Human Autoimmune Diseases Research Articles

Human Papillomavirus Infection and Autoimmune Diseases: A Two-Sample Bidirectional Mendelian Randomization Study.

Although earlier observational studies have revealed a connection between human papillomavirus (HPV) infection and several autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), the exact causative mechanism underlying this association is still unknown. This two-sample bidirectional MR study was conducted based on publicly released data from genome-wide association studies (GWAS). Our results were mainly derived from the inverse variance weighted (IVW) model, with the remaining three models also being calculated. The MR Steiger test was used to examine the correctness of our causal direction. Sensitivity analysis was performed using Mendelian randomized pleiotropy residual sum and outlier (MR-PRESSO), MR-Egger regression. The IVW results showed that there was a positive causal association between HPV16 E7 protein and SLE (odds ratio (OR) = 1.075, 95% confidence interval (CI), 1.003-1.151, FDR-p = 0.04), however, there was a negative causal association between HPV18 E7 protein and SLE (OR = 0.884, 95% CI, 0.804-0.972, FDR-p = 0.02). No causal associations of HPV16 E7 protein and HPV18 E7 protein with RA, IBD was observed including its subtypes Ulcerative colitis (UC) and Crohn's disease (CD). Sensitivity analysis showed that there was no significant heterogeneity (p > 0.05) or genetic pleiotropy (p > 0.05). Our two-sample bidirectional Mendelian randomization study identifies a causal association between HPV infection and SLE, but no causal association between HPV infection and RA and IBD.

Multiplexed Methylated DNA Immunoprecipitation Sequencing (Mx-MeDIP-Seq) to Study DNA Methylation Using Low Amounts of DNA

Background/Objectives: DNA methylation is a key epigenetic mark involved in regulating gene expression. Aberrant DNA methylation contributes to various human diseases, including cancer, autoimmune disorders, atherosclerosis, and cardiovascular diseases. While whole-genome bisulfite sequencing and methylated DNA immunoprecipitation (MeDIP) are standard techniques for studying DNA methylation, they are typically limited to a few samples per run, making them expensive and low-throughput. Therefore, an automation-friendly method is needed to increase throughput and reduce costs without compromising data quality. Methods and Results: We developed a novel method called Multiplexed Methylated DNA Immunoprecipitation Sequencing (Mx-MeDIP-Seq), which can be used to analyze many DNA samples in parallel, requiring only small amounts of input DNA. In this method, 10 different DNA samples were fragmented, purified, barcoded, and pooled prior to immunoprecipitation. In a head-to-head comparison, we observed a 99% correlation between MeDIP-Seq performed individually or combined as Mx-MeDIP-Seq. Moreover, multiplexed MeDIP led to more than 95% normalized percent recovery and a 25-fold enrichment ratio by qPCR, like the enrichment of the conventional method. This technique was successfully performed with as little as 25 ng of DNA, equivalent to 3400 to 6200 cells. Up to 10 different samples were processed simultaneously in a single run. Overall, the Mx-MeDIP-Seq method is cost-effective with faster processing to analyze DNA methylome, making this technique more suitable for high-throughput DNA methylome analysis. Conclusions: Mx-MeDIP-Seq is a cost-effective and efficient method for high-throughput DNA methylation analysis, offering faster processing and reduced sample requirements. This technique makes DNA methylome analysis more accessible for large-scale studies.

Exposure to Gold Induces Autoantibodies against Nuclear Antigens in A.TL Mice.

