Production Of IgG Autoantibodies Research Articles

Association between sialic acid, sialidase activity and cholesterol of lipid-containing circulating immune complexes in the blood serum of patients with atherosclerosis

Atherosclerosis is the most common chronic non-infectious diseases, in the pathogenesis of which the accumulation of lipids in the subendothelial layer of the arteries and the local inflammatory reaction play a significant role. The source of lipid accumulation in the vascular wall is modified low-density lipoproteins. Desialylation is one of the known modifications that leads to the emergence of atherogenic properties in low-density lipoproteins. Enzymes that have sialidase activity circulate in human blood, i.e., the ability to cleave sialic acid from low-density lipoproteins. Desialylated low-density lipoproteins are autoantigens and induce the production of IgG autoantibodies, which form immune complexes with low-density lipoproteins, which aggravates the course of atherosclerosis. The purpose of the study was to establish associations between the levels of sialic acid in low-density lipoproteins, sialidase activity and the cholesterol content of lipid-containing circulating immune complexes in the blood serum of patients with atherosclerosis. Blood sera from patients with coronary heart disease were used as biological material to determine indicators of sialidase activity, cholesterol content of lipid-containing circulating immune complexes and sialic acid in low-density lipoproteins, which were isolated from blood serum. Serum samples were obtained from the laboratory of clinical biochemistry of the Institute of Clinical Cardiology, A.L. Myasnikov Federal State Budgetary Institution National Medical Research Center of Cardiology named after Academician E.I. Chazov as unutilized residues after performing routine biochemical tests. Fifty-one samples of blood serum and low-density lipoproteins isolated from it were analyzed. A significant positive relationship was revealed between the cholesterol content of circulating immune complexes and sialidase activity in the blood serum (r = 0.305 at p = 0.029). At the same time, no correlation was found between the content of sialic acid in low-density lipoproteins and sialidase activity in the blood serum, as well as between the cholesterol content of circulating immune complexes in the blood serum and sialic acid in low-density lipoproteins. It should be assumed that increased sialidase activity in the blood serum leads to the formation of desialylated immunogenic low-density lipoproteins with the subsequent appearance of autoantibodies and the formation of lipid-containing circulating immune complexes.

Edwardsiella tarda induces airways inflammation and production of autoantibodies against lung tissues through regulation of the IL-33-ST2 axis.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic respiratory disease characterised by irreversible airways obstruction associated with chronic airways inflammation and remodelling, while the pathogenesis and the mechanistic differences between patients remain to be fully elucidated. We previously reported that alarmin cytokine IL-33 may contribute to the production of autoantibodies against respiratory epithelial cells. Here we expand the hypothesis that pulmonary autoimmune responses induced by airway microbiota also contribute to the progression of COPD. We focused on Edwardsiella tarda which we detected uniquely in the induced sputum of patients with acute exacerbations of COPD. Pernasal challenge of the airways of WT mice with supernatants of cultured E. tarda induced marked, elevated expression of IL-33 in the lung tissues. Immunisation of animals with supernatants of cultured E. tarda resulted in significantly elevated airways inflammation, the formation of tertiary lymphatic structures and significantly elevated proportions of T follicular helper T cells in the lung tissue and mediastinal lymph nodes. Interestingly, such challenge also induced production of IgG autoantibodies directed against lung tissue lysate, alveolar epithelial cell proteins and elastin fragment, while putrescine, one of metabolites generated by the bacterium, might play an important role in the autoantibody production. Furthermore, all of these effects were partly but significantly abrogated in mice with deletion of the IL-33 receptor ST2. Collectively, these data support the hypothesis that COPD is progressed at least partly by airways microbiota such as E. tarda initiating autoimmune attack of the airways epithelium mediated at least partly through the IL-33-ST2 axis.

