The landscape and diagnostic potential of T and B cell repertoire in Immunoglobulin A Nephropathy

Liu, X.; Huang, C.; Li, X.; Wu, J.; Zhang, W.; Sun, S.; Lin, L.; Wang, X.; Li, H.; Wu, X.; Zhang, P.; Xu, G.; Wan, H.; Liu, H.; Liu, Y.; Chen, D.; Zhuo, L.; Yang, H.; Wang, J.; Wang, L.

doi:10.1101/316216

bioRxiv · 10.1101/316216

The landscape and diagnostic potential of T and B cell repertoire in Immunoglobulin A Nephropathy

Liu, X.·Huang, C.·Li, X.·Wu, J.·Zhang, W.·Sun, S.·Lin, L.·Wang, X.·Li, H.·Wu, X.·Zhang, P.·Xu, G.·Wan, H.·Liu, H.·Liu, Y.·Chen, D.·Zhuo, L.·Yang, H.·Wang, J.·Wang, L.

View original source ↗Export metadata ↓

Abstract

Immunoglobulin A Nephropathy (IgAN) is the most common glomerulonephritis worldwide. In IgAN, immune complex deposite in glomerular mesangium, which induce inflammation and affect the kidneys normal functions. However, the exact pathogenesis of IgAN is still incompletely understood. Further, in current practice the clinical diagnosis relies on needle biopsy on renal tissue. Therefore, a non-invasive method for clinical diagnosis and prognosis surveillance of the disease is in high demand. In this paper, we investigated both the T cell receptor bata chain (TCRB) and immunoglobulin heavy chain (IGH) repertoire of kidney infiltrating and circulating lymphocytes of IgAN patients by immune repertoire high throughput sequencing. We found that the features of TCRB and IGH in the renal tissues were remarkably different from that in blood, including a decreased repertoire diversity and increased IgA and IgG frequency, and more activated B cells. The CDR3 length of PBMC TCRB and IGH in patients is significantly shorter than that in healthy controls, which is the result of both VDJ rearrangement and clone selection. We also found that the IgA1 frequency in the PBMC of IgAN is significant higher than that in other Nephropathy (NIgAN) and healthy control, which is consistent with the previous reports on the level of IgA1 producing B cells and serum IgA1. Significantly, we identified a set of IgAN disease related TCRB and IGH CDR3s, which can be used to distinguish IgAN from NIgAN and healthy controls from the blood with high accuracy. These results indicated that TCRB and IGH repertoire can potentially serve as non-invasive biomarkers for IgAN diagnosis. The characteristics of kidney infiltrating and circulating lymphocytes repertoire shed light on IgAN detection, treatment and surveillance.

Source connections

Published article ↗

Explore related subjects

immunology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Liu, X., Huang, C., Li, X., Wu, J., Zhang, W., Sun, S., Lin, L., Wang, X., Li, H., Wu, X., Zhang, P., Xu, G., Wan, H., Liu, H., Liu, Y., Chen, D., Zhuo, L., Yang, H., Wang, J., Wang, L.. 2018-05-09. The landscape and diagnostic potential of T and B cell repertoire in Immunoglobulin A Nephropathy. https://doi.org/10.1101/316216

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

CD19-CAR T-cell therapy resets the EBV+ autoreactive B cell repertoire in autoimmune disease

Epstein-Barr virus (EBV) reprograms autoreactive B cells into activated antigen-presenting cells that drive pathogenic T- and B-cell responses in autoimmune disease. Using EBV B-cell sequencing (EBV-seq), we profiled EBV+ B cells in patients treated with CD19 chimeric antigen receptor (CAR) T cells (systemic lupus, n=6; idiopathic inflammatory myopathies, n=3; systemic sclerosis, n=3) or rituximab (n=15). CAR T cells, but not rituximab, depleted EBV+ B cells, resetting the repertoire toward a naive state: predominantly IgM+ with minimal somatic hypermutation. Post-rituximab B-cells remained class-switched, hypermutated, and activated. Monoclonal antibodies cloned from EBV+ B cells lost autoreactivity after CAR T cells but not rituximab. Sustained drug-free remission occurred in 8/12 CAR-treated but 0/15 rituximab-treated patients. EBV+ B cells were predominantly Latency III and resisted anti-CD20 and anti-CD19 antibodies, yet were killed by CAR T cells and T-cell engagers. CD19-CAR T-cell therapy resets the autoreactive EBV+ B-cell repertoire, which may underlie sustained drug-free remission.

immunology↗

bioRxiv2026

A minimal two-residue C-terminal truncation of AID in adult-onset hyper-IgM syndrome type 2 (HIGM2)

Activation-induced cytidine deaminase (AID), encoded by AICDA, facilitates class-switch recombination (CSR) and somatic hypermutation (SHM) in activated B cells. Loss of AID function causes hyper-IgM syndrome type 2 (HIGM2). While typically autosomal recessive, three C-terminal truncation variants have been reported to act in autosomal dominant manner. We describe a novel heterozygous AICDA nonsense variant, c.589G>T (p.G197*), that truncates the final two C-terminal residues of AID and results in adult-onset HIGM2. Single-cell sequencing of primary patient B cells revealed a complete block in CSR and a [~]10-fold reduction in SHM. AICDA mRNA expression was balanced between wild-type and variant alleles, yet AID protein abundance was reduced to [~]56% with normal subcellular localization. Remarkably, inducible germinal center (iGB) cultures restored CSR in purified naive patient B cells. CRISPR-Cas9 editing of healthy donor B cells confirmed that the iGB platform can rescue B cells harboring heterozygous, but not homozygous, AICDA variants. These results demonstrate that even a two-amino-acid truncation at the AID C-terminus is sufficient to disrupt its function and cause HIGM2.

immunology↗

bioRxiv2026

Defining the Functional Consequence of the Human Ocular Microbiome

The ocular surface is one of the body's most environmentally exposed mucosal barriers, yet it is considered low biomass and harbors orders of magnitude fewer bacteria than microbe-rich sites like the gut. This has cast doubt on whether a functional core ocular microbiome exists at all. Having previously defined a protective gd T cell and IL-17 axis engaged by the murine commensal Corynebacterium mastitidis, we asked whether human-derived bacteria could do the same. Pairing sequencing and culturomics of healthy human conjunctiva from two geographically distinct cohorts, we define a stable core microbiome and identify Corynebacterium bovis as a consistent eye-resident commensal rather than a transient contaminant. In humans, C. bovis elicits a non-pathogenic response marked by IL-17 secretion by {gamma}{delta} T cells and circulating C. bovis-specific IgG, which suggests commensalism rather than pathology. Colonizing mice with human C. bovis strains from Pittsburgh or Miami reproduced this program and conferred protection against ocular infection with Staphylococcus aureus. Together, these findings identify C. bovis as a human-derived ocular commensal that can drive protective {gamma}{delta} T cell immunity, translating a mechanism previously defined only in mice into human relevance and a rational target against sight-threatening infection.

immunology↗