To demonstrate causation or/and assess pathogenic mechanisms of environment-induced autoimmunity, various animal models that mimic the characteristics of the human autoimmune diseases need to be developed. Experimental studies in mice reveal the genetic factors that contribute to autoimmune diseases. Here, the immune response of two mouse strains congenic for non-H-2 genes, A.TL (H-2tl) and A.SW (H-2s), was evaluated after 15 weeks' exposure to gold aurothiomalate (AuTM). AuTM-treated A.TL mice showed anti-nuclear antibodies (ANA) with homogenous and/or fine speckled staining patterns and serum autoantibodies to ds-DNA, chromatin, histones, and ribonucleoproteins (RNP). Female A.TL mice showed a stronger immune response than males, as well as an increase of B cells in their spleen after 15 weeks of gold exposure. A.SW exposed for AuTM showed the induction of anti-nucleolar antibodies (ANoA) with a clumpy staining pattern, as well as an increase in splenic B and T cells. The serum autoantibodies levels in A.SW mice were limited compared to those of A.TL mice. Overall, A.TL presents a stronger immune response after gold exposure than A.SW. The immune response developed in A.TL presents similarities with the clinical manifestations in human autoimmune diseases. Thus, gold-exposed A.TL could constitute a potential experimental mouse model for the study of autoimmunity.

DNA-sensing pathways in health, autoinflammatory and autoimmune diseases.

Detection of microbial DNA is a primary means of host defense. In mammalian cells, DNA-sensing pathways induce robust anti-microbial responses and initiation of adaptive immunity, leading to the eventual clearance of the infectious agent. However, while conferring the advantage of broad detection capability, the sequence-independent recognition mechanisms of most DNA sensors pose a significant challenge for mammalian cells to maintain ignorance to self-DNA under homeostatic conditions. In this Review, we summarize the fundamentals of DNA-sensing pathways and the intricate regulatory networks that keep these pathways in check. In addition, we describe how regulatory restraints can be defective and underlie human autoinflammatory and autoimmune diseases. Further, we discuss therapies in development that limit inflammation fueled by self-DNA or inappropriate activation of DNA-sensing pathways.

Targeting T cells with tetravalent bispecific antibodies for the treatment of graft-versus-host disease

AbstractAllogeneic hematopoietic stem cell transplantation is an established treatment for hematological malignancies and some genetic diseases. Acute graft-versus-host disease (GVHD) is the most common and debilitating side effect with poor survival rates of 5% to 30% for severe cases. In this manuscript, we describe a tetravalent T-cell–engaging bispecific antibody (BsAb) based on the immunoglobulin G-[L]-single-chain variable fragment (IgG-[L]-scFv) platform, with all 4 binding domains specific for CD3. In vitro, picomolar concentrations of the CD3×CD3 BsAb induced potent lysis of activated CD4 and CD8 T cells. In immunodeficient mice, in which human T cells induced xenogeneic GVHD, administration of 0.1 μg BsAb per dose depleted the majority of T cells from the peripheral blood, and 10 μg per dose completely reversed established GVHD and achieved a 100% survival rate. In mice bearing NALM6-luc xenografts, treatment with CD3×CD19 BsAb and activated human T cells induced complete remission of the leukemia, and all treated mice developed GVHD by 50 days after treatment. CD3×CD3 BsAb (3-30 μg doses) reversed clinical signs of GVHD, allowing long term follow-up beyond 250 days. T cells were undetectable by polymerase chain reaction in 4 of 5 mice in the 30 μg CD3×CD3 BsAb group 180 days after leukemia injection, and complete necropsies on day 259 revealed no evidence of human T cells or leukemia cells. Curing GVHD allows for long-term follow-up of tumor response heretofore impossible in humanized mouse models. Further studies are warranted to determine whether the CD3×CD3 BsAb has potential for treating clinical GVHD and other autoimmune diseases in humans.

M6A RNA methylation controls salivary gland epithelial cell function and has a protective role in Sjögren’s disease

ObjectivesThe RNA epitranscriptomic modification known as N6-methyladenosine (m6A) represents a novel mechanism of gene regulation that is poorly understood in human autoimmune diseases. Our research explores the role of this...

Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases

Pro-inflammatory autoantigen-specific CD4+ T helper (auto-Th) cells are central orchestrators of autoimmune diseases (AIDs). We aimed to characterize these cells in human AIDs with defined autoantigens by combining human leukocyte antigen (HLA)-tetramer-based and activation-based multidimensional exvivo analyses. In aquaporin4-antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) patients, auto-Th cells expressed CD154, but proliferative capacity and pro-inflammatory cytokines were strongly reduced. Instead, exhaustion-associated co-inhibitory receptors were expressed together with FOXP3, the canonical regulatory Tcell (Treg) transcription factor. Auto-Th cells responded invitro to checkpoint inhibition and provided potent B cell help. Cells with the same exhaustion-like (ThEx) phenotype were identified in soluble liver antigen (SLA)-antibody-autoimmune hepatitis and BP180-antibody-positive bullous pemphigoid, AIDs of the liver and skin, respectively. While originally described in cancer and chronic infection, our data point to Tcell exhaustion as a common mechanism of adaptation to chronic (self-)stimulation across AID types and link exhausted CD4+ Tcells to humoral autoimmune responses, with implications for therapeutic targeting.

Recipient IL-17A polymorphism rs2275913 is associated with acute graft-versus-host disease after single-unit cord blood transplantation

BackgroundInterleukin-17 (IL-17) is elevated in human inflammatory and autoimmune diseases. The polymorphism in the promoter region of the IL-17 A gene is associated with susceptibility to several inflammatory diseases, including acute graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation from adult donors. However, the impacts of IL-17 A polymorphism on cord blood transplantation (CBT) outcomes remain unclear. ObjectiveThe objective of this study was to assess the impact of IL-17 A polymorphism rs2275913 on GVHD, survival, relapse, non-relapse mortality (NRM), and hematopoietic recovery after CBT. Study DesignWe conducted a retrospective analysis of data from adult patients who underwent single-unit CBT at our institution from January 2005 to March 2023 for whose recipient or donor DNA samples were available. IL-17 A genotyping was performed using real-time polymerase chain reaction with the TaqMan® SNP genotyping assay for rs2275913. ResultsA total of 158 recipients and 136 donors were evaluated in this study. Multivariate analysis showed that rs2275913 GA or AA recipients were associated with increased risk of grades II to IV acute GVHD compared to GG recipients (hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.00–2.13; P = 0.047). Serum IL-17 A levels at eight weeks were significantly higher in rs2275913 GA or AA recipients compared to GG. The rs2275913 polymorphism did not affect survival, relapse, NRM, or hematopoietic recovery after single-unit CBT. ConclusionOur data showed recipient IL-17 A polymorphism rs2275913 was associated with the risk of grade II to IV acute GVHD in adults undergoing single-unit CBT. However, the rs2275913 polymorphism in recipients and donors did not affect survival or relapse. Thus, the polymorphism of IL-17 A rs2275913 in recipients might predict the risk of acute GVHD after single-unit CBT.

The function of long non-coding RNA IFNG-AS1 in autoimmune diseases.

The prevalence of autoimmune diseases ranks as the third most common disease category globally, following cancer and heart disease. Numerous studies indicate that long non-coding RNA (lncRNA) plays a pivotal role in regulating human growth, development, and the pathogenesis of various diseases. It is more than 200 nucleotides in length and is mostly involve in the regulation of gene expression. Furthermore, lncRNAs are crucial in the development and activation of immune cells, with an expanding body of research exploring their association with autoimmune disorders in humans. LncRNA Ifng antisense RNA 1 (IFNG-AS1), a key regulatory factor in the immune system, also named NeST or TMEVPG1, is proximally located to IFNG and participates in the regulation of it. The dysregulation of IFNG-AS1 is implicated in the pathogenesis of several autoimmune diseases. This study examines the role and mechanism of IFNG-AS1 in various autoimmune diseases and considers its potential as a therapeutic target.