Case Report: Acquired hemophilia A following COVID-19 vaccine

Background: In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified and has subsequently been responsible for immense morbidity and mortality. This resulted in the development of vaccines in record time, potentially posing safety issues. Several cases of acquired hemophilia A (AHA) following coronavirus disease 2019 (COVID-19) vaccines have been described in the literature. AHA is a rare autoimmune disease due to the production of IgG autoantibodies to coagulation FVIII that burdens high morbidity and mortality. It is presumed mainly on identifying an increased activated partial thromboplastin time (aPTT), even without bleeding and is confirmed by determining a FVIII inhibitor. To the best of our knowledge, this is the first report of AHA after inactivated virus COVID-19 treated with low dose rituximab (RTX). Lower RTX doses may lead to shorter infusion duration, lower risk of adverse events and lower costs. Case presentation: We report a case of AHA occurring in a 69-year-old man 60 days after an inactivated Sinovac-coronavac COVID-19 vaccine. Diagnosis of AHA was based on clinical presentation and confirmed with prolonged activated partial thromboplastin time, Factor VIII deficiency and the presence of an FVIII inhibitor. Follow-up showed a significant clinical and biological improvement, aPTT was normalized as of 18 days of treatment with corticosteroids along with low dose rituximab. Conclusions: In the literature, the reported cases of AHA following COVID-19 vaccination occurred after Adenoviral Vector DNA- and SARS-CoV-2 mRNA-based COVID-19 vaccines. Here, AHA was presented following inactivated virus COVID-19 vaccine. AHA treated with low dose rituximab can limit occurrence of side effects and the cost of treatment.

The cytokine milieu of bullous pemphigoid: Current and novel therapeutic targets.

Bullous pemphigoid (BP) is the most common autoimmune bullous disease, characterized by severe pruritus and skin blistering. The loss of tolerance against Collagen XVII, also referred to as BP180, is the main pathogenic event of BP, leading to production of IgG autoantibodies which mainly target the juxtamembranous extracellular non-collagenous 16th A (NC16A) domain of BP180. A complex inflammatory network is activated upon autoantibody binding to the basement membrane zone; this inflammatory loop involves the complement cascade and the release of several inflammatory cytokines, chemokines and proteases from keratinocytes, lymphocytes, mast cells and granulocytes. Collectively, these events disrupt the integrity of the dermal-epidermal junction, leading to subepidermal blistering. Recent advances have led to identify novel therapeutic targets for BP, whose management is mainly based on the long-term use of topical and systemic corticosteroids. As an example, targeting type-2 T-helper cell-associated cytokines, such as Interleukin-4 and interleukin-13 has shown meaningful clinical efficacy in case series and studies; targeting IL-17 and IL-23 has also been tried, owing to an important role of these cytokines in the chronic maintenance phase of BP. In this review article, we discuss the complex cytokine milieu that characterized BP inflammation, highlighting molecules, which are currently investigated as present and future therapeutic targets for this life-threatening disease.

Serum autoantibodies and exploratory molecular pathways in rural miners: A pilot study

IntroductionThe Southwestern United States (SWUS) has an extensive history of coal and metal mining, including uranium (U) mining. Lung diseases, including but not limited to, lung cancer and pulmonary fibrosis, have been studied extensively in miners due to occupational, dust-related exposures. However, high-throughput autoimmune biomarkers are largely understudied in miners, despite the fact that ore miners, such as U-miners, are at an increased risk for the development of autoimmune diseases such as systemic sclerosis and systemic lupus erythematosus (SLE). Additionally, there are current gaps in knowledge regarding which signaling pathways may play a role in occupational exposure-associated autoimmunity. MethodsMost current and former miners in the SWUS live close to their previous workplaces, in remote areas, with limited access to healthcare. In this pilot study, by leveraging a mobile clinical platform for patient care and clinical outreach, we recruited 44 miners who self-identified as either U (n = 10) or non-U miners (n = 34) and received health screenings. Serum IgG and IgM autoantibodies against 128 antigens were assessed using a high-throughput molecular technique, as a preliminary health screening opportunity. ResultsEven when adjusting for age as a covariate, there was a significant (p < 0.05) association between self-reported U-mining exposure and biomarkers including IgM alpha-actinin, histones H2B, and H4, myeloperoxidase (MPO) and myelin basic protein. However, adjusting for age did not result in significant associations for IgG autoantibody production in U-miners. Bioinformatic pathway analysis revealed several altered signaling pathways between IgM and IgG autoantibodies among both U and non-U miners. ConclusionsFurther research is warranted regarding the mechanistic connection between U-exposure and autoantibody development, especially regarding histone-related alterations and IgM autoantibody production.

