Deposition Of Autoantibodies Research Articles

Mice with Lymphatic Dysfunction Develop Pathogenic Lung Tertiary Lymphoid Organs that Model an Autoimmune Emphysema Phenotype of COPD.

We have previously shown that mice with loss of C-type lectin-like type II (CLEC2), which have lymphatic dysfunction due to the role of CLEC2 in platelets for maintaining separation between the venous and lymphatic system, develop lung tertiary lymphoid organ (TLO) formation and lung injury that resembles an emphysema phenotype of chronic obstructive pulmonary disease (COPD). We now sought to investigate whether and how TLOs in these mice may play a pathogenic role in lung injury that is relevant to human disease. We found that inhibiting TLO formation using an anti-CD20 antibody in CLEC2-deficient mice partially blocked the development of emphysema. TLOs in CLEC2-deficient mice were rich in plasma cells and were a source of a broad array of autoantibodies. Chronic cigarette smoke exposure increased the size and number of lung TLOs in CLEC2-deficient mice, and was associated with increased markers of antigen presentation and maturation, leading to increased autoantibody deposition. Using lung tissue from COPD patients, we found an increase in lymphatic markers in patients with an emphysema phenotype and autoreactive TLOs compared to COPD patients without emphysema that lack prominent TLOs. Taken together, these results demonstrate that emphysema in mice with lymphatic dysfunction can be partially rescued by blocking TLO formation, and that these TLOs are source of autoantibodies that are exacerbated by cigarette smoke. Our work suggests that lymphatic dysfunction in mice may recapitulate some aspects an autoimmune emphysema phenotype that is seen in a subset of patients with COPD.

Abstract 34: Elevation of Plasma anti-Endothelin A Receptor Autoantibodies in Lupus Subjects Correlates with Plasma Vascular Adhesion Molecule-1 Independent of Blood Pressure

Systemic Lupus Erythematosus (SLE) is an autoimmune disease that is characterized by deposition of autoantibodies and their immune complexes, resulting in inflammation, and end-organ damage to the kidney and vasculature. SLE disproportionally affects women to men (9:1 ratio), with a high prevalence in African American women and patients often have cardiovascular complications including hypertension (HTN). The activation of the endothelin (ET) system has been implicated in numerous pathological disease states including HTN, SLE, and diabetes. Recently, dual ET receptor antagonism was approved for treatment of patients with uncontrolled hypertension. Studies have demonstrated the presence of biologically active endothelin A receptor autoantibodies (ETAR-AAs) in systemic sclerosis and cystic fibrosis patients. Few studies have investigated the role of the synergistic interplay of SLE and HTN on ETAR-AAs. We hypothesized that women with SLE and HTN would have elevated plasma ETAR-AAs compared to control or SLE only subjects. To investigate this, we recruited non-SLE non-HTN controls (n=10), non-SLE HTN (n=10), SLE non-HTN (n=8), and SLE-HTN (n=10) female human subjects and analyzed clinical characteristics, plasma ETAR-AAs, soluble vascular adhesion molecule-1 (sVCAM-1) and soluble intracellular adhesion molecule-1 (sICAM-1). Plasma ETAR-AAs did not significantly correlate with either age (r=-0.1375; p=0.4453) or body mass index (r=-0.3149; p=0.0743). When subjects were categorized by SLE or HTN diagnosis, we found that subjects with SLE had a profound increase in ETAR-AAs compared to non-SLE controls (p<0.0001) while the levels were similar between HTN and non-HTN controls (p=0.7626). Next, we stratified subjects by blood pressure status and found a significant elevation in plasma ETAR-AAs in SLE non-HTN over non-SLE HTN subjects (p=0.0121), while SLE-HTN subjects had significant elevations in ETAR-AAs compared to both non-SLE non-HTN (p=0.0183) and non-SLE HTN (p=0.0014) subjects. We correlated plasma levels of ETAR-AA with sVCAM-1 and sICAM-1 and found that plasma ETAR-AAs were positively associated with plasma sVCAM-1 (r=0.4288; p=0.0114) and sICAM-1 (r=0.3812; p=0.0286). These data indicate that irrespective of blood pressure status, elevated plasma ETAR-AAs are associated with markers of vascular dysfunction in SLE subjects. Further investigation of cell-specific ETAR-AA and ETAR signaling should be performed in murine models and human subjects with SLE.

