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Front Immunol. 2018 Nov 21;9:2679. doi: 10.3389/fimmu.2018.02679. eCollection 2018.

Non-coding Class Switch Recombination-Related Transcription in Human Normal and Pathological Immune Responses.

Author information

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

Abstract

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 Iμ 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 Iμ, Iγ3, and Iγ1 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 Iγ4 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 Iδ 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:

B cell; Class Switch Recombination; Crohn's disease; RNA-seq; antibody; non-coding transcription; tumor microenvironment; vaccination

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