Biology subjects

Karimi, M.

Publications and source records attributed to Karimi, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Differentiation-coupled intron retention reveals a candidate NKG2D-TR-like isoform at the murine Klrk1 locus

NKG2D (encoded by KLRK1 in humans and Klrk1 in mice) is an activating receptor expressed by cytotoxic lymphocytes. In humans, NKG2D signaling is regulated post-transcriptionally: activated T cells retain intron 4 of KLRK1 to generate NKG2D-TR, a truncated dominant-negative isoform that limits receptor signaling. Whether mice, the principal preclinical model for NKG2D-directed therapies, possess an analogous regulatory mechanism remains unknown. Across four murine RNA-seq datasets comprising 50 samples and spanning T-cell differentiation, graft-versus-host disease, and acute and chronic LCMV infection, we examined the retained-intron isoform Klrk1-203. The transcript retains the canonical start codon, while its predicted stop codon lies within the terminal exon downstream of the final exon-exon junction, suggesting that it may escape nonsense-mediated decay. If translated, Klrk1-203 is predicted to encode a truncated product that retains the cytoplasmic and transmembrane domains but lacks most of the ligand-binding ectodomain. This predicted architecture resembles human NKG2D-TR, although the murine product contains a short C-terminal sequence encoded by the retained intron. Klrk1-203 was below the detection limit in unchallenged naive and early-effector T cells but was induced in differentiated effector and memory populations, reaching approximately one-fifth of total Klrk1 transcripts in one effector-memory sample. Read-level analyses independently demonstrated increased intron 4 retention with differentiation; however, short-read sequencing cannot fully distinguish Klrk1-203 from the co-retained Klrk1-204 transcript, making isoform-specific abundance dependent on model-based quantification. An independent coding-potential algorithm classified Klrk1-203 as non-coding, providing an important counterpoint to the structural predictions. Together, these findings identify Klrk1-203 as a candidate NMD-resistant, differentiation-associated regulator of murine NKG2D and a potential counterpart of human NKG2D-TR that warrants experimental validation.

immunology↗

bioRxiv2026

ITK Deficiency Attenuates Alveolar Hemorrhage by Enhancing Regulatory T Cell-Mediated Tissue Resilience

Pulmonary hemorrhage (PH) is a life-threatening manifestation of systemic autoimmunity caused by immune-mediated disruption of the alveolar capillary barrier. Despite high mortality, the molecular checkpoints that shift destructive inflammation toward protective immune regulation remain poorly defined. Here, using the pristane-induced PH model, we identify interleukin-2-inducible T cell kinase (ITK) as a critical regulator of autoimmune lung injury. ITK deficiency (ITK-/- ) conferred near-complete protection from PH and associated multiorgan injury, accompanied by reduced proinflammatory monocytes and neutrophils and increased Foxp3 regulatory T cells (Tregs). Adoptive transfer of ITK-/-; Tregs protected wild-type recipients from PH and suppressed systemic proinflammatory cytokines, identifying Tregs as key mediators of tissue protection. Mechanistically, lung ITK-/- ; Tregs exhibited increased amphiregulin, a mediator of tissue repair. Transcriptomic profiling further showed that ITK loss reprogrammed Tregs toward a metabolically and functionally enhanced state, with enrichment of oxidative phosphorylation, mTORC1 and STAT5 signaling, and tissue-repair programs. These findings establish ITK as a regulator of the balance between pulmonary injury and reparative immunity and support targeting the ITK axis in severe inflammatory lung disease.

immunology↗

bioRxiv2025

Deep Learning Bridges Histology and Transcriptomics to Predict Molecular Subtypes and Outcomes in Muscle-Invasive Bladder Cancer

