Injectable, Drug-Eluting Nanocrystals Prevent Fibrosis and Stricture Formation In Vivo.

BACKGROUND & AIMS: Tissue fibrosis results from uncontrolled healing responses leading to excessive mesenchymal cell activation and collagen and other extracellular matrix deposition. In the gastrointestinal tract, fibrosis leads to narrowing of the lumen and stricture formation. A drug treatment to prevent fibrosis and strictures in the gastrointestinal tract would be transformational for patient care. We aimed to develop a stricture treatment with the following characteristics and components: a small molecule with strong antifibrotic effects that is delivered locally at the site of the stricture to ensure correct lesional targeting while protecting the systemic circulation, and that is formulated with sustained-release properties to act throughout the wound healing processes. METHODS: A high-throughput drug screening was performed to identify small molecules with antifibrotic properties. Next, we formulated an antifibrotic small molecule for sustained release and tested its antifibrotic potential in 3 animal models of fibrosis. RESULTS: Sulconazole, a US Food and Drug Administration-approved drug for fungal infections, was found to have strong antifibrotic properties. Sulconazole was formulated as sulconazole nanocrystals for sustained release. We found that sulconazole nanocrystals provided superior or equivalent fibrosis prevention with less frequent dosing in mouse models of skin and intestinal tissue fibrosis. In a patient-like swine model of bowel stricture, a single injection of sulconazole nanocrystals prevented stricture formation. CONCLUSIONS: The current data lay the foundation for further studies to improve the management of a range of diseases and conditions characterized by tissue fibrosis.

[THE MUSCULAR COMPONENT OF FIBROMYALGIA PATHOPHYSIOLOGY].

INTRODUCTION: Fibromyalgia syndrome (FMS) is a chronic pain syndrome, prevalent in women more than men. The main symptoms are widespread musculoskeletal pain, fatigue, and weakness. To date, the pathophysiological mechanisms are unclear, and there are several pathogenic theories elucidating this condition. In this review, we summarized articles published in the past few years, regarding the effect of musculoskeletal dysfunction on FMS. We focused on the musculoskeletal system and central nervous system (CNS) disarrays.

Cross-sectional analysis reveals autoantibody signatures associated with COVID-19 severity.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with increased levels of autoantibodies targeting immunological proteins such as cytokines and chemokines. Reports further indicate that COVID-19 patients may develop a broad spectrum of autoimmune diseases due to reasons not fully understood. Even so, the landscape of autoantibodies induced by SARS-CoV-2 infection remains uncharted territory. To gain more insight, we carried out a comprehensive assessment of autoantibodies known to be linked to diverse autoimmune diseases observed in COVID-19 patients in a cohort of 231 individuals, of which 161 were COVID-19 patients (72 with mild, 61 moderate, and 28 with severe disease) and 70 were healthy controls. Dysregulated IgG and IgA autoantibody signatures, characterized mainly by elevated concentrations, occurred predominantly in patients with moderate or severe COVID-19 infection. Autoantibody levels often accompanied anti-SARS-CoV-2 antibody concentrations while stratifying COVID-19 severity as indicated by random forest and principal component analyses. Furthermore, while young versus elderly COVID-19 patients showed only slight differences in autoantibody levels, elderly patients with severe disease presented higher IgG autoantibody concentrations than young individuals with severe COVID-19. This work maps the intersection of COVID-19 and autoimmunity by demonstrating the dysregulation of multiple autoantibodies triggered during SARS-CoV-2 infection. Thus, this cross-sectional study suggests that SARS-CoV-2 infection induces autoantibody signatures associated with COVID-19 severity and several autoantibodies that can be used as biomarkers of COVID-19 severity, indicating autoantibodies as potential therapeutical targets for these patients.

Possible Association Between Anti-Trisulfated-Heparin-Disaccharide (TS-HDS) Immunoglobulin M Autoantibody and Fibromyalgia Syndrome.

