Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

Protein-based profiling of the human IgA1 clonal repertoire revealed shared clones of serum polymeric IgA1 and milk secretory IgA1

Cellular & Molecular Immunology volume 20, pages 305–307 (2023)Cite this article

Subjects

A Correction to this article was published on 25 January 2023

This article has been updated

Human adaptive immunity involves the production and secretion of antibodies by differentiated B cells (i.e., antibody-secreting cells, also called plasma cells) in response to antigens. These secreted antigen-specific antibodies are immunoglobulins that are present at substantial concentrations in blood, mucosal secretions, and breast milk. Structurally, human immunoglobulins consist of two identical heavy (H) chains and two identical light (L) chains that are connected by disulfide bridges to form a homodimer of heterodimers (i.e., [H + L]2). Each heterodimer consists of one H chain linked with one L chain, whereas the homodimer is formed by linking two H chains together. The genes for both the L and H chains are encoded by ligated gene segments that are genetically rearranged during V(D)J recombination, a process that endows each B cell with a unique receptor, giving rise to the enormous diversity of the B-cell antigen receptor repertoire. H chain genes are assembled from one functional variable (V), one diversity (D), and one joining (J) segment encoded within a single locus to produce a single open reading frame expressed with an H-chain constant (C) segment that determines the type (isotype) of antibody produced, i.e., IgM, IgD, IgE, IgG, or IgA. Within these antibody isotypes, IgG includes four subclasses, and IgA includes two. L chains are encoded by one of two genes, either kappa or lambda, and are similarly rearranged from genetic loci that include V, J, and C segments. In addition to the diversity generated by the combinatorial strategy of gene assembly and junctional diversity, which is the addition of nucleotides to the V(D)J during rearrangement, antigen receptors can be further altered by somatic hypermutation, a process that introduces point mutations during B-cell activation and maturation. The combination of these processes can theoretically generate a staggering number of antibodies with distinct amino acid sequences. Despite extensive studies, we still do not fully understand many aspects of antibody production, for example, the sites of resident B cells responsible for the secretion of antibodies in different biofluids, how B cells enter these sites, and to what extent antibodies within these biofluids share a common origin. In this study [1], the authors describe a proteome-based assessment of the IgA1 clonal repertoire in two biofluids, blood and breast milk. Specifically, top-down liquid chromatography‒mass spectrometry (LC‒MS) profiling of serum and milk IgA1 repertoires was used to determine the most dominant clones in the respective fluids and assess their stability over time. Using well-controlled experiments and specific standards, the authors found a relatively small number of dominant clones in serum and milk IgA1, with many clones shared between the two biofluids. This study demonstrates the power of top-down LC‒MS for profiling antibody repertoires and provides a protein complement to single-cell transcriptomic profiling approaches.

IgA antibodies neutralize pathogens, promote their clearance by various mechanisms, and mediate mucosal and systemic responses to food antigens and intestinal microbes. The two human IgA subclasses differ in their glycosylation: IgA2 has five N-glycans per H chain, while IgA1 has two. Moreover, IgA1 has clustered O-glycans in the hinge region of the H chains [5]. These distinct glycosylation patterns confer the different effector functions of IgA1 and IgA2 (for review, see [5]). For example, IgA2 can induce more robust proinflammatory responses in neutrophils and macrophages than IgA1. This difference is due to the extensive sialylation of IgA1 that imparts anti-inflammatory properties, somewhat analogous to the glycan-dependent effector functions of IgG [6, 7]. Notably, the serum concentration of IgA as well as IgA1 O-glycosylation are genetically codetermined, and elevated levels of some IgA1 O-glycoforms are associated with several diseases [8,9,10]. Serum IgA is predominantly monomeric and is thought to originate mainly from bone marrow-residing plasma cells. Approximately 10% of serum IgA is polymeric, assembled with the J chain, and is thought to be produced by plasma cells in mucosal tissues. Most polymeric IgA is thought to be transported through epithelial cells onto mucosal surfaces. This transcytosis is mediated by the attachment of polymeric IgA to the polymeric immunoglobulin receptor of the epithelial cells. Subsequently, the complex is internalized and transported through the vesicular compartment, during which the polymeric immunoglobulin receptor is cleaved [11]. The released 80-kDa part of the receptor, the secretory component, is attached through a disulfide bridge to polymeric IgA that is to be released at the mucosal surface as secretory IgA.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Change history

References

  1. Dingess KA, Hoek M, van Rijswijk DMH, Tamara S, den Boer MA, Veth T, et al. Identification of common and distinct origins of human serum and breastmilk IgA1 by mass spectrometry-based clonal profiling. Cell Mol Immunol. 2023;20:26–37.

