Biology subjects

Vazquez, S. E.

Publications and source records attributed to Vazquez, S. E..

3 recordsLinked to original sources

bioRxiv2020

The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development

Memory B cells (MBCs) are essential for long-lived humoral immunity. However, the transcription factors (TFs) involved in MBC differentiation are poorly defined. Here, by single cell RNAseq analysis, we identified a population of germinal center (GC) B cells in the process of differentiating into MBCs. Using an inducible Crispr/Cas9 screening approach we identified the hematopoietically-expressed homeobox gene Hhex as a transcription factor regulating MBC differentiation. The co-repressor Tle3 was also identified in the screen and was found to interact with Hhex. Bcl6 directly repressed Hhex in GC B cells. Reciprocally, Hhex-deficient MBCs exhibited derepressed Bcl6 and reduced expression of Bcl6-repressed Bcl2. Overexpression of Bcl2 was able to rescue MBC differentiation in Hhex-deficient cells. We also identified Ski as an Hhex-induced transcription factor involved in MBC differentiation. These findings establish an important role for Hhex-Tle3 in regulating the transcriptional circuitry governing MBC differentiation.

immunology↗

bioRxiv2020

Identification of novel, clinically correlated autoantigens in the monogenic autoimmune syndrome APS1 by PhIP-Seq

The identification of autoantigens remains a critical challenge for understanding and treating autoimmune diseases. Autoimmune polyendocrine syndrome type 1 (APS1), a rare monogenic form of autoimmunity, presents as widespread autoimmunity with T and B cell responses to multiple organs. Importantly, autoantibody discovery in APS1 can illuminate fundamental disease pathogenesis, and many of the antigens found in APS1 extend to common autoimmune diseases. Here, we performed proteome-wide programmable phage-display (PhIP-Seq) on sera from an APS1 cohort and discovered multiple common antibody targets. These novel autoantigens exhibit tissue-restricted expression, including expression in enteroendocrine cells and dental enamel. Using detailed clinical phenotyping, we find novel associations between autoantibodies and organ-restricted autoimmunity, including between anti-KHDC3L autoantibodies and premature ovarian insufficiency, and between anti-RFX6 autoantibodies and diarrheal-type intestinal dysfunction. Our study highlights the utility of PhIP-Seq for interrogating antigenic repertoires in human autoimmunity and the importance of antigen discovery for improved understanding of disease mechanisms.

immunology↗

bioRxiv2018

Exploration of Anti-Yo and Anti-Hu paraneoplastic neurological disorders by PhIP-Seq reveals a highly restricted pattern of antibody epitopes

Paraneoplastic neurological disorders (PNDs) are immune-mediated diseases of the nervous system understood to manifest as part of a misdirected anti-tumor immune response. Identifying PND-associated autoantibodies and their cognate antigens can assist with proper diagnosis and treatment while also enhancing our understanding of tumor-associated immune processes, triggers for autoimmune disease, and the functional significance of onconeuronal proteins. Here, we employed an enhanced version of phage display immunoprecipitation and sequencing (PhIP-Seq) leveraging a library of over 731,000 unique phage clones tiling across the entire human proteome to detect autoantibodies and create high-resolution epitope profiles in serum and CSF samples from patients suffering from two common PNDs, the anti-Yo (n = 36 patients) and anti-Hu syndromes (n = 44 patients). All patient samples positive for anti-Yo antibody by a validated clinical assay yielded polyspecific enrichment of phage presenting peptides from the canonical anti-Yo (CDR2 and CDR2L) antigens, while 38% of anti-Hu patients (17/44) had a serum and/or CSF sample that significantly enriched peptides deriving from the ELAVL family of proteins, the anti-Hu autoantigenic target. The anti-Hu antibodies showed a remarkably convergent antigenic signature across 15/17 patients corresponding to residues surrounding and including the degenerate motif, RLDxLL, shared by ELAVL2, 3 and 4. Lastly, PhIP-Seq identified several known and novel autoantigens in these same patient samples, representing potential biomarkers that could aid in the diagnosis and prognosis of PND and cancer.

immunology↗