Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Systemic Lupus Erythematosus

• Germinal Centers

• Extrafollicular Responses

Main Findings

The Germinal Center (GC) reaction is considered to be the main driver of autoimmunity, by continuously producing highly specific autoantibodies and long-lived autoantibody-producing memory B cells, but is also the site of tight immunological tolerance regulation. In recent years, an emerging role for the Extrafollicular Pathway (EF) in the production of autoantibodies and autoantibody-producing B cells has been established in patients suffering from Systemic Lupus Erythematosus, an autoimmune disease that is characterised by the presence of anti-nuclear antibodies (like anti-dsDNA) and mainly affects the kidneys. However, studying the relative contributions of both GC and EF pathways to the initiation and maintenance of the autoimmune reaction has been challenging. Driven by the hypothesis that genetically blocking the GC pathway would prevent autoimmune disease, Voss et al. generated a mouse model with a B-cell specific knock out of B-cell lymphoma 6 (Bcl-6), a master transcription factor that regulates cell fates across GC B cells, T follicular helper cells and T regulatory cells. Surprisingly, despite the absence of GCs and GC B cells, they measured higher levels of pathogenic anti-dsDNA autoantibodies and a higher percentage of plasmablasts (PBs) and plasma cells (PCs), which they claim suggests an exacerbated autoimmune response. Next, they sought to find out where these autoantibodies and PBs/PCs came from. They found that GC-blocked B cells in vitro had a lower capacity to proliferate but an increased capacity to differentiate in contrast to their GC-sufficient counterparts. They confirmed these results in vivo by leveraging a mixed bone-marrow chimera model, in which they show PCs that arose from GC-blocked B cells still contributed to the autoimmune reaction, together with PCs that arose from GC-sufficient B cells and that they were not outcompeted. In this way, Voss et al. succeeded at uncoupling the GC response from the EF response in vivo and show that EF B cells efficiently contribute to autoimmune disease, both at initiation and during maintenance of the disease.

​

Limitations

• Although the authors clearly display the absence of GCs in the secondary lymphoid tissues, it would have been interesting to see the absence of GCs in the tertiary tissues, like the kidneys. Especially since they claim an accelerated autoimmune disease progression in GC-blocked mice, but the assessment of kidney disease by IF seems to be insufficient to support the hypothesis.

• The authors previously claimed that spMBL levels correlated with the formation of GCs and can drive the loss of immunological tolerance. Here they additionally claim that spMBL levels are not affected by the absence of GC B cells, but the link with the EF pathway is not yet clear and therefore it is unclear why and how this data supports the main findings.

• Furthermore, it would be valuable to look at SHM and clonality of the anti-dsDNA autoantibodies to assess their origin. Maybe even assessing the in vitro autoantibody-producing capacity of the PCs would be interesting.

​

Significance/Novelty

Although GC and EF pathways are extensively described in the literature and their contribution to SLE has become abundantly clear, studying the relative contribution of each pathway was challenging. The authors successfully block the GC pathway in vivo, but not the EF pathway and in vitro confirmed there are differences in B cell subtypes generated through both pathways. By combining 2 different animal models of Lupus, they could show that the EF B cells can play a crucial role in both the initiation and the maintenance of the autoimmune reaction. These results indicate that, contrary to the long-standing hypothesis that autoreactive B cells mainly arise through the GC pathway and that the autoimmune reaction is highly specific, autoimmunity could also be initiated and maintained through the less specific and less closely regulated EF pathway. Thus, treatment strategies solely aimed at blocking the GC might not be sufficient to abolish the immune reaction and should therefore be accompanied by EF blocking strategies.

​

Credit

Reviewed by Eveline Van Gompel as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai, the Kennedy Institute of Rheumatology and the Oxford Centre for Immuno-Oncology  (OXCIO) (University of Oxford, GB) and Karolinska Institute’s Center for Infectious Medicine (CIM) & Center for Molecular Medicine (CMM). You can follow her on Twitter.