BACKGROUND: Fibromyalgia syndrome (FMS) is estimated to affect 2-4% of the general population. While FMS has some known environmental and genetic risk factors, the disorder has no clear etiology. A common coexisting disorder with FMS is small fiber neuropathy (SFN). High levels of serum immunoglobulin M (IgM) binding to trisulfated-heparin-disaccharide (TS-HDS) were recently found to be associated with SFN. OBJECTIVES: To evaluate potential differences in anti-TS-HDS antibody titers in women with FMS compared to healthy controls. METHODS: In this cross-sectional study, we evaluated 51 female participants: 30 with a diagnosis of FMS and 21 healthy controls who had been recruited at the Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Israel. All of the participants were older than 18 years of age. Anti-TS-HDS IgM levels were measured in their sera using the enzyme immunoassay technique. RESULTS: The mean anti-TS-HDS IgM levels were significantly lower in the FMS group, compared with the control group (7.7 ± 5 vs. 13.2 ± 8.6 U/ml, respectively; P = 0.013). CONCLUSIONS: There is a possible association between FMS and anti-TS-HDS IgM. This association might be the missing link for the coexistence of SFN and FMS, but further study should be performed to assess this association and this auto-antibody characteristic.

Cannabis and Autoimmune Diseases.

BACKGROUND: Cannabis and cannabinoids have been known for thousands of years for their promising potential as analgesics. Chronic pain is a common complaint among many patients with rheumatic conditions. These disorders have revisited the medical approach toward cannabis and its potential role in pain relief. In addition, in recent years, information has mounted about the immunomodulatory effects of cannabis. In this review we discuss findings on the benefits cannabis may have in rheumatic and autoimmune disorders.

Autoimmune dysautonomia in women with silicone breast implants.

IMPORTANCE AND OBJECTIVES: There is unmet medical need to understand the pathogenic mechanism of the panoply of clinical manifestations associated with silicone breast implants (SBIs) such as severe fatigue, widespread pain, palpitations, dry mouth and eyes, depression, hearing loss etc. We aimed to determine whether autoantibodies against the autonomic nervous system receptors can explain the enigmatic and subjective clinical manifestation reported by women with SBIs. RESULTS: Circulating level of autoantibodies against G protein-coupled receptors (GPCRs) of the autonomic nervous system (adrenergic, muscarinic, endothelin and angiotensin receptors) have been evaluated in symptomatic women with SBIs using an ELISA method. These women with SBIs addressed our clinic due to various subjective and autonomic-related manifestations such as chronic severe fatigue, cognitive impairment, widespread pain, memory loss, sleep disorders, palpitations, depression, hearing abnormalities etc. We report for the first time, a significant reduction in the sera level of anti-ß1 adrenergic receptor (p < 0.001), anti-angiotensin II type 1 receptor (p < 0.001) and anti-endothelin receptor type A (p = 0.001) autoantibodies in women with SBIs (n = 93) as compared with aged matched healthy women (n = 36). Importantly, anti-ß1 adrenergic receptor autoantibody was found to significantly correlate with autonomic-related manifestations such as: sleep disorders and depression in women with SBIs. CONCLUSIONS: Chronic immune stimulation by silicone material may lead to an autoimmune dysautonomia in a subgroup of potentially genetically susceptible women with SBIs. The appearance of autoantibodies against GPCRs of the autonomic nervous system serve as an explanation for the subjective autonomic-related manifestations reported in women with SBIs.

Infusion of anti-DFS70 antibodies prolonged survival of lupus-prone mice.