Muscle-Invasive Bladder Cancer (MIBC) is a heterogeneous disease with distinct molecular subtypes influencing prognosis and therapeutic response. However, molecular profiling through RNA sequencing remains costly, time-consuming and complicated by intratumoral heterogeneity. We developed a Deep Learning (DL) approach to infer molecular subtypes from routine histopathological slides and to evaluate its prognostic value in patients treated with neoadjuvant chemotherapy (NAC). We developed an DL-model predicting the expression of 848 subtype-associated genes from histological images of transurethral resection of bladder tumor, enabling spatial molecular subtyping at tile level. The model was trained on 297 NAC-treated patients from the VESPER clinical trial and evaluated on three independent cohorts (COBLAnCE, n=224; Saint-Louis, n=30 and TCGA, n=315), covering diverse staining protocols and scanner types. Spatial transcriptomics from six VESPER patients confirmed the spatial consistency of the inferred expression profiles. Our approach achieved a ROC AUC of 0.94 for molecular subtype prediction, with 95% of genes significantly predicted, demonstrating its ability to capture transcriptomic dysregulations from histological morphology. Predicted expression maps revealed spatially coherent patterns and intratumoral molecular heterogeneity. Importantly, tumors predicted with basal/squamous features (pure or mixed), were associated with significantly worse progression-free and overall survival after NAC (log-rank p=0.014 and 0.037, respectively). This DL-based framework enables accurate and spatially resolved inference of gene expression and molecular subtypes in MIBC without sequencing. These findings could improve patient stratification in clinical practice and support the design of more targeted clinical trials. Further validation in larger cohorts is needed before routine clinical implementation.

cancer biology↗

bioRxiv2025

Engineering HIV antibodies with enhanced breadth and potency of neutralization through multistate affinity maturation

Broadly neutralizing antibodies (bnAbs) against HIV hold promise as therapeutic and prophylactic agents, but realizing this potential requires antibodies that function across the antigenic heterogeneity of the HIV envelope glycoprotein (Env). Although numerous bnAbs have been isolated from infected individuals, their breadth and potency may not be sufficient to tackle global viral diversity, motivating efforts to further improve their neutralization capacity. Here, we address this challenge using a multistate antibody engineering approach integrating deep mutational scanning with combinatorial library screening across diverse Env variants. This strategy enables identification of mutation patterns that confer improved binding across antigenically distinct targets. Starting from one of the best-in-class CD4-binding site bnAbs, we performed iterative optimization to increase binding affinity across diverse Env variants. The resulting lead candidate exhibited improved breadth and up to 100-fold higher potency against pseudoviruses from large cross-clade historical and contemporary panels while maintaining biophysical and pharmacokinetic profiles conducive to clinical development. Structural and molecular dynamics analyses revealed a unique tri-tyrosine aromatic triad and reinforced electrostatic contacts that stabilized the bnAb/Env interface. These findings demonstrate that systematic in vitro engineering can generate bnAbs with enhanced breadth and potency, providing a generalizable strategy for developing therapeutic antibodies against highly diverse pathogens.

bioengineering↗

bioRxiv2025

β-Catenin Stabilization Protects Against Pulmonary Hemorrhage Through Amphiregulin and BATF- Mediated Regulatory T Cells

