Human Autoimmune Diseases Research Articles

Proinflammatory phenotype of B10 and B10pro cells elicited by TNF-α in rheumatoid arthritis

ObjectivesB10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these...

Muscarinic control of cardiovascular function in humans: a review of current clinical evidence.

To review the available evidence on the impact of muscarinic receptor modulation on cardiovascular control in humans. In this narrative Review we summarize data on cardiovascular endpoints from clinical trials of novel subtype-selective or quasi-selective muscarinic modulators, mostly PAMs, performed in the last decade. We also review the cardiovascular phenotype in recently described human genetic and autoimmune disorders affecting muscarinic receptors. Recent advancements in the development of compounds that selectively target muscarinic acetylcholine receptors are expanding our knowledge about the physiological function of each muscarinic receptor subtype (M1, M2, M3, M4, M5). Among these novel compounds, positive allosteric modulators (PAMs) have emerged as the preferred therapeutic to regulate muscarinic receptor subtype function. Many muscarinic allosteric and orthosteric modulators (including but not limited to xanomeline-trospium and emraclidine) are now in clinical development and approaching regulatory approval for multiple indications, including the treatment of cognitive and psychiatric symptoms in patients with schizophrenia as well as Alzheimer's disease and other dementias. The results of these clinical trials provide an opportunity to understand the influence of muscarinic modulation on cardiovascular autonomic control in humans. While the results and the impact of each of these therapies on heart rate and blood pressure control have been variable, in part because the clinical trials were not specifically designed to measure cardiovascular endpoints, the emerging data is valuable to elucidate the relative cardiovascular contributions of each muscarinic receptor subtype. Understanding the muscarinic control of cardiovascular function is of paramount importance and may contribute to the development of novel therapeutic strategies for treating cardiovascular disease.

Biomarkers in skin autoimmunity-An update on localised scleroderma.

Human autoimmune diseases are complex and highly diverse conditions that can be of localised or systemic nature. Understanding the basic biology of autoimmune diseases goes hand in hand with providing the clinics with valuable biomarkers for managing these diseases. The focus of this review is paid to localised scleroderma, an autoimmune disease affecting skin and subcutaneous tissue. Localised scleroderma has very few serological biomarkers for clinical analyses distinguishing it from main differentials, and yet noneffective prognostic biomarkers. With this regard, the review covers well-established and new biomarkers such as cell surface proteins, autoantibodies and cytokines. In recent few years, several new biomarkers have been suggested, many provided with modern genomic studies. This includes epigenetic regulation of DNA, RNA transcriptomics and regulatory RNA such as microRNA and long non-coding RNA. These findings can for the first time shed light on the genetic mechanisms behind the disease and contribute to improved diagnosis and treatment.

Stochastic Sensing of Organotin Compounds with Alpha-Hemolysin Nanopore

Organotin compounds (OTCs) are pollutants that affect the reproduction of some marine organisms and can cause autoimmune diseases in humans. Most of the techniques used for detection and monitoring of OTCs in the environment have limitations due to several stages of sample pre-processing. Here, we demonstrated the use of the α-hemolysin (αHL) nanopore as an alternative platform for the detection of the cyhexatin and diphenyltin dichloride (DPhT) in aqueous systems. The detection process is based on the analysis of the residence times of each OTCs within the unitary nanopore, as well as, on the amplitudes of the blockages in the ionic current flowing through it. Cyhexatin and DPhT induced two and three patterns in the amplitude of the blockages in the ionic current, respectively. Residence time value of the cyhexatin inside the nanopore was higher than the value presented by the DPhT. Molecular docking was used to evaluate the interactions between OTCs and nanopore constriction, mainly identifying cation-π and hydrogen interactions. Classical atomistic molecular dynamic simulations confirm moderate aggregative behavior of these OTCs in solution in cationic form, especially for cyhexatin species. The nanopore detects OTCs at nanomolar level and it is possible to use this nanopore to monitor OTCs in aqueous systems.

Germinal center versus extrafollicular responses in systemic autoimmunity: Who turns the blade on self?

