Vanja Sisirak

New York University | NYU · Department of Pathology

Autoantibodies to chromatin and dsDNA are a hallmark of systemic lupus erythematosus (SLE). In a mouse model of monogenic human SLE caused by DNASE1L3 deficiency, the anti-DNA response is dependent on endosomal nucleic acid-sensing TLRs TLR7 and TLR9. In this study, we report that this response also required TLR2, a surface receptor for microbial p...

Dendritic cells (DCs) are antigen-presenting cells (APCs) that shape innate and adaptive immunity. There are multiple subsets of DCs distinguished according to their phenotype and functional specialization. DCs are present in lymphoid organs and across multiple tissues. However, their frequency and numbers at these sites are very low making their f...

Dendritic cells are cells of hematopoietic origin that are specialized in antigen presentation and instruction of innate and adaptive immune responses. They are a heterogenous group of cells populating lymphoid organs and most tissues. Dendritic cells are commonly separated in three main subsets that differ in their developmental paths, phenotype,...

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (T reg ) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interact...

[This corrects the article DOI: 10.3389/fimmu.2021.629922.].

Antibodies to double-stranded DNA (dsDNA) are prevalent in systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis, yet the nature and regulation of antigenic cell-free DNA (cfDNA) are poorly understood. Null mutations in the secreted DNase DNASE1L3 cause human monogenic SLE with anti-dsDNA autoreactivity. We report that >...

Detection of microbial nucleic acids by the innate immune system is mediated by numerous intracellular nucleic acids sensors. Upon the detection of nucleic acids these sensors induce the production of inflammatory cytokines, and thus play a crucial role in the activation of anti-microbial immunity. In addition to microbial genetic material, nucleic...

Obesity and overweight are a global health problem affecting almost one third of the world population. There are multiple complications associated with obesity including metabolic syndrome that commonly lead to development of type II diabetes and non-alcoholic fatty liver disease. The development of metabolic syndrome and severe complications assoc...

Dendritic cells (DCs) are at the interface between innate and adaptive immune responses. The implication of DCs is clearly established in autoimmune diseases. In systemic lupus erythematosus (SLE), activation of the DC system is a key player causing immunologic dysfunctions. Plasmacytoid dendritic cells (pDC) are activated indirectly or directly by...

Background: Microparticles (MPs) are vesicular structures that derive from multiple cellular sources. MPs play important roles in intercellular communication, regulation of cell signaling or initiation of enzymatic processes. While MPs were characterized in Systemic Sclerosis (SSc) patients, their contribution to SSc pathogenesis remains unknown....

Class-switched antibodies to double-stranded DNA (dsDNA) are prevalent and pathogenic in systemic lupus erythematosus (SLE), yet mechanisms of their development remain poorly understood. Humans and mice lacking secreted DNase DNASE1L3 develop rapid anti-dsDNA antibody responses and SLE-like disease. We report that anti-DNA responses in Dnase1l3−/−...

Circulating DNA in plasma consists of short DNA fragments. The biological processes generating such fragments are not well understood. DNASE1L3 is a secreted DNASE1-like nuclease capable of digesting DNA in chromatin, and its absence causes anti-DNA responses and autoimmunity in humans and mice. We found that the deletion of Dnase1l3 in mice result...

Inflammatory bowel disease (IBD) is a chronic inflammatory condition caused by an aberrant immune response to microbial components of the gastrointestinal tract. Plasmacytoid dendritic cells (pDCs) are innate immune cells specialized in the production of type I interferons and were recently implicated in the pathogenesis of autoimmune disorders suc...

Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by three interconnected hallmarks (i) vasculopathy, (ii) aberrant immune activation, and (iii) fibroblast dysfunction leading to extracellular matrix deposition and fibrosis. Blocking or reversing the fibrotic process associated with this devastating disease is still an un...

Although targeted therapies have greatly improved the prognosis of several tumors, they do not achieve complete remission and do not prevent secondary resistance. In addition, while the immune system is one of the main barriers protecting the body against tumor development, the anti-tumor immune response is compromised in cancer patients. In this c...

Graphical Abstract Highlights d Rapid anti-DNA antibody response, followed by SLE in Dnase1l3-deficient mice d Autoreactivity is repressed by circulating DNASE1L3 and is independent of STING d DNASE1L3 digests genomic DNA in microparticles released from apoptotic cells d DNASE1L3 prevents autoantibody binding to chromatin on microparticle surface I...

Graphical Abstract Highlights d Rapid anti-DNA antibody response, followed by SLE in Dnase1l3-deficient mice d Autoreactivity is repressed by circulating DNASE1L3 and is independent of STING d DNASE1L3 digests genomic DNA in microparticles released from apoptotic cells d DNASE1L3 prevents autoantibody binding to chromatin on microparticle surface I...

Antibodies to DNA and chromatin drive autoimmu- nity in systemic lupus erythematosus (SLE). Null mu- tations and hypomorphic variants of the secreted deoxyribonuclease DNASE1L3 are linked to familial and sporadic SLE, respectively. We report that DNASE1L3-deficient mice rapidly develop autoanti- bodies to DNA and chromatin, followed by an SLE- like...

Intestinal dendritic cells (DCs) orchestrate gut immune homeostasis by dampening pro-inflammatory T-cell responses and inducing anti-inflammatory IgA responses. Although no specific DC subset has been strictly assigned so far to govern IgA response, some candidate subsets emerge. In particular, plasmacytoid DCs (pDCs), which notoriously promote ant...

