Biology subjects

Roskin, K. M.

Publications and source records attributed to Roskin, K. M..

6 recordsLinked to original sources

bioRxiv2025

Co-Stimulatory Blockade Prevents Intragraft Accrual of Class-Switched, Activated B Cells Despite Failing to Prevent T-Cell Mediated Rejection

Previously, we defined the transcriptomes and clonality of intragraft CD8+ T cell during renal allograft rejection. Here, using single cell RNA sequencing (scRNAseq), we investigated non-CD8+ immune cells during T-cell-mediated rejection (TCMR) under different maintenance immunosuppression (mIS) regimens: tacrolimus, and co-stimulatory blockade (CoB) with belatacept (CTLA4-Ig) or iscalimab (anti-CD40). Myeloid cells comprised of DCs, monocytes and macrophages whose proportion and gene expression were similar between mIS regimens. Given their transcriptiomic similarities, we analyzed publicly-available scRNAseq/CITEseq datasets as well as immunofluorescence staining to resolve independent subpopulations of {gamma}/{delta} T cells and NK cells. Intragraft B cells consisted of clusters of naive, plasmablast, and class-switched B (BCS) cells, with the latter being diminished in CoB mIS. Intragraft CD4+ T cells consisted of FoxP3+ regulatory (Treg), exhausted, Th17, and CXCL13+ peripheral helper (Tph) cells whose proportions differed based in mIS, and the latter two had increased clonal expansion. Notably, cell-cell communication analysis indicated Th17 and Tph cell interactions with BCS cells in tacrolimus, but not CoB, samples. Thus, although failing to prevent TCMR, CoB mIS modulates the accrual of CD4+ T cells and inhibits the intragraft accrual of BCS cells, possibly reflective of clinical observations of less chronic antibody-mediated rejection under CoB mIS.

immunology↗

bioRxiv2024

Use of Antibody Structural Information in Disease Prediction Models Reveals Antigen Specific B Cell Receptor Sequences in Bulk Repertoire Data

Convergent antibodies are highly similar antibodies elicited in multiple individuals in response to the same antigen. Convergent antibodies provide insight into shared immunological responses and show great promise as diagnostic biomarkers. They have typically been identified using methods that consider the amino acid sequence of the third complementarity-determining region (CDR3) of immunoglobulin heavy chain (IgH). In this study, we extend the definition of convergent antibodies to use structural information about the three IgH CDR regions (CDR1-3). We benchmark the performance of both definitions of convergence by their ability to predict disease status from bulk IgH sequencing data for two different diseases (HIV infection and food sensitization). We show that using predicted structural information outperforms prior approaches for the prediction of food sensitization status and performs on par for HIV infection status. Additionally, the structurally convergent antibody groups driving HIV prediction are from known HIV binders. Thus, the use of structural information allows for the identification of antigen specific antibody groups from bulk IgH sequencing data.

immunology↗

bioRxiv2024

Defining the T cell transcriptional landscape in pediatric liver transplant rejection at single cell resolution

Acute cellular rejection (ACR) affects >80% of pediatric liver transplant recipients within 5 years, and late ACR is associated with graft failure. Traditional anti-rejection therapy for late ACR is ineffective and has remained unchanged for six decades. Although CD8+ T cells promote late ACR, little has been done to define their specificity and gene expression. Here, we used single-cell sequencing and immune repertoire profiling (10X Genomics) on 30 cryopreserved 16G liver biopsies from 14 patients (5 pre-transplant or with no ACR, 9 with ACR). We identified expanded intragraft CD8+ T cell clonotypes (CD8EXP) and their gene expression profiles in response to anti-rejection treatment. Notably, we found that expanded CD8+ clonotypes (CD8EXP) bore markers of effector and CD56hiCD161- NK-like T cells, retaining their clonotype identity and phenotype in subsequent biopsies from the same patients despite histologic ACR resolution. CD8EXP clonotypes localized to portal infiltrates during active ACR, and persisted in the lobule after histologic ACR resolution. CellPhoneDB analysis revealed differential crosstalk between KC and CD8EXP during late ACR, with activation of the LTB-LTBR pathway and downregulation of TGF{beta} signaling. Therefore, persistently-detected intragraft CD8EXP clones remain active despite ACR treatment and may contribute to long-term allograft fibrosis and failure of operational tolerance. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/582173v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@50a954org.highwire.dtl.DTLVardef@19ccc02org.highwire.dtl.DTLVardef@115be16org.highwire.dtl.DTLVardef@72a858_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

B cell repertoire in children with skin barrier dysfunction supports altered IgE maturation associated with allergic food sensitization

IgE B cells produce antibodies responsible for the inappropriate specificity seen in allergic disease. In this study, we sequence antibody gene repertoires from a large, well-characterized early life cohort at risk for developing food allergy. We found that food allergen sensitization was associated with lower IgE mutation frequencies that was abrogated in children living with a pet dog, suggesting potential molecular mechanisms underlying the hygiene hypothesis (i.e., protective effects of pet ownership and non-antiseptic environs reported for allergic disease). We also observed increased IgE diversity and increased isotype-switching to IgE, suggesting that B cell development is altered in those with food allergen sensitizations relative to those without. IgE diversity was even more extreme in subjects who were highly likely to be peanut allergic. Unlike food antigen sensitization, we detected no effect of aeroallergen sensitization on IgE mutation levels and diversity. Consistent patterns of antibody rearrangement were associated with food allergen sensitization. These results have important implications for the allergic response driven by mast cells and basophils and the underlying drivers of the atopic march.

immunology↗

bioRxiv2022

Disease diagnostics using machine learning of immune receptors

Clinical diagnosis typically incorporates physical examination, patient history, and various laboratory tests and imaging studies, but makes limited use of the human systems own record of antigen exposures encoded by receptors on B cells and T cells. We analyzed immune receptor datasets from 593 individuals to develop MAchine Learning for Immunological Diagnosis (Mal-ID), an interpretive framework to screen for multiple illnesses simultaneously or precisely test for one condition. This approach detects specific infections, autoimmune disorders, vaccine responses, and disease severity differences. Human-interpretable features of the model recapitulate known immune responses to SARS-CoV-2, Influenza, and HIV, highlight antigen-specific receptors, and reveal distinct characteristics of Systemic Lupus Erythematosus and Type-1 Diabetes autoreactivity. This analysis framework has broad potential for scientific and clinical interpretation of human immune responses.

immunology↗

bioRxiv2020

Shared B cell memory to coronaviruses and other pathogens varies in human age groups and tissues

Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells encoding humoral immune memory. We evaluated convergent antigen-specific antibody genes of similar sequences shared between individuals in pediatric and adult blood, and deceased organ donor tissues. B cell memory varied for different pathogens. Polysaccharide antigen-specific clones were not exclusive to the spleen. Adults convergent clones often express mutated IgM or IgD in blood and are class-switched in lymphoid tissues; in contrast, children have abundant class-switched convergent clones in blood. Consistent with serological reports, pre-pandemic children had class-switched convergent clones to SARS-CoV-2, enriched in cross-reactive clones for seasonal coronaviruses, while adults showed few such clones in blood or lymphoid tissues. These results extend age-related and anatomical mapping of human humoral pathogen-specific immunity. One Sentence SummaryChildren have elevated frequencies of pathogen-specific class-switched memory B cells, including SARS-CoV-2-binding clones.

immunology↗