A Two Part Case Series on Acquired Hemophilia A

Abstract Introduction/Objective Acquired Hemophilia A is a rare condition with an incidence of 1 per 1.5 million per year. The average age at presentation is 74 years. It is due to spontaneous production of IgG autoantibodies that target endogenous factor viii. This disease should be considered when a patient presents with bleeding, an abnormal prolongation of activated partial thromboplastin time and /or no prior personal or family history of bleeding. Autoimmune disorders and malignancy are common associations. Pregnancy and surgery are common presenting scenarios. Methods/Case Report Case 1: 71 year old female with a history of deep venous thrombosis, and rheumatoid arthritis. Patient presented to the emergency department with a hemoglobin of 4.7 and coagulation studies showed a prolonged partial thromboplastin time of 119 seconds. Imaging revealed retroperitoneal bleeding. A mixing study showed no correction of partial thromboplastin time. The patient was treated with packed red blood cell transfusions until hemodynamically stable. Further coagulation studies revealed a factor VIII activity of 3L and factor VIII inhibitor level of 103 bethesda units. This confirmed suspicion of an acquired factor VIII inhibitor associated with the patient’s rheumatoid arthritis as the source of abnormal lab values and bleeding. Patient was treated with recombinant factor VIIa, novoseven, along with continuous prednisone and cyclophosphamide. Case 2: 82 year old male with history of IgG Kappa Monoclonal Gammopathy of Undetermined Significance. Patient presented with gastrointestinal bleeding and 4g/Dl hemoglobin. He received 5 units of packed red blood cells. Sigmoidoscopy revealed a rectal ulcer causing lower gastrointestinal bleeding. An advanced coagulation study revealed factor VIII activity of 1%, and inhibitor levels of 17 bethesda units. Patient was started on prednisone initially, followed by cyclophosphamide. However, bleeding continued. He was treated with 6 units of recombinant factor VIIa and packed red blood cell transfusions as required to keep hemoglobin levels at 7g/Dl. He was continued on prednisone at an increased dosage and discharged. Results (if a Case Study enter NA) NA. Conclusion Acquired Hemophilia A is a rare disease. It should be suspected anytime there is unprecedented bleeding and/or unexplained prolongation of partial thromboplastin time. It is diagnosed with factor VIII panel, including inhibitor. Treatment includes immunosuppresants, intravenous immunoglobulins, and recombinant factor VIIa.

Serum WT1-271 IgM antibody as a novel diagnostic marker for Gastric Cancer.

The Wilms tumor 1 gene, WT1, is overexpressed in various types of cancer, including gastric cancer. The product of WT1 is highly immunogenic and is a promising target molecule for cancer immunotherapy. The current study aimed to examine the production of WT1-specific IgG and IgM autoantibodies to identify biomarkers of diagnostic value in patients with gastric cancer. IgG antibodies that bind to WT1-derived peptides were obtained, the serum levels of which correlate with those of IgG antibodies against the WT1 protein in patients with intestinal malignancies. The serum levels of IgG and IgM antibodies against the WT1-271 peptide (271-288 amino acids) were examined in 39 healthy individuals and 97 patients with gastric cancer. The positivity cutoff value was determined according to the receiver operating characteristic curve. The association between WT1-271 IgM and the clinicopathological factors and prognosis of patients was additionally analyzed. The results revealed that serum WT1-271 IgM antibody levels in patients with gastric cancer were significantly higher than those in healthy individuals. The sensitivity and specificity of this antibody for gastric cancer were 67.0 and 71.8%, respectively; this sensitivity was improved when compared with conventional tumor markers (P<0.001). There was no statistical difference in WT1-271 IgG antibody levels between patients with gastric cancer and healthy individuals. Serum WT1-271 IgM antibody levels were not significantly associated with clinicopathological factors but were associated with unfavorable prognosis. Serum WT1-271 IgM antibody levels could serve as a diagnostic biomarker in patients with gastric cancer.