Whether fibroblasts regulate immune response is a crucial issue in the modulation of inflammatory responses. Herein, we demonstrate that foreskin fibroblasts (FFs) potently inhibit CD3(+) T cell proliferation through a mechanism involving early apoptosis of activated T cells. Using blocking antibodies, we demonstrate that the inhibition of T cell p...

Plasmacytoid dendritic cells (pDCs) are primary producers of type I interferon (IFN) in response to viruses. The IFN-producing capacity of pDCs is regulated by specific inhibitory receptors, yet none of the known receptors are conserved in evolution. We report that within the human immune system, receptor protein tyrosine phosphatase sigma (PTPRS)...

Plasmacytoid dendritic cells (pDC) are the main producers of type I IFNs in response to viral and self nucleic acids that trigger endosomal TLR7 and 9. They have been recently described in various solid tumors. In breast tumors, we demonstrated that tumor-associated (TA)pDC exhibit a partially mature phenotype, suggesting that endogenous activating...

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of antibodies to self-nucleic acids, immune complex deposition, and tissue inflammation such as glomerulonephritis. Innate recognition of self-DNA and -RNA and the ensuing production of cytokines such as type I interferons (IFNs) contribute to SLE developme...

Plasmacytoid dendritic cells (pDCs) rapidly produce type I interferon (IFN-I) in response to viruses and are essential for antiviral immune responses. Although related to classical DCs (cDCs) in their development and expression profile, pDCs possess many distinct features. Unlike cDCs, pDCs develop in the bone marrow (BM) and emerge into peripheral...

We previously reported that plasmacytoid dendritic cells (pDCs) infiltrating breast tumors are impaired for their interferon-α (IFN-α) production, resulting in local regulatory T cells amplification. We designed our study to decipher molecular mechanisms of such functional defect of tumor-associated pDC (TApDC) in breast cancer. We demonstrate that...

Dendritic cells (DCs) initiate and shape both the innate and adaptive immune responses. Accordingly, recent evidence from clinical studies and experimental models implicates DCs in the pathogenesis of most autoimmune diseases. However, fundamental questions remain unanswered concerning the actual roles of DCs in autoimmunity, both in general and, i...

Plasmacytoid dendritic cells (pDC) are key regulators of antiviral immunity. In previous studies, we reported that pDC infiltrating human primary breast tumors represent an independent prognostic factor associated with poor outcome. In order to understand this negative impact of tumor-associated pDC (TApDC) we developed an orthotopic murine mammary...

The accumulation of plasmacytoid dendritic cells (pDCs) within breast carcinoma lesions is associated with a poor clinical outcome. We demonstrated that the deleterious impact of tumor-associated pDCs (TApDCs) is due to their impaired capacity to produce Type I interferon, which in turn potentiates their ability to sustain the proliferation of immu...

Regulatory T cells (Tregs) and plasmacytoid dendritic cells (pDCs) that infiltrate primary breast tumors impair patient survival. The ICOS-mediated interaction between tumor-infiltrating CD4(+) T cells and pDCs leads to the amplification of Tregs and interleukin-10 secretion. Importantly, ICOS(+) cell infiltration correlates with adverse patient pr...

Infiltration and dysfunction of immune cells have been documented in many types of cancers. We previously reported that plasmacytoid dendritic cells (pDC) within primary breast tumors correlate with an unfavorable prognosis for patients. The role of pDC in cancer remains unclear but they have been shown to mediate immune tolerance in other pathophy...

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Tumor immunosubversion occurs through various mechanisms including the selective recruitment of CD4+ regulatory T cell (Treg) and the alteration of dendritic cell (DC) physiology. We reported that the presence of high number of both Treg and/or plasmacytoid DC (pDC) corr...

Overexpression of the ErbB2 receptor tyrosine kinase in breast cancer contributes to tumor development and is associated with poor prognosis. However, the mechanism by which ErbB2 might contribute to metastasis is not well defined. To identify genes that mediate ErbB2-driven cell motility, we performed differential gene expression analysis of ErbB2...

Absent in peripheral tissues during homeostasis, human plasmacytoid dendritic cells (pDCs) are described in inflamed skin or mucosa. Here, we report that, unlike blood pDCs, a subset of tonsil pDCs express functional CCR6 and CCR10, and their respective ligands CCL20 and CCL27are detected in inflamed epithelia contacting blood dendritic cell antige...

In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patients. In the tumor and malignant...

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Ovarian carcinomas are usually considered as immunogenic tumors, as they are capable of inducing tumor-associated antigen immunity. However, immune system fails to eradicate established tumors partly due to alteration of immunosurveillance and induction of an active proc...

Plasmacytoid dendritic cells (pDCs) are specialized in rapid and massive secretion of type I interferon (IFN-α/β) in response to foreign nucleic acids. Combined with their antigen presentation capacity, this powerful functionality enables pDCs to orchestrate innate and adaptive immune responses. pDCs combine features of both lymphocytes and classic...

Dendritic cells (DC) are APCs essential for the development of primary immune responses. In pluristratified epithelia, Langerhans cells (LC) are a critical subset of DC which take up Ags and migrate toward lymph nodes upon inflammatory stimuli. TLR allow detection of pathogen-associated molecular patterns (PAMP) by different DC subsets. The reperto...