A Tissue Atlas of Human B-Cell Receptor Populations Reveals Two Separate Immune Networks in the Gut and in the Blood

The function of the immune system cannot be reduced to the action of a single immune cell, rather it is the result of a cooperative interaction of multiple immune cells, each with its own context of interaction and environmental feedback and each with a repertoire of antibodies that have different binding capabilities. For instance, while immune receptors with some level of affinity to one`s self are often observed, only some individuals suffer from autoimmunity. A key element in the comparison of the behavior of immune cells and repertoires is the definition of individual clonotypes (sets of cells that are derived from a common progenitor cell with a common B-cell receptor, or BCR). Clonotypes comprise the basic building blocks of repertoires and their response.

In our study published in Nature Biotechnology we analyzed in depth the repertoires of 6 individual organ donors in 8 different tissues, from one of which we analyzed over 50 samples per tissue and identified ~50 million unique sequences and ~1,000,000 different clonotypes. Due to this extreme depth of sequencing and our exact assessment of sampling sufficiency and levels of overlap, we could determine that the human immune repertoire is divided into two nearly orthogonal clone networks. These networks–one in the gut and the other in the blood/lung/spleen–show different levels of mixing internally amongst themselves and do not mix between each other. These findings have great implications regarding how we monitor and treat diseases in the different organs and are a first step in the science of tissue specific immune manipulation.