Identification of common and distinct origins of human serum and breastmilk IgA1 by mass spectrometry-based clonal profiling

Kelly A Dingess; Max Hoek; Danique M H van Rijswijk; Sem Tamara; Maurits A den Boer; Tim Veth; Mirjam J A Damen; Arjan Barendregt; Michelle Romijn; Hannah G Juncker; Britt J van Keulen; Gestur Vidarsson; Johannes B van Goudoever; Albert Bondt; Albert J R Heck

doi:10.1038/s41423-022-00954-2

Identification of common and distinct origins of human serum and breastmilk IgA1 by mass spectrometry-based clonal profiling

Kelly A Dingess, Max Hoek, Danique M H van Rijswijk, Sem Tamara, Maurits A den Boer, Tim Veth, Mirjam J A Damen, Arjan Barendregt, Michelle Romijn, Hannah G Juncker, Britt J van Keulen, Gestur Vidarsson, Johannes B van Goudoever, Albert Bondt, Albert J R Heck

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The most abundant immunoglobulin present in the human body is IgA. It has the highest concentrations at the mucosal lining and in biofluids such as milk and is the second most abundant class of antibodies in serum. We assessed the structural diversity and clonal repertoire of IgA1-containing molecular assemblies longitudinally in human serum and milk from three donors using a mass spectrometry-based approach. IgA-containing molecules purified from serum or milk were assessed by the release and subsequent analysis of their Fab fragments. Our data revealed that serum IgA1 consists of two distinct structural populations, namely monomeric IgA1 (∼80%) and dimeric joining (J-) chain coupled IgA1 (∼20%). Also, we confirmed that IgA1 in milk is present solely as secretory (S)IgA, consisting of two (∼50%), three (∼33%) or four (∼17%) IgA1 molecules assembled with a J-chain and secretory component (SC). Interestingly, the serum and milk IgA1-Fab repertoires were distinct between monomeric, and J-chain coupled dimeric IgA1. The serum dimeric J-chain coupled IgA1 repertoire contained several abundant clones also observed in the milk IgA1 repertoire. The latter repertoire had little to no overlap with the serum monomeric IgA1 repertoire. This suggests that human IgA1s have (at least) two distinct origins; one of these produces dimeric J-chain coupled IgA1 molecules, shared in human serum and milk, and another produces monomeric IgA1 ending up exclusively in serum.

Original language	English
Pages (from-to)	26-37
Number of pages	12
Journal	Cellular and Molecular Immunology
Volume	20
Issue number	1
Early online date	29 Nov 2022
DOIs	https://doi.org/10.1038/s41423-022-00954-2
Publication status	Published - Jan 2023

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

Funding

We acknowledge support from the Netherlands Organization for Scientific Research (NOW) funding the Netherlands Proteomics Centre through the X-omics Road Map program (project 184.034.019) and Gravitation Subgrant 00022 from the Institute for Chemical Immunology. AJRH acknowledges support from the Netherlands Organization for Scientific Research (NOW) through the Spinoza Award SPI.2017.028 to AJRH. The COVID MILK studies was funded by Stichting Steun Emma Kinderziekenhuis. KAD acknowledges the Amsterdam Reproduction and Development Institute for funding this work though the AR&D grant (V.000296).

Funders	Funder number
Amsterdam Reproduction and Development Institute	000296
Netherlands Proteomics Centre	184.034.019, 00022
Stichting Steun Emma Kinderziekenhuis
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Keywords

Antigen binding fragment
Clonal repertoires
Immunoglobulin A1
Serum
human milk

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Dingess, K. A., Hoek, M., van Rijswijk, D. M. H., Tamara, S., den Boer, M. A., Veth, T., Damen, M. J. A., Barendregt, A., Romijn, M., Juncker, H. G., van Keulen, B. J., Vidarsson, G., van Goudoever, J. B., Bondt, A., & Heck, A. J. R. (2023). Identification of common and distinct origins of human serum and breastmilk IgA1 by mass spectrometry-based clonal profiling. Cellular and Molecular Immunology, 20(1), 26-37. https://doi.org/10.1038/s41423-022-00954-2

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abstract = "The most abundant immunoglobulin present in the human body is IgA. It has the highest concentrations at the mucosal lining and in biofluids such as milk and is the second most abundant class of antibodies in serum. We assessed the structural diversity and clonal repertoire of IgA1-containing molecular assemblies longitudinally in human serum and milk from three donors using a mass spectrometry-based approach. IgA-containing molecules purified from serum or milk were assessed by the release and subsequent analysis of their Fab fragments. Our data revealed that serum IgA1 consists of two distinct structural populations, namely monomeric IgA1 (∼80\%) and dimeric joining (J-) chain coupled IgA1 (∼20\%). Also, we confirmed that IgA1 in milk is present solely as secretory (S)IgA, consisting of two (∼50\%), three (∼33\%) or four (∼17\%) IgA1 molecules assembled with a J-chain and secretory component (SC). Interestingly, the serum and milk IgA1-Fab repertoires were distinct between monomeric, and J-chain coupled dimeric IgA1. The serum dimeric J-chain coupled IgA1 repertoire contained several abundant clones also observed in the milk IgA1 repertoire. The latter repertoire had little to no overlap with the serum monomeric IgA1 repertoire. This suggests that human IgA1s have (at least) two distinct origins; one of these produces dimeric J-chain coupled IgA1 molecules, shared in human serum and milk, and another produces monomeric IgA1 ending up exclusively in serum.",

