Background/Purpose: IgG4-related disease (IgG4-RD) is an immune-mediated disease characterized by fibrotic masses with expansion of IgG4^–producing plasma cell in multiple organs such as pancreas, lacrimal and salivary glands, and retroperitoneal tissues. Antibody secreting cells (ASC) such as plasmablasts expand in peripheral blood in IgG4-RD, resulting in high titer of serum IgG4 in active state.

ASC accumulated in extrafollicular masses, suggesting that B cell precursors of ASC may differentiate through extrafollicular pathways. However, the detail of B cell profile in IgG4-RD remains unclear. Clinically, IgG4-RD responds very well glucocorticoid and B cell depleting therapy, but the change of B cell profile including extrafollicular B cells after these treatments are unknown.

Methods: IgG4-RD patients were enrolled from Emory IgG4-RD Clinic. Disease activity was assessed by IgG4-RD responder index. Fresh and frozen peripheral blood mononuclear cells (PBMCs) were stained by 3 sets of antibody panels and analyzed by flow cytometer. The first cohort used fresh PBMCs and a simple B cell panel (n: 11 healthy control (HC), 13 inactive and 12 active IgG4-RD). The second cohort and third cohort used the same frozen PBMCs with an extended B cell panels (n: 10 HC, 10 or 11 RTX-naïve and 13 RTX-treated (6-51 months after RTX) IgG4-RD).

Results: Analysis of cohort 1 focused on the difference of B cell profile by disease activity. IgD and CD27 double negative (DN) B cells were increased, and unswitched memory B cells (USM) were reduced in active patients. However, IgG4-RD patients were split into the high or low proportion of DN B cells in CD19⁺ B cells. In DN B cells, DN2 (CD19^+/++/CD38^–/CD27^–/IgD^–) expanded, while DN1 (CD19^+/++/CD38^-/+ CD27^–/IgD^–) were decreased, resulting in high DN2+DN3/DN1 ration in IgG4-RD. In 2nd and 3rd cohorts, we compared HC, RTX-naïve and -treated IgG4-RD. increased DN2 (CD19⁺/CD27^–/IgD^–/CD11c⁺/CD21^–) and reduced USM (CD19⁺/CD27⁺/IgD⁺) were consistent with 1st cohort though DN B cells did not expand. In addition to DN2, increased ASC, DN3 (CD19⁺/CD27^–/IgD^–/CD11c^–/CD21^–) and CD11c⁺switched memory (SWM) B cells also were observed. Moreover, these expanded populations in IgG4-RD were repressed by RTX treatment. In CD3⁺ T cells, CD4/CD8 ratio was elevated in IgG4-RD, and this ratio was reverted by RTX.

Conclusion: Extrafollicular effector B cells including DN2, DN3, CD11c⁺ SWM and ASC were expanded in IgG4-RD. Intriguingly, this abnormal expansion was mostly reverted by RTX treatment, consistently with a good clinical response. In addition to B cells, elevated CD4/CD8 ratio was also normalized by RTX. These results suggest that promoted extrafollicular pathway-derived B cell might be a precursor of tissue-infiltrating plasma cell in IgG4-RD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/expanded-extrafollicular-b-cells-were-improved-by-rtx-in-igg4-related-disease/