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Maternal and Infant Immune Repertoire Sequencing Analysis Identifies Distinct Immunoglobulin and T Cell Receptor Development in Term and Preterm Infants

39 Pages Posted: 1 Mar 2021 Publication Status: Review Complete

See all articles by Brian L. Le

Brian L. Le

University of California, San Francisco (UCSF) - Institute for Computational Health Sciences

Renan Sper

Department of Surgery, UCSF

Sandra C. A. Nielsen

Department of Pathology, Stanford University

Silvia Pineda

University of California, San Francisco (UCSF)

Quoc-Hung Nguyen

Department of Surgery, UCSF

Scott D. Boyd

Stanford University - Sean N. Parker Center for Allergy and Asthma Research

Tippi C. Mackenzie

Department of Surgery, UCSF

Marina Sirota

University of California, San Francisco (UCSF) - Institute for Computational Health Sciences

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Abstract

Preterm labor (PTL) is the leading cause of neonatal morbidity and mortality worldwide. While many studies have focused on investigating the maternal immune responses that cause PTL, fetal immune cell activation has recently been raised as an important contributor to the pathogenesis of PTL. Here, we analyzed lymphocyte receptor repertoires in maternal and cord blood from 14 term and 10 preterm deliveries and  hypothesized that the high incidence of infection in patients with PTL may result in specific changes in the TCR and BCR repertoires. We analyzed T-cell receptor beta chain (TCR-β) and immunoglobulin heavy chain (IgH) diversity, CDR3 lengths, clonal sharing, and preferential usage of variable (V), diversity (D), and joining (J) gene segments. Additionally, we studied the rates of somatic hypermutation (SHM) in IgH.  Overall, the cord blood IgH repertoires had significantly (padj < 0.05) lower rates of SHM and both TCR-β and IgH repertoires had shorter CDR3s compared to maternal blood. When comparing term and PPROM cord blood samples, we found that CDR3 lengths correlated with gestational age, with the shorter CDR3s in preterm neonates suggesting a ‘less developed’ repertoire. Preterm cord blood displayed preferential usage of a number of V genes and J genes. Furthermore, the term maternal repertoires displayed significant preferential usage of TRBV7-8 compared to preterm maternal repertoires. In preterm pregnancies, we observed significantly higher prevalence of convergent clones between mother/baby pairs than in term pregnancies. Together, our results suggest the repertoire of preterm infants displays a combination of immature features yet preferential use of particular genes and convergence with maternal TCR-β clones compared to term infants. While the higher TCR-β diversity might reflect less clonal expansion, the higher clonal convergence between mothers and infants in PTL could represent mother and fetus both responding to a shared stimulus like an infection. These data provide a detailed analysis of the maternal-fetal immune repertoire in term and preterm patients, and contribute to a better understanding of neonate immune repertoire development and potential changes associated with preterm labor.

Suggested Citation

Le, Brian L. and Sper, Renan and Nielsen, Sandra C. A. and Pineda, Silvia and Nguyen, Quoc-Hung and Boyd, Scott D. and Mackenzie, Tippi C. and Sirota, Marina, Maternal and Infant Immune Repertoire Sequencing Analysis Identifies Distinct Immunoglobulin and T Cell Receptor Development in Term and Preterm Infants. Available at SSRN: https://ssrn.com/abstract=3793962 or http://dx.doi.org/10.2139/ssrn.3793962
This version of the paper has not been formally peer reviewed.

Brian L. Le (Contact Author)

University of California, San Francisco (UCSF) - Institute for Computational Health Sciences ( email )

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Renan Sper

Department of Surgery, UCSF ( email )

Third Avenue and Parnassus
San Francisco, CA CA 94143
United States

Sandra C. A. Nielsen

Department of Pathology, Stanford University ( email )

Stanford, CA 94305
United States

Silvia Pineda

University of California, San Francisco (UCSF) ( email )

Third Avenue and Parnassus
San Francisco, CA CA 94143
United States

Quoc-Hung Nguyen

Department of Surgery, UCSF ( email )

Third Avenue and Parnassus
San Francisco, CA CA 94143
United States

Scott D. Boyd

Stanford University - Sean N. Parker Center for Allergy and Asthma Research ( email )

Tippi C. Mackenzie

Department of Surgery, UCSF ( email )

Third Avenue and Parnassus
San Francisco, CA CA 94143
United States

Marina Sirota

University of California, San Francisco (UCSF) - Institute for Computational Health Sciences ( email )

Third Avenue and Parnassus
San Francisco, CA 94143
United States

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