Human C. difficile toxin–specific memory B cell repertoires encode poorly neutralizing antibodies

Abstract

Clostridioides difficile is a leading cause of nosocomial infection responsible for significant morbidity and mortality with limited options for therapy. Secreted C . difficile toxin B (TcdB) is a major contributor to disease pathology, and select TcdB-specific Abs may protect against disease recurrence. However, the high frequency of recurrence suggests that the memory B cell response, essential for new Ab production following C . difficile reexposure, is insufficient. We therefore isolated TcdB-specific memory B cells from individuals with a history of C . difficile infection and performed single-cell deep sequencing of their Ab genes. Herein, we report that TcdB-specific memory B cell–encoded antibodies showed somatic hypermutation but displayed limited isotype class switch. Memory B cell–encoded mAb generated from the gene sequences revealed low to moderate affinity for TcdB and a limited ability to neutralize TcdB. These findings indicate that memory B cells are an important factor in C . difficile disease recurrence.

The adaptive immune response toClostridioides difficile: A tricky balance between immunoprotection and immunopathogenesis

“…In fact, several reports show that defective B responses might be an important factor in C. difficile disease recurrence. Low concentrations of neutralizing anti‐TcdB and anti‐TcdA Abs, 88 memory B cell‐encoded Abs with low to moderate affinity for TcdB, and limited ability to neutralize TcdB, 89 as well as host genetic variations located in the extended major histocompatibility complex, 90 have been proposed to explain recurrent CDI.…”

A Multi-Factorial Observational Study on Sequential Fecal Microbiota Transplant in Patients with Medically Refractory Clostridioides difficile Infection

“…It is possible that a lack of T cell help may have limited memory B cell expansion and differentiation into antibody-secreting plasma cells in this non-responder, or that their toxin A-and B-expressing memory B cells, which increased 2 weeks post-final FMT, only encoded low-affinity antibodies incapable of toxin neutralization. In support of this latter hypothesis, Shah and colleagues recently demonstrated that human C. difficile toxin-specific memory B cell repertoires encode poorly neutralizing antibodies, with limited class switching and IgM dominance [71]. These findings indicate that memory B cells may be an important factor in C. difficile disease recurrence.…”

Clostridioides difficile infection: traversing host–pathogen interactions in the gut

“…Maintenance of toxin B memory cell response was poor, as mice were unable to elicit protection upon rechallenging with C. difficile spores [278]. Sequencing revealed somatic hypermutations but limited isotype class switching in anti-toxin B antibodies in B memory cells and monoclonal antibodies generated displayed low to moderate affinity without a strong neutralizing ability [279]. Despite the brief longevity of circulating antibodies from B memory cells, anti-toxin antibodies have been long described to be effective at protecting the host against CDI.…”