Germinal center and extrafollicular dysregulation in systemic lupus erythematosus: Mechanisms and therapeutic opportunities.

Germinal centers (GCs) are specialized microanatomical structures within secondary lymphoid organs where B cells undergo somatic hypermutation, affinity-based selection, and differentiation into high-affinity antibody-secreting plasma cells and memory B cells. In systemic lupus erythematosus (SLE), the dysregulated GC response is a major contributor to the production of pathogenic autoantibodies that promote immune complex formation and multi-organ damage. Autoantibodies are also produced through non-GC extrafollicular (EF) responses. This review examines the cellular and molecular mechanisms underlying GC and EF dysfunction in SLE, with emphasis on aberrant B cell selection and T follicular helper (Tfh) cell expansion, and metabolic reprogramming of these cells. We discuss current therapeutic strategies targeting GC and EF components, including B cell depletion and cytokine blockade, and highlight emerging approaches such as metabolic inhibitors and T follicular regulatory (Tfr) cell-based immunotherapy. Understanding the complex interplay between immune cells within dysregulated GC and EF responses offers promising avenues for developing more targeted and effective treatments for SLE while preserving protective immune responses.