Autoimmune Phenomena Research Articles

INVESTIGATION OF IMMUNOGENICITY AND SAFETY OF 23-VALENT POLYSACCHARIDE PNEUMOCOCCAL VACCINE IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Objective: to investigate the safety and immunogenicity of 23-valent polysaccharide pneumococcal vaccine (PPV-23) in patients with systemic lupus erythematosus (SLE). Subjects and methods. The investigation enrolled 30 patients with a reliable diagnosis of SLE; of them there were 27 women and 3 men at the age of 19 to 62 years. The disease duration ranged from 9 months to 20 years. At the time of inclusion in the investigation, the disease activity was high in 2 patients, moderate in 3, and low in 20; five patients were in remission. During a year before vaccination, pneumonia was detected in 5 (16.7%) of the 30 patients; there were a total of 18 episodes of various respiratory and ENT infections. The patients were examined at baseline and at 1, 3 and 12 months after vaccination. Standard clinical and laboratory studies and a detailed blood immunological analysis were carried out at visits. The levels of IgG antibodies to capsular polysaccharide pneumococcus were determined during each visit. Twenty-nine patients received glucocorticoids (GCs) at a dose of 5–30 mg/day; 24 – hydroxychloroquine; 14 – cytostatics (CS); 10 – biological agents (BAs) (5 – rituximab, 5 – belimumab). A single dose of 0.5 ml of PPV-23 (Pneumo 23, Aventis) was subcutaneously injected into the upper outer arm. Vaccination was done during the ongoing therapy with GC/CS and belimumab, as well as at least 1 month before the first (next) administration and/or 4.5–5 months after the last rituximab infusion. Results and discussion. 60% of patients were observed to have mild and moderate standard local vaccine reactions; 1 (3.3%) patient had a local hyperergic reaction eliminated within 7 days of the local application of antihistamines and GCs. During the follow-up, there was no SLE exacerbation significantly associated with the vaccination performed. No new autoimmune phenomena were found in any of the cases. A year after vaccination, a significant (2-fold or more) increase in anti-pneumococcal antibody levels remained in 19 (63.3%) patients (respondents); 36.7% of patients were nonrespondents. Among the patients who received a BA, the non-responders were significantly more than among those who did not take the drug (7 (70%) and 4 (20%), respectively) (p = 0.01). When treated with rituximab and belimumab, the number of non-respondents was comparable (4 and 3, respectively). The immunogenicity of PPV-23 was independent of the degree of SLE activity: the vaccine response was absent in 1 out of the 5 patients with high (n = 2) and medium (n = 3) SLE activities, as well as in 10 out of the 25 patients with low disease activity and remission. There was no development of considerable adverse reactions after vaccination in patients with high and medium SLE activity. The overall clinical efficiency of vaccination was 93.3%. Conclusion. Thus, PPV-23 shows a good tolerability and a sufficient immunogenicity in patients with SLE. There is a need for further investigations conducted in large samples of patients during long-term follow-ups in order to more fully evaluate the clinical efficacy, tolerability, and immunogenicity of PPV-23.

The role of immune-checkpoints in mycosis fungoides

Aims: The mechanisms involved in mycosis fungoides (MF) progression from early to advanced stages have not been completely clarified. In a previous experience, an increase in myeloid derived suppressor cells (MDSCs) was observed comparing patches/plaques to tumours. MDSCs are a heterogeneous group of cells whose antitumor response has been related to the activity of the immune checkpoints, such as programmed death-1 (PD-1) and its ligand (PD-L1), whose function is to physiologically depress immune cell response avoiding autoimmune phenomena. It has been hypothesised that the same mechanism is used by neoplastic cells to depress the anti-tumour response, gaining tumour advantages. Recently, immune checkpoint inhibitors have become available, changing the therapeutic scenarios in different types of cancer. Few data are present in the literature on PD-1 and PD-L1 expression in MF, mostly showing heterogeneous results. The aim of the present study was to assess immune checkpoint expression and role in MF.

Effect of Prolonged Anti-HM1: IMSS Entamoeba histolytica Antibody Activity in Humoral and Cellular Immunity of Experimentally Induced Animal Model.

