2025.09.28
B cells stand at the epicenter of autoimmune pathology, wielding paradoxical powers to both ignite and extinguish disease. While traditionally known for driving autoimmunity through autoantibody production and pro-inflammatory cytokine secretion [1][2][3][4], recent research reveals their equally critical role as immunological peacekeepers. This duality makes B cells fascinating therapeutic targets—and formidable challenges.
In diseases like rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE), B cells become rogue agents by:
Producing cytotoxic autoantibodies that attack host tissues [1][2][5].
Presenting autoantigens to autoreactive T cells, amplifying inflammatory cascades [6][3].
Secreting pathogenic cytokines (e.g., IL-6, TNF-α) that sustain chronic inflammation [7][8][3].
Differentiating into antibody-secreting plasma cells, perpetuating autoantibody-mediated damage [1][4].
Notably, dual receptor B cells—expressing two distinct B-cell receptors (BCRs)—may exacerbate autoimmunity through "abnormal clonal expansion and autoantigen presentation" [9]. These cells, detected in both murine models and human blood, could represent novel therapeutic bullseyes.
Conversely, regulatory B cells (Bregs) emerge as vital suppressors of inflammation. These cells:
Secrete anti-inflammatory cytokines like IL-10 and IL-35 [10][11][12], curbing T-cell activation and dendritic cell maturation.
Maintain peripheral tolerance, preventing immune attacks against self-antigens [10][11][12].
Dampen autoimmune flares; their functional loss correlates with disease severity in SLE and MS [10][13][12].
Despite lacking consensus surface markers [14], Bregs’ immunosuppressive prowess positions them as endogenous healers—ones we risk destroying with blunt-force therapies.
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B cell-depleting therapies (e.g., rituximab) have revolutionized autoimmune treatment. Yet, their efficacy is inconsistent. Why? Indiscriminate depletion:
- They eliminate pathogenic B cells alongside protective Bregs, potentially worsening disease [8][6][15].
- For example, depleting IL-10-secreting Bregs may unleash unchecked inflammation [8][11].
This has spurred interest in precision approaches:
Targeting pathogenic B cell subsets while sparing Bregs [6][2].
Inhibiting BAFF/BLyS (a B cell-activating factor), which fuels autoreactive B cell survival [16][17][18]. BAFF antagonists show promise by starving pathologic cells without wholesale depletion.
CAR-T cell therapy could achieve "deep B cell depletion," potentially resetting the immune system [1].
B cells don’t act alone. Their synergy with stromal cells in inflamed tissues (e.g., RA joints) shapes disease severity [19][19]. Disrupting these interactions offers new therapeutic angles [19][20].
Moreover, metabolic reprogramming of B cells—shifts in glucose utilization, mitochondrial function—controls their pathogenicity. Correcting these pathways could restore tolerance [21][22][23].
Future treatments must navigate B cells’ dual identities. As we delineate pathogenic subsets (e.g., T peripheral helper (Tph) cells that drive aberrant T-B interactions [20][20]), dual-BCR B cells [9][24], or atypical autoimmune B cells [25], therapies can evolve from broad suppression to precision edits.
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