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Front. Immunol. | doi: 10.3389/fimmu.2018.02679

Non-coding Class Switch Recombination-related transcription in human normal and pathological immune responses

  • 1Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública (INSP), Mexico
  • 2Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Mexico
  • 3Lieber Institute for Brain Development, United States
  • 4Center for Computational Biology, Johns Hopkins University, United States
  • 5Department of Mental Health. Bloomberg School of Public Health, Johns Hopkins, United States
  • 6Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins, United States
  • 7Unidad de Investigacion Medica en Inmunoquimica., Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico

Antibody class switch recombination (CSR) to IgG, IgA or IgE is a hallmark of adaptive immunity, allowing antibody function diversification beyond IgM. CSR involves a deletion of the IgM/IgD constant region genes placing a new acceptor Constant gene, downstream of the VDJH exon. CSR depends on non-coding (CSRnc) transcription of donor I and acceptor IH exons, located 5’ upstream of each CH coding gene. Although our knowledge of the role of CSRnc transcription has advanced greatly, its extension and importance in healthy and diseased humans is scarce. We analyzed CSRnc transcription in 70,603 publicly available RNA-seq samples, including GTEx, TCGA and the Sequence Read Archive using recount2, an online resource consisting of normalized RNA-seq gene and exon counts, as well as coverage BigWig files that can be programmatically accessed through R. CSRnc transcription was validated with a qRT-PCR assay for Imu, Igamma1 and Igamma3 in humans in response to vaccination. We mapped IH transcription for the human IGH locus, including the less understood IGHD gene. CSRnc transcription was restricted to B cells and is widely distributed in normal adult tissues, but predominant in blood, spleen, MALT-containing tissues, visceral adipose tissue and some so-called “immune privileged” tissues. However, significant Igamma4 expression was found even in non-lymphoid fetal tissues. CSRnc expression in cancer tissues mimicked the expression of their normal counterparts, with notable pattern changes in some common cancer subsets. CSRnc transcription in tumors appears to result from tumor infiltration by B cells, since CSRnc transcription was not detected in corresponding tumor-derived immortal cell lines. Additionally, significantly increased Idelta transcription in ileal mucosa in Crohn’s disease with ulceration was found. In conclusion, CSRnc transcription occurs in multiple anatomical locations beyond classical secondary lymphoid organs, representing a potentially useful marker of effector B cell responses in normal and pathological immune responses. The pattern of IH exon expression may reveal clues of the local immune response (i.e. cytokine milieu) in health and disease. This is a great example of how the public recount2 data can be used to further our understanding of transcription, including regions outside the known transcriptome.

Keywords: Class switch DNA recombination (CSR), B cell, non-coding RNAs, RNA-Seq, Tumor Microenvironment, antibody, Vaccination, Crohns disease.

Received: 16 Sep 2018; Accepted: 30 Oct 2018.

Edited by:

Amy L. Kenter, University of Illinois at Chicago, United States

Reviewed by:

Jayanta Chaudhuri, Memorial Sloan Kettering Cancer Center, United States
Alberto Martin, University of Toronto, Canada  

Copyright: © 2018 Martinez-Barnetche, Kuri-Magaña, Collado-Torres, Jaffe, Valdovinos-Torres, Ovilla-Muñoz, Téllez-Sosa and Bonifaz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Jesus Martinez-Barnetche, Instituto Nacional de Salud Pública (INSP), Centro de Investigación Sobre Enfermedades Infecciosas, Cuernavaca, Mexico,