BACKGROUND: Systemic-lupus-nephritis is a chronic autoimmune disease characterized by immune complex deposition and a flare of autoantibodies and leading to renal injury. OBJECTIVES: To expose anti-Dense-Fine-Speckled-70 (DFS70)-antibodies to genetically-prone-lupus-mice. METHODS: NZBXW/F1 female mice were monitored for the onset of glomerulonephritis by proteinuria upon infusion of anti-DFS70 (40 µg/mouse), commercial-human-IgG (cIgG) or phosphate-buffered-saline (PBS) as controls. The survival time was detected by mice death. Circulating anti-dsDNA were tested by ELISA. Proteinuria, was defined by a standard semi-quantitative-Bayer-Multistix-dipstick. Kidney histology was analyzed by periodic-acid-Schiff-PAS staining. RESULTS: A significantly higher percentage of anti-DFS70-infused mice exhibited prolonged survival time as compared with cIgG and PBS-subjected mice (p < 0.022). One mouse out of 10 mice injected with anti-DFS70-antibodies died at week 36, whereas, 6 out of 10 mice subjected with PBS found dead at this time. Eighty percent of anti-DFS70 injected mice did not show severe glomerulonephritis by histology. CONCLUSIONS: anti-DFS70 attenuated the progression of glomerulonephritis and prolonged the survival time. Circulating anti-DFS70-autoantibodies may confer a protective role against renal injury in murine-lupus-nephritis. Our data may propose a novel therapy approach for lupus patients.

[SILICONE BREAST IMPLANTS - HISTORICAL MEDICAL ERROR].

INTRODUCTION: Silicone is a foreign material to our body and therefore, has been found to stimulate the immune system. Silicone breast implants (SBIs), made of silicone polymer, have been used for aesthetic and medical purposes since the 1960s, and were found to trigger acute/chronic inflammation, eventually leading to the formation of fibrotic capsules on the surface of the implant. Silicone implants have been found to be associated with the development of severe and sometimes unexplained clinical manifestations such as: chronic fatigue, sleep and memory problems, widespread pain, dry mouth and eye, depression, arthralgia, myalgia, palpitations, tinnitus and hearing loss, skin rash, hair loss, vision problems, hyperhidrosis, allergic reactions, etc. Furthermore, SBIs have been found to be associated with the development of rheumatologic/autoimmune diseases and the development of rare lymphoma. The FDA has expressed concern over the years about the implications of SBIs and requested that the companies involved provide data of any concern regarding the implants. However, the companies continued to sell the implants without reporting data, as agreed. In October 2019, the FDA recommended boxed warnings describing the dangers facing women applying for SBIs such as lymphoma. Importantly, our lab recently found the presence of autoantibodies against the autonomic nervous system in the blood of women with SBIs, which might explain some of the patients' severe symptoms. Owing to the numerous data that had been accumulated (since 1960s) indicating a direct link between silicone, autoimmune diseases and cancer, we believe that the use of SBIs has been a historical medical error.

The small tellurium-based compound SAS suppresses inflammation in human retinal pigment epithelium.

PURPOSE: Pathological angiogenesis and chronic inflammation greatly contribute to the development of choroidal neovascularization (CNV) in chorioretinal diseases involving abnormal contact between retinal pigment epithelial (RPE) and endothelial cells (ECs), associated with Bruch's membrane rupture. We explored the ability of the small organotellurium compound octa-O-bis-(R,R)-tartarate ditellurane (SAS) to mitigate inflammatory processes in human RPE cells. METHODS: Cell adhesion assays and analyses of gene and protein expression were used to examine the effect of SAS on ARPE-19 cells or primary human RPE cells that were grown alone or in an RPE-EC co-culture. RESULTS: Adhesion assays showed that SAS inhibited αv integrins expressed on RPE cells. Co-cultures of RPE cells with ECs significantly reduced the gene expression of PEDF, as compared to RPE cells cultured alone. Both SAS and the anti-αvß3 antibody LM609 significantly enhanced the production of PEDF at both mRNA and protein levels in RPE cells. RPE cells co-cultured with EC exhibited increased gene expression of CXCL5, COX1, MMP2, IGF1, and IL8, all of which are involved in both angiogenesis and inflammation. The enhanced expression of these genes was greatly suppressed by SAS, but interestingly, remained unaffected by LM609. Zymography assay showed that SAS reduced the level of MMP-2 activity in RPE cells. We also found that SAS significantly suppressed IL-1ß-induced IL-6 expression and secretion from RPE cells by reducing the protein levels of phospho-IkappaBalpha (pIκBα). CONCLUSIONS: Our results suggest that SAS is a promising anti-inflammatory agent in RPE cells, and may be an effective therapeutic approach for controlling chorioretinal diseases.