Refractory Immune Mediated ITP in a Patient with Metastatic Melanoma

Background: Immune check point inhibitors have changed the treatment landscape of many tumors including melanoma. They disrupt the immunoinhibitory signals mediated by programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to use the body's immune system to destroy the tumor. Consequently, they also predispose patients to immune related toxicity which may affect any organ, commonly skin, gastrointestinal, hepatic, pulmonary and endocrine. Hematological immune-related adverse events are less common and include neutropenia, autoimmune hemolytic anemia, immune thrombocytopenia (ITP) and aplastic anemia. Herein we present a case of refractory ITP in a patient receiving immunotherapy for metastatic malignant melanoma.Case Presentation: A 54-year-old female with metastatic melanoma harboring the BRAF V600E was started on ipilimumab and nivolumab. After 3 cycles of immunotherapy, she was found to have sudden onset thrombocytopenia requiring hospital admission. Complete blood counts showed platelet counts10k/mcL, hemoglobin 13.0 g/dL and white blood cell 4.1 K/uL. She did not manifest any overt bleeding or bruising on history and exam. There was no evidence of hemolysis on labs and peripheral blood smear; thrombotic microangiopathy was ruled out. She received high dose dexamethasone 40 mg intravenous daily and 1 mg/kg intravenous immune globulin daily for three days for suspected ITP due to immunotherapy. Her platelet counts did not improve and therefore a bone marrow biopsy was performed which revealed a normocellular marrow without evidence of melanoma. Imaging revealed excellent radiological response; it was decided to hold further doses of immunotherapy due to severe thrombocytopenia. She received rituximab 375 mg/m 2, with no response and platelet counts continued to between 2-5 K/mcL and required daily platelet transfusions. Romiplostim was initiated which improved platelet count to 10K/mcL and she was discharged. The following day her platelet counts dropped to 5K/mcL and she was sent back to the emergency room where she received 1 unit of platelet transfusion. Unfortunately, she developed a cold limb and was found to have a complete occlusion of the right distal popliteal artery and left tibio-peroneal trunk. Initiation of heparin infusion was discussed with the patient, however due to the significant bleeding risk from refractory ITP, the patient decided to pursue comfort measures only and was discharged home for hospice care.Discussion: About 0.5% of metastatic melanoma patients experience immune thrombocytopenia, deaths caused by this severe adverse event are even rarer. It is postulated that the activation of CD4+ helper T cells and CD8+ cytotoxic T cells can result in the damage to hematopoietic stem cells. Furthermore, nivolumab induced increased production of platelet-specific IgG autoantibodies also promote platelet destruction. Diagnosis is particularly challenging due lack of specific test or markers, and it remains a diagnosis of exclusion. The risk of bleeding, arterial thromboembolism and venous thrombosis is higher in ITP patients. ITP due to immunotherapy may be profound and refractory. One may consider the use of second line agents, such as TPO mimetics earlier in these patients.Conclusions: Our case highlights refractory ITP as a serious immune related adverse event that failed several lines of treatment strategies. Early diagnosis and combination treatment measures early in the course of the disease is imperative to mitigate associated morbidity and mortality. Combination of steroids immunoglobulins and second line agents may be warranted in some cases, and earlier use of tier 2 agents such as azathioprine should also be considered. DisclosuresNo relevant conflicts of interest to declare.

MHC haplotype and B cell autoimmunity: Correlation with pathogenic IgG autoantibody subclasses and Fc glycosylation patterns.