keywords = "Antigen binding fragment, Clonal repertoires, Immunoglobulin A1, Serum, human milk",

author = "Dingess, \{Kelly A\} and Max Hoek and \{van Rijswijk\}, \{Danique M H\} and Sem Tamara and \{den Boer\}, \{Maurits A\} and Tim Veth and Damen, \{Mirjam J A\} and Arjan Barendregt and Michelle Romijn and Juncker, \{Hannah G\} and \{van Keulen\}, \{Britt J\} and Gestur Vidarsson and \{van Goudoever\}, \{Johannes B\} and Albert Bondt and Heck, \{Albert J R\}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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month = jan,

doi = "10.1038/s41423-022-00954-2",

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Dingess, KA, Hoek, M, van Rijswijk, DMH, Tamara, S , den Boer, MA, Veth, T, Damen, MJA , Barendregt, A, Romijn, M, Juncker, HG, van Keulen, BJ, Vidarsson, G, van Goudoever, JB, Bondt, A & Heck, AJR 2023, 'Identification of common and distinct origins of human serum and breastmilk IgA1 by mass spectrometry-based clonal profiling', Cellular and Molecular Immunology, vol. 20, no. 1, pp. 26-37. https://doi.org/10.1038/s41423-022-00954-2

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T1 - Identification of common and distinct origins of human serum and breastmilk IgA1 by mass spectrometry-based clonal profiling

AU - Dingess, Kelly A

AU - Hoek, Max

AU - van Rijswijk, Danique M H

AU - Tamara, Sem

AU - den Boer, Maurits A

AU - Veth, Tim

AU - Damen, Mirjam J A

AU - Barendregt, Arjan

AU - Romijn, Michelle

AU - Juncker, Hannah G

AU - van Keulen, Britt J

AU - Vidarsson, Gestur

AU - van Goudoever, Johannes B

AU - Bondt, Albert

AU - Heck, Albert J R

PY - 2023/1

Y1 - 2023/1

N2 - The most abundant immunoglobulin present in the human body is IgA. It has the highest concentrations at the mucosal lining and in biofluids such as milk and is the second most abundant class of antibodies in serum. We assessed the structural diversity and clonal repertoire of IgA1-containing molecular assemblies longitudinally in human serum and milk from three donors using a mass spectrometry-based approach. IgA-containing molecules purified from serum or milk were assessed by the release and subsequent analysis of their Fab fragments. Our data revealed that serum IgA1 consists of two distinct structural populations, namely monomeric IgA1 (∼80%) and dimeric joining (J-) chain coupled IgA1 (∼20%). Also, we confirmed that IgA1 in milk is present solely as secretory (S)IgA, consisting of two (∼50%), three (∼33%) or four (∼17%) IgA1 molecules assembled with a J-chain and secretory component (SC). Interestingly, the serum and milk IgA1-Fab repertoires were distinct between monomeric, and J-chain coupled dimeric IgA1. The serum dimeric J-chain coupled IgA1 repertoire contained several abundant clones also observed in the milk IgA1 repertoire. The latter repertoire had little to no overlap with the serum monomeric IgA1 repertoire. This suggests that human IgA1s have (at least) two distinct origins; one of these produces dimeric J-chain coupled IgA1 molecules, shared in human serum and milk, and another produces monomeric IgA1 ending up exclusively in serum.

AB - The most abundant immunoglobulin present in the human body is IgA. It has the highest concentrations at the mucosal lining and in biofluids such as milk and is the second most abundant class of antibodies in serum. We assessed the structural diversity and clonal repertoire of IgA1-containing molecular assemblies longitudinally in human serum and milk from three donors using a mass spectrometry-based approach. IgA-containing molecules purified from serum or milk were assessed by the release and subsequent analysis of their Fab fragments. Our data revealed that serum IgA1 consists of two distinct structural populations, namely monomeric IgA1 (∼80%) and dimeric joining (J-) chain coupled IgA1 (∼20%). Also, we confirmed that IgA1 in milk is present solely as secretory (S)IgA, consisting of two (∼50%), three (∼33%) or four (∼17%) IgA1 molecules assembled with a J-chain and secretory component (SC). Interestingly, the serum and milk IgA1-Fab repertoires were distinct between monomeric, and J-chain coupled dimeric IgA1. The serum dimeric J-chain coupled IgA1 repertoire contained several abundant clones also observed in the milk IgA1 repertoire. The latter repertoire had little to no overlap with the serum monomeric IgA1 repertoire. This suggests that human IgA1s have (at least) two distinct origins; one of these produces dimeric J-chain coupled IgA1 molecules, shared in human serum and milk, and another produces monomeric IgA1 ending up exclusively in serum.

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KW - Clonal repertoires

KW - Immunoglobulin A1

KW - Serum

KW - human milk

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DO - 10.1038/s41423-022-00954-2

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JO - Cellular and Molecular Immunology

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ER -

Identification of common and distinct origins of human serum and breastmilk IgA1 by mass spectrometry-based clonal profiling

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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