Interconnected lineage trajectories link conventional and natural killer (NK)-like exhausted CD8+ T cells beneficial in type 1 diabetes

Distinct Natural Killer (NK)-like CD57+ and PD-1+ CD8+ exhausted-like T cell populations (Tex) have both been linked to beneficial immunotherapy response in autoimmune type 1 diabetes (T1D) patients. The origins and relationships between these cell types are poorly understood. Here we show that while PD-1+ and CD57+ Tex populations are epigenetically similar, CD57+ Tex cells display unique increased chromatin accessibility of inhibitory Killer Cell Immunoglobulin-like Receptor (iKIR) and other NK cell genes. PD-1+ and CD57+ Tex also show reciprocal expression of Inhibitory Receptors (IRs) and iKIRs accompanied by chromatin accessibility of Tcf1 and Tbet transcription factor target sites, respectively. CD57+ Tex show unappreciated gene expression heterogeneity and share clonal relationships with PD-1+ Tex, with these cells differentiating along four interconnected lineage trajectories: Tex-PD-1+, Tex-CD57+, Tex-Branching, and Tex-Fluid. Our findings demonstrate new relationships between Tex-like populations in human autoimmune disease and suggest that modulating common precursor populations may enhance response to autoimmune disease treatment.

Exploring the relationship between infectious agents and autoimmune diseases: a review.

The relationship between infectious agents and autoimmune diseases is a complex issue. In recent years, increasing clinical cases have indicated that infectious agents play an important role in the development of autoimmune diseases. Molecular mimicry is currently widely regarded as the primary pathogenic mechanism of various autoimmune diseases in humans. Components of infectious agents can undergo molecular mimicry with components in patients' bodies, leading to the development of various autoimmune diseases. In this article, we provide a brief overview of current research of the current research status on the relationship between infectious agents and autoimmune diseases, and describe our current understanding of their mechanisms of action in order to better understand the pathogenesis, diagnosis, and treatment of autoimmune diseases.

Topical ophthalmic instillation of engineered hMSCs-derived exosomes: A novel non-invasive therapeutic strategy for ocular posterior-segment disorder

Due to the presence of protective mechanisms and blood-ocular barriers in the eye, drugs aimed at treating posterior segment ophthalmic disorder have to be administrated mostly through periocular or intravitreal injection. In the current study, we sought to investigate whether topical ophthalmic instillation of human mesenchymal stem cells (hMSCs)-derived exosomes can prevent and treat experimental autoimmune uveitis (EAU), a posterior segment ophthalmic disease induced in animals and considered a model of human autoimmune diseases of the eye. Our studies reveal that topical ophthalmic instillation of hMSCs-derived exosomes can effectively ameliorate EAU. More importantly, we demonstrate that exosomes modified by trans-activator of transcription peptide (TAT) were more effective than naive exosomes in penetrating ocular barrier and preventing/treating EAU. Taken together, these results indicate that topical ophthalmic instillation of TAT-peptide modified exosomes represents a novel non-invasive therapeutic strategy for posterior-segment ophthalmic disorders.

Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans.

Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. Disruption of UNC93B1-mediated regulation by these mutations led to enhanced TLR7/8 responses, and both variants resulted in systemic autoimmune or inflammatory disease when introduced into mice via genome editing. Altogether, our results implicate the UNC93B1-TLR7/8 axis in human monogenic autoimmune diseases and provide a functional resource to assess the impact of yet-to-be-reported UNC93B1 mutations.

Translational kinetic-pharmacodynamics of mRNA-6231, an investigational mRNA therapeutic encoding mutein interleukin-2.

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis by serving as negative regulators of adaptive immune system effector cell responses. Reduced production or function of Tregs has been implicated in several human autoimmune diseases. The cytokine interleukin 2 plays a central role in promoting Treg differentiation, survival, and function invivo and may therefore have therapeutic benefits for autoimmune diseases. mRNA-6231 is an investigational, lipid nanoparticle-encapsulated, mRNA-based therapy that encodes a modified human interleukin 2 mutein fused to human serum albumin (HSA-IL2m). Herein, we report the development of a semi-mechanistic kinetic-pharmacodynamic model to quantify the relationship between subcutaneous dose(s) of mRNA-6231, HSA-IL2m protein expression, and Treg expansion in nonhuman primates. The nonclinical kinetic-pharmacodynamic model was extrapolated to humans using allometric scaling principles and the physiological basis of pharmacological mechanisms to predict the clinical response to therapy a priori. Model-based simulations were used to inform the dose selection and design of the first-in-human clinical study (NCT04916431). The modeling approach used to predict human responses was validated when data became available from the phase I clinical study. This validation indicates that the approach is valuable in informing clinical decision-making.