Pulmonary hemorrhaging (PH) is a life-threatening condition with a high mortality rate, yet the role of immune cells in its pathogenesis remains poorly defined. Here, we investigated the protective function of {beta}-catenin stabilization in T cells and its impact on PH. Using a novel transgenic mouse model (CAT-Tg) with stabilized {beta}-catenin, we demonstrate that {beta}-catenin stabilization induces a distinct T-cell phenotype characterized by an expansion of central effector memory cells (CD44, CD122, Eomes, T-bet). Mechanistically, this effect was associated with suppression of key proinflammatory pathways, including reduced phosphorylation of STAT1, STAT3, and JAK1. PH was induced using pristane, and CAT-Tg mice were significantly protected from lung damage, showing reduced proteinuria and decreased pulmonary proinflammatory cytokine production compared with wild-type (WT) and T cell-specific {beta}-catenin knockout (cKO) mice. This protection correlated with a marked increase in FOXP3 regulatory T cells (Tregs) in CAT-Tg mice. We further identified a novel mechanism in which {beta}-catenin stabilization enhances lung expression of Amphiregulin and BATF, two molecules essential for Treg function and tissue repair. Adoptive transfer of CAT-Tg Tregs into WT mice with pristane-induced PH conferred superior protection, as evidenced by reduced lung inflammation and proteinuria. The systemic administration of a {beta}-catenin agonist to mice with PH significantly attenuated disease severity. Our bioinformatic analysis confirmed that {beta}-catenin stabilization upregulates pathways associated with tissue repair and immune homeostasis, including PI3K-Akt, angiogenesis, and STAT5 signaling. Collectively, these findings reveal that {beta}-catenin stabilization protects against pulmonary hemorrhage by inducing a specialized T-cell phenotype and establishing a protective Amphiregulin-BATF-Treg axis. This study identifies a novel immunomodulatory pathway with therapeutic potential for PH and other inflammatory lung diseases.

immunology↗

bioRxiv2025

Comparative susceptibility of Old World and New World bat cell lines to Zika virus: Insights into viral replication and inflammatory responses

BackgroundFrom the first isolation of Zika virus (ZIKV) in Uganda in 1947, ZIKV had primarily been associated with sporadic human cases in Africa and Asia until ZIKV emerged as an epidemic in the Americas in 2015. As ZIKV spread into new geographic regions, it now has the potential to interact with many novel potential host species whose susceptibility to the virus has yet to be determined. Bats, with their ability to fly and live in or near human structures, are plausible ZIKV reservoirs. However, their competence as hosts for ZIKV remains unresolved. In this study, we investigate the immune response of Old World and New World bats to ZIKV infection in vitro. ResultsWe demonstrate that Egyptian Rousette bat (Rousettus aegyptiacus; Old World) cells are susceptible to ZIKV, while we observed little to no ZIKV replication in Jamaican fruit bat (Artibeus jamaicensis) cells. Notably, both the Asian and African ZIKV lineages elicited a strong proinflammatory response in the R. aegyptiacus cell line including upregulation of IL6, CXCL8, and CCL5. These data contrast with the dampened inflammatory response detected in these bats to other viruses. ConclusionsThe findings reveal that R06E cells derived from Egyptian Rousette bats exhibit robust proinflammatory and antiviral responses upon Zika virus (ZIKV) infection, characterized by significant upregulation of proinflammatory cytokines. This suggests that while these cells support productive ZIKV replication, they also mount a strong immune response, challenging the notion of these bats as immune-tolerant reservoirs and indicating a more complex interaction with the virus.

microbiology↗

bioRxiv2025

A strategy for genome-wide seamless tagging of human protein-coding genes

Comprehensive and systematic proteome-wide experiments require financial and technical resources unavailable to most researchers. Here we describe a scalable CRISPR/Cas9-non-homologous end joining (NHEJ) based method for Pooled Recombinant Integration of Seamless Markers (PRISM) into protein coding genes. We created two gRNA libraries for 5- and 3-tagging of 18,804 human protein-coding genes. Selection for in-frame integration of the donor cassette can be guaranteed by fusing it to an antibiotic resistance enzyme (ARE) and P2A self-cleaving peptide, resulting in tagged proteins and free ARE to select for clones with inserted donor cassettes. We achieved a library integration rate of 19.75% and tagging of [~]80% for genes expressed in Hek293T cells and notably, 89.7% of essential genes, with donor DNA. Our strategy is scalable, specific, and selective, paving the way for genome-scale construction of human cell lines tagged with different types of reporter genes for protein functional characterization. Significance statementHere we report the first practical method to achieve near complete 5- or 3-end integration of reporter protein-coding sequences to express seamless fusions of human protein and reporter proteins that we call Pooled Recombinant Integration of Seamless Markers (PRISM). PRISM is independent of homology templates, yet it works with high efficiency and precision. Using gRNA-directed CRISPR/Cas9 genome editing and mini-plasmid donor cassettes we were able to tag about 80% of the protein-coding sequences of human genes with a green florescent protein at an integration efficiency of about 20% and most notably, of 90% of essential genes in the human cell line HEK 293T. This is important because the characterization of gene functions in a particular cell type usually begins with essential genes.