The Cellular immunity plays an important role in amoebic infections, whereas humoral immune responses have little influence on the outcome of the disease. Chronic infestation with Entameoba histolytica, a common protozoan parasite, has been associated with autoimmune phenomena, including the appearance of antibodies to colonic epithelial cells. The mechanism whereby the protozoan parasite E. histolytica causes suppression of the immune response to allow it to survive in humans is unclear. Both parasite and parasite-induced host factors appear to be important in immunoregulation. This study was designed to evaluate prolonged antibody response to E. histolytica (HM1: IMSS) which may contribute and might identify antigens implicated in the disease pathology and throw light on the massive T-cell infiltration causing inflammation. An in vivo study was undertaken against experimentally induced animal model by evaluating total protein, Radial Immunodiffusion and Antiamoebic IgG antibody detection by ELISA using serum samples from rabbit collected weekly from day 7-28th (RS1: day-7; RS2: day-14, RS3: day-21 and RS4: day-28) which were immunized with amoebic antigen. Serological and cytokines profile- like interleukin- 6 (IL-6), IL-10 and tumor necrosis factor-α (TNF-α) were also analyzed. Our result indicated that RS4 showed a significant 167.3 ± 0.333 mg/dl value for IgG antibodies whereas, RS3 showed significant elevated 0.57 ± 0.033mg/dL C' reactive protein and 7.6667 ± 0.333 IU/mL Rheumatoid factor level. Similarly, RS3 775.00 ± 0.57 pg/ml showed maximum significant values for TNF-α, whereas IL-6 level was higher in RS4 701.00 ±0.577 pg/ml but IL-10 level was found low in RS1 62.33 ± 0.33 pg/ml, respectively. Thus, our study demonstrated the efficacy of amoebic antigen in immune response mechanism and how they provoked inflammation and acted as an immunomodulator. This article also summarized some relevant patents with respect to E. histolytica against inflammation and other diseases.

Current and evolving treatment strategies in adult immune thrombocytopenia.

SummaryImmune thrombocytopenia (ITP) is an acquired autoimmune phenomenon resulting in low platelet count and increased bleeding risk. Goals of upfront management include prompt control of severe bleeding—which is rare—as well as induction and maintenance of a hemostatic platelet count. Thus, optimal management of ITP patients is often challenging and requires a highly individualized approach. Many patients may not suffer significant bleeding despite severe thrombocytopenia and the risk of toxicity associated with treatment may outweigh its benefit. Most patients treated with standard first-line regimen of glucocorticoids achieve an initial response. However, the rate of long-term remission remains low and multiple lines of therapy are often required. Current investigations aim at defining the subgroup of patients at risk of relapse and providing intensified risk-balanced induction regimens to improve long-term disease control.This short review summarizes current and emerging treatment strategies in adult ITP.

Neonatal corticosterone mitigates autoimmune neuropsychiatric disorders associated with streptococcus in mice

Increased glucocorticoid concentrations have been shown to favor resilience towards autoimmune phenomena. Here, we addressed whether experimentally induced elevations in circulating glucocorticoids mitigate the abnormalities exhibited by an experimental model of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS). This is a pathogenic hypothesis linking repeated exposures to Group-A-beta-hemolytic streptococcus (GAS), autoantibodies targeting selected brain nuclei and neurobehavioral abnormalities. To persistently elevate glucocorticoid concentrations, we supplemented lactating SJL/J mice with corticosterone (CORT; 80 mg/L) in the drinking water. Starting in adolescence (postnatal day 28), developing offspring were exposed to four injections - at bi-weekly intervals - of a GAS homogenate and tested for behavioral, immunological, neurochemical and molecular alterations. GAS mice showed increased perseverative behavior, impaired sensorimotor gating, reduced reactivity to a serotonergic agonist and inflammatory infiltrates in the anterior diencephalon. Neonatal CORT persistently increased circulating glucocorticoids concentrations and counteracted these alterations. Additionally, neonatal CORT increased peripheral and CNS concentrations of the anti-inflammatory cytokine IL-9. Further, upstream regulator analysis of differentially expressed genes in the striatum showed that the regulatory effect of estradiol is inhibited in GAS-treated mice and activated in GAS-treated mice exposed to CORT. These data support the hypothesis that elevations in glucocorticoids may promote central immunomodulatory processes.

Autoimmunity in Autologous Islet Transplantation.