Multifunctional activity of a small tellurium redox immunomodulator compound, AS101, on dextran sodium sulfate-induced murine colitis.

Inflammatory bowel diseases (IBDs) are a group of idiopathic, chronic immune-mediated diseases characterized by an aberrant immune response, including imbalances of inflammatory cytokine production and activated innate and adaptive immunity. Selective blockade of leukocyte migration into the gut is a promising strategy for the treatment of IBD. This study explored the effect of the immunomodulating tellurium compound ammonium trichloro (dioxoethylene-o,o') tellurate (AS101) on dextran sodium sulfate (DSS)-induced murine colitis. Both oral and intraperitoneal administration of AS101 significantly reduced clinical manifestations of IBD. Colonic inflammatory cytokine levels (IL-17 and IL-1ß) were significantly down-regulated by AS101 treatment, whereas IFN-γ was not affected. Neutrophil and α4ß7(+) macrophage migration into the tissue was inhibited by AS101 treatment. Adhesion of mesenteric lymph node cells to mucosal addressin cell adhesion molecule (MAdCAM-1), the ligand for α4ß7 integrin, was blocked by AS101 treatment both in vitro and in vivo. DSS-induced destruction of colonic epithelial barrier/integrity was prevented by AS101, via up-regulation of colonic glial-derived neurotrophic factor, which was found previously to regulate the intestinal epithelial barrier through activation of the PI3K/AKT pathway. Indeed, the up-regulation of glial-derived neurotrophic factor by AS101 was associated with increased levels of colonic pAKT and BCL-2 and decreased levels of BAX. Furthermore, AS101 treatment reduced colonic permeability to Evans blue and decreased colonic TUNEL(+) cells. Our data revealed multifunctional activities of AS101 in the DSS-induced colitis model via anti-inflammatory and anti-apoptotic properties. We suggest that treatment with the small, nontoxic molecule AS101 may be an effective early therapeutic approach for controlling human IBD.

Palpitation in women with silicone breast implants: association with autoantibodies against autonomic nervous system.

We explored a possible association between palpitation manifestation in women with silicone breast implants (SBIs) with circulating level of autoantibodies directed against autonomic nervous system (ANS) receptors. The study was conducted in 93 women with SBIs who arrived to our clinic with diverse symptoms thought to be associated with their implants. Titers of 11 various autoantibodies were measured in the sera of women with SBIs who experienced palpitations (Palpitations, n = 47), did not experience palpitations (Non, n = 46), and healthy women (Control, n = 36). A significant reduction in anti-α2-adrenergic receptor (A2AR, P = 0.035), anti-ß2-adrenergic receptor (B2AR, P = 0.027), antimuscarinic receptors M1R (P = 0.048), and anti-M2R (P = 0.039) autoantibodies was found in the 'Palpitations' group as compared with the 'Non' group. Anti-B2AR (P = 0.042), anti-M1R (P = 0.017), and anti-M2R (P = 0.0015) autoantibodies were also significantly reduced in 'Palpitations' as compared with the 'Control' group. Our study shows possible association between autoantibodies directed against ANS receptors, with existing complaints of palpitations in women with SBIs.

Allergic manifestations in women with silicone breast implants.

INTRODUCTION: Silicone breast implants (SBI) result in immune dysregulation and are associated with autoimmune diseases. Recently, we reported dysregulated levels of IgG autoantibodies directed against G protein-coupled receptors (GPCRs) of the autonomic nervous system which were linked to the autoimmune dysautonomia in silicone breast implant illness (SBII). AIMS: We aimed to explore the possible association between allergy with dysregulated IgE autoantibodies directed against GPCRs of the autonomic nervous system in women with SBI. METHODS: Circulating levels of IgE autoantibodies against GPCRs of the autonomic nervous system (adrenergic, muscarinic, endothelin and angiotensin receptors) have been evaluated in women with SBIs who complained of allergic symptoms, and compared to subjects with SBI without allergic manifestations and to age-matched healthy women without SBI. RESULTS: We report a significant dysregulation in three circulating autoantibodies: IgE-beta1 adrenergic receptor (B1AR), IgE-alpha 1 adrenergic receptor (A1AR) and IgE-muscarinic acetylcholine receptor type 1 (M1R) autoantibodies in women with SBI who complained of allergic symptoms. CONCLUSIONS: Allergic reactions associated with SBI are not uncommon. Imbalance of circulating levels of IgE autoantibodies against GPCRs of the autonomic nervous system might play a role not only in allergic reactions, but also in other enigmatic aspects of SBII such as autoimmune dysautonomia.

