Clinical and Immunological Features in ACKR1/DARC Associated Neutropenia.

ACKR1/DARC associated neutropenia (ADAN; OMIM 611862), caused by a gene variation in the ACKR1/DARC gene (rs2814778), is common in persons of African or Middle East decent. In a cohort of 66 genetically confirmed ADAN subjects, we show that absolute neutrophil counts (ANCs) occasionally may be lower than previously recognized (0.1-0.49 x109 / L for 9% of the subjects), being similar to ANCs in severe chronic NP (SCNP). ANCs often normalized during inflammation, even mild. The ADAN individuals (comprising 327 observed person-years), showed no cases of myelodysplastic syndromes (MDS), as frequently encountered in SCNP. Unexpectedly, 22% presented with autoantibodies to neutrophils compared to <1% in controls. Compared to healthy donors, ADAN subjects demonstrated significantly lower hCAP-18/pro-LL-37 plasma levels, higher levels of non-classical pro-inflammatory SLAN-expressing monocytes, and differentially expressed plasma levels of 28/239 analyzed cytokines of relevance for immunity/inflammation, cell signaling, neutrophil activation and angiogenesis. Collectively, more severe neutropenia in ADAN than previously assumed may complicate differential diagnoses as to other SCNPs, and various (auto)immune/inflammatory reactions with a distinct profile may be a cause or a consequence of this hereditary neutropenia.

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