Class switched bovine ultralong CDR H3 amplicons versus canonical in immune and non-immune tissues

Within the bovine immune response, a distinct type of immunoglobulin (Ig), known as ultralong complementarity-determining region 3 (CDR3) antibodies, coexists alongside canonical Igs. These ultralong heavy chains (HC) feature a remarkable structure with a lengthened CDR3 of the heavy chain (CDR H3), allowing them to adopt either a smaller and more extended paratope than canonical antibodies. However, very little is known about the distribution of ultralong CDR H3s in cattle tissues and which isotypes they are ultimately associated with. This study analyzed and quantified the amplicons of the five immunoglobulin isotypes (IgM, IgD, IgG, IgA, and IgE) for both the canonical and ultralong CDR H3 throughout 24 Bos taurus tissues. IgH amplicons analysis identified an extensive repertoire of expressed canonical and ultralong CDR H3s of each isotype in most tissues. Ultralong cattle Igs were preferentially switched to the IgG isotype, especially in the medial retropharyngeal lymph node draining the immunization site. Additionally, B cells producing canonical Igs in bone marrow switched most to the IgG isotype. These data suggest that ultralong CDR H3 may be uniquely qualified to handle some antigens. A more comprehensive understanding of isotype and tissue-specific immune responses of these unusual antibodies can provide a deeper insight into their function within the overall cattle immune system, offering unique opportunities for innovations for in both bovine health and human immunotherapeutics.