Simulations of the NK cell immune synapse reveal that activation thresholds can be established by inhibitory receptors acting locally.

NK cell activation is regulated by a balance between activating and inhibitory signals. To address the question of how these signals are spatially integrated, we created a computer simulation of activating and inhibitory NK cell immunological synapse (NKIS) assembly, implementing either a "quantity-based" inhibition model or a "distance-based" inhibition model. The simulations mimicked the observed molecule distributions in inhibitory and activating NKIS and yielded several new insights. First, the total signal is highly influenced by activating complex dissociation rates but not by adhesion and inhibitory complex dissociation rates. Second, concerted motion of receptors in clusters significantly accelerates NKIS maturation. Third, when the potential of a cis interaction between Ly49 receptors and MHC class I on murine NK cells was added to the model, the integrated signal as a function of receptor and ligand numbers was only slightly increased, at least up to the level of 50% cis-bound Ly49 receptors reached in the model. Fourth, and perhaps most importantly, the integrated signal behavior obtained when using the distance-based inhibition signal model was closer to the experimentally observed behavior, with an inhibition radius of the order 3-10 molecules. Microscopy to visualize Vav activation in NK cells on micropatterned surfaces of activating and inhibitory strips revealed that Vav is only locally activated where activating receptors are ligated within a single NK cell contact. Taken together, these data are consistent with a model in which inhibitory receptors act locally; that is, that every bound inhibitory receptor acts on activating receptors within a certain radius around it.

Shared Pathogenicity Features and Sequences between EBV, SARS-CoV-2, and HLA Class I Molecule-binding Motifs with a Potential Role in Autoimmunity.

Epstein-Barr virus (EBV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are extraordinary in their ability to activate autoimmunity as well as to induce diverse autoimmune diseases. Here we reviewed the current knowledge on their relation. Further, we suggested that molecular mimicry could be a possible common mechanism of autoimmunity induction in the susceptible individuals infected with SARS-CoV-2. Molecular mimicry between SARS-CoV-2 and human proteins, and EBV and human proteins, are present. Besides, relation of the pathogenicity associated with both coronavirus diseases and EBV supports the notion. As a proof-of-the-concept, we investigated 8mer sequences with shared 5mers of SARS-CoV-2, EBV, and human proteins, which were predicted as epitopes binding to the same human leukocyte antigen (HLA) supertype representatives. We identified significant number of human peptide sequences with predicted-affinities to the HLA-A*02:01 allele. Rest of the peptide sequences had predicted-affinities to the HLA-A*02:01, HLA-B*40:01, HLA-B*27:05, HLA-A*01:01, and HLA-B*39:01 alleles. Carriers of these serotypes can be under a higher risk of autoimmune response induction upon getting infected, through molecular mimicry-based mechanisms common to SARS-CoV-2 and EBV infections. We additionally reviewed established associations of the identified proteins with the EBV-related pathogenicity and with the autoimmune diseases.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) in 2023.