Spontaneously formed germinal centers (GCs) have been reported in most mouse models of human autoimmune disease and autoimmune patients, and have long been considered a source of somatically-mutated and thus high affinity autoantibodies, but their role in autoimmunity is becoming increasingly controversial, particularly in the context of systemic autoimmune diseases like lupus. On the one hand, there is good evidence that some pathogenic lupus antibodies have acquired somatic mutations that increase affinity for self-antigens. On the other hand, recent studies that have genetically prevented GC formation, suggest that GCs are dispensable for systemic autoimmunity, pointing instead to pathogenic extrafollicular (EF) B-cell responses. Furthermore, several lines of evidence suggest germinal centers may in fact be somewhat protective in the context of autoimmunity. Here we review how some of the conflicting evidence arose, and current views on the role of GCs in autoimmunity, outlining mechanisms by which GC may eliminate self-reactivity. We also discuss recent advances in understanding extrafollicular B cell subsets that participate in autoimmunity.

The Intricate Dance of Infections and Autoimmunity: An Interesting Paradox.

Besides genetic susceptibility, infections due to viruses, bacteria and protozoa have been implicated in the development of autoimmune diseases (AD). AD can be triggered in a genetically susceptible individual by infections that disrupt immunological tolerance towards self-antigens. Pathogens can initiate autoimmunity by way of molecular mimicry, bystander activation, epitope spreading or persistent infection with polyclonal activation. This review covers two main topics: (i) the mechanisms by which an infectious agent can trigger or worsen autoimmunity; and (ii) the correlation between specific infectious agents and AD in humans with special emphasis on multisystem inflammatory syndrome in children (MIS-C).

N-3 Polyunsaturated Fatty Acid (N-3 PUFA) Derived Lipid Mediators Increase Hematopoiesis during Zebrafish Embryogenesis

Polyunsaturated fatty acids (PUFAs), which include n-3 PUFAs and n-6 PUFAs, are essential fatty acids that we can only get from diet. The richest source of PUFAs is fish oil. N-3 PUFAs have been used in the prevention and treatment of coronary artery disease, diabetes, hypertension, arthritis, cancer, and other inflammatory and autoimmune disorders in humans. Lipid mediators derived from n-3 PUFAs are implicated in mediating the resolution of inflammation. However, their effect on hematopoietic stem and progenitor cell (HSPC) proliferation and differentiation and on hematopoiesis has not been studied. Therefore, in this project, we investigated the pro-hematopoietic effects of n-3 PUFA-derived lipid mediators. We exposed wild-type zebrafish embryos to different n-3 PUFA-derived lipid mediators. After fixation, we performed whole mount in situ hybridization (WISH) using antisense RNA probes such as c-myb (hematopoietic stem cell marker), gata1 (erythroid progenitor cell marker), hbbe1 (erythrocyte marker), l-plastin (macrophage and neutrophil cell marker ), mpx (neutrophil cell marker), lyz (neutrophil cell marker), and rag1 (immature lymphocyte marker); reverse transcription-quantitative polymerase chain reaction (RT-qPCR); and fluorescence-activated cell sorting (FACS) to understand the effect of lipid mediator exposure on the proliferation of HSPCs, erythroid progenitor cells, erythrocytes, granulocytic cells, neutrophils, macrophages, and T lymphocytes in different development stages during vertebrate hematopoiesis. In addition, we also used o-dianisidine staining to study red blood cell (RBC) formation and transgenic zebrafish to observe different blood lineages including HSPCs, neutrophils, macrophages, erythroid progenitors, and erythrocytes with fluorescent microscopy. We identified two novel lipid mediators which promote HSPC proliferation, enhance erythroid progenitor cell and erythrocyte production, and increase neutrophil cell number. These two molecules could be applied as novel therapeutics for blood disorders and blood cancers such as anemia and leukemia in humans. These two compounds can be intensely investigated to become candidate supplements to enhance HSPC amplification before HSPC transplantation for leukemia patients.

Rs10924104 in the expression enhancer motif of CD58 confers susceptibility to human autoimmune diseases.