Type XVII Collagen–Specific CD4+ T Cells Induce Bullous Pemphigoid by Producing IL-5

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease caused by anti-type XVII collagen (COL17) antibodies. BP has some immunological features such as eosinophilic infiltration and the deposition of IgE autoantibodies in the skin; however, the mechanism behind such features remains largely unclear. We focused on the autoantigen-specific CD4+ T cells, which are considered to regulate immune response. We established COL17-specific CD4+ T cell lines in vitro. Wild-type mice were immunized with synthesized peptides that include a pathogenic epitope of COL17, and lymphocytes were subjected to a limiting dilution assay. We established 5 T cell lines and examined the pathogenicity by transferring them with COL17-primed B cells into Rag-2-/-/COL17-humanized mice that express human COL17 but not mouse COL17 in the skin. Notably, 3 lines induced BP-like skin changes associated with subepidermal separation and eosinophilic infiltration histologically, and the production of anti-COL17 antibodies. The other 2 lines did not induce such phenotypes. RNA-sequencing analysis revealed that Th2 cytokines, particularly IL-5, were highly expressed in the pathogenic T cell lines. Anti-IL-5 antibody administration significantly reduced the skin changes and attenuated the production of autoantibodies. Thus, the production of IL-5 is critical for COL17-specific CD4+ T cells to induce BP phenotypes in vivo.

C3aR-initiated signaling is a critical mechanism of podocyte injury in membranous nephropathy.

The deposition of antipodocyte autoantibodies in the glomerular subepithelial space induces primary membranous nephropathy (MN), the leading cause of nephrotic syndrome worldwide. Taking advantage of the glomerulus-on-a-chip system, we modeled human primary MN induced by anti-PLA2R antibodies. Here we show that exposure of primary human podocytes expressing PLA2R to MN serum results in IgG deposition and complement activation on their surface, leading to loss of the chip permselectivity to albumin. C3a receptor (C3aR) antagonists as well as C3AR gene silencing in podocytes reduced oxidative stress induced by MN serum and prevented albumin leakage. In contrast, inhibition of the formation of the membrane-attack-complex (MAC), previously thought to play a major role in MN pathogenesis, did not affect permselectivity to albumin. In addition, treatment with a C3aR antagonist effectively prevented proteinuria in a mouse model of MN, substantiating the chip findings. In conclusion, using a combination of pathophysiologically relevant in vitro and in vivo models, we established that C3a/C3aR signaling plays a critical role in complement-mediated MN pathogenesis, indicating an alternative therapeutic target for MN.

The murine meninges acquire lymphoid tissue properties and harbour autoreactive B cells during chronic Trypanosoma brucei infection.