Genome-wide association studies (GWAS) have identified many genes that are associated with the development of certain autoimmune disorders, but the MHC haplotypes still represent the most prevalent genetic risk factor for many autoimmune diseases. The mechanisms by which MHC-associated genetic susceptibility translates into B cell autoimmunity and the development of autoimmune diseases are complex. There is increasing evidence that the MHC haplotype modulates autoreactive B cell responses in multiple ways. Instead of merely inhibiting the production of IgG autoantibodies and mediating complete immunological tolerance, the non-permitting MHC haplotypes seem to facilitate the production of IgG autoantibodies exhibiting Fc glycosylation patterns that are associated with reduced pathogenicity and a protective cytokine profile of T follicular helper (Tfh) cells. Here, we discuss mechanisms linking MHC haplotypes to the production of pathogenic IgG autoantibodies, which could be relevant for the development of improved diagnosis, particularly in the context of individual medicine.

Oxidative stress-induced aberrant lipid metabolism is an important causal factor for dysfunction of immunocytes from patients with systemic lupus erythematosus

There exist close relationships among oxidative stress, dyslipidaemia, inflammation, and autoimmune response in patients with systemic lupus erythematosus (SLE). Dysfunction and/or dysregulation of immunocytes is one of the major characteristics of SLE pathogenesis. Lipids play many important roles in biological processes and cellular functions. We hypothesized that oxidative stress-induced aberrant lipid metabolism and integrity presented in immunocytes is one of the early events in patients, thereby leading to enhanced production of IgG autoantibodies and cytokines. Herein, shotgun lipidomics was employed for quantitative analysis of cellular lipidomes in peripheral blood mononuclear cells (PBMC) both freshly isolated from SLE patients and cultured with treatment. The levels of IgG autoantibodies and cytokines in cell culture media and serum samples from lupus-prone mice treated with a natural, powerful antioxidant isotonix OPC-3 were measured by ELISA kits. IgG antibody deposition in glomeruli of the mice was determined by immunofluorescence analysis. Lipidomics analysis of PBMC from 33 SLE patients and 28 healthy controls revealed aberrant lipid metabolism in PBMC from the patients. The changes included significantly reduced plasmalogens, markedly increased lysophospholipids, altered phosphatidylserines, and accumulated 4-hydroxyalkenals. These alterations of lipids in SLE PBMC could be significantly corrected after cultured with the antioxidant in vitro. Parallel to the IgG antibody deposition in glomeruli, the concentrations of cytokines (i.e., IL-10, IL-6, and TNF-α) and autoantibodies (e.g., IgG antiphospholipid and anti-dsDNA antibodies) in culture medium and serum samples from the mice after treatment with the antioxidant were also significantly reduced compared with those of the SLE group. The results clearly demonstrated that correction of the aberrant lipid metabolism led to inhibition of the autoimmune reactions of PBMC after reduction of the increased oxidative stress. The current study also revealed potential drug treatment of SLE with lesser adverse effects through reducing the aberrant lipid metabolism with an effective antioxidant.

Epstein-Barr Virus Reactivation-Induced Immunoglobulin Production: Significance on Autoimmunity.

Epstein–Barr virus (EBV) mainly persists in B cells, which differentiate into antibody-producing cells, and thus, EBV has been implicated in autoimmune diseases. We aimed to describe the EBV reactivation and its relevance to autoimmune disease, focusing on Graves’ disease, which is an autoimmune hyperthyroidism caused by thyrotropin receptor antibodies. Circulating autoreactive B cells that have evaded from the selection have difficulties differentiating to produce antibodies. However, once EBV infects such B cells and reactivates, the B cells may become plasma cells and produce autoantibody. We herein proposed an EBV reactivation-induced Ig production system, which is a distinct pathway from the antibody production system through germinal centers and bone marrow and has the following characteristics: 1. IgM dominance, 2. ubiquitous Ig production, and 3. the rescue of autoreactive B cells, which skews Ig production toward autoantigens. IgM autoantibodies induced by EBV reactivation may activate the classical complement pathway and injure healthy tissue, which supply autoantigens for the production of affinity-matured IgG autoantibodies. Antibodies induced by EBV reactivation may play important roles in the development and exacerbation of autoimmune diseases.