CD58 plays roles in cell adhesion and co-stimulation with antigen presentation from major histocompatibility complex class II on antigen-presenting cells to T-cell antigen receptors on naïve T cells. CD58 reportedly contributes to the development of various human autoimmune diseases. Recently, genome-wide association studies (GWASs) identified CD58 as a susceptibility locus for autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and primary biliary cholangitis (PBC). However, the primary functional variant and molecular mechanisms of susceptibility to autoimmune diseases in the CD58 locus were not clarified. Here, rs10924104, located in the ZNF35-binding motif within the gene expression regulatory motif, was identified as the primary functional variant for SLE, MS, and PBC among genetic variants showing stronger linkage disequilibrium (LD) with GWAS-lead variants in the CD58 locus. Expression-quantitative trait locus (e-QTL) data for each distinct blood cell type and in vitro functional analysis using the CRISPR/Cas9 system corroborated the functional role of rs10924104 in the upregulation of CD58 transcription by the disease-risk allele. Additionally, the strength of disease susceptibility observed in the CD58 locus could be accounted for by the strength of LD between rs10924104 and each GWAS-lead variant. In conclusion, the present study demonstrated for the first time the existence of a shared autoimmune disease-related primary functional variant (i.e., rs10924104) that regulates the expression of CD58. Clarifying the molecular mechanism of disease susceptibility derived from such a shared genetic background is important for understanding human autoimmune diseases and human immunology.

Beyond the surface - Autoreactive B cells in human autoimmune diseases

BackgroundThe generation and persistence of autoreactive B and plasma cells is crucial to the pathogenesis of many human autoimmune diseases. Secreted autoantibodies frequently serve as biomarkers in clinical practice and, in some cases, function as pathogenic effector molecules. Nonetheless, the primary break of B cell tolerance against autoantigens, the triggers that maintain autoreactive B cell memory, and the phenotype that autoreactive B cells adopt during the disease course are poorly understood. ObjectivesTo study phenotype and functional characteristics of human autoreactive B cells in the course of human disease using rheumatoid arthritis and the B cell response against posttranslationally modified antigens as prototype. MethodsCombinatorial, antigen-specific identification and multiparameter phenotyping of autoreactive B cells by conventional and spectral flow cytometry in cohorts with well-defined clinical phenotypes, including patients in the phase preceding disease and in those reaching long-term, drugfree remission. ResultsAutoreactive B cells against post-translationally modified proteins operate as remarkably activated effector memory cells in patients with established disease and maintain this state throughout the disease course. The activation generates cytokine-secreting germinal center emigrants that resist conventional therapy, and migratory plasmablasts expressing homing markers that can direct the cells to sites of inflammation. In the pre-clinical at-risk phase, the degree of activation is lower, and migratory plasmablasts are less frequent. The cells are cross-reactive to different posttranslational modifications and express B cell receptors that are extensively glycosylated in the variable domain. ConclusionsImmune phenotyping of disease-specific, autoreactive B cells reveals heterogeneous features of human autoimmunity that reflect disease stage and course and that are only revealed upon antigen-specific cellular analysis. In rheumatoid arthritis, the picture of germinal center-derived B cell autoreactivity against post-translationally modified antigens emerges that displays extensive cross-reactivity and a likely dependence on T cell help. Such features may be different for other human autoimmune diseases with different disease kinetics, which each may require different strategies for (autoreactive) B cell targeting.

The Role of Chlamydia pneumoniae in the Aetiology of Autoimmune Diseases.

Introduction The most prevalent chronic human autoimmune disorder worldwide is rheumatoid arthritis. Synovial samples from acute-phase patients are polymerase chain reaction-positive for Chlamydia pneumoniae (C. pneumoniae)DNA and express chlamydial hsp60. Furthermore, anti-cyclic citrullinated peptide (anti-CCP) antibodies promote apoptosis of mature human Saos-2 osteoblasts via cell surface binding to citrullinated heat shock protein 60 (HSP60). Hence, we hypothesised that C. pneumoniae infection is associated with anti-CCP antibodies. Methods C. pneumoniae IgA and anti-CCP antibody levels were determined in 26 healthy subjects in this cross-sectional study. Serum C. pneumoniae IgA antibody levels were assessed using an enzyme-linked immunosorbent assay. Serum anti-CCP antibody levels were assessed using fluoroenzymeimmunoassay. Results There was a highly significant positive correlation between the two sets of antibodies (rs = 0.621; P = 0.0007). Linear regression analysis showed that this correlation was not the result of age or sex. Discussion A biologically plausible mechanism is put forward for these results, involving HSP60 acting as an endogenous ligand for toll-like receptor 4 (TLR4) and the interaction of TLR4 with lipopolysaccharides, which occur in the outer membrane of the C. pneumoniae elementary body. Pronounced pro-inflammatory mediator secretion then takes place. The release of Ca2+ ions may then activate local peptidylarginine deiminases, leading to the formation of CCPs and thus the reported finding. Confirmation of these results may have potential clinical implications in terms of diagnosis, including pre-symptomatic diagnosis, and treatment.

