Significant Differences in Physicochemical Properties of Human Immunoglobulin Kappa and Lambda CDR3 Regions.

Catherine L. Townsend,David Kipling,Franca Fraternali,Joselli Silva O’Hare,Julie M. J. Laffy,Victoria Martin,Deborah K. Dunn-Walters,Yu-Chang Bryan Wu

doi:10.3389/fimmu.2016.00388

Catherine L. Townsend, David Kipling + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2016.00388

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Abstract

Antibody variable regions are composed of a heavy and a light chain, and in humans, there are two light chain isotypes: kappa and lambda. Despite their importance in receptor editing, the light chain is often overlooked in the antibody literature, with the focus being on the heavy chain complementarity-determining region (CDR)-H3 region. In this paper, we set out to investigate the physicochemical and structural differences between human kappa and lambda light chain CDR regions. We constructed a dataset containing over 29,000 light chain variable region sequences from IgM-transcribing, newly formed B cells isolated from human bone marrow and peripheral blood. We also used a published human naïve dataset to investigate the CDR-H3 properties of heavy chains paired with kappa and lambda light chains and probed the Protein Data Bank to investigate the structural differences between kappa and lambda antibody CDR regions. We found that kappa and lambda light chains have very different CDR physicochemical and structural properties, whereas the heavy chains with which they are paired do not differ significantly. We also observed that the mean CDR3 N nucleotide addition in the kappa, lambda, and heavy chain gene rearrangements are correlated within donors but can differ between donors. This indicates that terminal deoxynucleotidyl transferase may work with differing efficiencies between different people but the same efficiency in the different classes of immunoglobulin chain within one person. We have observed large differences in the physicochemical and structural properties of kappa and lambda light chain CDR regions. This may reflect different roles in the humoral immune response.

Highlights

Immunoglobulins are a crucial component of the humoral immune system
We have shown that kappa and lambda complementarity-determining region (CDR)-L3 regions differ significantly in their physicochemical properties, indicating that kappa and lambda light chains may have differing roles in antibody binding
In accordance with previous publications, we found that lambda CDR-L3 regions are, on average, significantly longer and more hydrophobic than kappa [20], and, in addition, we found that lambda CDR-L3 regions have a higher aliphatic index than kappa CDR-L3 regions

Summary

Introduction

Immunoglobulins are a crucial component of the humoral immune system They are Y-shaped heterodimeric proteins expressed by B cells that are composed of two identical heavy chains and two identical light chains. They can be cell-surface bound as B cell receptors (BCRs) or released into the extracellular environment as antibodies. Variability in the antigen-binding sites is achieved by V(D)J recombination, combinatorial diversity via heavy and light chain pairing, and the post-activation processes of somatic hypermutation and class switching. There are five heavy chain isotypes (IgM, IgD, IgG, IgE, and IgA), which confer different antibody functions, and two light chain isotypes (kappa and lambda). The contribution of light chains to the antigen-binding sites must not be overlooked

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