systems biology↗

bioRxiv2025

Intrinsic immunity against HAdV is achieved by a novel epigenetic silencing complex

The DNA double-stranded genome of human adenoviruses (HAdV) is preferentially targeted by host factors involved in chromatin remodeling, such as SPOC1 and KAP1 to inhibit efficient viral gene expression. HAdV genomes undergo alterations through association with host histones and epigenetic modifications; however, the precise underlying mechanism remains elusive. A recently discovered silencing mechanism for retrotransposons and retroviruses involves the Human Silencing Hub (HUSH) complex. This complex of MPP8, TASOR, and PPHLN1 safeguards the human genome by utilizing histone H3 Lys9 trimethylation (H3K9me3) to block transcription. Through the recruitment of SETDB1 and MORC2, the HUSH complex silences host genes and condenses target genomes to combat infections such as HIV, MLV, and AAV. Here, we present evidence that the HUSH complex effectively restricts HAdV infection. To counteract the repressive function of this epigenetic silencing complex, HUSH factors are inhibited through binding of HAdV proteins and subsequent relocalization. We observe that MPP8 is targeted by the adenoviral E3 ubiquitin ligase, thus recruited by the viral early proteins E1B-55K and E4orf6 for proteasomal degradation. In summary, we provide evidence that the HUSH complex is a previously unrecognized host factor that restricts HAdV gene expression and replication. Based on these novel findings, we propose that HUSH represents a promising therapeutic target to combat HAdV infection.

cell biology↗

bioRxiv2024

The scaffold protein CasL regulates T cell migration by restricting membrane blebbing

T cell migration into inflamed tissue is a key control point in the inflammatory response and relies on integrin interactions with their endothelial ligands. Here, we identify the signaling scaffold CasL (Hef1, NEDD9) as a central regulator of integrin-dependent migration in primary T cells. We found CasL is specifically needed for efficient migration on ICAM-1, but not VCAM-1 coated surfaces. While WT T cells migrating on ICAM-1 form an actin-rich cell front and move smoothly, T cells lacking CasL instead form numerous, aberrant membrane blebs. The abnormal blebbing observed in CasL KO T cells likely stems from diminished F-actin in the cell front coupled with increased contractile forces behind the nucleus, suggesting CasL regulates the cytoskeletal architecture in migrating T cells. Importantly, using an in vivo allogeneic hematopoietic transplant model we found that CasL promotes T cell migration into inflamed peripheral tissue, but was dispensable for trafficking to secondary lymphoid organs. Together, these results indicate CasL functions to control the balance of cytoskeletal components during integrin-dependent migration and highlight the importance of integrin signaling for proper migration into inflamed tissue.

cell biology↗

bioRxiv2024

A Comprehensive Engineering Strategy Improves Potency and Manufacturability of a Near Pan-neutralizing Antibody Against HIV

Anti-HIV envelope broadly neutralizing antibodies (bnAbs) are alternatives to conventional antiretrovirals with the potential to prevent and treat infection, reduce latent reservoirs, and/or mediate a functional cure. Clinical trials with "first generation" bnAbs used alone or in combination show promising antiviral effects but also highlight that additional engineering of "enhanced" antibodies will be required for optimal clinical utility, while preserving or enhancing cGMP manufacturing capability. Here we report the engineering of an anti-CD4 binding-site (CD4bs) bnAb, N49P9.3, purified from the plasma of an HIV elite-neutralizer. Through a series of rational modifications we produced a variant that demonstrates: enhanced potency; superior antiviral activity in combination with other bnAbs; low polyreactivity; and longer circulating half-life. Additional engineering for manufacturing produced a final variant, eN49P9, with properties conducive to cGMP production. Overall, these efforts demonstrate the feasibility of developing enhanced anti-CD4bs bnAbs with greatly improved antiviral properties as well as potential translational value.