Chicken IFI6 inhibits avian reovirus replication and affects related innate immune signaling pathways.

Interferon-alpha inducible protein 6 (IFI6) is an important interferon-stimulated gene. To date, research on IFI6 has mainly focused on human malignant tumors, virus-related diseases and autoimmune diseases. Previous studies have shown that IFI6 plays an important role in antiviral, antiapoptotic and tumor-promoting cellular functions, but few studies have focused on the structure or function of avian IFI6. Avian reovirus (ARV) is an important virus that can exert immunosuppressive effects on poultry. Preliminary studies have shown that IFI6 expression is upregulated in various tissues and organs of specific-pathogen-free chickens infected with ARV, suggesting that IFI6 plays an important role in ARV infection. To analyze the function of avian IFI6, particularly in ARV infection, the chicken IFI6 gene was cloned, a bioinformatics analysis was conducted, and the roles of IFI6 in ARV replication and the innate immune response were investigated after the overexpression or knockdown of IFI6 in vitro. The results indicated that the molecular weight of the chicken IFI6 protein was approximately 11 kDa and that its structure was similar to that of the human IFI27L1 protein. A phylogenetic tree analysis of the IFI6 amino acid sequence revealed that the evolution of mammals and birds was clearly divided into two branches. The evolutionary history and homology of chickens are similar to those of other birds. Avian IFI6 localized to the cytoplasm and was abundantly expressed in the chicken lung, intestine, pancreas, liver, spleen, glandular stomach, thymus, bursa of Fabricius and trachea. Further studies demonstrated that IFI6 overexpression in DF-1 cells inhibited ARV replication and that the inhibition of IFI6 expression promoted ARV replication. After ARV infection, IFI6 modulated the expression of various innate immunity-related factors. Notably, the expression patterns of MAVS and IFI6 were similar, and the expression patterns of IRF1 and IFN-β were opposite to those of IFI6. The results of this study further advance the research on avian IFI6 and provide a theoretical basis for further research on the role of IFI6 in avian virus infection and innate immunity.

TIPE proteins control directed migration of human T cells by directing GPCR and lipid second messenger signaling.

Tissue infiltration by circulating leukocytes via directed migration (also referred to as chemotaxis) is a common pathogenic mechanism of inflammatory diseases. G protein-coupled receptors (GPCRs) are essential for sensing chemokine gradients and directing the movement of leukocytes during immune responses. The tumor necrosis factor α-induced protein 8-like (TIPE or TNFAIP8L) family of proteins are newly described pilot proteins that control directed migration of murine leukocytes. However, how leukocytes integrate site-specific directional cues, such as chemokine gradients, and utilize GPCR and TIPE proteins to make directional decisions are not well understood. Using both gene knockdown and biochemical methods, we demonstrated here that 2 human TIPE family members, TNFAIP8 and TIPE2, were essential for directed migration of human CD4+ T cells. T cells deficient in both of these proteins completely lost their directionality. TNFAIP8 interacted with the Gαi subunit of heterotrimeric (α, β, γ) G proteins, whereas TIPE2 bound to PIP2 and PIP3 to spatiotemporally control immune cell migration. Using deletion and site-directed mutagenesis, we established that Gαi interacted with TNFAIP8 through its C-terminal amino acids, and that TIPE2 protein interacted with PIP2 and PIP3 through its positively charged amino acids on the α0 helix and at the grip-like entrance. We also discovered that TIPE protein membrane translocation (i.e. crucial for sensing chemokine gradients) was dependent on PIP2. Collectively, our work describes a new mechanistic paradigm for how human T cells integrate GPCR and phospholipid signaling pathways to control directed migration. These findings have implications for therapeutically targeting TIPE proteins in human inflammatory and autoimmune diseases.

From the sideline: Tissue-specific nucleoporin function in health and disease, an update.

