Distinct transcriptional programs define human IgG4 + memory B cells

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Human immunoglobulin G4 (IgG4) shapes both protective and pathogenic immunity, influencing conditions ranging from allergy and autoimmunity to cancer. However, subclass-specific targeting of memory B cells remains challenging due to limited knowledge of their phenotypic and functional heterogeneity. Here, we show that IgG4 + memory B cells are overrepresented in a niche of FCER2 + BAFFR + memory B cells, can be classified in several subtypes, have a distinct transcription factor profile and are the only memory B cell subset to express sterile IGHE transcripts. While IgG4 + B cells display a unique transcriptional profile, only BAFFR, IL5Rb and the B cell receptor were upregulated on protein level on IgG4 + cells. IgG4 + B cells have normal repertoire diversity, but a distinct germline V-gene usage, suggesting IgG4 responses are driven by specific antigens. By labeling autoreactive B cells, we confirmed that MuSK myasthenia gravis (an archetypal IgG4-mediatedautoimmune disease) patients have a normal memory B cell profile and that autoreactive IgG4 + memory B cells are extremely rare. These results highlight the unique features of IgG4 + B cells, provide insight on potential subclass-specific therapeutic targets and point towards an antigen-driven IgG4 response within a largely non-autoreactive memory B cell pool.

Authors 11

1. Laurent M. Paardekooper Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

2. Jessica M van Bokkum Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

3. Yvonne E. Fillié‐Grijpma Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

4. Dana L.E. Vergoossen Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

5. Isabel Benner Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

6. Theresa Kissel Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands;

7. Susan L. Kloet Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

8. Martijn Rudolf Tannemaat Aachen Department of Neurology, Leiden University Medical Center (LUMC)

   Leiden University Medical Center

   Affiliation as printed

   Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands;

9. Jan J.G.M. Verschuuren Aachen Department of Neurology, Leiden University Medical Center (LUMC)

   Leiden University Medical Center

   Affiliation as printed

   Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands;

10. Silvère M. van der Maarel Aachen Department of Human Genetics

    Leiden University Medical Center

    Affiliation as printed

    Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

11. Maartje G. M. Huijbers corresponding Aachen Department of Human Genetics Department of Neurology, Leiden University Medical Center (LUMC)

    Leiden University Medical Center

    Affiliation as printed

    Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

    Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands;