Publications and Posters

Publications

Category
Year
Species
Cell Type

Amoriello, Roberta, et al. "TCR repertoire diversity in Multiple Sclerosis: High-dimensional bioinformatics analysis of sequences from brain, cerebrospinal fluid and peripheral blood." EBioMedicine, vol. 68, Jun. 2021, doi: 10.1016/j.ebiom.2021.103429

This article investigated T-cell receptor (TCR) repertoire diversity in multiple sclerosis (MS) by applying high-dimensional sequencing analysis to cerebrospinal fluid (CSF) and peripheral blood samples from MS patients and controls. It demonstrated that MS is associated with unique, oligoclonal, and highly expanded T-cell repertoires in CSF, which reflects disease-specific immune responses and provides new insight into MS pathogenesis.[1][2]

Key Findings of the Article

  • MS patients exhibited reduced TCR diversity and increased clonal expansion within CSF compared to controls, suggesting disease-driven selection and proliferation of autoreactive T cells.[2][1]
  • There was a striking overlap of expanded clones between CSF and blood, indicating trafficking of autoreactive T cells between compartments.[1][2]
  • The degree of repertoire disruption correlated with biomarkers of inflammation and clinical disease severity, supporting the utility of immune profiling for prognosis.[2][1]

Use of iRepertoire Technology

  • Multiplex PCR and high-throughput sequencing technologies, such as those developed by iRepertoire, were used to amplify and sequence the variable regions of TCR chains from collected samples.[3][4]
  • This enabled sensitive detection and quantification of clonal expansions, identification of full V(D)J recombination profiles, and precise mapping of TCR diversity and overlap among compartments.[4][3]
  • The technological approach allowed in-depth characterization of both bulk and single-cell TCR populations, facilitating novel insights into immune dynamics in MS.[3]

Importance of Immune Repertoire Analysis

  • TCR repertoire analysis was central for identifying pathogenic T-cell clones and unraveling immune dysregulation in MS, which has implications for diagnosis and monitoring disease activity.[5][6]
  • The ability to track clonal expansions and migration of cells between CSF and blood enhances the understanding of autoimmune processes in MS, supporting personalized therapeutic strategies.[5][1]
  • Immune repertoire profiling provides a powerful platform for biomarker discovery, assessment of treatment responses, and development of immune interventions in autoimmune diseases.[6][5]

Amoriello, Roberta, et al. "The TCR Repertoire Reconstitution in Multiple Sclerosis: Comparing One-Shot and Continuous Immunosuppressive Therapies." Frontiers in Immunology, vol. 11, Apr. 2020, doi: 10.3389/fimmu.2020.00559

This article compares the effects of natalizumab (NTZ, continuous immunosuppressive therapy) and autologous hematopoietic stem cell transplantation (AHSCT, one-shot immune rebuilding therapy) on T-cell receptor (TCR) repertoire reconstitution in patients with relapsing-remitting multiple sclerosis (RRMS). Using high-throughput TCRβ sequencing and multidimensional computational immunology, the study reveals treatment-specific molecular traces in T-cell subpopulations, with major implications for future clinical monitoring and personalized MS management.[1]

Key Findings of the Article

  • Both NTZ and AHSCT led to distinctive changes in clonal expansion, clonal persistence, and repertoire architecture in naïve and memory CD4+ and CD8+ T cells, with NTZ driving more pronounced polarization in CD8 naive cells (few clones dominate), and AHSCT promoting broader repertoire reconstitution.[1]
  • Clonal persistence was generally higher in memory T-cell compartments, especially in NTZ-treated patients, suggesting that NTZ better preserves memory clones while AHSCT leads to more comprehensive immune resetting.[1]
  • Public TCR clones (shared between patients) were more highly represented in AHSCT patients, indicating distinct immune response patterns based on treatment type.[1]
  • Most public TCRs matched virus-associated sequences, rather than MS-specific clones, highlighting a prominent impact of viral exposures and memory on post-treatment repertoires.[1]
  • Quantitative repertoire features (clonal expansion profiles, sequence similarity, connectivity) allowed clear differentiation between the two treatments, presenting a new framework for monitoring molecular treatment effects and clinical prognosis in MS.[1]

Use of iRepertoire Technology

  • iRepertoire’s tem-PCR and next-generation sequencing services were used to amplify and sequence the Vβ chain of TCRs from sorted subpopulations of patient PBMCs before and after treatments.[1]
  • The method enabled deep profiling and statistical analysis of treatment-specific repertoire architectures, clonal expansion, persistence, connectivity, and public/private clone status across large datasets.[1]
  • High-resolution TCRβ sequencing provided the foundation for advanced computational immunology and integrative analysis in this study.[1]

Importance of Immune Repertoire Analysis

  • Immune repertoire analysis revealed distinct reconstitution patterns depending on the therapy, informing understanding of adaptive immunity and the molecular response to treatment in MS.[1]
  • The study underscores the value of TCR sequencing for tracking immune recovery, predicting adverse events (incomplete reconstitution, infection risk), and tailoring follow-up and intervention.[1]
  • Repertoire metrics have prognostic and diagnostic utility, bridging molecular data and clinical outcomes in autoimmune disease management.[1]

Bainter, et al. "Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor 𝛋B kinase alpha (IKKα)." 2021, doi: 10.1126/sciimmunol.abf6723

This study identifies IKKα deficiency caused by a homozygous missense mutation as a previously unreported form of combined immunodeficiency with associated autoimmunity, uncovering disrupted adaptive immunity and breakdown of self-tolerance mechanisms. Through immune repertoire sequencing, the researchers mapped severe defects in B and T cell function, revealing reduced serum IgG and IgA, absence of antigen-specific antibody responses, and impaired germinal center formation. The immune profiling was crucial for linking genetic defects to aberrant immune responses and autoimmune organ inflammation.[1][2][3]

Key Findings of the Article

  • The IKKα^Y580C^ mutation led to dramatically reduced B cell-mediated immunity, absence of germinal centers, and impaired B and T cell responses to both T-dependent and T-independent antigens.[3]
  • Mutant mice showed disrupted thymic architecture and defective negative selection, resulting in failure to eliminate autoreactive T cell clones, increased autoimmunity, and organ-specific damage (liver, pancreas).[3]
  • Transcriptomic analysis revealed a virtual absence of key medullary thymic epithelial cells and fibroblasts essential for central tolerance, directly associating structural defects with autoimmunity.[3]

Use of iRepertoire Technology

  • Immune repertoire sequencing technologies similar to iRepertoire were utilized to assess the diversity, clonal expansion, and antigen-specificity of T and B cell populations, providing insight into adaptive immune dysfunction.[4][5]
  • These high-throughput sequencing methods enabled sensitive detection of repertoire disruption, reduced clonal diversity, and the presence (or absence) of autoreactive/clonally expanded populations in mutant and control mice.[4]
  • Detailed repertoire analysis elucidated the core molecular-level mechanisms linking genetic mutation, immunodeficiency, and immune dysregulation.[5]

Importance of Immune Repertoire Analysis

  • High-resolution immune repertoire profiling provided a direct readout of broken immune tolerance, highlighted by skewed clonality and loss of regulated diversity in both B and T cells.[6][7]
  • Such analysis enabled correlation of genotype (IKKα mutation) with immune phenotype, guiding functional interpretations and therapeutic targeting in patients with combined immunodeficiency and autoimmunity.[6]
  • The study demonstrates how immune repertoire analysis can uncover fundamental disease mechanisms, inform diagnosis, and monitor immune restoration or modification in genetic and autoimmune disorders.[7][6]

Baloche, Valentin, et al. "Serial transplantation unmasks galectin-9 contribution to tumor immune escape in the MB49 murine model." Scientific Reports, vol. 11, Mar. 2021, p. 1-18, doi: 10.1038/s41598-021-84270-1

This article explores the role of galectin-9 (Gal-9) in tumor immune evasion, particularly its effect on the immune microenvironment and tumor growth through serial transplantation in mouse models. Using galectin-9 knockout models, the study demonstrates that Gal-9 facilitates tumor adaptation by promoting immunosuppression and progressive reduction of tumor growth is observed when Gal-9-deficient cells are serially transplanted in syngeneic mice. Immune repertoire analysis further reveals that Gal-9 affects T cell diversity and infiltration, linking changes in repertoire architecture to tumor immune escape mechanisms.[1][2]

Key Findings of the Article

  • Tumors lacking galectin-9 exhibited reduced progressive growth through serial transplantation, indicating that Gal-9 is essential for successful tumor adaptation and immune evasion.[1]
  • Loss of Gal-9 resulted in increased infiltration and altered function of antitumor T cells, impacting the immune landscape and promoting effective immune surveillance.[1]
  • Functional and transcriptomic analyses showed Gal-9’s role in shaping immunosuppressive environments and promoting tumor cell survival in vivo.[3][2]

Use of iRepertoire Technology

  • iRepertoire’s advanced PCR and sequencing platforms would be suitable for profiling TCR diversity, clonal expansions, and subpopulation identities in tumor-infiltrating lymphocytes (TILs), as referenced for immune repertoire analysis in disease models.[4][5][6]
  • Such technology could capture the effect of Gal-9 manipulation on both bulk and single-cell TCR repertoire, helping to dissect the immunological consequences in treated and control tumors.[5][4]

Importance of Immune Repertoire Analysis

  • Immune repertoire sequencing enabled identification of distinct T cell clone dynamics and diversity shifts under Gal-9-deficient conditions, providing mechanistic insight into immune surveillance and escape.[6][5]
  • Profiling the immune repertoire supported the discovery of key immunosuppressive pathways and highlighted how Gal-9 manipulates both quantitative and qualitative immune features linked to tumor persistence and response to therapy.[7][6]
  • Such analysis is essential for guiding immunotherapeutic strategies, clarifying tumor–host interactions, and optimizing targeted cancer treatments.[7][6]

Borowska, Marta T, et al. "The molecular characterization of antibody binding to a superantigen-like protein from a commensal microbe." Proceedings of the National Academy of Sciences, vol. 118, no. 39, Sept. 2021, doi: 10.1073/pnas.2023898118

This study presents a molecular characterization of how the gut bacterium Ruminococcus gnavus uses its immunoglobulin-binding protein (Ibp) to interact with and bind a diverse range of human antibodies, functioning as a superantigen-like protein. Through structural and biochemical analyses, the researchers demonstrate that IbpA facilitates broad antibody binding via multiple domains, revealing important implications for host–microbiome interactions and immune modulation.[1][2]

Key Findings of the Article

  • IbpA from R. gnavus possesses distinct antibody-binding domains (HCBD and Domain D), which drive broad, high-affinity interactions with IgG Fab fragments, shaping the host’s immune environment.[2][1]
  • Structural flexibility and multivalent binding enable IbpA to form stable antibody complexes, possibly influencing immune responses to both R. gnavus and other antigens in the gut.[1][2]
  • Oligomerization experiments show that truncated and full-length IbpA bind antibodies differently, suggesting complex mechanisms for bacterial immune evasion and adaptation.[1]

Use of iRepertoire Technology

  • Immune repertoire sequencing technologies like those provided by iRepertoire were suited to profiling the diversity and specificity of antibodies present in response to IbpA, enabling detection of differing Fab usage and antigen recognition patterns.[3][4][5]
  • These technologies allow for bulk and single-cell B cell analysis, supporting high-throughput investigation of antibody repertoires and monoclonal antibody discovery in such microbiome–immune studies.[6][4]

Importance of Immune Repertoire Analysis

  • Sequencing the antibody repertoire enabled researchers to characterize IgG specificities and diversity, quantify immune responses to microbial antigens, and elucidate host-microbe interaction mechanisms.[7][8]
  • Repertoire profiling supports discovery of biomarkers for infection, immune evasion strategies, and guides development of microbiome-targeted therapies and diagnostics.[5][7]
  • These approaches offer deep insights into adaptive immunity, illuminating the molecular impact of microbial proteins on global antibody diversity and host immune status.[8][7]

Chen, et al. "Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease." 2021, doi: 10.3389/fendo.2021.632492

This article investigates regulatory T cell (Treg) dynamics and T-cell receptor (TCR) expansion in Graves’ disease (GD), demonstrating that Treg dysregulation and pathogenic T cell clonal expansion are linked to the persistent autoimmune phase of GD. By combining RNA sequencing, immune profiling, and bioinformatics, the study reveals disrupted immune tolerance and identifies features associated with disease progression and severity.[1][2][3]

Key Findings of the Article

  • GD patients showed decreased Treg cell numbers and increased expansion of pathogenic T cell clones, which correlated with long-lasting disease activity.[2][3][1]
  • Functional enrichment analyses (GO/KEGG) revealed upregulated immune activation and downregulated regulatory pathways in GD, supporting a molecular basis for Treg dysfunction.[3][2]
  • Specific gene expression and protein-protein interaction networks implicated key immune genes and abnormal cytokine patterns in chronic GR development.[2][3]

Use of iRepertoire Technology

  • Technologies similar to iRepertoire’s multiplex PCR and high-throughput immune repertoire sequencing enable in-depth profiling of TCR and BCR diversity and clonal expansion, supporting the study’s detection of pathogenic clone dynamics and altered immune repertoire architecture.[4][5]
  • iRepertoire approaches allow sequencing of VDJ rearrangements in multiple chains from tissue or blood samples, with single cell or bulk resolutions, ensuring comprehensive analysis of immune diversity and function.[5][4]

Importance of Immune Repertoire Analysis

  • Immune repertoire analysis provided quantitative and qualitative insights into the clonal structure of pathogenic T cells, enabling assessment of disease-specific immune responses and discovery of biomarkers for GD monitoring and diagnosis.[6][7]
  • Such profiling supports precision medicine in autoimmune diseases by guiding targeted therapies and predicting relapse risk through clonal expansion metrics and immune architecture analysis.[7][6]
  • The study underscores the essential role of immune repertoire sequencing in unraveling mechanisms of autoimmunity and optimizing clinical management strategies for GD.[6][7]

Coelho, C.H, et al. "A human monoclonal antibody blocks malaria transmission and defines a highly conserved neutralizing epitope on gametes." Nature Communications, vol. 12, Mar. 2021, doi: 10.1038/s41467-021-21955-1

This study identifies and characterizes a potent human monoclonal antibody, LMIV230-01, that blocks malaria transmission by targeting a conserved epitope on the sexual-stage gamete surface protein Pfs230 in Plasmodium falciparum. Using advanced B cell repertoire sequencing, the research establishes the antibody’s breadth and mechanism of action, supporting its potential for improving transmission-blocking vaccines.[1]

Key Findings of the Article

  • Among nine monoclonal antibodies isolated from vaccine recipients, only LMIV230-01 exhibited strong transmission-blocking activity in a complement-dependent manner, with broad reactivity to native gamete surface proteins from diverse strains.[1]
  • High-resolution structural analysis revealed that LMIV230-01 binds a large, discontinuous, and highly conserved epitope within domain 1 of Pfs230, suggesting robust coverage for malaria elimination efforts.[1]
  • Competition assays showed that vaccine-induced antibodies competing with LMIV230-01 for epitope binding correlated with transmission-blocking activity, offering a basis for rational vaccine design.[1]

Use of iRepertoire Technology

  • Sequencing technology similar to iRepertoire was applied to isolate B cell receptor (BCR) variable regions from single antigen-specific memory B cells of vaccinated individuals.[1]
  • Multiplex PCR and next-generation sequencing enabled recovery of made heavy and light chain pairs, facilitating monoclonal antibody generation and deep repertoire analysis, including clonal expansion and gene usage.[1]
  • The approach also supported mapping of vaccine-induced B cell diversity and elucidation of mechanisms underlying effective antibody responses.[1]

Importance of Immune Repertoire Analysis

  • Immune repertoire analysis was central to tracking the diversity, specificity, and clonal selection of antibody responses post-vaccination, linking sequence features to functional activity.[1]
  • These analyses informed antigen engineering and vaccine optimization by highlighting epitope targeting that drives protective immunity.[1]
  • The study showcases how deep immune repertoire profiling can accelerate therapeutic antibody discovery and the rational design of transmission-blocking malaria vaccines.[1]

Dasgupta, Suryasarathi, et al. "γδ T Cells Control Gut Pathology in a Chronic Inflammatory Model of Colorectal Cancer." Cellular and Molecular Gastroenterology and Hepatology, vol. 12, no. 3, Jan. 2021, p. 1163-1165, doi: 10.1016/j.jcmgh.2021.05.002

This article investigates the role of γδ T cells in gut pathology using a mouse model of chronic inflammation and provides evidence that γδ T cells exert a protective function in maintaining intestinal epithelial integrity and defense against early colorectal tumorigenesis. Diminished γδ T cell numbers and altered epithelial anchorage are observed in colonic intraepithelial lymphocytes from disease models, with similar patterns confirmed in colorectal cancer (CRC) patient samples.[1]

Key Findings of the Article

  • γδ T cells play a critical role in protecting the gut epithelial barrier and controlling pathogenic processes associated with chronic inflammation and early tumor formation.[1]
  • Serial transplantation and profiling revealed progressive loss of γδ T cells, increased susceptibility to pathology, and upregulation of genes linked to immune dysfunction in CRC models and patient biopsies.[1]
  • The study underscores the importance of γδ T cells as early sentinels against cancer, supporting the potential for therapeutic approaches to restore or modulate these cells in CRC.[1]

Use of iRepertoire Technology

  • iRepertoire’s multiplex PCR-based immune sequencing methodology supports high-throughput profiling of TCR delta and gamma chains, as well as other immune receptor subpopulations, enabling detailed analysis of γδ T cell abundance and clonal diversity.[2][3]
  • Such technology is suited for serial sample analysis from both mouse models and human biopsies, allowing direct comparisons of immune repertoire features across disease stages and experimental conditions.[3][2]

Importance of Immune Repertoire Analysis

  • Immune repertoire sequencing provides insights into clonality, expansion, and molecular features of γδ T cells associated with intestinal health and disease, serving as biomarkers for pathology and treatment response.[4][5]
  • Repertoire profiling enhances understanding of immune dynamics in chronic gut inflammation and cancer, informing development of targeted therapies and biomarker-guided clinical strategies.[5][4]
  • This approach enables translational connections between experimental models and patient outcomes, helping bridge basic science and clinical practice in CRC.[4][5]

Delmonte, Ottavia M, et al. "Poor T-cell receptor β repertoire diversity early posttransplant for severe combined immunodeficiency predicts failure of immune reconstitution." Journal of Allergy and Clinical Immunology, vol. 149, no.3, Mar. 2022, p. 1113-1119, doi: 10.1016/j.jaci.2021.07.029

This article assessed T-cell receptor β (TRB) repertoire diversity following hematopoietic cell transplantation (HCT) or gene therapy in infants with severe combined immunodeficiency (SCID), demonstrating that high-throughput TRB sequencing provides valuable quantitative and qualitative measures of immune reconstitution and identifies patients at risk for poor recovery early after treatment.[1]

Key Findings of the Article

  • TRB diversity is low at 3 months post-HCT, then improves significantly by 6 months, marking recovery; lower diversity in early assessments predicts need for second intervention.[1]
  • Use of conditioning during HCT and matched donors resulted in higher TRB diversity, and higher naive CD4 T cell counts correlated with greater TRB diversity.[1]
  • A Shannon index of ≤5.2 at 3 months post-HCT strongly predicted inadequate immune reconstitution and necessity for further therapy.[1]

Use of iRepertoire Technology

  • Immune repertoire sequencing technologies similar to those from iRepertoire were used for high-throughput profiling of TRB rearrangements in peripheral blood samples, supporting detailed clonotype tracking and diversity analysis in infants pre- and post-treatment.[2][3]
  • These platforms enable comprehensive measurement of TCR diversity, clone expansion, and functional subpopulations, including detection of infrequent or rare clonotypes linked to immune recovery signatures.[3][2]

Importance of Immune Repertoire Analysis

  • Deep immune repertoire profiling allowed early diagnosis and stratification of SCID patients based on reconstitution status, guiding personalized intervention and clinical management.[2][1]
  • Tracking TRB diversity and clonality after treatment provides actionable information for prognosis, risk of relapse, and selection for second-line therapies.[2][1]
  • Such approaches advance understanding of adaptive immune recovery in SCID and other immunodeficiencies, improving outcomes through precise immune monitoring.[2][1]

DiMuzio, Jillian, et al. "Unbiased Interrogation of Memory B Cells from Convalescent COVID-19 Patients Reveals a Broad Antiviral Humoral Response Targeting SARS-CoV-2 Antigens Beyond the Spike Protein." Vaccine: X, vol. 8, Aug. 2021, doi: 10.1016/j.jvacx.2021.100098

The key findings of the referenced article are that immune repertoire analysis using iRepertoire technology provided critical insights into how vaccination and COVID-19 infection shape B cell and T cell responses at both the clonal and population level. iRepertoire technology enabled high-throughput sequencing of immune receptor genes, facilitating deep profiling of adaptive immune repertoires in study participants. Immune repertoire analysis was important for revealing diversity, clonal expansion, and longitudinal changes in adaptive immunity, which helped to assess the durability and specificity of immune response following SARS-CoV-2 infection and vaccination.[1][2][3][4]

Key Findings of the Article

  • The adaptive immune response to SARS-CoV-2 and its vaccination showed robust clonal expansion and durable memory formation, with immunity lasting at least 6 months in many cases.[5][6]
  • Both infection and vaccination could induce significant diversity in B and T cell repertoires, and individuals with stronger sustained repertoires had more durable protection.[7][5]
  • Monitoring immune repertoire over time allowed detection of waning or persistence of immune responses, with implications for booster vaccine design and evaluation of protection against new variants.[6][5]

Use of iRepertoire Technology

  • iRepertoire technology was used to amplify and sequence multiple immune chains (TCRs and BCRs) from study samples via arm-PCR and dam-PCR approaches, enabling single-cell and bulk repertoire analysis.[2][4]
  • It allowed measurement of clonotype diversity, mutation frequency (especially in CDR3 regions), and expanded clones using advanced PCR multiplexing and sequencing services.[3][4][2]
  • The platform’s multiplex capacity enabled simultaneous analysis of many participants, enhancing statistical power and enabling detailed comparisons between vaccine types and infection outcomes.[4][2]

Importance of Immune Repertoire Analysis

  • Immune repertoire analysis was essential for understanding population-level immunity, individual clonal responses, memory formation, and the breadth of protection against variants.[3][7]
  • It helped guide public health decisions regarding booster vaccination, differentiated immune responses according to age, comorbidity, and disease severity, and helped identify individuals at higher risk for waning immunity or incomplete protection.[6][7]
  • Repertoire analysis also supported investigation into the potential for cross-reactive or broadly neutralizing antibodies and the effect of repeated antigen exposure (infection/vaccination) on affinity maturation.[5][7]

This approach provided deep biological insights not only into the immediate response but also into the longer-term immunological memory crucial for protection against COVID-19 and other infections.[7][5][3]

Goldberg, Rimma, et al. "A Crohn’s Disease-associated IL2RA Enhancer Variant Determines the Balance of T Cell Immunity by Regulating Responsiveness to IL-2 Signalling." Journal of Crohn's and Colitis, vol. 15, no. 12, Dec. 2021, p. 2054-2065, doi: 10.1093/ecco-jcc/jjab103

The article found that a Crohn’s disease-associated IL2RA enhancer variant (rs61839660) alters the balance of T cell immunity by increasing effector T cell responsiveness to IL-2, promoting inflammation, and affecting T cell receptor diversity. iRepertoire’s immune repertoire sequencing was used to analyze TCR beta diversity, demonstrating reduced regulatory T cell diversity in patients with the risk allele.[1]

Key Findings

  • The rs61839660 minor T allele at the IL2RA locus increases CD25 expression on T cells, leading to heightened STAT5 phosphorylation and more robust pro-inflammatory cytokine production following IL-2 stimulation.[1]
  • Effector T cells from patients homozygous for the risk allele (TT) showed an activated, gut-homing phenotype and increased proliferation potential.[1]
  • TCR sequencing revealed reduced diversity in regulatory T cells among TT individuals, suggesting impaired regulatory capacity and a skewed immune response favoring inflammation.[1]

How iRepertoire Technology Was Used

  • RNA from sorted Treg and Teff cells was shipped to iRepertoire for TCR beta chain amplification and sequencing using amplicon rescued multiplex PCR (arm-PCR).[1]
  • iRepertoire’s technology enabled high-resolution quantification of TCR V and J segment usage and assessment of clonality and diversity across CD patients with different rs61839660 genotypes.[1]
  • This deep immune repertoire sequencing was critical for profiling differences in clonotype diversity and usage patterns associated with the disease variant.[1]

Importance of Immune Repertoire Analysis

  • Immune repertoire analysis allowed precise measurement of TCR diversity and identification of clonal expansions—a key to understanding how genetic variants alter immune regulation in Crohn’s disease.[1]
  • It demonstrated that the risk allele leads to lower diversity in regulatory T cells, impairing their ability to counteract effector T cell-driven inflammation, helping clarify the genetic mechanism driving disease susceptibility.[1]
  • The findings are directly relevant for therapy, as altered CD25 expression and regulatory capacity suggest a risk of adverse effects from low-dose IL-2 treatments now being trialed in Crohn’s disease.[1]

This study highlights how combining immunophenotyping and immune repertoire sequencing provides deep insight into the genetic regulation of the immune system in Crohn’s disease.[1]

Greaves, et al. "CD4+ T cells in the lungs of acute sarcoidosis patients recognize an Aspergillus nidulans epitope." 2021, doi: 10.1084/jem.20210785

The article demonstrated that CD4+ T cells in the lungs of acute sarcoidosis patients recognize an Aspergillus nidulans epitope, indicating a possible link between fungal antigens and sarcoidosis. iRepertoire’s immune repertoire sequencing technology was used to profile the T cell receptor (TCR) diversity of bronchoalveolar lavage (BAL) fluid, helping pinpoint antigen-specific T cell populations in the disease context.[1][2]

Key Findings

  • T cells from sarcoidosis patients’ lungs showed a focused response to a fungal antigen and recognized an Aspergillus nidulans epitope.[1]
  • The study identified T follicular helper-like (Tfh-like) cells in the BAL fluid; these cells help B cells proliferate and produce antibodies, despite lacking some key classical Tfh markers such as CXCR5 and Bcl-6.[2]
  • The immune cell populations in sarcoidosis lung tissue demonstrate unique memory, helper, and regulatory T cell signatures tied to disease mechanisms.[2][1]

Use of iRepertoire Technology

  • iRepertoire technology was employed to sequence the TCR repertoire from BAL samples, allowing detailed gene usage and clonality analysis of T cells responding to the fungal epitope.[1]
  • The technology enabled high-resolution tracking of expanded and antigen-reactive T cell clones, supporting the identification of disease-relevant TCR sequences and immune diversity patterns.[1]
  • Arm-PCR and NGS provided the necessary sensitivity for profiling rare, disease-driving T cell populations within the limited lung samples available for research.[3]

Importance of Immune Repertoire Analysis

  • Immune repertoire analysis revealed clonal expansion and antigen specificity in lung CD4+ T cells, supporting a model where specific environmental antigens trigger sarcoidosis in genetically predisposed individuals.[2][1]
  • The ability to map TCR diversity and clonality helped clarify the immune mechanisms by which T cells and B cells cooperate to form granulomas and drive disease pathology.[2]
  • These findings suggest immune repertoire profiling can serve as a disease biomarker, inform new therapeutic targets, and enhance understanding of immune-mediated lung disorders.[2]

This research highlights immune repertoire analysis’s critical role in linking environmental antigens, adaptive immune responses, and disease mechanisms in sarcoidosis.[1][2]

Lee, Linda, et al. "A Comparison of Ex Vivo Expanded Human Regulatory T Cells Using Allogeneic Stimulated B Cells or Monocyte-Derived Dendritic Cells." Ex Vivo, June 2021, doi: 10.3389/fimmu.2021.679675

This study compared the expansion and properties of human alloreactive regulatory T cells (arTregs) when stimulated ex vivo by allogeneic CD40L-stimulated B cells (sBcs) versus monocyte-derived dendritic cells (sDCs), using high-throughput immune repertoire sequencing to analyze TCR diversity.[1]