Total pancreatectomy (TP) is increasingly being utilized for definitive treatment in patients with debilitating chronic pancreatitis (CP). In an effort to prevent surgical diabetes, the procedure can be performed in conjunction with transplantation of islets of Langerhans recovered from the patients’ own resected pancreas (autologous islet transplantation, AIT). Given that patients undergoing TP and AIT are traditionally assumed not to be at risk for the development of beta-cell autoimmunity, it is possible that the presence of autoimmune islet graft failure has been overlooked and underreported in this patient population. Herein, we describe two cases who underwent TP and AIT and later developed new-onset beta-cell autoimmunity (as evidenced by de novo glutamic acid decarboxylase antibody positivity), accompanied by complete insulin-dependent states. These cases emphasize the need for considering a possible autoimmune phenomenon in the workup of TP and AIT patients who manifest with unexpected and rapid deterioration in their glycemic control.

Induction of Hypergammaglobulinemia and Autoantibodies by Salmonella Infection in MyD88-Deficient Mice.

Growing evidence indicates a link between persistent infections and the development of autoimmune diseases. For instance, the inability to control Salmonella infection due to defective toll-like receptor (TLR)/myeloid differentiation primary response 88 (MyD88) signaling has linked the development of persistent infections to a breakdown in B cell tolerance. However, the extent of immune dysregulation in the absence of TLR-MyD88 signaling remains poorly characterized. Here, we show that MyD88−/− mice are unable to eliminate attenuated Salmonella enterica serovar Typhimurium, even when challenged with a low-dose inoculum (200 CFUs/mouse), developing a persistent and progressive infection when compared to wild-type (MyD88+/+) animals. The splenic niche of MyD88−/− mice revealed increased counts of activated, Sca-1-positive, myeloid subpopulations highly expressing BAFF during persistent Salmonella infection. Likewise, the T cell compartment of Salmonella-infected MyD88−/− mice showed increased levels of CD4+ and CD8+ T cells expressing Sca-1 and CD25 and producing elevated amounts of IL-4, IL-10, and IL-21 in response to CD3/CD28 stimulation. This was associated with increased Tfh cell differentiation and the presence of CD4+ T cells co-expressing IFN-γ/IL-4 and IFN-γ/IL-10. Noteworthy, infected MyD88−/− mice had enhanced serum titers of both anti-Salmonella antibodies as well as autoantibodies directed against double-stranded DNA, thyroglobulin, and IgG rheumatoid factor, positive nuclear staining with HEp-2 cells, and immune complex deposition in the kidneys of MyD88−/− mice infected with live but not heat-killed Salmonella. Infection with other microorganisms (Acinetobacter baumanii, Streptococcus agalactiae, or Escherichia coli) was unable to trigger the autoimmune phenomenon. Our findings suggest that dysregulation of the immune response in the absence of MyD88 is pathogen-dependent and highlight potentially important genotype–environmental factor correlations.

Primary immunodeficiency and autoimmune diseases

Primary immunodeficiencies consist of a group of genetically heterogeneous immune disorders affecting distinct elements of the innate and adaptive immune system. Patients with primary immunodeficiency are more prone to develop not only recurrent infections, but non-infectious complications, like inflammatory or granulomatous conditions, lymphoproliferative and solid malignancies, autoinflammatory disorders, and a broad spectrum of autoimmune diseases. The concomitant appearance of primary immunodeficiency and autoimmunity appears to be rather paradoxical, therefore making the diagnosis of immunodeficiency patients with autoimmune complications challenging. Mutations of one or more genes playing a fundamental role in immunoregulation and/or immune tolerance network are thought to be responsible for primary immunodeficiencies. The diverse immunological abnomalities along with the compensatory and excessive sustained inflammatory response result in tissue damage and finally in manifestation of organ-, cell-specific or systemic autoimmune diseases. Several forms of primary immunodeficiency disorders are characterized by a variety of specific autoimmune phenomena. This overview addresses the spectrum of autoimmune diseases associated with primary immunodeficiencies, and explores the molecular and cellular mechanisms underlying abnormalities of the immune system. The case presented finally highlights that both the recognition of autoimmune diseases in association with immunodeficiencies and the diagnosis of immunodefiency in those phenotypes with predominant autoimmunity could be challenging. Orv Hetil. 2018; 159(23): 908-918.

Sex-Dependent Differences in Spontaneous Autoimmunity in Adult 3xTg-AD Mice.