bioengineering↗

bioRxiv2024

Pannexin 1 crosstalk with the Hippo pathway in malignant melanoma

In this study, we explored the intricate relationship between Pannexin 1 (PANX1) and the Hippo signaling pathway effector, Yes-associated protein (YAP). Analysis of The Cancer Genome Atlas (TCGA) data revealed a significant positive correlation between PANX1 mRNA and core Hippo components, YAP, TAZ, and Hippo scaffold, IQGAP1, in invasive cutaneous melanoma and breast carcinoma. Furthermore, we demonstrated that PANX1 expression is upregulated in invasive melanoma cell lines and is associated with increased YAP protein levels. Notably, our investigations uncovered a previously unrecognized interaction between endogenous PANX1 and the Hippo scaffold protein IQGAP1 in melanoma cells. Moreover, our findings revealed that IQGAP1 exhibits differential expression in melanoma cells and plays a regulatory role in cellular morphology. Functional studies involving PANX1 knockdown provided compelling evidence that PANX1 modulates YAP protein levels and its co-transcriptional activity in both melanoma and breast carcinoma cells. Importantly, our study showcases the potential therapeutic relevance of targeting PANX1, as pharmacological inhibition of PANX1 using selective FDA-approved inhibitors or PANX1 knockdown reduced YAP abundance in melanoma cells. Furthermore, our Clariom S analysis unveiled key genes implicated in cell proliferation, such as neuroglin1 (NRG1), {beta}-galactoside binding protein, galectin-3 (LGALS3), that are affected in PANX1- deficient cells. In summary, our investigation delves into the intricate interplay between PANX1 and YAP in the context of invasive melanoma, offering valuable insights into potential therapeutic strategies for effective treatment.

cell biology↗

bioRxiv2022

Pannexin 3 channels regulate architecture, adhesion, barrier function and inflammation in the skin

The channel-forming glycoprotein Pannexin 3 (PANX3) functions in cutaneous wound healing and keratinocyte differentiation, but its role in skin homeostasis through aging is not yet understood. We found that PANX3 is absent in newborn skin but becomes upregulated with age. We characterized the skin of global Panx3 knockout mice (KO) and found that KO dorsal skin showed sex-differences at different ages, but generally had reduced dermal and hypodermal areas compared to aged-matched controls. Transcriptomic analysis of KO epidermis revealed reduced E-cadherin stabilization and Wnt signaling compared to WT, consistent with the inability of primary KO keratinocytes to adhere in culture, and diminished epidermal barrier function in KO mice. We also observed increased inflammatory signaling in KO epidermis and higher incidence of dermatitis in aged KO mice compared to wildtype controls. These findings suggest that during skin aging, PANX3 is critical in the maintenance of dorsal skin architecture, keratinocyte cell-cell and cell-matrix adhesion and inflammatory skin responses.

cell biology↗

bioRxiv2021

Mucosal and systemic responses to SARS-CoV-2 vaccination in infection naive and experienced individuals