Clinical and biological activity of rituximab in the treatment of pemphigus.

B-cells are major effector cells in autoimmunity since they differentiate into plasmocytes that produce pathogenic auto-antibody such as anti-desmoglein antibodies in pemphigus patients. Major advances were obtained using whole B-cell depleting therapies including anti-CD20 antibodies in refractory pemphigus patients that lead to rituximab approval in pemphigus patients in EU and USA. This review summarizes the data supporting the efficacy of rituximab in pemphigus and provides an overview of the reported immunological changes underlying its therapeutic action. Short and long-term remission in pemphigus is explained by the removal of autoreactive B-cells involved in the production of pathogenic IgG auto-antibodies and by enhancement of the appearance of regulatory B-cells that could maintain long term immune tolerance.

A Case of Pemphigus Vegetans in a Girl with Oculocutaneous Albinism

Oculocutaneous Albinism (OCA) is a group of inherited disorders affecting melanin pigment in the body. It is an autosomal recessive inherited disorder, characterized by hypopigmentation of skin, hair, and eyes which may cause serious problems over time. Pemphigus vegetans is an unusual localized form of pemphigus vulgaris. It is an autoimmune disease characterized by the production of IgG autoantibodies against intercellular adhesion protein desmoglein, forming acantholysis. In this case report, we’ve reported a very rare case of Pemphigus vegetans in a 24-year-old girl with Oculocutaneous albinism.

Autoantibodies from SLE patients induce programmed cell death in murine fibroblast cells through interaction with TNFR1 receptor

Various pathological processes are known to be associated with the production of IgG autoantibodies, which have high affinity for self-antigens and often cause tissue injury and the development of autoimmune diseases. However, the mechanism of their cytotoxic activity is not clearly understood yet. Here, we have shown that the action of these autoantibodies on cells expressing TNFR1 (the cell surface receptor for TNFα) can cause both caspase-dependent apoptosis and necroptosis of these cells, with suppression of apoptosis resulting in switching to RIP1-dependent necroptosis. Analysis of necroptotic mechanisms has shown that a critical point of necroptosis is phosphorylation of RIP1 and RIP3 kinases, which is followed by the involvement of lysosomes and mitochondria in this process. The induction of cytotoxicity is initiated by the interaction of autoantibodies with TNFR1, and autoantibodies can therefore be regarded as a new functional ligand for this receptor. The innate immunity protein Tag7 (PGLYRP1) described in our recent studies is also a ligand for TNFR1 and competes with autoantibodies for binding with it. Supposedly, the cytotoxic effect of autoantibodies is one of the factors responsible for autoimmune diseases that lead to tissue injury.

Blockade of BAFF Reshapes the Hepatic B Cell Receptor Repertoire and Attenuates Autoantibody Production in Cholestatic Liver Disease.

Defects in biliary transport proteins, MDR3 in humans and Mdr2 in mice, can lead to a spectrum of cholestatic liver disorders. Although B cell disorders and the aberrant Ab production are the leading extrahepatic manifestations of cholestatic liver diseases, the mechanism underlying this phenomenon is incompletely understood. Using mice with deficiency of Mdr2 that progressively develop cholestatic liver disease, we investigated the contributions of BAFF to aberrant IgG autoantibody production and hepatic fibrosis. In Mdr2-/- mice, hepatic B lymphocytes constitutively produced IgG during fibrosis progression, which correlated with elevated serum levels of BAFF, antinuclear Abs (ANA) and immune complexes. The elevated BAFF and ANA titers were also detected in human patients with primary sclerosing cholangitis and hepatobiliary cholangiopathies. Consistent with the higher BAFF levels, liver-specific selection of the focused BCR IgH repertoire was found on hepatic B cells in Mdr2-/- mice. Interestingly, the administration of anti-BAFF mAb in Mdr2-/- mice altered the BCR repertoire on hepatic B lymphocytes and resulted in reduced ANA and immune complex titers. However, anti-BAFF treatment did not attenuate hepatic fibrosis as measured by collagen deposition, hepatic expressions of collagen-1a, α-smooth muscle actin, and mononuclear cell infiltration (CD11b+ Ly-6chi monocytes and CD11b+ Gr1+ neutrophils). Importantly, depletion of B cells by anti-CD20 mAb reduced both hepatic fibrosis and serum levels of ANA and immune complexes. Our findings implicate B cells as the potential therapeutic targets for hepatic fibrosis and targeting BAFF specifically for attenuating the autoantibody production associated with cholestatic liver disease.