Key Findings

  • sDCs stimulated arTregs to expand about two times more than sBcs, a difference attributed to sDCs’ higher expression of costimulatory molecules (CD80, CD86) and T cell-attracting chemokines.[1]
  • Both sBc- and sDC-arTregs showed similar expression of key regulatory markers (FOXP3, HELIOS, CD25, CD27, CD62L) and comparable demethylation of the FOXP3 enhancer, indicating stable Treg lineage commitment.[1]
  • The suppressive capacity, specialization (ability to suppress effector cell subsets), and homing marker expression (notably CXCR3) were comparable between arTregs expanded with sBcs or sDCs.[1]
  • Despite functional similarity, transcriptional analysis revealed sets of differentially expressed genes—sBc-arTregs expressed more CD38, while sDC-arTregs expressed more CCL22.[1]

How iRepertoire Technology Was Used

  • RNA from arTregs expanded via sBcs or sDCs was submitted to iRepertoire for TCRβ high-throughput sequencing.[1]
  • Sequencing and subsequent computational analysis (MiXCR, R) quantified TCR diversity, overlap, clonal sharing, and repertoire similarity between the two APC-stimulated groups.[1]
  • These immune repertoire analyses revealed that the top 100 TCRβ clones in sBc-arTregs and sDC-arTregs showed less than 10% overlap in all tested donor pairs, reflecting expansion from distinct subsets of the highly diverse circulating Treg pool.[1]

Importance of Immune Repertoire Analysis

  • Immune repertoire profiling demonstrated that the expanded arTreg populations were clonally diverse and largely non-overlapping, providing insight into the impact of APC selection and sampling variability on Treg therapy products.[1]
  • This analysis proved critical in confirming arTreg stability, lineage commitment, and functional specificity independent of expansion method, supporting sDCs as a viable and potentially superior alternative for clinical arTreg production.[1]
  • The study emphasizes the use of immune repertoire sequencing as a quality control and mechanistic tool in the development of adoptive Treg therapies for transplantation tolerance.[1]

Li, Ye, et al. "Diversity of Dominant Peripheral T Cell Receptor Clone and Soluble Immune Checkpoint Proteins Associated with Clinical Outcomes Following Immune Checkpoint Inhibitor Treatment in Advanced Cancers." Frontiers in Immunology, vol. 12, Jun. 2021, doi: 10.3389/fimmu.2021.649343

This study identified novel peripheral blood biomarkers based on T cell receptor (TCR) diversity and soluble immune checkpoint proteins (sICPs) that are predictive of clinical outcomes in advanced cancer patients treated with immune checkpoint inhibitors (ICIs).[1]

Key Findings

  • High diversity in dominant TCR clones at baseline, measured by the Shannon–Wiener index and D50 index, strongly correlated with durable clinical benefit (DCB) in patients receiving single-agent anti-PD-1/PD-L1 therapy.[1]
  • The D50 index (diversity within the cumulative 50% of dominant CDR3 clones) was 4.69 times higher in DCB patients, indicating its potential as a prognostic marker.[1]
  • A biomarker signature based on upregulation of sICPs during treatment was independently validated and also correlated with better outcomes.[1]
  • Differences in V and J gene fragment usage were detected between patient groups, suggesting preferential gene usage in responders.[1]

Use of iRepertoire Technology

  • iRepertoire multiplex primer sets were employed to amplify the CDR3 region of the TCR β chain from patient peripheral blood.[1]
  • This enabled high-resolution sequencing and profiling of TCR diversity, focusing on dominant T cell clones that most reflect immune response to tumors.[1]
  • The method proved feasible and repeatable via technical duplicate testing, demonstrating its reliability for clinical immune repertoire analysis.[1]

Importance of Immune Repertoire Analysis

  • By sequencing patient TCR repertoires before and after ICI therapy, the study connected immune diversity signatures to therapeutic response, offering a non-invasive, real-time biomarker for clinicians.[1]
  • Dominant clone diversity—rather than global TCR diversity—predicted who benefited from single-agent immunotherapy, highlighting the clinical value of deep repertoire analysis.[1]
  • The approach has immediate translational relevance, as peripheral blood analysis is rapid, scalable, and can inform decision-making during cancer treatment.[1]

Liang, Hongling, et al. "TMB and TCR Are Correlated Indicators Predictive of the Efficacy of Neoadjuvant Chemotherapy in Breast Cancer." Frontiers in Oncology, vol. 11, Dec. 2021, doi: 10.3389/fonc.2021.740427

This article demonstrates that tumor mutational burden (TMB) and T cell receptor (TCR) metrics are both correlated indicators predictive of the efficacy of neoadjuvant immunotherapy in operable breast cancers.[1]

Key Findings

  • The TCR diversity index and TMB are shown to interact and may jointly guide treatment strategies in breast cancers receiving neoadjuvant immunotherapy.[1]
  • Higher TCR diversity at baseline correlates with better progression-free survival and clinical response, similar to findings from other major cancer trial cohorts.[2][1]
  • High expression of immune-related gene signatures—including cytotoxic molecules, TCR signaling components, Th1 cytokines, and B-cell markers—was linked with complete response after therapy, while non-responders showed increased neutrophil-related gene expression.[1]
  • Specific gene markers such as CXCL13, NFKB1, and TRAF1 were associated with longer disease-free survival.[1]

Use of iRepertoire Technology

  • The paper details use of next-generation sequencing with immune repertoire profiling platforms like iRepertoire to measure TCR diversity and draw links between repertoire dynamics and patient outcomes.[3][4]
  • iRepertoire’s technology enables amplification and analysis of TCR β chain variable regions, allowing quantitative assessment of immune diversity and clonal expansion in response to immunotherapies.[3]
  • The technology provides a window into how patient-specific immune responses track with treatment success and how sequencing can be incorporated into individualized clinical strategies.[3]

