Production of Autoreactive Heavy Chain-Only Antibodies in Systemic Lupus Erythematosus

Shu Xu,Yinshi Yue,Zhixin Zhang,Song Li,Hong Yang,Kaihong Su,Yangsheng Yu,Hongyan Liao,Yue Zhuo

doi:10.3389/fimmu.2020.00632

Abstract

Systemic lupus erythematosus (SLE) is characterized by the overproduction of high-affinity autoreactive antibodies. Here, we show that more than 65.8% of 222 recombinant antibodies derived from 8 SLE patients can be secreted as heavy chain-only antibodies (HCAbs) when expressed in HEK-293T cells. The secretion of HCAbs follows the conventional endoplasmic reticulum-Golgi apparatus pathway, despite triggering a weaker unfolded protein response (UPR). Many of the purified SLE HCAbs remain autoreactive and have an even higher affinity for dsDNA, Sm, nucleosome, and cardiolipin than HCAbs from healthy individuals. Extended analyses of the CDR3 region and the heavy chain variable (VH) region of HCAb F3 show that the VH region is responsible for IgH secretion, while the CDR3 region determines its reactivity. Such a high frequency of HCAb secretion cannot fully concur with our current understanding of antibody assembly and secretion. The presence of a large proportion of autoreactive HCAbs in SLE reveals a novel mechanism for the generation of autoreactive antibodies in lupus.

Highlights

Antibodies (Abs), known as immunoglobulins, are important effector molecules in humoral immunity
In the analyses of 222 immunoglobulin heavy chains (IgHs) genes derived from Systemic lupus erythematosus (SLE) and 99 IgH genes derived from healthy individuals, we found that many IgH genes derived from healthy individuals and SLE patients can be expressed and secreted independently of immunoglobulin light chains (IgLs) when transiently expressed in HEK-293T cells
heavy chain-only antibodies (HCAbs) are widely found in recombinant antibodies derived from healthy individuals and SLE patients

Summary

Introduction

Antibodies (Abs), known as immunoglobulins, are important effector molecules in humoral immunity. At the early differentiation stages of B cells, Abs are expressed as the membrane-bound forms and serve as the B cell antigen receptors. When the development of B cells reaches the terminal differentiation stage, namely, plasma cells, antibodies, are secreted in soluble forms. It is known that antibodies must form a tetramer containing two IgH and two IgL peptide chains to be successfully secreted [1]. A special category of antibodies, named heavy chain-only antibodies (HCAbs), are secreted as IgH dimers without IgL. An early description of HCAbs appeared in 1964, when γ heavy chain was detected in the serum of a patient with heavy chain disease (HCD), a malignant B cell disease of lymphoplasma cells characterized by the secretion of a large number of IgHs independent of IgLs [2]. A few IgMs presented as μ chain dimers devoid of kappa chains in some HCD patients [3]

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Conclusion