The meningeal space is a critical brain structure providing immunosurveillance for the central nervous system (CNS), but the impact of infections on the meningeal immune landscape is far from being fully understood. The extracellular protozoan parasite Trypanosoma brucei, which causes human African trypanosomiasis (HAT) or sleeping sickness, accumulates in the meningeal spaces, ultimately inducing severe meningitis and resulting in death if left untreated. Thus, sleeping sickness represents an attractive model to study immunological dynamics in the meninges during infection. Here, by combining single-cell transcriptomics and mass cytometry by time-of-flight (CyTOF) with in vivo interventions, we found that chronic T. brucei infection triggers the development of ectopic lymphoid aggregates (ELAs) in the murine meninges. These infection-induced ELAs were defined by the presence of ER-TR7+ fibroblastic reticular cells, CD21/35+ follicular dendritic cells (FDCs), CXCR5+ PD1+ T follicular helper-like phenotype, GL7+ CD95+ GC-like B cells, and plasmablasts/plasma cells. Furthermore, the B cells found in the infected meninges produced high-affinity autoantibodies able to recognise mouse brain antigens, in a process dependent on LTβ signalling. A mid-throughput screening identified several host factors recognised by these autoantibodies, including myelin basic protein (MBP), coinciding with cortical demyelination and brain pathology. In humans, we identified the presence of autoreactive IgG antibodies in the cerebrospinal fluid (CSF) of second stage HAT patients that recognised human brain lysates and MBP, consistent with our findings in experimental infections. Lastly, we found that the pathological B cell responses we observed in the meninges required the presence of T. brucei in the CNS, as suramin treatment before the onset of the CNS stage prevented the accumulation of GL7+ CD95+ GC-like B cells and brain-specific autoantibody deposition. Taken together, our data provide evidence that the meningeal immune response during chronic T. brucei infection results in the acquisition of lymphoid tissue-like properties, broadening our understanding of meningeal immunity in the context of chronic infections. These findings have wider implications for understanding the mechanisms underlying the formation ELAs during chronic inflammation resulting in autoimmunity in mice and humans, as observed in other autoimmune neurodegenerative disorders, including neuropsychiatric lupus and multiple sclerosis.

Plasmodium curtails autoimmune nephritis via lasting bone marrow alterations, independent of hemozoin accumulation.

The host response against infection with Plasmodium commonly raises self-reactivity as a side effect, and antibody deposition in kidney has been cited as a possible cause of kidney injury during severe malaria. In contrast, animal models show that infection with the parasite confers long-term protection from lethal lupus nephritis initiated by autoantibody deposition in kidney. We have limited knowledge of the factors that make parasite infection more likely to induce kidney damage in humans, or the mechanisms underlying protection from autoimmune nephritis in animal models. Our experiments with the autoimmune-prone FcγR2B[KO] mice have shown that a prior infection with P. yoelii 17XNL protects from end-stage nephritis for a year, even when overall autoreactivity and systemic inflammation are maintained at high levels. In this report we evaluate post-infection alterations, such as hemozoin accumulation and compensatory changes in immune cells, and their potential role in the kidney-specific protective effect by Plasmodium. We ruled out the role of pigment accumulation with the use of a hemozoin-restricted P. berghei ANKA parasite, which induced a self-resolved infection that protected from autoimmune nephritis with the same mechanism as parasitic infections that accumulated normal levels of hemozoin. In contrast, adoptive transfer experiments revealed that bone marrow cells were altered by the infection and could transmit the kidney protective effect to a new host. While changes in the frequency of bone marrow cell populations after infection were variable and unique to a particular parasite strain, we detected a sustained bias in cytokine/chemokine expression that suggested lower fibrotic potential and higher Th1 bias likely affecting multiple cell populations. Sustained changes in bone marrow cell activation profile could have repercussions in immune responses long after the infection was cleared.

Histamine deficiency inhibits lymphocyte infiltration in the submandibular gland of aged mice via increased anti-aging factor Klotho

ObjectivesHistidine decarboxylase (HDC), a histamine synthase, is expressed in various tissues and is induced by proinflammatory cytokines such as TNFα. As they age, C57BL/6 mice show auto-antibody deposition and lymphocyte infiltration into various tissues, including salivary glands. However, the mechanism underlying cell infiltration and the change in HDC expression in salivary glands with aging remain unclear. Thus, we aimed to elucidate the relationship between histamine and inflammaging. MethodsWe investigated the change in histology and HDC expression in the major salivary glands (parotid, submandibular, and sublingual) of 6-week- and 9-month-old wild-type mice. We also determined the histological changes, cytokine expression, and anti-aging factor Klotho in the salivary glands of 9-month-old wild-type and HDC-deficient (HDC-KO) mice. ResultsCell infiltration was observed in the submandibular gland of 9-month-old wild-type mice. Although most cells infiltrating the submandibular glands were CD3-positive and B220-positive lymphocytes, CD11c-positive and F4/80-positive monocyte lineages were also detected. HDC, TNFα, and IL-1β mRNA expression increased in the submandibular gland of 9-month-old wild-type mice. The expression of PPARγ, an anti-inflammatory protein, declined in 9-month-old wild-type mice, and Klotho expression increased in 9-month-old HDC-KO mice. Immunohistochemistry showed that Klotho-positive cells disappeared in the submandibular gland of 9-month-old wild-type mice, while Klotho was detected in all salivary glands in HDC-KO mice of the same age. ConclusionOur findings demonstrate the multifunctionality of histamine and can aid in the development of novel therapeutic methods for inflammatory diseases such as Sjogren's syndrome and age-related dysfunctions.

