Background/Purpose: Systemic lupus erythematosus (SLE) is a common, complex inflammatory autoimmune disease in which dysregulation of both innate and adaptive immune responses has been implicated in disease pathogenesis. Leukopenia is a common hematologic manifestation in SLE, yet the mechanisms remain incompletely defined. Our published data show that anti-Ro autoantibodies can bind neutrophil surface proteins and potentially fix complement leading to leukopenic conditions. Additionally, the Duffy null genotype (ACKR1 rs2814778-CC), enriched in individuals of African and Arab ancestry, is associated with low neutrophil counts. Therefore, we investigated whether this Duffy null genotype, combined with autoantibody-mediated neutrophil targeting, contributes to more severe leukopenia and worse immunologic outcomes in SLE.

Methods: DNA from subjects who met the ACR classification criteria were obtained from the Oklahoma Medical Research Foundation (OMRF) Lupus Family Registry and Repository (LFRR). These subjects were genotyped for ACKR1 (rs2814778-CC) using biallelic discrimination assays. We analyzed the subjects corresponding clinical and serologic data and stratified them by autoantibody status and Duffy genotype (ACKR1 CC vs. CT/TT). Finally, we assessed white blood cell (WBC) counts across these groups. Statistical analysis was performed using the Kruskal-Wallis test to assess significant differences in WBC counts among stratified subgroups.

Results: WBC counts were lowest among SLE patients who were both anti-Ro or anti-dsDNA positive and Duffy antigen negative (ACKR1-CC genotype) compared to autoantibody negative/Duffy antigen positive (ACKR1-TT/CT genotype) SLE subjects. Additionally, subjects that were both anti-dsDNA positive and Duffy null had a significant decrease in WBC compared to subjects with anti-dsDNA antibodies and Duffy positive. These findings suggest an additive or synergistic effect of anti-dsDNA autoantibodies and Duffy null status on the severity of leukopenia.

Conclusion: Our previously published data support a model in which autoantibodies (anti-Ro60) directly contribute to leukopenia in SLE by binding neutrophil surface proteins and subsequently fixing complement. The current findings suggest this effect is amplified in subjects with the Duffy null genotype. These results highlight the importance of integrating ancestry-specific genetics (such as Duffy null genotype) and immunologic factors into our understanding of SLE pathogenesis and personalized care strategies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/duffy-null-genotype-and-autoantibodies-synergistically-contribute-to-severe-leukopenia-in-systemic-lupus-erythematosus/