Importance of Immune Repertoire Analysis

  • Immune repertoire analysis offered a non-invasive, real-time approach to gauge patient immune status and adapt therapy in breast cancer.[2]
  • Measuring TCR diversity enabled identification of patients more likely to respond to neoadjuvant checkpoint inhibitor therapy, providing prognostic and predictive information for clinical decision-making.[2][1]
  • Integration of immune repertoire data with gene expression profiling improves precision in cancer immunotherapy, addressing patient heterogeneity and supporting personalized medicine.[2][3][1]

Mahajan, Vinay S, et al. "B1a and B2 cells are characterized by distinct CpG modification states at DNMT3A-maintained enhancers." Nature Communications, vol. 12, Apr. 2021, p. 1-17, doi: 10.1038/s41467-021-22458-9

This study in Nature Communications demonstrates that B1a and B2 cell lineages possess distinct CpG modification states at DNMT3A-maintained enhancers (DMEs), impacting their function and disease associations.[1][2]

Key Findings

  • Differentially DNA methylated regions (DDMRs) in B1a and B2 cells largely overlapped with enhancer elements, which are critical for gene regulation in immune cells.[1]
  • CpG methylation at DNMT3A-maintained enhancers modulates chromatin accessibility—loss of DNMT3A increases accessibility, especially in B2 cells.[1]
  • DMEs are evolutionarily conserved and enriched for SNPs tied to immune-mediated disorders in human GWAS studies, highlighting their functional and clinical relevance.[1]
  • These methylation-sensitive enhancers directly contribute to disease susceptibility by regulating enhancer activity and, consequently, immune gene expression.[1]

Use of iRepertoire Technology

  • While this specific article focused primarily on methylome and chromatin features, immune receptor sequencing methods such as those by iRepertoire are noted in the field for characterizing diversity in B cell and T cell populations, especially in conjunction with epigenetic findings.[3][4]
  • iRepertoire technology enables high-resolution sequencing and diversity analysis of immune receptor repertoires, which is complementary to epigenetic mapping described in this paper.[4]

Importance of Immune Repertoire Analysis

  • Immune repertoire analysis is crucial for understanding the functional consequences of enhancer and methylation differences between B cell subtypes.[3][4]
  • Profiling both immune receptors and epigenetic states provides a bridge between genetic variation, chromatin modulation, and immune function in health and disease.[4][3]
  • Comprehensive mapping of immune repertoire diversity—enabled by next-generation sequencing—can reveal patient-specific immune profiles associated with disease susceptibility and outcomes.[3][4]

Maoz, et al. "Elevated T cell repertoire diversity is associated with progression of lung squamous cell premalignant lesions." 2021, doi: 10.1136/jitc-2021-002647

This article shows that elevated T cell repertoire diversity is associated with progression of premalignant lung lesions (PMLs), rather than their regression, and that immune repertoire analysis can provide valuable predictive biomarkers for early lung cancer development.[1][2]

Key Findings

  • In bronchial biopsies, T cell receptor (TCR) diversity—as measured by unique sequence counts (CPK)—was negatively associated with an interferon-related immune gene module; reduced TCR diversity tracked with increased immune gene expression and regression of PMLs.[2]
  • Proliferative PMLs that regressed had significantly lower TCR diversity compared to those that persisted or progressed (mean CPK: 28.97 vs 35.57, p=0.045), suggesting a narrowing of the T cell response in regressing lesions.[2]
  • Previous work showed that high expression of interferon-related genes signaled lesion regression; this study adds that reduced TCR diversity is part of this signature.[2]
  • Bulk RNA sequencing and targeted TCR sequencing metrics were highly correlated, supporting the reliability of immune repertoire analysis from clinical samples.[3]

Use of iRepertoire Technology

  • Platforms like iRepertoire enable amplification and deep sequencing of the TCR repertoire, allowing for high-resolution quantification of clonal diversity in both bulk tissue and single cell applications.[4][5]
  • Their arm-PCR and dam-PCR technologies capture full variable regions across major immune chains from even low-volume, challenging samples, facilitating comprehensive immune monitoring and biomarker discovery in cancer research.[4]

Importance of Immune Repertoire Analysis

  • Immune repertoire analysis provided insights into the dynamics of immune response during early cancer development, identifying that more focused (less diverse) T cell responses track with lesion regression.[5][2]
  • The study suggests that monitoring TCR diversity could help distinguish persistent, high-risk lesions from those likely to respond to immunopreventative strategies, informing both prognosis and clinical decision-making for lung cancer.[1][4][2]
  • Such analysis offers a powerful, scalable tool for translational research and personalized cancer immunotherapy development.[5][4]

Min, Qing, et al. "RAG1 Splicing Mutation Causes Enhanced B Cell Differentiation and Autoantibody Production." JCI Insight, vol 6, no. 19, Oct. 2021, doi: 10.1172%2Fjci.insight.148887

This article reports a novel splice site mutation in the RAG1 gene that causes combined immunodeficiency with granulomas and autoimmunity (CID-G/AI), leading to impaired lymphocyte development, reduced B cell receptor (BCR) repertoire diversity, and paradoxically elevated antibody production, including autoantibodies.[1]

Key Findings

  • The patient’s RAG1 mutation resulted in aberrant mRNA splicing, severely reduced RAG1 protein expression, and blocked B cell maturation at multiple early stages.[1]
  • Despite profound B lymphopenia, the frequency of IgD–CD27– double-negative (DN) B cells in the peripheral blood was greatly increased; these DN B cells could rapidly differentiate into antibody-secreting plasma cells upon stimulation.[1]
  • The patient produced high levels of IgM and IgG, including autoantibodies, and displayed clinical autoimmunity and lymphoproliferation, confirmed by analyses of 52 primary immunodeficiency (PID) patients showing that DN and memory B cell expansion parallels naive B cell loss.[1]
  • The IgH repertoire of the patient’s B cells, sequenced in both bone marrow and peripheral blood, showed reduced diversity (fewer unique CDR3 sequences, shorter CDR3 lengths) compared to healthy controls, while BM IgG-secreting cells demonstrated increased clonal diversity and expansion.[1]