The triple-transgenic (3xTg-AD) mouse strain is a valuable model of Alzheimer's disease (AD) because it develops both amyloid-β (Aβ) and tau brain pathology. However, 1-year-old 3xTg-AD males no longer show plaques and tangles, yet early in life they exhibit diverse signs of systemic autoimmunity. The current study aimed to address whether females, which exhibit more severe plaque/tangle pathology at 1 year of age, show similar autoimmune phenomena and if so, whether these immunological changes coincide with prodromal markers of AD pathology, markers of learning and memory formation, and epigenetic markers of neurodegenerative disease. Six-month-old 3xTg-AD and wild-type mice of both sexes were examined for T-cell phenotype (CD3+, CD8+, and CD4+ populations), serological measures (autoantibodies, hematocrit), soluble tau/phospho-tau and Aβ levels, brain-derived neurotrophic factor (BDNF) expression, and expression of histone H2A variants. Although no significant group differences were seen in tau/phospho-tau levels, 3xTg-AD mice had lower brain mass and showed increased levels of soluble Aβ and downregulation of BDNF expression in the cortex. Splenomegaly, depleted CD+ T-splenocytes, increased autoantibody levels and low hematocrit were more pronounced in 3xTg-AD males than in females. Diseased mice also failed to exhibit sex-specific changes in histone H2A variant expression shown by wild-type mice, implicating altered nucleosome composition in these immune differences. Our study reveals that the current 3xTg-AD model is characterized by systemic autoimmunity that is worse in males, as well as transcriptional changes in epigenetic factors of unknown origin. Given the previously observed lack of plaque/tangle pathology in 1-year-old males, an early, sex-dependent autoimmune mechanism that interferes with the formation and/or deposition of aggregated protein species is hypothesized. These results suggest that more attention should be given to studying sex-dependent differences in the immunological profiles of human patients.

The Mayo Clinic Experience With the Neurological Complications of the CTLA-4 Inhibitor Ipilimumab.

Neurological complications are an increasingly recognized complication of the use of the immune checkpoint inhibitors in the treatment of solid tumors. Ipilimumab is a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, an immune checkpoint inhibitor that suppresses T-cell effector function. The clinical spectrum of ipilimumab-associated neurological complications and optimum treatment approach is not established. We describe our institution's experience with ipilimumab and illustrate 2 cases of presumed autoimmune neurological phenomenon resulting from its use.

Salmonella infection induces autoantibody production in MyD88-deficient host: Identification of candidate bacterial proteins with homology to murine antigens

Abstract Persistent bacterial infections have been causally linked to the development of autoimmune diseases, but the precise mechanisms underlying this remain largely unknown. Of note, we demonstrated that systemic infection by attenuated Salmonella enterica serovar Typhimurium induces a breakdown in B cell tolerance in MyD88-deficient mice, as evidenced by the production of autoantibodies to nuclear and cytoplasmic antigens and immune complex deposition in the kidneys. The splenic niche of infected MyD88−/− mice revealed increased counts of activated myeloid cell subpopulations as well as CD4+ and CD8+ T cells. Moreover, this was associated with increased Th21 cell differentiation and the appearance of CD4+ T cells co-expressing IFN-g/IL-4 and IFN-g/IL-10. Importantly, infection with other bacteria (e.g. Acinetobacter baumanii, Streptococcus agalactiae or Escherichia coli) was unable to trigger the autoimmune phenomenon. We reasoned that the autoimmune response could be triggered by a process of molecular mimicry between mouse and Salmonella proteins. Bioinformatic analysis was used to identify potential Salmonella antigens with a high degree of homology to mouse proteins. This analysis revealed several candidate bacterial proteins with high homology to murine immune system proteins. The identified bacterial proteins were all uniquely expressed by Salmonella but not by the other three bacterial species that were incapable of inducing the autoimmune response in MyD88−/− mice. Therefore, our data suggest a mechanism for pathogen-specific induction of autoantibody production in the absence of MyD88 signaling pathway and provide important clues concerning the genotype-environmental factor correlations.