Sexual Dimorphism in Autoimmune Disorders

Sexual dimorphism exists in Homo sapiens in many systems. Lately, it was found that it also exists in autoimmune disorders. Generally, it was known that the two genders in humans have different endocrine systems, and therefore hormone hormone-regulated systems show sexual dimorphism. However, in the case of autoimmune disorders, it is not due to directly on hormonal milieu but depends on X-chromosome inactivation in males. Whereas every cell in a woman’s body produces Xist; this ribonucleoprotein contains about 81 proteins. This chromosomal inactivation in males and formation of Xist ribonucloprotein in females is responsible for sexual dimorphism in autoimmune disorders in humans.

Lysophosphatidylserine: A Signaling Lipid with Implications in Human Diseases.

Lysophosphatidylserine (lyso-PS) has emerged as yet another important signaling lysophospholipid in mammals, and deregulation in its metabolism has been directly linked to an array of human autoimmune and neurological disorders. It has an indispensable role in several biological processes in humans, and therefore, cellular concentrations of lyso-PS are tightly regulated to ensure optimal signaling and functioning in physiological settings. Given its biological importance, the past two decades have seen an explosion in the available literature toward our understanding of diverse aspects of lyso-PS metabolism and signaling and its association with human diseases. In this Review, we aim to comprehensively summarize different aspects of lyso-PS, such as its structure, biodistribution, chemical synthesis, and SAR studies with some synthetic analogs. From a biochemical perspective, we provide an exhaustive coverage of the diverse biological activities modulated by lyso-PSs, such as its metabolism and the receptors that respond to them in humans. We also briefly discuss the human diseases associated with aberrant lyso-PS metabolism and signaling and posit some future directions that may advance our understanding of lyso-PS-mediated mammalian physiology.

Antigen-specific Fab profiling achieves molecular-resolution analysis of human autoantibody repertoires in rheumatoid arthritis

The presence of autoantibodies is a defining feature of many autoimmune diseases. The number of unique autoantibody clones is conceivably limited by immune tolerance mechanisms, but unknown due to limitations of the currently applied technologies. Here, we introduce an autoantigen-specific liquid chromatography-mass spectrometry-based IgG1 Fab profiling approach using the anti-citrullinated protein antibody (ACPA) repertoire in rheumatoid arthritis (RA) as an example. We show that each patient harbors a unique and diverse ACPA IgG1 repertoire dominated by only a few antibody clones. In contrast to the total plasma IgG1 antibody repertoire, the ACPA IgG1 sub-repertoire is characterised by an expansion of antibodies that harbor one, two or even more Fab glycans, and different glycovariants of the same clone can be detected. Together, our data indicate that the autoantibody response in a prominent human autoimmune disease is complex, unique to each patient and dominated by a relatively low number of clones.

Infectious mononucleosis: new concepts in clinical presentation, epidemiology, and host response.

Infectious mononucleosis (IM) is an infectious disease that presents clinically in only a small percentage of individuals despite almost universal infection with the causative agent. Here, we review the latest concepts in the clinical presentation, epidemiology, and host response of this disease. Several recently published papers/reviews describe IM as a condition caused by one of several etiologic agents including, cytomegalovirus (HHV-5), Roseola virus (HHV-6) and Toxoplasmosis amongst others; this review focuses on IM as solely caused by the human herpes virus 4 (HHV-4). Since the initial discovery of the virus in the 1960s and its subsequent discovery as the primary etiologic agent for IM it has been associated with several human cancers and autoimmune disorders. Recent published findings show a correlation between HHV-4 and the autoimmune disorder, multiple sclerosis (MS), suggesting earlier IM could possibly act as a causative factor. Considering the important links being made with IM to so many cancers and autoimmune disorders it is surprising that a standard investigative procedure has yet to be determined for this disease. A standard approach to the investigation of IM would ensure more cases are diagnosed, particularly atypical cases, this would benefit epidemiological studies, and more immediately help practitioners distinguish viral from bacterial throat infections, enabling them to treat accordingly. The understanding of the latest concepts in clinical presentation, epidemiology and host response to IM would benefit greatly from the introduction of a standard procedure for its investigation and diagnosis.