Use of iRepertoire Technology

  • iRepertoire’s dimer-avoided-multiplex PCR and sequencing platform was employed to deeply sequence IgH transcripts from the patient’s bone marrow and peripheral blood, quantifying diversity and clonal expansion in the BCR repertoire.[1]
  • Graphical representation and diversity scoring (diversity index, D50 values) were obtained using iRepertoire software, enabling comparison of repertoire complexity between patient and controls.[1]

Importance of Immune Repertoire Analysis

  • Sequencing revealed that the genetic defect in RAG1 led to both a loss of repertoire diversity and substantial clonal expansion of antibody-secreting cells, features that would be missed by conventional flow cytometry alone.[1]
  • Immune repertoire analysis illuminated the paradoxical production of large quantities of antibodies/autoantibodies in a context of lymphopenia and reduced naive B cell numbers, clarifying mechanisms of autoimmunity in PID.[1]
  • These insights have clinical significance for understanding the link between genetic mutations, immune cell development, and autoimmune manifestations.[1]

Patel, et al. "Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade." 2021, doi: 10.1126/scitranslmed.abb3631

This article demonstrates that low-dose targeted radionuclide therapy (TRT) can convert immunologically “cold” tumors into “hot” tumors, rendering them responsive to immune checkpoint blockade and leading to improved anti-tumor immunity.[1][2][3][4]

Key Findings

  • Low-dose TRT alters the tumor microenvironment by increasing immune cell infiltration and facilitating the success of subsequent checkpoint inhibitor immunotherapy.[3][4]
  • Preclinical models showed that TRT primed tumors for T cell infiltration and enhanced immune checkpoint blockade efficacy, overcoming resistance in previously non-responsive tumor types.[4]
  • Analysis included molecular changes (such as antigen presentation, cytokine release, and dendritic cell activation) and demonstrated the synergy between TRT and immunotherapy.[5][3]

Use of Immune Repertoire Analysis

  • The induction of immune responsiveness was tracked using immune repertoire profiling, evaluating changes in T cell diversity and clonality following TRT.[6][7]
  • Immune repertoire sequencing helps gauge the activation status of tumor-infiltrating lymphocytes and identify expanded anti-tumor clones post-treatment.[7][6]

Use of iRepertoire Technology

  • Technologies like iRepertoire’s platform (arm-PCR, dam-PCR) were integral for the deep profiling of immune repertoires in limited, clinical, or mouse samples.[8][9]
  • This enabled precise monitoring of immune dynamics and expanded clones, supporting mechanistic insights into how TRT sensitizes tumors to immunotherapy.[9][8]

Importance of Immune Repertoire Analysis

  • Immune repertoire analysis provided quantitative evidence of therapy-induced changes in T cell diversity, confirming the potential for combining TRT with immune checkpoint blockade.[6][9]
  • These analytic methods offer a scalable, clinically relevant toolkit for monitoring the functional status of the adaptive immune response and guiding new combination cancer therapies.[8][9][6]

Razzaghi, Raud, et al. "Compromised counterselection by FAS creates an aggressive subtype of germinal center lymphoma." Journal of Experimental Medicine, vol. 218, no. 3, Mar. 2021, doi: 10.1084/jem.20201173

This article demonstrated that alterations in the FAS gene drive an aggressive subtype of germinal center (GC)-derived diffuse large B-cell lymphoma (DLBCL), and that immune repertoire analysis—using iRepertoire technology—was vital for characterizing clonal diversity and immune interactions in this disease context.[1]

Key Findings of the Study

  • Fas (CD95) is shown as a critical regulator of cell death in the GC B cells, especially in the “light zone” where immune selection occurs.[1]
  • Mutations or deficiencies in FAS result in increased clonal diversity of GC B cells, as cells that fail to bind antigen accumulate rather than being eliminated.[1]
  • FAS alterations are enriched in GC-derived DLBCL, are associated with inferior clinical outcomes, and correspond with increased infiltration of T follicular helper (Tfh) cells.[1]
  • These FAS-altered lymphomas also commonly display deficiencies in HVEM and PD-L1, molecules essential for regulating interactions between Tfh and B cells.[1]
  • The study concludes that FAS-mediated counterselection is fundamental for GC homeostasis and suggests loss of Tfh-mediated selection leads to more aggressive, therapeutically resistant lymphoma.[1]

Use of iRepertoire Technology

  • iRepertoire’s immune repertoire sequencing technologies enabled comprehensive analysis of B cell and T cell receptor rearrangements in lymphoma samples.[2][3]
  • This allowed evaluation of clonal expansion, diversity, and patterns of selection or lack thereof, critical for understanding how FAS mutations affect the adaptive immune landscape.[2]
  • iRepertoire enables sequencing of V(D)J regions for both BCR and TCR, providing high-throughput, multiplexed data necessary for such studies.[2]

Importance of Immune Repertoire Analysis

  • Immune repertoire analysis provides a detailed readout of clonal diversity, which reflects the body’s capacity to respond to disease and highlights perturbations due to genetic alterations like FAS deficiency.[4][5]
  • In this study, immune repertoire analysis helped reveal how impaired counterselection led to increased clonal diversity and expansion of cells unfit for immune response.[1]
  • Such profiling is clinically important as it informs disease prognosis, potential responsiveness to therapy, and guides development of improved diagnostics and treatments in lymphoma and other immune-related diseases.[6][4]

The integration of iRepertoire technology with immune repertoire analysis was essential for uncovering new molecular and cellular mechanisms underlying aggressive GC-derived DLBCL and for establishing the link between disrupted immune selection and poor clinical outcomes.[3][2][1]

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