Cytomegalovirus aggravates the autoimmune phenomenon in systemic autoimmune diseases

BackgroundHuman Cytomegalovirus (CMV), because of its ability to extensively manipulate host immunity during active infection, has been suggested to be involved in autoimmunity. However, its influence on T-cells and cytokines in systemic autoimmune diseases like systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is indistinct. MethodsWe investigated the in-vitro response of T lymphocytes from SLE and SSc patients to CMV antigen. Functional activity of T lymphocytes was determined by estimating Th1 (IL-2 and IFN-γ) and Th2 (IL-4 and IL-10) cytokines. ResultsWe observed that CMV antigen stimulation in-vitro resulted in significant increase in CD4:CD8 T-cell ratio in peripheral blood mononuclear cells (PBMCs) from SLE and SSc patients; response dominated by CD4+ than CD8+ memory T-cells. SSc T-cell response was differentiated by aberrant increase in CD4+CD25+ T-cells. CMV antigen caused elevation in IL-4 and IFN-γ production in both patient PBMCs, whereas IL-2 was also raised in SLE PBMCs. The development of large pool of memory T-cells and overproduction of IFN-γ may result in flare-up of autoimmunity in these patients. ConclusionOur study provides an insight into the immunopathological potential of CMV-reactive immune cells to develop new potential strategies for targeted therapeutic intervention.

Making Sense of Immunotherapy in Lung Cancer: What the Pulmonologist Needs to Know?

The landscape of lung cancer therapy has completely shifted in the last decade. From the surge of targeted therapy to the resurrection of immunotherapy, the need for adequate lung tissue specimen is critical to evaluate tumor specimens for predictive biomarkers for both types of therapies, hence, the importance of obtaining several samples via endoscopic bronchial ultrasound performed by pulmonologists or thoracic surgeons. Moreover, these novel therapies have also been associated with respiratory side effects which will require prompt evaluation and aggressive management by pulmonologists, oncologists, and intensive care unit personnel. Pneumonitis is commonly coined to refer to interstitial lung disease. It is a side effect from checkpoint inhibitors, a type of immunotherapy, which has proved overall survival advantage in lung cancer patients in different clinical settings: first- and second-line therapy for metastatic non-small cell lung cancers as well as for locally advanced disease after being treated with concurrent chemoradiation. Thus, the number of patients who will be exposed to these agents is considerable, and we should expect to see an increased management of this autoimmune phenomenon as well as others. The mechanism of checkpoint inhibitor-induced pneumonitis is not well understood yet, but its management is like that of other autoimmune complications that affect the lung parenchyma. Prompt recognition is critical to avoid a fatal outcome.

Autoimmune phenomena and disease in cancer patients treated with immune checkpoint inhibitors.

The discovery and approved treatment with immune checkpoint inhibitors (ICIs) for a variety of cancers has changed dramatically the morbidity and mortality rates for these patients. Despite the obvious benefits, their use is associated with unique immune-related adverse effects (irAEs), including autoimmune conditions such as: inflammatory arthritis, myositis, vasculitis and Sicca syndrome. The appearance of ICIs-induced autoimmune irAE requires from oncologists and rheumatologists a different approach to the identification and treatment of these conditions, which may differ from the classic and traditional approach to rheumatologic diseases. It should be taken into consideration that ICIs therapy in patients with preexisting autoimmunity could be possible, but with a cost of causing disease exacerbation. In this extensive review, we present the autoimmune irAEs, mostly as phenomena, but also as classic autoimmune diseases as well as therapeutic options for the side effects.

Monoclonal Gammopathy in Chronic Lymphocytic Leukemia: A Case Report and Review of its Literature

AbstractThe presence of monoclonal gammopathies in B-cell malignancies occurs frequently. Monoclonal proteins are present in a significant number of patients with chronic lymphocytic leukemia (CLL), which is a disorder of antigen-stimulated mature B-cells. The recognition of monoclonal proteins or light chains in the serum and/or urine is increased in the majority of CLL patients with the use of highly sensitive laboratory methods such as serum immunofixation studies. A different autoimmune phenomenon may explain the presence of some of these monoclonal proteins. Some reports indicate that the finding of monoclonal proteins has a negative impact on patients' survival. However, there is no clear evidence to suggest the prognostic significance of monoclonal proteins in patients with CLL. Although the presence of monoclonal proteins in CLL occurs usually at an incidence of 60%–80%, there are very few cases reported in literature. We report a case of CLL diagnosed in 2009 who developed disease progression along with the presence of immunoglobulin kappa monoclonal gammopathy. Although the presence of monoclonal gammopathy might be due to the use of highly sensitive methods, this can be due to autoimmune phenomenon or development from the same or different clone of B-cells.