The subcellular compartmentalisation of eukaryotic cells requires selective exchange between the cytoplasm and the nucleus. Intact nucleocytoplasmic transport is vital for normal cell function and mutations in the executing machinery have been causally linked to human disease. Central players in nucleocytoplasmic exchange are nuclear pore complexes (NPCs), which are built from ~30 distinct proteins collectively termed nucleoporins. Aberrant nucleoporin expression was detected in human cancers and autoimmune diseases since quite some time, while it was through the increasing use of next generation sequencing that mutations in nucleoporin genes associated with mainly rare hereditary diseases were revealed. The number of newly identified mutations is steadily increasing, as is the number of diseases. Mutational hotspots have emerged: mutations in the scaffold nucleoporins seemingly affect primarily inner organs, such as heart, kidney, and ovaries, whereas genetic alterations in peripheral, cytoplasmic nucleoporins affect primarily the central nervous system and development. In this review, we summarise latest insights on altered nucleoporin function in the context of human hereditary disorders, with a focus on those where mechanistic insights are beginning to emerge.

Structure-Activity Relationship and Biological Investigation of a REV-ERBα-Selective Agonist SR-29065 (34) for Autoimmune Disorders.

Autoimmune diseases affect 50 million Americans, predominantly women, and are thought to be one of the top 10 leading causes of death among women in age groups up to 65 years. A central role for TH17 cells has been highlighted by genome-wide association studies (GWAS) linking genes preferentially expressed in TH17 cells to several human autoimmune diseases. We and others have reported that the nuclear receptors REV-ERBα and β are cell-intrinsic repressors of TH17 cell development and pathogenicity and might therefore be therapeutic targets for intervention. Herein, we describe detailed SAR studies of a novel REV-ERBα-selective scaffold. Metabolic stability of the ligands was optimized allowing for in vivo interrogation of the receptor in a mouse model of multiple sclerosis (EAE) with a ligand (34). Reduction in frequency and number of T-cells in the CNS as well as key REV-ERB target genes is a measure of target engagement in vivo.

Autoreactive B cells in rheumatoid arthritis include mainly activated CXCR3+ memory B cells and plasmablasts.

Many autoimmune diseases (AIDs) are characterized by persistence of autoreactive B cell responses which is often directly implicated in disease pathogenesis. How and why these cells are generated or how they are maintained for years is largely unknown. Rheumatoid arthritis is among the most common AIDs and characterized by autoantibodies recognizing proteins with post-translational modifications (PTMs). This PTM-directed, autoreactive B cell compartment is ill defined. Here, we visualized the B cell response against the three main types of PTM antigens implicated in RA by spectral flow cytometry. Our results showed extensive cross-reactivity of PTM-directed B cells against all three PTM antigens (citrulline, homocitrulline and acetyllysine). Unsupervised clustering revealed several distinct memory B cell (mBC) populations. PTM-directed cells clustered with the most recently activated, class-switched mBC phenotype, expressing high CD80, low CD24 and low CD21. Notably, patients also harbored large fractions of PTM-directed plasmablasts (PB). Both PTM-directed mBC and PB showed high expression of CXCR3, a receptor for chemokines abundantly present in arthritic joints. Together, our data provide detailed insight into the biology of B cell autoreactivity and its remarkable, seemingly exhaustless persistence in a prominent human AID.

Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling

Toll-like receptors (TLRs) are a class of proteins that play critical roles in recognizing pathogens and initiating innate immune responses. TASL, a recently identified innate immune adaptor protein for endolysosomal TLR7/8/9 signaling, is recruited by the lysosomal proton-coupled amino-acid transporter SLC15A4, and then activates IRF5, which in turn triggers the transcription of type I interferons and cytokines. Here, we report three cryo-electron microscopy (cryo-EM) structures of human SLC15A4 in the apo monomeric and dimeric state and as a TASL-bound complex. The apo forms are in an outward-facing conformation, with the dimeric form showing an extensive interface involving four cholesterol molecules. The structure of the TASL-bound complex reveals an unprecedented interaction mode with solute carriers. During the recruitment of TASL, SLC15A4 undergoes a conformational change from an outward-facing, lysosomal lumen-exposed state to an inward-facing state to form a binding pocket, allowing the N-terminal helix of TASL to be inserted into. Our findings provide insights into the molecular basis of regulatory switch involving a human solute carrier and offers an important framework for structure-guided drug discovery targeting SLC15A4-TASL-related human autoimmune diseases.

Complement.