Abstract 6202: Integrating public single-cell transcriptomics and patient profiles to guide clinical development

Abstract Background: Single-cell technologies provide invaluable insights into disease biology and drug development by revealing complex interactions among different cell types within patients. However, harnessing the potential of publicly available single-cell data remains challenging due to the lack of integrated data across diverse single cell platforms. Methods: To maximize the potential of single cell insights, we have created an AI/ML powered curation and data integration process within our Drug Intelligence Science (DIS®) platform. This automated process integrates single cell transcriptomic data from publicly available sources with our in-house generated datasets from ex vivo translational efforts and clinical programs. Relevant public datasets are identified and retrieved using an automated Python-based GEO dataset crawler tool, and standardized metadata are curated. A reference atlas of 31 immune and 4 non-immune cell types is generated from the database and is used to consistently label cells across datasets. Additionally, cell-level gene expression integration and normalization across datasets is achieved using generative modeling techniques. To facilitate multiuser visualization and interrogation of the curated and integrated datasets, we have developed Cellect, a customized version of CellxGene Gateway. Results: The current single-cell database comprises 15 million cells analyzed in >5,000 samples collected from >2,500 patients across 160 curated unique human studies, spanning oncology (56%), autoimmune disease (AID, 21%), and viral infection (15%), with the remaining being from reference healthy tissues (8%). We focused dataset curation on indications of interest for our internal clinical development efforts. Uniquely, data from approximately 300 patients who received standard of care (SOC) treatment including immune checkpoint inhibitor (IO) therapy were integrated to delineate mechanisms of drug response and resistance. The post-SOC resource was used to identify (1) treatment settings where these mechanisms are enriched and (2) markers co-expressed with targets of interest (e.g., PD1, CTLA4, OX40, TNFR2, etc.) in specific cell populations to inform combination strategies. Conclusions: We have presented an AI/ML guided approach to address the key challenge of integrating single-cell data across platforms and demonstrated that relevant disease biology is retained upon integration. We outline a path for deploying this solution at scale for bench and computational scientists to guide target as well as indication selection, as was done for our ongoing clinical programs, including our first-in-class TNFR2 agonist (HFB200301, NCT05238883) and second-generation OX40 agonist (HFB301001, NCT05229601). Citation Format: Jack Russella-Pollard, Joshua Whitener, Jordan Byck, Monika Manne, Hani Alostaz, Marianna Elia, Kamil Krukowski, Gabrielle Wong, Francisco Adrian, Liang Schweizer, Robert H. Andtbacka, Christos Hatzis. Integrating public single-cell transcriptomics and patient profiles to guide clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6202.

Alternative splicing of pre-mRNA modulates the immune response in Holstein cattle naturally infected with Mycobacterium avium subsp. paratuberculosis.

Little is known about the role of alternative splicing (AS) in regulating gene expression in Mycobacteria-infected individuals in distinct stages of infection. Pre-mRNA AS consists of the removal of introns and the assembly of exons contained in eukaryotic genes. AS events can influence transcript stability or structure with important physiological consequences. Using RNA-Seq data from peripheral blood (PB) and ileocecal valve (ICV) samples collected from Holstein cattle with focal and diffuse paratuberculosis (PTB)-associated histopathological lesions in gut tissues and without lesions (controls), we detected differential AS profiles between the infected and control groups. Four of the identified AS events were experimentally validated by reverse transcription-digital droplet PCR (RT-ddPCR). AS events in several genes correlated with changes in gene expression. In the ICV of animals with diffuse lesions, for instance, alternatively spliced genes correlated with changes in the expression of genes involved in endocytosis, antigen processing and presentation, complement activation, and several inflammatory and autoimmune diseases in humans. Taken together, our results identified common mechanisms of AS involvement in the pathogenesis of PTB and human diseases and shed light on novel diagnostic and therapeutic interventions to control these diseases.