Structural and genetic diversity in antibody repertoires from diverse species

Rios, Miguel de los; Criscitiello, Michael F.; Smider, Vaughn V.

doi:10.1016/j.sbi.2015.06.002

Cited by 63 publications

(49 citation statements)

References 130 publications

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“…Furthermore, deimination of Ig's in teleost fish was recently described (Magnadóttir et al, 2019a), as well as in shark (Criscitiello et al, 2019). Given the increased focus on understanding of Ig diversity throughout phylogeny (Smith et al, 2012;Zhang et al, 2013;de los Rios et al, 2015;Zhang et al, 2016Zhang et al, , 2017Stanfield et al, 2018) and the unique features of camelid immunoglobulins (Plasil et al, 2019), our current finding of deimination of llama Ig's highlights a novel concept that may further understanding of Ig diversity throughout evolution. Of additional interest is the finding that some deiminated Ig proteins were also found to be exported in EVs.…”

Section: Discussionmentioning

confidence: 65%

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

Criscitiello

Kraev

Lange

2020

Molecular Immunology

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A B S T R A C TPeptidylarginine deiminases (PADs) are phylogenetically conserved calcium-dependent enzymes which posttranslationally convert arginine into citrulline in target proteins in an irreversible manner, causing functional and structural changes in target proteins. Protein deimination causes generation of neo-epitopes, affects gene regulation and also allows for protein moonlighting. Furthermore, PADs have been found to be a phylogenetically conserved regulator for extracellular vesicle (EVs) release. EVs are found in most body fluids and participate in cellular communication via transfer of cargo proteins and genetic material. In this study, post-translationally deiminated proteins in serum and serum-EVs are described for the first time in camelids, using the llama (Lama glama L. 1758) as a model animal. We report a poly-dispersed population of llama serum EVs, positive for phylogenetically conserved EV-specific markers and characterised by TEM. In serum, 103 deiminated proteins were overall identified, including key immune and metabolic mediators including complement components, immunoglobulin-based nanobodies, adiponectin and heat shock proteins. In serum, 60 deiminated proteins were identified that were not in EVs, and 25 deiminated proteins were found to be unique to EVs, with 43 shared deiminated protein hits between both serum and EVs. Deiminated histone H3, a marker of neutrophil extracellular trap formation, was also detected in llama serum. PAD homologues were identified in llama serum by Western blotting, via cross reaction with human PAD antibodies, and detected at an expected 70 kDa size. This is the first report of deiminated proteins in serum and EVs of a camelid species, highlighting a hitherto unrecognized post-translational modification in key immune and metabolic proteins in camelids, which may be translatable to and inform a range of human metabolic and inflammatory pathologies.

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Section: Discussionmentioning

confidence: 65%

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

Criscitiello

Kraev

Lange

2020

Molecular 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

149

192

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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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“…Due to this deletion in the framework of the 2-CDR2-region, the β-sandwich fold only consists of eight instead of 10 β-strands, which made the IgNAR V domain the smallest antigen binding unit known at the time [65]. (since ultralong-CDR3 cattle antibodies have claimed this title [66,67]).…”

Section: Cartilaginous Fish Ighmentioning

confidence: 99%

Fish Immunoglobulins

Mashoof

Criscitiello

2016

Biology

152

106

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The B cell receptor and secreted antibody are at the nexus of humoral adaptive immunity. In this review, we summarize what is known of the immunoglobulin genes of jawed cartilaginous and bony fishes. We focus on what has been learned from genomic or cDNA sequence data, but where appropriate draw upon protein, immunization, affinity and structural studies. Work from major aquatic model organisms and less studied comparative species are both included to define what is the rule for an immunoglobulin isotype or taxonomic group and what exemplifies an exception.

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Structural and genetic diversity in antibody repertoires from diverse species

Cited by 63 publications

References 130 publications

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

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

Fish Immunoglobulins

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