A new study investigating gene expression in cold agglutinin disease (CAD) identified the complement receptor 1 (CR1) gene, which encodes a protein that acts as receptor for C3b and C4b complement peptides, as one of the genes most significantly downregulated in the disease, a study found.

“This may be an important finding in the context of CAD, because complement controls B and T cell responses, and regulates the adaptive immunity,” the study’s authors said. “Therefore, downregulation of CR1 in CAD might be responsible for increased proliferation, survival of autoreactive B cells and IgM autoantibody secretion.”

The authors identified a subset of 93 most differentially expressed genes in CAD, including IGHV4-34, KANK2, RGCC, SLC4A1, CRYM, SPTA1, RHAG, AHSP, YBX3, TESC, CA1, HBD, TRAF1, HBA2, CR1,SPTB, IL10, ALAS2, HBA1, and UBASH3B (top 20). CR1 was downregulated approximately 11 times in clonal B cells from CAD patients compared to healthy controls, whereas the other genes were all upregulated at least 8 times.

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The expression of CR1 protein was higher in CAD patients’ IGL+ B cells than IGK+ B cells as assessed by flow cytometry. The difference in median fluorescence intensity between the 2 cell types was 10.8 times. Moreover, the authors observed a common bimodal CR1 expression in CAD patients’ IGK+ B cells, but not in IGL+ B cells.

On the other hand, healthy controls had similar levels of CR1 in IGK+ and IGL+ B cells and did not show heterogeneity of CR1 expression in IGM+ memory B cell populations.

The authors analyzed clonal B cells from 12 CAD patients and IGM+ memory B cells from 4 healthy by RNA sequencing. Moreover, they assessed the expression of CR1 protein by flow cytometry in blood or bone marrow samples from 15 CAD patients and blood samples from 5 healthy controls.


Malecka A, Ostlie I, Trøen G, et al. Gene expression analysis reveals downregulation of complement receptor 1 in cold agglutinin disease. Blood. Published online November 15, 2022. doi:10.1182/blood-2022-156489