Loss of FOXP3+ CD25+ Tregs is independent of type I interferon signaling in lupus-prone mice

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by deposition of autoantibodies that leads to tissue damage and inflammation. Our lab has generated the ARE mice strain that has low, chronic levels of IFNg and lupus-like disease. Regulatory T cells (Tregs) play an important role in preventing autoimmunity by suppressing T cell activation, making them an important therapeutic target. In addition, type I interferon (IFN) has also been broadly implicated in SLE but its specific effect on Tregs remain unknown. To address the impact of a type I IFN signature on the dynamics of regulatory T cells (Tregs), we investigated marker expression on Tregs in type I interferon receptor (IFNAR)-deficient ARE mice. Single cell suspensions harvested from spleens and kidneys of ARE −/−, IFNAR −/−, and IFNAR −/−/ARE −/−female mice between 150 to 200 days old were stained with a panel of markers associated with Treg function for analysis by flow cytometry. In the spleen, the proportion of CD4+ FOXP3+ expressing CD25 (IL2Ra) decreased in ARE −/−and IFNAR −/−/ARE −/−, but not IFNAR −/−, compared to wild type (wt). Thus, the disease progression in ARE mice may be due to the loss of bona fide Treg population (FOXP3+ CD25+), as IL-2 contributes to Tregs’ expansion and function. Furthermore, the kidneys of ARE −/−and IFNAR −/−/ARE −/−experienced increased CD4 infiltration as well as a similar decrease in FOX3+ CD25+ Tregs, which might explain the increased inflammation of the kidneys. IFNg-mediated chronic inflammation appears to downregulate the population of FOXP3+ CD25+ Tregs, independent of type I IFN signaling. Future experiments aim to perform in vitroassays to compare the suppressive ability of Tregs with and without CD25.

Interleukin-17A knockout or self-recovery alleviated autoimmune reaction induced by fluoride in mouse testis

Fluoride (F) is usually treated as a hazardous material, and F-caused public health problem has attracted global attention. Previous studies demonstrate that interleukin-17A (IL-17A) plays a crucial role in F-elicited autoimmune orchitis and self-recovery reverses F-induced testicular toxicity to some extent, but these basic mechanisms remain unclear. Thus, we established a 180 d F exposure model of wild type (WT) mice and IL-17A knockout mice (C57BL/6 J background), and 60 d & 120 d self-recovery model based on F exposure model of WT mice, and used various techniques like qRT-PCR, western blot, immunohistochemistry and ELISA to further explore the mechanism of F-induced autoimmune reaction, the role of IL-17A in it and the reversibility of F-caused toxicity in testis. The results indicated that F exposure for 180 d caused the decreased sperm quality, the damaged testis histopathology, the enhanced mRNA and protein expression levels of inflammatory cytokines, the changes of autoantibody such as the appearance and increased content of anti-testicular autoantibodies in sera and the autoantibody deposition in testis, the alterations of autoimmune related genes containing the decreased mRNA and protein expressions of AIRE and FOXP3 with an increase of MHCII, and the reduced protein expressions of CTLA4, and the activation of IL-17A signaling cascade like the elevated mRNA and protein expressions of IL-17A, Act1, NF-κB, AP-1 and CEBPβ, and the increased protein expressions of IL-17RC, with a decrease of IκBα. After IL-17A knockout, 29 of 35 F-induced changes were alleviated. In two self-recovery models, all F-caused differences except fluorine concentration in femur were gradually restored in a time-dependent manner. This study concluded that IL-17A knockout or self-recovery attenuated F-induced testicular injury and decrease of sperm quality through alleviating autoimmune reaction which was involved with the activation of IL-17A pathway, the damage of self-tolerance and the enhancement of antigen presentation.

