Antibody Repertoire in Health & Disease | NYU Langone Health

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B-cell Immunobiology Lab Research Antibody Repertoire in Health & Disease

Antibody Repertoire in Health & Disease

B lymphocytes produce antibodies that augment host defenses via their capability for recognizing infectious agents, toxins, and other virulence factors with great specificity and high affinity. The adaptive immune system is remarkable; a limited repertoire of germ-line precursor genes can be recombined to produce antibodies with virtually any binding specificity. Therefore, antibodies play central roles in the defense from external threats that include bacteria and viruses. In turn, microbial pathogens have developed virulence factors that subvert host defenses by targeting secreted antibodies and their membrane-associated forms (such as B-cell receptors, BCR).

In the B-cell Immunobiology Lab, we are investigating how putative microbial B-cell superantigens affect in vivo B-cell repertoires (see Silverman and Goodyear, Nature Reviews in Immunology, 2006). As shown below (see figure 1), we reported the first B-cell repertoire surveys using next generation sequencing that showed the capacity of limited exposure to prototypic B-cell superantigen induced global shifts in the in vivo B-cell repertoire that reflected binding interactions of a major subset of BCR with Protein L (Grönwall et al., 2012, Journal of Immunology) (see figure 1). For these analyses we worked with Sergei K. Pond and colleagues on a high throughput computational pipeline that will now be applied to human repertoires (see Frost et al., 2015, Philos Trans R Soc Lond B Biol Sci)(see figure 2).

Visualization of the Repertoires Defined by Next Generation Sequencing of 8 Igκ V-J Repertoire in C57BL/6 Mice With and Without Exposure to the Superantigen PpL
Figure 1: Visualization of the repertoires defined by next generation sequencing of 8 Igκ V-J repertoire in C57BL/6 mice with and without exposure to the superantigen PpL. Results are depicted for the frequency of clonotypes with a specific V-J pairing in four control mice (libraries 1-4) and four PpL exposed mice (libraries 5-8) either when evaluated for treatment groups or individually. Underlined Vκ subgroups were predicted to have PpL interactions with products of one or more associated members. ND, represents the small number of clonotypes that could not be assigned to a specific Vκ subgroup or Jκ gene. The results are based on analyses of a total of 84,771 unique clonotypes from the eight libraries.

In autoimmune diseases, such as systemic lupus erythematosus (SLE), high levels of circulating autoantibodies are a hallmark of the disease, and animal models have confirmed that disease and premature death occur only after the skewing of the B-cell repertoire toward autoreactivity. While the pathophysiology of SLE is complex, there is overwhelming evidence that pathogenic autoantibodies are largely responsible for the organ damage, particularly the renal disease that is the primary cause of disability and death. We are investigating antibody responses in the gut and in the periphery in both human and murine systems to better understand the initiators and drivers of this autoimmune disease.

Phylogenetic Trees of Clonally Related IGH Sequences, Reconstructed by Maximum Likelihood, and Rooted on the Center of the Tree
Phylogenetic trees of clonally related IGH sequences, reconstructed by maximum likelihood, and rooted on the center of the tree (see material and methods §2g(iii)). These illustrate the high level of genetic diversity in these datasets (13.4%, 11.7% and 12.0% for (a), (b) and (c), respectively), as well as the variable divergence from the root sequence, despite all sequences in a dataset being sampled at the same time.