High throughput profiling of the B cell repertoire identifies systematic changes in the repertoire of individuals with Crohn’s disease

Abstract The B cell repertoire contains the recombined DNA sequences that encodes the entire antibody repertoire of an individual. The repertoire is made from three antigenic binding chains, namely the immunoglobulin heavy chain (IGH) and two immunoglobulin light chains, κ (IGK) and λ (IGL). Compared to the T cell repertoire, the B cell repertoire is understudied in inflammatory bowel diseases (IBD) even though different antibodies such as ASCA and ANCA have been shown to be elevated in individuals with IBD. Furthermore, most IBD B cell repertoire studies have profiled the repertoire of treated individuals, thus capturing the combined effect of treatment and disease on the repertoire. To address this limitation, we profiled the repertoire of 24 treatment-naive individuals with CD with matching 24 symptomatic controls. The repertoire of individuals with CD showed a significant reduction in diversity and an increase in clonality, suggesting an antigen-driven expansion of clonotypes that might be driving the disease. Furthermore, we observed a significant reduction in the expansion of IgM and IgD and an expansion of IgA2 and IgG2 clonotypes in individuals with CD relative to controls. Lastly, we observed a reduction in the somatic hypermutation rate in the IGH J gene, particularly in IgM and IgA1 clonotypes, among individuals with CD relative to controls. Thus, despite the small sample size, we identified multiple alterations in the B cell repertoire of individuals with CD, highlighting the potential of the B cell repertoire in identifying antigenic exposures implicated in the diseases, demanding now larger international studies ideally including also treatment-naive and pre-clinical cases. Competing Interest Statement M.L.H received investigator-initiated research grants from Takeda, Pfizer, Tilllotts, Ferring and Janssen. Speaker honoraria from Takeda, Tillotts, Ferring, AbbVie, Galapagos and Meda. She is also on the advisory board of Takeda, Galapagos, MSD, Lilly and AbbVie. All other co-authors declare no-competing interests.