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<p>Autoantibody flares are important drivers of pathology in systemic lupus erythematosus (SLE), highlighting the pivotal role of B cells in initiating and propagating chronic autoimmunity. Although autoreactive specificities are a normal feature of the naive B cell repertoire, these cells are normally suppressed by layered tolerance checkpoints that limit inappropriate activation. Autoimmune-prone environments can lower these tolerance thresholds, rendering naive autoreactive B cells more sensitive to aberrant cues. Cytokines and other microenvironmental signals shape tissue niches that direct autoreactive B cells towards either germinal-centre or extrafollicular differentiation pathways. Germinal centres support the entry, selection and diversification of autoreactive B cells, with T cell help sustaining these repertoires. By contrast, naive autoreactive B cells entering the extrafollicular pathway&#xa0;exhibit&#xa0;an attenuated&#xa0;requirement for&#xa0;cognate&#xa0;T cell help and strong dependence on complement and TLR signalling. Emerging evidence continues to refine our understanding of germinal-centre and extrafollicular responses as complementary sources of autoreactive effector cells. With this progress, investigations into the origin, development, longevity and tissue dynamics of autoreactive memory B cells as chronic sources of autoantibodies are warranted. Although broad B cell depletion therapies have yielded benefit, a key challenge now is developing precision strategies that selectively target pathogenic B cell subsets.</p>

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Germinal-centre and extrafollicular B cell pathways in systemic lupus erythematosus

  • 期刊论文

  • 发表日期：

    2026年4月7日

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  • Danni Yi-Dan Zhu,
  • Carlos Castrillon,
  • Elliot Akama-Garren,
  • Michael C. Carroll

摘要

Autoantibody flares are important drivers of pathology in systemic lupus erythematosus (SLE), highlighting the pivotal role of B cells in initiating and propagating chronic autoimmunity. Although autoreactive specificities are a normal feature of the naive B cell repertoire, these cells are normally suppressed by layered tolerance checkpoints that limit inappropriate activation. Autoimmune-prone environments can lower these tolerance thresholds, rendering naive autoreactive B cells more sensitive to aberrant cues. Cytokines and other microenvironmental signals shape tissue niches that direct autoreactive B cells towards either germinal-centre or extrafollicular differentiation pathways. Germinal centres support the entry, selection and diversification of autoreactive B cells, with T cell help sustaining these repertoires. By contrast, naive autoreactive B cells entering the extrafollicular pathway exhibit an attenuated requirement for cognate T cell help and strong dependence on complement and TLR signalling. Emerging evidence continues to refine our understanding of germinal-centre and extrafollicular responses as complementary sources of autoreactive effector cells. With this progress, investigations into the origin, development, longevity and tissue dynamics of autoreactive memory B cells as chronic sources of autoantibodies are warranted. Although broad B cell depletion therapies have yielded benefit, a key challenge now is developing precision strategies that selectively target pathogenic B cell subsets.