In 2011, a syndrome entitled ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants; Shoenfeld's syndrome) was first described. ASIA aimed to organize under a single umbrella, the existing evidence regarding certain environmental factors which possess immune stimulatory properties, in order to shed light on a common pathway of autoimmune pathogenesis. Such environmental immune stimulators, or adjuvants, include among others: aluminum salts as in vaccines, various medical implants, as well as various infectious agents. After the launch of the ASIA syndrome, the expansion and recognition of this syndrome by different researchers from different countries began. During the past decades, evidence had been accumulating that (auto)immune symptoms can be triggered by exposure to environmental immune stimulatory factors that act as an adjuvant in genetically susceptible individuals. A panoply of unexplained subjective and autonomic-related symptoms has been reported in patients with ASIA syndrome. The current review summarizes and updates accumulated knowledge from the past decades, describing new adjuvants- (e.g. polypropylene meshes) and vaccine- (e.g. HPV and COVID vaccines) induced ASIA. Furthermore, a direct association between inflammatory/autoimmune diseases with ASIA syndrome, will be discussed. Recent cases will strengthen some of the criteria depicted in ASIA syndrome such as clear improvement of symptoms by the removal of adjuvants (e.g. silicone breast implants) from the body of patients. Finally, we will introduce additional factors to be included in the criteria for ASIA syndrome such as: (1) dysregulated non-classical autoantibodies directed against G-protein coupled receptors (GPCRs) of the autonomic nervous system and (2)) small fiber neuropathy (SFN), both of which might explain, at least in part, the development of 'dysautonomia' reported in many ASIA patients.

The Prevalence of Hearing Impairments in Women with Silicone Breast Implants.

Many women with silicone breast implants (SBIs) report non-specific complaints, including hearing impairments. Hearing impairment appears to be associated with a number of autoimmune conditions. The current study aimed to evaluate the prevalence and severity of hearing impairments among women with SBIs and to explore potential improvements in their hearing capability following implant removal. Symptomatic women with SBIs (n = 160) underwent an initial anamnestic interview, and women who reported hearing impairments were selected for the study. These women completed self-report telephone questionnaires regarding their hearing difficulties. Some of these women underwent subjective and objective hearing tests. Out of 159 (50.3%) symptomatic women with SBIs, 80 reported hearing impairments, including hearing loss (44/80; 55%) and tinnitus (45/80; 56.2%). Five out of seven (71.4%) women who underwent an audiologic evaluation exhibited hearing loss. Of women who underwent silicone implant removal, 27 out of 47 (57.4%) reported the improvement or resolution of their hearing complaints. In conclusion, hearing impairment is a frequent complaint among symptomatic women with SBIs, and tinnitus was found to be the most common complaint. A significant reduction in hearing difficulties was observed following silicone implant removal. Further studies using larger populations are needed to verify the occurrence of hearing impairments in these women.

The possible onset of fibromyalgia following acute COVID-19 infection.

INTRODUCTION: The exact pathogenesis of fibromyalgia (FM) syndrome is unclear. However, various infectious have been implicated with the development of FM after their acute phase. We aimed to investigate the incidence of FM syndrome among convalesced individuals following hospitalization for Acute Coronavirus Disease-2019 (COVID-19). METHODS: We performed a cross-sectional study on patients who were discharged after COVID-19 hospitalization from the Sheba Medical Center, Israel, between July 2020 to November 2020. A phone interview was performed consisting of the following questionnaires: the Fibromyalgia Survey Diagnostic Criteria Questionnaire, Sense of Coherence Questionnaire to evaluate resilience, and the Subjective Traumatic Outlook Questionnaire to assess the associated psychological aspects of the trauma. The incidence of post-COVID FM was calculated and regression models were performed to identify predictors. RESULTS: The study population consisted of 198 eligible patients who completed the phone interview. The median age was 64 (52-72) and 37% were women. The median follow-up was 5.2 months (IQR 4.4-5.8). The incidence of FM was 15% (30 patients) and 87% (172 patients) had at least one FM-related symptom. Female gender was significantly associated with post-COVID FM (OR 3.65, p = 0.002). In addition, high median Subjective Traumatic Outlook scores and low median Sense of Coherence scores were both significantly associated with post-COVID FM (OR 1.19, p<0.001 and OR 0.92, p<0.001, respectively). CONCLUSIONS: FM is highly prevalent among COVID-19 convalescent patients. Our finding suggests that a significant subjective traumatic experience and a low resilience are highly associated with post-COVID FM.