Nutrients and Botanical Medicines in Systemic Lupus Erythematosus

Lupus is a chronic autoimmune disease which can affect multiple systems throughout the body, characterized by the formation and deposition of autoantibodies and immune complexes in vital organs. The goals of standard lupus treatment include the prevention of chronic organ damage and reduction of disease flares, and may include hydroxychloroquine, corticosteroids, and immunosuppressives. A number of botanical medicines or nutrients may have a role alongside conventional management of lupus. These include green tea extract, curcumin, Traditional Chinese Medicine herbal formulas, N-acetylcysteine, vitamin D, and fish oil. This article reviews the clinical evidence for these nutrient or herbal medicine-based interventions and discusses outcomes in people with lupus.

Perturbed autophagy intervenes systemic lupus erythematosus by active ingredients of traditional Chinese medicine.

Systemic lupus erythematosus (SLE) is a common multisystem, multiorgan heterozygous autoimmune disease. The main pathological features of the disease are autoantibody production and immune complex deposition. Autophagy is an important mechanism to maintain cell homeostasis. Autophagy functional abnormalities lead to the accumulation of apoptosis and induce the autoantibodies that result in immune disorders. Therefore, improving autophagy may alleviate the development of SLE. For SLE, glucocorticoids or immunosuppressive agents are commonly used in clinical treatment, but long-term use of these drugs causes serious side effects in humans. Immunosuppressive agents are expensive. Traditional Chinese medicines (TCMs) are widely used for immune diseases due to their low toxicity and few side effects. Many recent studies found that TCM and its active ingredients affected the pathological development of SLE by regulating autophagy. This article explains how autophagy interferes with immune system homeostasis and participates in the occurrence and development of SLE. It also summarizes several studies on TCM-regulated autophagy intervention in SLE to generate new ideas for basic research, the development of novel medications, and the clinical treatment of SLE.

Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients.

Bullous pemphigoid (BP), the by far most frequent autoimmune subepidermal blistering disorder (AIBD), is characterized by the deposition of autoantibodies against BP180 (type XVII collagen; Col17) and BP230 as well as complement components at the dermal-epidermal junction (DEJ). The mechanisms of complement activation in BP patients, including the generation of C5a and regulation of its two cognate C5aRs, i.e., C5aR1 and C5aR2, are incompletely understood. In this study, transcriptome analysis of perilesional and non-lesional skin biopsies of BP patients compared to site-, age-, and sex-matched controls showed an upregulated expression of C5AR1, C5AR2, CR1, and C3AR1 and other complement-associated genes in perilesional BP skin. Of note, increased expressions of C5AR2 and C3AR1 were also observed in non-lesional BP skin. Subsequently, double immunofluorescence (IF) staining revealed T cells and macrophages as the dominant cellular sources of C5aR1 in early lesions of BP patients, while C5aR2 mainly expressed on mast cells and eosinophils. In addition, systemic levels of various complement factors and associated molecules were measured in BP patients and controls. Significantly higher plasma levels of C3a, CD55, and mannose-binding lectin-pathway activity were found in BP patients compared to controls. Finally, the functional relevance of C5aR1 and C5aR2 in BP was explored by two in vitro assays. Specific inhibition of C5aR1, resulted in significantly reduced migration of human neutrophils toward the chemoattractant C5a, whereas stimulation of C5aR2 showed no effect. In contrast, the selective targeting of C5aR1 and/or C5aR2 had no effect on the release of reactive oxygen species (ROS) from Col17-anti-Col17 IgG immune complex-stimulated human leukocytes. Collectively, this study delineates a complex landscape of activated complement receptors, complement factors, and related molecules in early BP skin lesions. Our results corroborate findings in mouse models of pemphigoid diseases that the C5a/C5aR1 axis is pivotal for attracting inflammatory cells to the skin and substantiate our understanding of the C5a/C5aR1 axis in human BP. The broad expression of C5aRs on multiple cell types critical for BP pathogenesis call for clinical studies targeting this axis in BP and other complement-mediated AIBDs.