With much of the world infected with or vaccinated against SARS-CoV-2, understanding the immune responses to the SARS-CoV-2 spike (S) protein in different situations is crucial to controlling the pandemic. We studied the clinical, systemic, mucosal, and cellular responses to two doses of SARS-CoV-2 mRNA vaccines in 62 individuals with and without prior SARS-CoV-2 exposure that were divided into three groups based on serostatus and/or degree of symptoms: Antibody negative, Asymptomatic, and Symptomatic. In the previously SARS-CoV-2-infected (SARS2-infected) Asymptomatic and Symptomatic groups, symptoms related to a recall response were elicited after the first vaccination. Anti-S trimer IgA and IgG levels peaked after 1st vaccination in the SARS2-infected groups, and were higher that the in the SARS2-naive group in the plasma and nasal samples at all time points. Neutralizing antibodies titers were also higher against the WA-1 and B.1.617.2 (Delta) variants of SARS-CoV-2 in the SARS2-infected compared to SARS2-naive vaccinees. After the first vaccination, differences in cellular immunity were not evident between groups, but the AIM+ CD4+ cell response correlated with durability of humoral immunity against the SARS-CoV-2 S protein. In those SARS2-infected, the number of vaccinations needed for protection, the durability, and need for boosters are unknown. However, the lingering differences between the SARS2-infected and SARS2-naive up to 10 months post-vaccination could explain the decreased reinfection rates in the SARS2-infected vaccinees recently reported and suggests that additional strategies (such as boosting of the SARS2-naive vaccinees) are needed to narrow the differences observed between these groups.

immunology↗

bioRxiv2021

Wnt/β-catenin regulates alloreactive T cells for the treatment of hematological malignancies

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most widely applied forms of adaptive immunotherapy. Both the detrimental graft-versus-host disease (GVHD) and the beneficial graft-versus-leukemia (GVL) effects occurring after allo-HSCT are largely mediated by alloantigen-reactive donor T cells in the graft. Separating GVHD from GVL effects is a formidable challenge, and a greater understanding of donor T cell biology is required to accomplish the uncoupling of GVHD from GVL. Here, we tested a novel mouse model of {beta}-catenin (Cat-Tg) in an allo-HSCT model. Our data show that T cells from Cat-Tg mice did not cause GVHD. Surprisingly, Cat-Tg T cells maintained the GVL effect. Donor T cells from Cat-Tg mice exhibited significantly lower inflammatory cytokine production and reduced donor T cell proliferation, while upregulating cytotoxic mediators that resulted in enhanced cytotoxicity. RNA sequencing data revealed changes in the expression of over 150 genes for CD4, and over 250 genes for CD8+T cells involved in essential aspects of immune response and GVHD pathophysiology. Transgenic over-expression of human {beta}-catenin primarily affects CD8+ T cell phenotype. Altogether, our data suggest that {beta}-catenin is a druggable target for developing therapeutic strategies to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

immunology↗

bioRxiv2021

TCF-1 in CD4 T cells regulates GVHD severity and persistence

Graft-versus-host disease (GVHD) is a leading cause of mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mature donor T cells in the graft mediate graft-versus-leukemia (GVL) responses against residual tumor cells, which may persist after pre-transplant conditioning regimens. Importantly, the same mature T cells also mediate GVHD. The transcription factor T Cell Factor-1 (TCF-1) is critical for T cell development in the thymus. Using a unique mouse model of allo-HSCT leading to GVHD, we investigated the role of TCF-1 in alloactivated T cell functioning and in GVHD. Here, we report that loss of TCF-1 in mature CD4 T cells reduces GVHD severity and persistence, improving survival of recipient mice. This was due to reduced proliferation, survival, and cytokine production of T cells, as well as increased exhaustion. Gene pathways involved in cytokine response, immune signaling, chemokine signaling, cell cycle, and T cell differentiation were altered by loss of TCF-1 in donor cells. Our companion paper shows that regulation of alloactivated CD4 T cells by TCF-1 differs from regulation of CD8 T cells, suggesting that TCF-1 plays a unique role in each subset. Therefore, targeting of TCF-1 or downstream signaling pathways may be an effective strategy for reducing GVHD following allo-HSCT.