Case of alopecia universalis associated with alemtuzumab treatment in MS

Alemtuzumab (Lemtrada®) is a monoclonal antibody recognizing CD52 that selectively depletes T- and B-lymphocytes1 and is indicated for the treatment of relapsing-remitting MS (RRMS). Although it is highly efficacious, its use is associated with secondary autoimmune phenomena, such as thyroid dysfunction, immune thrombocytopenia, and glomerulonephritis.2

The value of Autoimmune Syndrome Induced by Adjuvant (ASIA) - Shedding light on orphan diseases in autoimmunity.

Autoimmune Syndrome Induced by Adjuvant (ASIA) is a definition aimed to describe the common etiological process at the root of five clinical entities sharing similar symptomatology: macrophagic myofasciitis syndrome (MMF), Gulf War Syndrome (GWS), sick building syndrome (SBS), siliconosis, and post vaccination autoimmune phenomena. ASIA illustrates the role of environmental immune stimulating agents, or adjuvants, in the instigation of complex autoimmune reactions among individuals bearing a genetic preponderance for autoimmunity. The value of ASIA lies first in the acknowledgment it provides for patients suffering from these as yet ill-defined medical conditions. Equally important is the spotlight it sheds for further research of these poorly understood conditions sharing a common pathogenesis. In this article we elaborate on the significance of ASIA, review the current evidence in support of the syndrome, and address recent reservations raised regarding its validity.

Vaccine-induced autoimmunity: the role of molecular mimicry and immune crossreaction.

Since the early 1800s vaccines have saved numerous lives by preventing lethal infections. However, during the past two decades, there has been growing awareness of possible adverse events associated with vaccinations, cultivating heated debates and leading to significant fluctuations in vaccination rates. It is therefore pertinent for the scientific community to seriously address public concern of adverse effects of vaccines to regain public trust in these important medical interventions. Such adverse reactions to vaccines may be viewed as a result of the interaction between susceptibility of the vaccinated subject and various vaccine components. Among the implicated mechanisms for these reactions is molecular mimicry. Molecular mimicry refers to a significant similarity between certain pathogenic elements contained in the vaccine and specific human proteins. This similarity may lead to immune crossreactivity, wherein the reaction of the immune system towards the pathogenic antigens may harm the similar human proteins, essentially causing autoimmune disease. In this review, we address the concept of molecular mimicry and its application in explaining post vaccination autoimmune phenomena. We further review the principal examples of the influenza, hepatitis B, and human papilloma virus vaccines, all suspected to induce autoimmunity via molecular mimicry. Finally, we refer to possible implications on the potential future development of better, safer vaccines.

Circulating plasmablasts are elevated and produce pathogenic anti-endothelial cell autoantibodies in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is a devastating pulmonary vascular disease in which autoimmune and inflammatory phenomena are implicated. B cells and autoantibodies have been associated with IPAH and identified as potential therapeutic targets. However, the specific populations of B cells involved and their roles in disease pathogenesis are not clearly defined. We aimed to assess the levels of activated B cells (plasmablasts) in IPAH, and to characterize recombinant antibodies derived from these plasmablasts. Blood plasmablasts are elevated in IPAH, remain elevated over time, and produce IgA autoantibodies. Single-cell sequencing of plasmablasts in IPAH revealed repertoires of affinity-matured antibodies with small clonal expansions, consistent with an ongoing autoimmune response. Recombinant antibodies representative of these clonal lineages bound known autoantigen targets and displayed an unexpectedly high degree of polyreactivity. Representative IPAH plasmablast recombinant antibodies stimulated human umbilical vein endothelial cells to produce cytokines and overexpress the adhesion molecule ICAM-1. Together, our results demonstrate an ongoing adaptive autoimmune response involving IgA plasmablasts that produce anti-endothelial cell autoantibodies in IPAH. These antibodies stimulate endothelial cell production of cytokines and adhesion molecules, which may contribute to disease pathogenesis. These findings suggest a role for mucosally-driven autoimmunity and autoimmune injury in the pathogenesis of IPAH.

MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation.

Different proinflammatory cytokines enhance the expression of miR-506 in biliary epithelial cells; miR-506 induces PBC-like features in cholangiocytes and promotes immune activation, representing a potential therapeutic target for PBC patients. (Hepatology 2018;67:1420-1440).