The role of complement in human autoimmune, inflammatory, and infectious diseases is reviewed, focusing on clinical applicability. A typical case is presented in which serum testing for C3 and C4 is performed to help assess a syndrome with a broad differential diagnosis. The review includes a discussion of complement deficiency states, consumption of complement by diseases characterized by immune-complex formation and deposition, usefulness and interpretation of laboratory tests for complement, and development of drugs targeting specific components of the complement pathway for a growing number of indications.

Proliferative glomerulonephritis with monoclonal IgG Lambda deposits caused by plasmablastic lymphoma: a case report

IntroductionAs a very rare form of B-cell lymphoma, plasmablastic lymphoma (PBL) typically occurs in patients with underlying immunosuppression, including human immunodeficiency virus (HIV), organ transplantation, and autoimmune diseases. For HIV-positive patients, PBL normally originates in the gastrointestinal tract, especially from the oral cavity in most cases. It is extremely rare to find abdominal cavity involvement in PBL, and there has been no previously reported instance of proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) attributed to monoclonal IgG (MIgG) lambda secreted by PBL.Case presentationWe report the case of an HIV-negative female with nephrotic syndrome, renal insufficiency, and multiple swollen lymph nodes. Ascitic fluid cytology revealed a high level of plasmablast-like lymphocytes with the restriction of lambda light chains. Besides, the renal biopsy revealed PGNMID, which could presumably be secondary to MIgG-lambda-secreting by PBL. MIgG-lambda-restricted expression was discovered earlier in the kidney tissue than in the blood.ConclusionThe diagnostic landscape for PBL is notoriously intricate, necessitating a multifaceted and nuanced approach to mitigate the risks of erroneous identification.

Bioinformatics-based analysis of the roles of basement membrane-related gene AGRN in systemic lupus erythematosus and pan-cancer development.

Systemic lupus erythematosus (SLE) is an autoimmune disease involving many systems and organs, and individuals with SLE exhibit unique cancer risk characteristics. The significance of the basement membrane (BM) in the occurrence and progression of human autoimmune diseases and tumors has been established through research. However, the roles of BM-related genes and their protein expression mechanisms in the pathogenesis of SLE and pan-cancer development has not been elucidated. In this study, we applied bioinformatics methods to perform differential expression analysis of BM-related genes in datasets from SLE patients. We utilized LASSO logistic regression, SVM-RFE, and RandomForest to screen for feature genes and construct a diagnosis model for SLE. In order to attain a comprehensive comprehension of the biological functionalities of the feature genes, we conducted GSEA analysis, ROC analysis, and computed levels of immune cell infiltration. Finally, we sourced pan-cancer expression profiles from the TCGA and GTEx databases and performed pan-cancer analysis. We screened six feature genes (AGRN, PHF13, SPOCK2, TGFBI, COL4A3, and COLQ) to construct an SLE diagnostic model. Immune infiltration analysis showed a significant correlation between AGRN and immune cell functions such as parainflammation and type I IFN response. After further gene expression validation, we finally selected AGRN for pan-cancer analysis. The results showed that AGRN's expression level varied according to distinct tumor types and was closely correlated with some tumor patients' prognosis, immune cell infiltration, and other indicators. In conclusion, BM-related genes play a pivotal role in the pathogenesis of SLE, and AGRN shows immense promise as a target in SLE and the progression of multiple tumors.

An unexpected role of neutrophils in clearing apoptotic hepatocytes in vivo.

Billions of apoptotic cells are removed daily in a human adult by professional phagocytes (e.g. macrophages) and neighboring nonprofessional phagocytes (e.g. stromal cells). Despite being a type of professional phagocyte, neutrophils are thought to be excluded from apoptotic sites to avoid tissue inflammation. Here, we report a fundamental and unexpected role of neutrophils as the predominant phagocyte responsible for the clearance of apoptotic hepatic cells in the steady state. In contrast to the engulfment of dead cells by macrophages, neutrophils burrowed directly into apoptotic hepatocytes, a process we term perforocytosis, and ingested the effete cells from the inside. The depletion of neutrophils caused defective removal of apoptotic bodies, induced tissue injury in the mouse liver, and led to the generation of autoantibodies. Human autoimmune liver disease showed similar defects in the neutrophil-mediated clearance of apoptotic hepatic cells. Hence, neutrophils possess a specialized immunologically silent mechanism for the clearance of apoptotic hepatocytes through perforocytosis, and defects in this key housekeeping function of neutrophils contribute to the genesis of autoimmune liver disease.