Deficiency of CFHR plasma proteins and autoantibody positive hemolytic uremic syndrome: treatment rationale, outcomes, and monitoring.

Deficiency of Complement Factor H Related (CFHR) plasma proteins and Autoantibody Positive Hemolytic Uremic Syndrome (DEAP-HUS) is a subtype of atypical hemolytic uremic syndrome, known to be associated with significant morbidity. Its pathogenesis is linked to the production of IgG autoantibodies against complement factor H, a regulator of the alternative complement pathway. The binding of the autoantibodies to the C terminal of complement factor H interferes with its regulatory function, leading to increased activation of the alternative complement pathway and consequent endothelial cellular damage. Early diagnosis and initiation of appropriate therapy is reported to lead to favorable outcomes. Institution of plasma exchange therapy within 24h of diagnosis has been shown to rapidly lower antibody levels, leading to clinical improvement. Adjunctive immunosuppression therapy suppresses antibody production and helps in maintaining long-term clinical remission of the disease. Available data advocates a treatment regimen that combines plasma therapy (preferably plasma exchange) and immunosuppression to halt disease process and sustain long-term disease remission.

An Update on the Pathogenesis of Skin Damage in Lupus

Lupus erythematosus (LE) is characterized by broad and varied clinical forms ranging from a localized skin lesion to a life-threatening form with severe systemic manifestations. The overlapping between cutaneous LE (CLE) and systemic LE (SLE) brings difficulties to physicians for early accurate diagnosis and sometimes may lead to delayed treatment for patients. We comprehensively review recent progress about the similarities and differences of the main three subsets of LE in pathogenesis and immunological mechanisms, with a particular focus on the skin damage. Recent studies on the mechanisms contributing to the skin damage in lupus have shown a close association of abnormal circulating inflammatory cells and abundant production of IgG autoantibodies with the skin damage of SLE, whereas few evidences if serum autoantibodies and circulating inflammatory cells are involved in the pathogenesis of CLE, especially for the discoid LE (DLE). Till now, the pathogenesis and molecular/cellular mechanism for the progress from CLE to SLE are far from clear. But more and more factors correlated with the differences among the subsets of LE and progression from CLE to SLE have been found, such as the mutation of IRF5, IFN regulatory factors and abnormalities of plasmacytoid dendritic cells (PDCs), Th1 cells, and B cells, which could be the potential biomarkers for the interventions in the development of LE. A further understanding in pathogenesis and immunological mechanisms for skin damage in different subsets of LE makes us think more about the differences and cross-links in the pathogenic mechanism of CLE and SLE, which will shed a light in predictive biomarkers and therapies in LE.

Bach2 deficiency leads autoreactive B cells to produce IgG autoantibodies and induce lupus through a T cell-dependent extrafollicular pathway

Class-switched IgG autoantibodies but not unswitched IgM autoantibodies play a crucial role in the development of systemic lupus erythematosus (SLE). Bach2 is known to be essential for class switch recombination of Ig genes, but recent genomic and clinical studies have suggested an association of Bach2 deficiency with SLE. This study was undertaken to examine the mechanism by which Bach2 regulates the development of SLE. Despite defects in Ig class switch recombination and germinal center formation when actively immunized, Bach2−/− mice spontaneously accumulated IgG autoantibody-secreting cells without germinal center reactions in a regulatory T cell-independent manner, and this phenomenon was accompanied by manifestations akin to SLE. Transcriptome analyses revealed that Bach2 regulated the expression of genes related to germinal center formation and SLE pathogenesis in B cells. B cell-specific deletion of Bach2 was sufficient to impair the development of germinal center B cells but insufficient to promote the production of IgG autoantibodies. Bach2 deficiency caused CD4+ T cells to overexpress Icos and differentiate into extrafollicular helper T cells in a cell-autonomous manner. These findings suggest that Bach2-deficient autoreactive B cells preferentially react at extrafollicular sites to give rise to IgG class-switched pathogenic plasma cells and that this effect requires the help of Bach2-Icoshi helper T cells. Thus, the cell-autonomous roles of Bach2 in B cells and in their cognate CD4+ T cells are required to maintain self-tolerance against SLE.