Patterns of Antinuclear Antibodies in a New Variant of Endemic Pemphigus in El Bagre, Colombia, Colocalizing with Antigens against MIZAP, ARVCF, p0071, and Desmoplakins I and II.

A new variant of endemic pemphigus foliaceus (EPF) has been documented, El Bagre-EPF. We aimed to study antinuclear antibodies (ANAs) in these patients. We performed a case-control study, testing 57 patients affected by this disease and 57 controls from the endemic area matched by work activity and demographics. The participants were evaluated clinically as well as by detection of ANAs utilizing HEp-2 cells. We utilized Triton-induced partial permeabilization of the cell membranes, allowing for the visualization of intracellular and intranuclear antigens. We also immunoadsorbed the ANAs using synthetic peptides to elucidate the nature of the ANA. We detected the presence of a new pattern of ANAs. The new pattern of ANAs was seen in 24% of the El Bagre-EPF patients, compared to our controls (P < 0.001). The new ANA pattern consisted of a thin nuclear and nucleolar rim, finely speckled nucleolar, nuclear membrane pores stains, and a positive intranuclear stain directed against small nuclear components, as well as cytoplasmic deposits of autoantibodies were also observed. The new ANAs pattern perfectly colocalized with commercial antibodies to miocardium-enriched zonula occlusans-1 associated protein (MIZAP), armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF), p0071 and desmoplakins I-II (all from Progen Biotechnik). Additionally in 14% of patients with El Bagre-EPF forme fruste and hyperpigmented clinical presentations, a classic homogeneous ANA pattern was observed with autoantibodies specific for Ro, La, Sm, and double-stranded DNA antigens. Immunoadsorption with peptide-based sequences from MIZAP, ARVCF, p0071 and desmoplakins I-II removed the new ANA pattern. We describe a new pattern of ANAs in El Bagre-EPF, colocalizing with autoantibodies directed against MIZAP, ARVCF, p0071, and desmoplakins I-II.

Antibody deposition on vascular endothelial cells contributes to localized inflammation in salivary glands.

Oral and ocular dryness due to reduced saliva and tear production, exocrine gland inflammation, and autoantibodies to multiple cellular proteins are the cardinal features of Sjögren's Disease. Among the autoantibody specificities, anti-Ro52 is linked with higher disease severity. We have previously reported that mice immunized with recombinant Ro52 developed IgG deposits in salivary and lacrimal glands and showed reduced saliva and tear production. Furthermore, passive transfer of sera from Ro52-immunized mice rapidly induced glandular dysfunction without immune cell infiltration in recipient mice. To identify mechanisms driving antibody-mediated salivary gland dysfunction, hyperimmune rabbit antiserum to mouse Ro52 was passively transferred into NZM2758 female mice, pretreated with alum adjuvant. Alum-pretreated mice given hyperimmune rabbit antiserum to maltose-binding protein served as controls. Antibody deposition and its distribution in the salivary glands were studied by immunofluorescence staining for rabbit IgG, nerve fibers, and endothelial cells. The nCounter inflammation panel was used to determine differentially expressed genes in the salivary gland. Rabbit IgG deposits were detected in salivary glands of anti-Ro52 immune sera recipients. The rabbit IgG was present on the endothelial cells in small blood vessels, and it did not co-localize with nerve fibers. Ingenuity pathway analysis of the gene expression dataset predicted the canonical vascular endothelial growth factor (VEGF) pathway as the most activated and Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) as the most inhibited pathway in the salivary glands of anti-Ro52 sera recipients. Our study suggests that autoantibody deposition on salivary gland endothelial cells might play a critical role in the pathogenesis of Sjögren's Disease.