immunology↗

bioRxiv2021

TCF-1 in CD8 T cells separates GVHD from GVL

T Cell Factor-1, encoded by TCF-7, is a transcription factor that plays an essential role during T cell development and differentiation. In this manuscript we utilized a pre-clinical model provided evidence that TCF-7 is dispensable for the anti-tumor response, and that TCF-7 suppresses key transcriptional factors Eomes and T-bet and molecules responsible for peripheral CD8 T cell cytolytic function. We discovered that TCF-7 regulates NKG2D expression on naive and activated mouse CD8 T cells, and that peripheral CD8 T cells from TCF-7 cKO utilize NKG2D to clear tumor cells. We also provide evidence that TCF-7 regulates key signaling molecules, including LCK, LAT, ITK, PLC-{gamma}1, P65, ERKI/II, and JAK/STATs required for peripheral CD8 T cell persistent function. Our data transcriptomic and protein data uncovered the mechanism of how TCF-7 impacting peripheral CD8 T cell inflammatory cytokine production, CD8 T cell activation, and apoptosis. Our pre-clinical model showed that CD8 T cells from TCF-7 cKO mice did not cause GVHD, but effectively cleared primary tumor cells.

immunology↗

bioRxiv2021

Loss of TCF-1 regulates the production of noncanonical Tregs in a prion-like manner

Regulatory T cells (Tregs) are suppressive immune cells used for a variety of clinical and therapeutic applications. Canonical Tregs express CD4, FOXP3, and CD25, which are considered definitive markers of Treg status when used together. However, a subset of noncanonical Tregs expressing only CD4 and FOXP3 have recently been described in some infection contexts. The transcriptional regulation of these cells is still unclear. We found that loss of TCF-1 in all T cells in mice leads to expansion of these cells in multiple tissues in a cell-intrinsic fashion. This effect was not due to aberrant expression of FOXP3, as other functional Treg markers were also expressed. In addition, presence of TCF-1-deficient cells in a chimeric mouse induced increased production of noncanonical Tregs from WT donor cells. Therefore, targeting of TCF-1 may remove suppression on this Treg lineage, increasing the yield of these cells for use in the clinic. Summary sentenceLoss of TCF-1 causes expansion of CD25- FOXP3+ noncanonical Tregs, and TCF-1-deficient T cells induce increased production of CD25- Tregs from WT cells.

immunology↗

bioRxiv2021

Metabolomic Signature of Amino Acids in Plasma of Patients with non-segmental Vitiligo

IntroductionVitiligo is an asymptomatic disorder that results from the loss of pigments (melanin), causing skin or mucosal depigmentation and impairs beauty. ObjectiveDue to the complexity of the pathogenesis of this disease and various theories including self-safety theory, oxidative stress, neurological theory and internal defects of melanocytes behind it, and finally, the vast role of amino acids in body metabolism and various activities of the body, amino acids targeted based metabolomics was set up to follow any fluctuation inside this disease. MethodologyThe study of amino acid profiles in plasma of people with non-segmental vitiligo using a liquid chromatography equipped with fluorescent detector was performed to find remarkable biomarkers for the diagnosis and evaluation of disease severity of patients with vitiligo. Twenty-two amino acids derivatized with o-phthalaldehyde (OPA) and fluorylmethyloxycarbonyl chloride (FMOC), were precisely determined. Next, the concentrations of these twenty-two amino acids and their corresponding molar ratios were calculated in 37 patients (including 18 females and 19 males) and corresponding 34 healthy individuals (18 females and 16 males). Using R programing, the data were completely analyzed between the two groups of patients and healthy to find suitable and reliable biomarkers. ResultsInterestingly, comparing the two groups, in the patient group, tyrosine, cysteine, the ratio of tyrosine to lysine and the ratio of cysteine to ornithine were increased while, arginine, lysine, ornithine and glycine ratios to cysteine have been decreased. These amino acids were selected for identification of patients with accuracy of detection of approximately 0.95 using the assessment of logistic regression. ConclusionThese results indicate a disruption of the production of melanin, increased immune activity and oxidative stress, which are also involved in the effects of vitiligo. Therefore, these amino acids can be used as biomarker for the evaluation of risk, prevention of complications in individuals at risk and monitoring of treatment process.

biochemistry↗