Exceptionally long CDR3H region with multiple cysteine residues in functional bovine IgM antibodies

Saini, S. S.; Allore, Brian; Jacobs, Robert M.; Kaushik, Azad

doi:10.1002/(sici)1521-4141(199908)29:08<2420::aid-immu2420>3.0.co;2-a

Cited by 114 publications

(113 citation statements)

References 18 publications

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“…The presence of additional cysteine residues has also been observed in cow (16), shark (43), and members of Camelidae (44 -46). V H sequences in cow sometimes have exceptionally long CDR3, with reports of sequences of up to 61 amino acid residues (16). These long CDR3 may contain six or eight cysteine residues, indicating the presence of three or four cysteine bridges.…”

Section: Discussionmentioning

confidence: 86%

Heavy Chain V Region Diversity in the Duck-Billed Platypus (Ornithorhynchus anatinus): Long and Highly Variable Complementarity-Determining Region 3 Compensates for Limited Germline Diversity

Johansson

Aveskogh

Munday

et al. 2002

The Journal of Immunology

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In this work, to study the emergence of the H chain V region repertoire during mammalian evolution, we present an analysis of 25 independent H chain V regions from a monotreme, the Australian duck-billed platypus, Ornithorhynchus anatinus. All the sequences analyzed were found to form a single branch within the clan III of mammalian V region sequences in a distance tree. However, compared with a classical V gene family this branch was more diversified in sequence. Sequence analysis indicates that the apparent lack of diversity in germline V segments is well compensated for by relatively long and highly diversified D and N nucleotides. In addition, extensive sequence variation was observed in the framework region 3. Furthermore, at least five and possibly seven different J segments seem to be actively used in recombination. Interestingly, internal cysteine bridges in the complementarity-determining region (CDR)3 loop, or between the CDR2 and CDR3 loops, are found in ∼36% of the platypus VH sequences. Such cysteine bridges have also been observed in cow, camel, and shark. Internal cysteine bridges may play a role in stabilizing long and diversified CDR3 and thereby have a role in increasing the affinity of the Ab-Ag interaction.

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Section: Discussionmentioning

confidence: 86%

Heavy Chain V Region Diversity in the Duck-Billed Platypus (Ornithorhynchus anatinus): Long and Highly Variable Complementarity-Determining Region 3 Compensates for Limited Germline Diversity

Johansson

Aveskogh

Munday

et al. 2002

The Journal of Immunology

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“…Therefore, in many species, relatively few antibody precursors can be affinity-matured to HIV bnAbs. Cows, however, produce antibodies with HCDR3s that average ~26 amino acids in length with an ultralong subset (10–15% of the repertoire) that can be over 70 amino acids in length 4–6,8,9,16 . Previous work has shown that repeated immunization over multiple years with a non-well-ordered Env trimer in cows can lead to some neutralization breadth in the immunoglobulin-rich colostrum 17–19 , although with relatively low potency.…”

Section: Main Textmentioning

confidence: 99%

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

Sok

Vadnais

et al. 2017

Nature

156

198

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No immunogen to date has reliably elicited broadly neutralizing antibodies (bnAbs) to HIV in humans or animal models. Advances in the design of immunogens (BG505 SOSIP) that antigenically mimic the HIV envelope glycoprotein (Env)1 have improved the elicitation of potent isolate-specific Ab responses in rabbits2 and macaques3, but so far failed to induce bnAbs. One possible contributor to this failure is that the relevant antibody repertoires are poorly suited to target somewhat occluded conserved epitope regions on Env relative to exposed variable epitopes. To test this hypothesis, we immunized four cows with BG505 SOSIP. The antibody repertoire of cows contains long third heavy chain complementary determining regions (HCDR3) with an ultralong subset that can reach over 70 amino acids in length4–9. Remarkably, BG505 SOSIP immunization resulted in rapid elicitation of broad and potent serum antibody responses in all four cows. Longitudinal serum analysis for one cow showed the development of neutralization breadth (20%, n = 117 cross-clade isolates) in 42 days and 96% breadth (n = 117) at 381 days. A monoclonal antibody (mAb) isolated from this cow harbored an ultralong HCDR3 of 60 amino acids and neutralized 72% of cross-clade isolates (n = 117) with a potent median IC50 of 0.028 μg/ml. We note that breadth was elicited with a single trimer immunogen and did not require additional envelope diversity. Immunization of cows may provide an avenue to rapidly generate antibody prophylactics and therapeutics to address disease agents that have evolved to avoid human antibody responses.

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“…In some areas, the approximate infection rate in adult cows can reach 30 -40%, as assessed by the presence of serum Abs. Approximately 30% of BLV-infected cattle develop a benign persistent lymphocytosis following infection, characterized by a polyclonal expansion of B cells generally expressing IgM and CD5 molecules at the cell surface (1)(2)(3)(4). Under these conditions, the level of lymphocytosis is generally in the range of 20,000 -80,000 lymphocytes/ l. After a prolonged incubation period, ϳ1-5% of infected cows will develop lymph node (LN) tumors.…”

mentioning

confidence: 99%

Cell Surface Expression of the Bovine Leukemia Virus-Binding Receptor on B and T Lymphocytes Is Induced by Receptor Engagement

Lavanya

Kinet

Montel‐Hagen

et al. 2008

The Journal of Immunology

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Bovine leukemia virus (BLV), one of the most common infectious viruses of cattle, is endemic in many herds. Approximately 30–40% of adult cows in the United States are infected by this oncogenic C-type retrovirus and 1–5% of animals will eventually develop a malignant lymphoma. BLV, like the human and simian T cell leukemia viruses, is a deltaretrovirus but, in contrast with the latter, the BLV receptor remains unidentified. In this study, we demonstrate that the amino-terminal 182 residues of the BLV envelope glycoprotein surface unit encompasses the receptor-binding domain. A bona fide interaction of this receptor-binding domain with the BLV receptor was demonstrated by specific interference with BLV, but not human T cell leukemia virus, envelope glycoprotein-mediated binding. We generated a rabbit Ig Fc-tagged BLV receptor-binding domain construct and ascertained that the ligand binds the BLV receptor on target cells from multiple species. Using this tool, we determined that the BLV-binding receptor is expressed on differentiating pro/pre-B cells in mouse bone marrow. However, the receptor was not detected on mature/quiescent B cells but was induced upon B cell activation. Activation of human B and T lymphocytes also induced surface BLV-binding receptor expression and required de novo protein synthesis. Receptor levels were down-regulated as activated lymphocytes returned to quiescence. In the human thymus, BLV-binding receptor expression was specifically detected on thymocytes responding to the IL-7 cytokine. Thus, expression of the BLV-binding receptor is a marker of enhanced metabolic activity in B cells, T cells, and thymocytes.

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Exceptionally long CDR3H region with multiple cysteine residues in functional bovine IgM antibodies

Cited by 114 publications

References 18 publications

Heavy Chain V Region Diversity in the Duck-Billed Platypus (Ornithorhynchus anatinus): Long and Highly Variable Complementarity-Determining Region 3 Compensates for Limited Germline Diversity

Heavy Chain V Region Diversity in the Duck-Billed Platypus (Ornithorhynchus anatinus): Long and Highly Variable Complementarity-Determining Region 3 Compensates for Limited Germline Diversity

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

Cell Surface Expression of the Bovine Leukemia Virus-Binding Receptor on B and T Lymphocytes Is Induced by Receptor Engagement

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