An Ultra-specific Avian Antibody to Phosphorylated Tau Protein Reveals a Unique Mechanism for Phosphoepitope Recognition

Shih, Heather H.; Tu, Chao; Cao, Wei; Klein, Anita S.; Ramsey, Renee; Fennell, Brian J.; Lambert, Matthew; Shúilleabháin, Deirdre Ní; Autin, Bénédicte; Kouranova, Eugenia; Laxmanan, Sri; Braithwaite, Steven P.; Wu, Liang; Ait-Zahra, Mostafa; Milici, Anthony J.; Dumin, Jo Ann; LaVallie, Edward R.; Arai, Mikki; Corcoran, Christopher; Paulsen, Janet; Gill, Davinder; Cunningham, Orla; Bard, Joel; Mosyak, Lydia; Finlay, William J. J.

doi:10.1074/jbc.m112.415935

Cited by 55 publications

(86 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, anti-protein antibodies tend to have larger, flat binding sites, and the prototypical topology was observed in the scFv B8 structure (Fig. 4, B and C) where the electrostatic surface reveals a predominantly positively charged (19). The chicken mature light chain is two residues shorter than that of the typical mammalian light chain and, therefore, begins at position number 3.…”

Section: Resultsmentioning

confidence: 99%

“…Structures of such disulfide-containing CDRH3 across species are rare, as cysteine residues are observed at low frequency in mature B-cells (20). However, selection of avian CDRH3 non-canonical disulfide-containing clones from Escherichia coli indicates that it is possible to efficiently sample the full breadth of the chicken repertoire by phage display (19).…”

mentioning

confidence: 99%

“…The use of chickens as diagnostic, and indeed therapeutic antibody generation hosts, is advantageous due to their phylogenetic distance from man, tolerance of multiple immunogens, and demonstrated successes in generating antibodies to a wide range of antigens (10,19). Furthermore, the simplistic arrangement of v-genes, high core temperature, and increased CDRH3 length provide potentially superior antibody biophysical attributes.…”

mentioning

confidence: 99%

“…The chicken immune system can, therefore, introduce variability at selected FWR residues, resulting in structural diversity of V H /V L angles (4,20). The D-segments of chickens (15 functional segments) are highly homologous, and hyperdiversification is achieved by gene conversion at D-D junctions, creating "mosaic CDRs" (19). These D-segments contain cysteine residues at a far higher frequency than humans or mice.…”

mentioning

confidence: 99%

“…As the hinge region is absent in IgY, its flexibility is derived from proline-glycine-rich regions at the C1-C2 and C2-C3 domains (18). At the genetic level, in contrast to humans, mice, and primates, the v-gene repertoire of chickens employs single functional v-genes for the heavy (V H 3 family) and light chains (exclusively light chains), which contain unique V L -J L and V H -D H -J H segments (19). In addition to somatic hypermutation, to generate a diverse functional antibody repertoire from such a restricted v-gene germ-line, chickens employ "gene conversion".…”

mentioning

confidence: 99%

See 4 more Smart Citations

Reconciling the Structural Attributes of Avian Antibodies

Conroy

Law

Gilgunn

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Antibodies from alternative immune hosts provide insights into novel mechanisms of antibody diversity in restricted germ-line repertoires. Results: The high-resolution crystal structures of the first two chicken single chain antibodies (scFv) with prototypical binding sites are described. Conclusion: Chickens exhibit unique canonical classes in the CDRL1. Significance: Aves employ distinct mechanisms to generate diversity resulting in unique binding-site topologies.

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Reconciling the Structural Attributes of Avian Antibodies

Conroy

Law

Gilgunn

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

Polyspecificity of Anti-lipid A Antibodies and Its Relevance to the Development of Autoimmunity

Haji-Ghassemi

Gagnon

Müller‐Loennies

et al. 2017

Advances in Experimental Medicine and Biology

View full text Add to dashboard Cite

The process of natural selection favours germ-line gene segments that encode CDRs that have the ability to recognize a range of structurally related antigens. This presents an immunological advantage to the host, as it can confer protection against a common pathogen and still cope with new or changing antigens. Cross-reactive and polyspecific antibodies also play a central role in autoimmune responses, and a link has been shown to exist between auto-reactive B cells and certain bacterial infections. Bacterial DNA, lipids, and carbohydrates have been implicated in the progression of autoimmune diseases such as systemic lupus erythematosus. As well, reports of anti-lipid A antibody polyspecificity towards single-stranded DNA together with the observed sequence homology amongst isolated auto- and anti-lipid A antibodies has prompted further study of this phenomenon. Though the lipid A epitope appears cryptic during Gram-negative bacterial infection, there have been several reported instances of lipid A-specific antibodies isolated from human sera, some of which have exhibited polyspecificity for single stranded DNA. In such cases, the breakdown of negative selection through polyspecificity can have the unfortunate consequence of autoimmune disease. This review summarizes current knowledge regarding such antibodies and emphasizes the features of S1-15, A6, and S55-5, anti-lipid A antibodies whose structures were recently determined by X-ray crystallography.

show abstract

Immunological memory to hyperphosphorylated tau in asymptomatic individuals

et al. 2017

View full text Add to dashboard Cite

Several reports have described the presence of antibodies against Alzheimer’s disease-associated hyperphosphorylated forms of tau in serum of healthy individuals. To characterize the specificities that can be found, we interrogated peripheral IgG+ memory B cells from asymptomatic blood donors for reactivity to a panel of phosphorylated tau peptides using a single-cell screening assay. Antibody sequences were recovered, cloned, and expressed as full-length IgGs. In total, 52 somatically mutated tau-binding antibodies were identified, corresponding to 35 unique clonal families. Forty-one of these antibodies recognize epitopes in the proline-rich and C-terminal domains, and binding of 26 of these antibodies is strictly phosphorylation dependent. Thirteen antibodies showed inhibitory activity in a P301S lysate seeded in vitro tau aggregation assay. Two such antibodies, CBTAU-7.1 and CBTAU-22.1, which bind to the proline-rich and C-terminal regions of tau, respectively, were characterized in more detail. CBTAU-7.1 recognizes an epitope that is similar to that of murine anti-PHF antibody AT8, but has different phospho requirements. Both CBTAU-7.1 and CBTAU-22.1 detect pathological tau deposits in post-mortem brain tissue. CBTAU-7.1 reveals a similar IHC distribution pattern as AT8, immunostaining (pre)tangles, threads, and neuritic plaques. CBTAU-22.1 shows selective detection of neurofibrillary changes by IHC. Taken together, these results suggest the presence of an ongoing antigen-driven immune response against tau in healthy individuals. The wide range of specificities to tau suggests that the human immune repertoire may contain antibodies that can serve as biomarkers or be exploited for therapy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1705-y) contains supplementary material, which is available to authorized users.

show abstract

An Ultra-specific Avian Antibody to Phosphorylated Tau Protein Reveals a Unique Mechanism for Phosphoepitope Recognition

Cited by 55 publications

References 69 publications

Reconciling the Structural Attributes of Avian Antibodies

Reconciling the Structural Attributes of Avian Antibodies

Polyspecificity of Anti-lipid A Antibodies and Its Relevance to the Development of Autoimmunity

Immunological memory to hyperphosphorylated tau in asymptomatic individuals

Contact Info

Product

Resources

About