The imbalance of gut microbiota and its correlation with plasma inflammatory cytokines in pemphigus vulgaris patients.

Pemphigus vulgaris (PV) is an autoimmune disease characterized by the production of IgG autoantibodies owing to an imbalance in the Th1/Th2 and Th17/Tregs cell pathways. The role of gut microbiota in the development of immune system and autoimmune diseases has been unraveled in the last two decades. However, data pertaining to gut microbiota of PV patients is largely lacking. We aimed to compare the gut microbiota of PV patients and healthy controls and assessed potential correlation with circulating cytokines of Th1/Th2/Th17 cell. Faecal bacterial diversity was analysed in 18 PV patients and 14 age‐ and gender‐matched healthy individuals using hypervariable tag sequencing of the V3‐V4 region of the 16S rRNA gene. Plasma levels of 20 inflammatory cytokines were assessed using the Luminex screening system. As a result, we identified 10 differentially abundant taxa between patients and controls. At the genera level, Lachnospiracea_incertae_sedis and Coprococcus decreased, while Granulicatella, Flavonifractor enriched in PV. Plasma levels of C5a, interleukin (IL)‐2R, IL‐6, IL‐8, IL‐7, IL‐1β, IL17A, IL‐5 and IL‐21 were significantly increased in PV Flavonifractor exhibited a positive correlation with C5a, IL‐6, IL‐8, IL‐7, IL‐1β, IL17A and IL‐21. Lachnospiracea_incertae_sedis and Coprococcus showed a negative correlation with IL‐17A. Our results are consistent with the hypothesis that PV patients have gut microbial dysbiosis which might contribute to the immune disorder and the development of PV.

Protein-engineered molecules carrying GAD65 epitopes and targeting CD35 selectively down-modulate disease-associated human B lymphocytes.

Type 1 diabetes mellitus is an autoimmune metabolic disorder characterized by chronic hyperglycemia, the presence of autoreactive T and B cells and autoantibodies against self-antigens. A membrane-bound enzyme on the pancreatic beta-cells, glutamic acid decarboxylase 65 (GAD65), is one of the main autoantigens in type 1 diabetes. Autoantibodies against GAD65 are potentially involved in beta-cell destruction and decline of pancreatic functions. The human complement receptor type 1 (CD35) on B and T lymphocytes has a suppressive activity on these cells. We hypothesized that it may be possible to eliminate GAD65-specific B cells from type 1 diabetes patients by using chimeric molecules, containing an anti-CD35 antibody, coupled to peptides resembling GAD65 B/T epitopes. These molecules are expected to selectively bind the anti-GAD65 specific B cells by the co-cross-linking of the immunoglobulin receptor and CD35 and to deliver a suppressive signal. Two synthetic peptides derived from GAD65 protein (GAD65 epitopes) and anti-CD35 monoclonal antibody were used for the construction of two chimeras. The immunomodulatory activity of the engineered antibodies was tested in vitro using peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients. A reduction in the number of anti-GAD65 IgG antibody-secreting plasma cells and increased percentage of apoptotic B lymphocytes was observed after treatment of these PBMCs with the engineered antibodies. The constructed chimeric molecules are able to selectively modulate the activity of GAD65-specific B lymphocytes and the production of anti-GAD65 IgG autoantibodies by co-cross-linking of the inhibitory CD35 and the B cell antigen receptor (BCR). This treatment presents a possible way to alter the autoimmune nature of these cells.