Systemic Lupus Erythematosus and Cardiovascular Disease.

Systemic lupus erythematosus (SLE) is a condition in which autoimmune inflammation affects nearly every organ in the human body; it is characterized by a relapsing-remitting pattern. Systemic inflammation and tissue damage can arise from autoantibodies, the creation of immune complexes, and the deposition of autoantibodies, all defined as autoimmune diseases. Women of reproductive age are at a high risk of developing lupus, a chronic systemic condition. Among women between the ages of 15 and 44 years, the female-to-male ratio for the occurrence of lupus is as high as 13:1, while it is only 2:1 in children and in the elderly. In addition to accelerated atherosclerosis, SLE is associated with an increased risk of cardiovascular (CV) events such as coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular accident (CVA). Several SLE-specific processes, including impaired immunological regulation, impaired endothelial cell (EC) function, impaired vascular repair, hyperleptinemia, and traditional risk factors, contribute to early atherosclerosis in the disease. CAD can occur at any stage of the disease's progression, with younger individuals being much more at risk than their age-matched counterparts. This review article aims to provide a unique insight into the relationship between SLE and cardiovascular disease (CVD) by discussing the pathophysiological role of CVD in SLE, outlining screening criteria, and highlighting the treatment options for CVD in connection with SLE.

Abstract 10884: B-Cell-Mediated Sodium and Water Retention Contributes to Heart Failure Pathogenesis

Background: B-cells have been shown to serve pathogenic roles in heart failure through cardiac-specific monocyte mobilization and autoantibody deposition. Beyond this, we recently showed that mice with hypomorphic c-Myb activity ( c-myb h/h ) have reduced B-cells and that B-cell deficiency is associated with increased sodium- and water-excretion and reduced blood pressure. Here, we determine the relevance of these responses in an experimental model of heart failure. Methods &amp; Results: C57BL/6J wild-type (WT) and B-cell deficient c-myb h/h mice (male and female; aged 10-12 weeks) underwent either: (i) permanent LAD ligation to induce myocardial infarction (MI); or (ii) sham surgery. Echocardiography showed that B-cell deficiency preserved ejection fraction (53±2 vs. 44±2 %; N=6-7/group; P&lt;0.01) and limited pathologic remodeling with reduced LVID (end-diastolic: 4.9±0.1 vs. 5.5±0.1 mm; N=6-7/group; P&lt;0.01; end-systolic: 3.8±0.2 vs. 4.5±0.1 mm; N=6-7/group; P&lt;0.001) at 4-weeks post-MI compared to WT. Heart weight/tibia length and right lung weight/tibia length ratios (g/mm; P&lt;0.01), as well as pleural effusion volumes (μl; P&lt;0.05) were increased post-MI in WT, rather than c-myb h/h mice. Indeed, mice with B-cell deficiency manifest reduced right lung weight/tibia length ratio (0.005±0.000 vs. 0.009±0.001 g/mm; N=5-6/group; P&lt;0.01) and pleural effusion volume (17±6 vs. 55±18 μl; N=6-7/group; P&lt;0.06) post-MI compared to WT. Underlying this decongestion, metabolic cage studies revealed that B-cell deficient mice had sustained increases in 24-h urine volume/body weight and 24-h sodium excretion/body weight ratios, which correlated with ejection fraction 4-weeks post-MI (r=0.53; N=13 pairs; P&lt;0.05; and r=0.50; N=13 pairs; P&lt;0.05, respectively). Conclusion: Together, these data show that B-cells play a role in sodium- and water-retention, and consequently, extracellular fluid volume expansion and congestion post-MI, and suggest that B-cells may represent a therapeutic target in heart failure.

Metabolic preconditioning in CD4+ T cells restores inducible immune tolerance in lupus-prone mice.