    Article  CAS  PubMed  Google Scholar 

  2. Boehm MK, Woof JM, Kerr MA, Perkins SJ. The Fab and Fc fragments of IgA1 exhibit a different arrangement from that in IgG: a study by X-ray and neutron solution scattering and homology modelling. J Mol Biol. 1999;286:1421–47.

    Article  CAS  PubMed  Google Scholar 

  3. Kumar N, Arthur CP, Ciferri C, Matsumoto ML. Structure of the secretory immunoglobulin A core. Science. 2020;367:1008–14.

    Article  CAS  PubMed  Google Scholar 

  4. Person T, King RG, Rizk DV, Novak J, Green TJ, Reily C. Cytokines and production of aberrantly O-glycosylated IgA1, the main autoantigen in IgA nephropathy. J Interferon Cytokine Res. 2022;42:301–15.

    Article  CAS  PubMed  Google Scholar 

  5. Hansen AL, Reily C, Novak J, Renfrow MB. Immunoglobulin A glycosylation and its role in disease. Exp Suppl. 2021;112:433–77.

    CAS  PubMed  Google Scholar 

  6. Cobb BA. The history of IgG glycosylation and where we are now. Glycobiology. 2020;30:202–13.

    Article  CAS  PubMed  Google Scholar 

  7. Reily C, Stewart TJ, Renfrow MB, Novak J. Glycosylation in health and disease. Nat Rev Nephrol. 2019;15:346–66.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Gale DP, Molyneux K, Wimbury D, Higgins P, Levine AP, Caplin B, et al. Galactosylation of IgA1 is associated with common variation in C1GALT1. J Am Soc Nephrol. 2017;28:2158–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kiryluk K, Li Y, Moldoveanu Z, Suzuki H, Reily C, Hou P, et al. GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. PLoS Genet. 2017;13:e1006609.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Liu L, Khan A, Sanchez-Rodriguez E, Zanoni F, Li Y, Steers N, et al. Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits. Nat Commun. 2022;13:6859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brandtzaeg P, Baekkevold ES, Farstad IN, Jahnsen FL, Johansen FE, Nilsen EM, et al. Regional specialization in the mucosal immune system: what happens in the microcompartments? Immunol Today. 1999;20:141–51.

    Article  CAS  PubMed  Google Scholar 

  12. Wiggins KJ, Scharer CD. Roadmap to a plasma cell: epigenetic and transcriptional cues that guide B cell differentiation. Immunol Rev. 2021;300:54–64.

    Article  CAS  PubMed  Google Scholar 

  13. Higgins BW, Shuparski AG, Miller KB, Robinson AM, McHeyzer-Williams LJ, McHeyzer-Williams MG. Isotype-specific plasma cells express divergent transcriptional programs. Proc Natl Acad Sci USA 2022;119:e2121260119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Price MJ, Hicks SL, Bradley JE, Randall TD, Boss JM, Scharer CD. IgM, IgG, and IgA influenza-specific plasma cells express divergent transcriptomes. J Immunol. 2019;203:2121–9.

    Article  CAS  PubMed  Google Scholar 

  15. Broketa M, Bruhns P. Single-cell technologies for the study of antibody-secreting cells. Front Immunol. 2021;12:821729.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are supported in part by NIH grants AI149431, GM098539, DK078244, DK082753, DK106341, AI14273, and AI162236. We apologize that we are not able to cite all relevant papers due to the maximal limit of references.

Author information

Authors and Affiliations

  1. Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA

    Jan Novak, R. Glenn King, Colin Reily & Todd J. Green

  2. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA

    Matthew B. Renfrow

  3. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Colin Reily

Authors
  1. Jan Novak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew B. Renfrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Glenn King
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Colin Reily
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Todd J. Green
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the completion of the manuscript and approved the submitted version. TJG generated molecular models for Fig. 1.

Corresponding author

Correspondence to Jan Novak.

Ethics declarations

Competing interests

JN and MBR are cofounders and co-owners of and consultants for Reliant Glycosciences, LLC. JN and MBR are coinventors on US patent application 14/318,082 (assigned to UAB Research Foundation).

Additional information

The original online version of this article was revised: In the sentence beginning “H chain genes are assembled from one functional variable (B), one diversity (D), and...” in this article, the text should have read “H chain genes are assembled from one functional variable (V), one diversity (D), and...”. The original article has been corrected.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Novak, J., Renfrow, M.B., King, R.G. et al. Protein-based profiling of the human IgA1 clonal repertoire revealed shared clones of serum polymeric IgA1 and milk secretory IgA1. Cell Mol Immunol 20, 305–307 (2023). https://doi.org/10.1038/s41423-022-00965-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-022-00965-z

Search

Advanced search

Quick links