The Unusual Genetics and Biochemistry of Bovine Immunoglobulins

Adv Immunol. 2018;137:135-164. doi: 10.1016/ Epub 2018 Feb 9.


Antibodies are the key circulating molecules that have evolved to fight infection by the adaptive immune system of vertebrates. Typical antibodies of most species contain six complementarity-determining regions (CDRs), where the third CDR of the heavy chain (CDR H3) has the greatest diversity and often makes the most significant contact with antigen. Generally, the process of V(D)J recombination produces a vast repertoire of antibodies; multiple V, D, and J gene segments recombine with additional junctional diversity at the V-D and D-J joints, and additional combinatorial possibilities occur through heavy- and light-chain pairing. Despite these processes, the overall structure of the resulting antibody is largely conserved, and binding to antigen occurs predominantly through the CDR loops of the immunoglobulin V domains. Bovines have deviated from this general paradigm by having few VH regions and thus little germline combinatorial diversity, but their antibodies contain long CDR H3 regions, with substantial diversity generated through somatic hypermutation. A subset of the repertoire comprises antibodies with ultralong CDR H3s, which can reach over 70 amino acids in length. Structurally, these unusual antibodies form a β-ribbon "stalk" and disulfide-bonded "knob" that protrude far from the antibody surface. These long CDR H3s allow cows to mount a particularly robust immune response when immunized with viral antigens, particularly to broadly neutralizing epitopes on a stabilized HIV gp140 trimer, which has been a challenge for other species. The unusual genetics and structural biology of cows provide for a unique paradigm for creation of immune diversity and could enable generation of antibodies against especially challenging targets and epitopes.

Keywords: Antibody; Antibody diversity; Antibody repertoire; Bovine immunoglobulin; Cow antibody; Knob; Long complementarity-determining region; Ruminant antibody; Stalk; Ultralong CDR3.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Neutralizing / metabolism
  • Antibody Diversity
  • Antibody Formation
  • Cattle / immunology*
  • Complementarity Determining Regions / genetics*
  • Epitopes / metabolism
  • Humans
  • Immunoglobulins / genetics
  • Immunoglobulins / metabolism*
  • Vaccines / immunology*


  • Antibodies, Neutralizing
  • Complementarity Determining Regions
  • Epitopes
  • Immunoglobulins
  • Vaccines