Autoimmune disease has presented an insurmountable barrier to restoration of durable immune tolerance. Previous studies indicate that chronic therapy with metabolic inhibitors can reduce autoimmune inflammation, but it remains unknown whether acute metabolic modulation enables permanent immune tolerance to be established. In an animal model of lupus, we determined that targeting glucose metabolism with 2-deoxyglucose (2DG) and mitochondrial metabolism with metformin enables endogenous immune tolerance mechanisms to respond to tolerance induction. A 2-week course of 2DG and metformin, when combined with tolerance-inducing therapy anti-CD45RB, prevented renal deposition of autoantibodies for 6 months after initial treatment and restored tolerance induction to allografts in lupus-prone mice. The restoration of durable immune tolerance was linked to changes in T cell surface glycosylation patterns, illustrating a role for glycoregulation in immune tolerance. These findings indicate that metabolic therapy may be applied as a powerful preconditioning to reinvigorate tolerance mechanisms in autoimmune and transplant settings that resist current immune therapies.

Implant and prosthetic rehabilitation of a patient with mucous membrane pemphigoid

Mucous membrane pemphigoid (MMP) is an autoimmune condition characterized by subepithelial separation and deposition of autoantibodies and complement along the basement membrane zone. The disease results in the development of vesiculobullous lesions of the mucous membranes and skin. This report discusses the surgical treatment and management and the prosthetic implant rehabilitation of a patient with mucous membrane pemphigoid. The rationale for this treatment was to fabricate a prosthesis that was stable and did not rub against the gingival tissues and that was easily cleaned. The overdenture attachment system used provides more stability than other attachment systems while allowing the prosthesis and abutments to be easily cleaned.

Galectin-9 regulates follicular helper T cells to inhibit humoral autoimmunity-induced pulmonary fibrosis

Interstitial pneumonia with autoimmune features (IPAF) is an unexplained disease state characterized by autoimmunity and pulmonary fibrosis. Exploring the pathogenesis of IPAF is helpful for the treatment of interstitial pneumonia and idiopathic pulmonary fibrosis. In this study, we observed that the lung Galectin-9 (Gal-9) of IPAF patients was significantly reduced, which was significantly related to lung dysfunction and abnormal humoral immunity. Moreover, an overreactive germinal center (GC) reaction in the lung lymph nodes (LNs) of Gal-9-deficient mice was found to be related to abnormally active follicular helper T cells (Tfh) cells. The lack of Gal-9 ligand in Tfh cells can lead to excessive transcriptional programming and differentiation and help GC B cells. Gal-9 deficiency caused an abnormal humoral immune response in mice, leading to excessive deposition of nonspecific autoantibodies in mice and chronic lung fibrosis. Our research reveals the important regulatory role of gal-9 in Tfh cells and a possible target for the treatment of IPAF.

Disease-Specific Autoantibodies Induce Trained Immunity in RA Synovial Tissues and Its Gene Signature Correlates with the Response to Clinical Therapy.

Much evidence suggests that trained immunity is inappropriately activated in the synovial tissue in rheumatoid arthritis (RA), but the underlying mechanism remains unclear. Here, we describe how RA-specific autoantibody deposits can train human monocytes to exert the hyperactive inflammatory response, particularly via the exacerbated release of tumor necrosis factor α (TNFα). Comparative transcriptomic analysis by plate-bound human IgG (cIgG) or β-glucan indicated that metabolic shift towards glycolysis is a crucial mechanism for trained immunity. Moreover, the cIgG-trained gene signatures were enriched in synovial tissues from patients with ACPA- (anticitrullinated protein antibody-) positive arthralgia and undifferentiated arthritis, and early RA and established RA bore a great resemblance to the myeloid pathotype, suggesting a historical priming event in vivo. Additionally, the expression of the cIgG-trained signatures is higher in the female, older, and ACPA-positive populations, with a predictive role in the clinical response to infliximab. We conclude that RA-specific autoantibodies can train monocytes in the inflamed lesion as early as the asymptomatic stage, which may not merely improve understanding of disease progression but may also suggest therapeutic and/or preventive strategies for autoimmune diseases.