secretion of pathogenic antibodies from long-lived plasma cells (PC), which are resistant to conventional treatments. We demonstrated that proteasome inhibitors can eliminate PC including long-lived ones and ameliorate lupus-like disease in mice. Recently, we identified long-lived PC within in­flamed kidneys of NZB/W F1 lupus mice. Approximately half of those renal PC was reac­tive with double stranded, native DNA or nucleolin, a markedly higher percentage than in spleen and bone marrow.

This project aims (I) to investigate the mechanisms of PC survival and differentiation at sites of in­flammation and (II) to develop strategies to re-establish a non-autoimmune PC memory.

The key questions to be addressed are:

(1) Are PC against other “lupus” autoantigens also enriched in inflamed kidneys, and if so, which mechanisms drive this enrich­ment? For this purpose we will compare frequencies of autoantibody producing cells by ELISPOT assays and investigate migration after adoptive transfer.

(2) What is the cellular and molecular nature of the “inflammatory PC survival niches”? Are there specific environmental effects on PC and antibodies?  To identify molecules and cells mediating PC survival in inflamed tissues, we will use immuno­histo­chemistry, intravital micros­copy, flow cytometry, KO-mice and cytokine antagonists.

(3) How can we efficiently deplete auto­reactive PC and replace them with harmless/useful PC? In order to increase efficacy and reduce toxicity of proteasome inhibitors we will explore combination therapies based on proteasome inhibition together with antagonists of survival factors such as APRIL. After depletion, we will try to occupy PC survival niches with non-autoreactive PC by vaccination and adoptive cell transfer strategies.

Understanding the mechanisms of PC survival in affected organs will allow the development of new treatment strategies for antibody-mediated diseases.    

A. After antigen stimulation B cells can differentiate into antibody producing plasma cells. Plasma cells are either short lived and die within a few days, or can become long lived, if they find specialized survival niches. Long-lived plasma cells can be found in bone marrow and spleen, and in inflamed kidneys or other sites of chronic inflammation. 

B. Immunohistochemical staining of plasma cells (red) within an inflamed kidney of a NZB/W F1 lupus mouse.