Autoimmune Attack Research Articles

Links between Breast and Thyroid Cancer: Hormones, Genetic Susceptibility and Medical Interventions.

Simple SummaryBreast and thyroid cancer are commonly diagnosed in women. Physicians have recognized and evaluated the phenomenon of two cancers occurring synchronously or asynchronously. The potential mechanisms are complex and various. Hormone, autoimmune attack and genetic predisposition are significant and shared factors influencing two cancers. Medical interventions for the first cancer and other life-related factors are reviewed and discussed, as well. This article aims to expound the relationship between breast and thyroid cancer, and suggests that physicians should monitor for the second cancer appropriately whenever one cancer occurs.Breast and thyroid glands are two common sites of female malignancies. Since the late 19th century, physicians have found that the cancers in either thyroid or mammary gland might increase the risk of second primary cancers in the other site. From then on, many observational clinical studies have confirmed the hypothesis and more than one theory has been developed to explain the phenomenon. Since the two glands both have secretory functions and are regulated by the hypothalamic–pituitary axis, they may share some common oncogenic molecular pathways. However, other risks factors, including medical interventions and hormones, are also observed to play a role. This article aims to provide a comprehensive review of the associations between the two cancers. The putative mechanisms, such as hormone alteration, autoimmune attack, genetic predisposition and other life-related factors are reviewed and discussed. Medical interventions, such as chemotherapy and radiotherapy, can also increase the risk of second primary cancers. This review will provide novel insights into the research designs, clinical managements and treatments of thyroid and breast cancer patients.

Type 1 diabetes: what is the role of autoimmunity in β cell death?

The current dogma of type 1 diabetes pathogenesis asserts that an autoimmune attack leads to the destruction of pancreatic β cells, with subsequent hyperglycemia. This dogma is based on islet autoantibodies emerging prior to the onset of type 1 diabetes. In this issue of the JCI, Warncke et al. report on their investigation of the development of hyperglycemia below the diabetes threshold as an early proxy of β cell demise. Surprisingly, they found that an elevation in blood glucose preceded the appearance of autoimmunity. This observation calls into question the importance of autoimmunity as the primary cause of β cell destruction and has implications for prevention and treatment in diabetes.

Molecular dynamics identifies semi-rigid domains in the PD-1 checkpoint receptor bound to its natural ligand PD-L1.

Cells in danger of being erroneously attacked by leucocytes express PD-L1 on their surface. These cells activate PD-1 on attacking leucocytes and send them to death, thus curbing erroneous, autoimmune attack. Unfortunately, cancer cells exploit this mechanism: By expressing PD-L1, they guard themselves against leucocyte attack and thereby evade immune clearance. Checkpoint inhibitors are drugs which re-enable immune clearance of cancer cells by blocking the binding of PD-L1 to PD-1 receptors. It is therefore of utmost interest to investigate these binding mechanisms. We use three 600 ns all-atom molecular dynamics simulations to scrutinize molecular motions of PD-1 with its binding partner, the natural ligand PD-L1. Usually, atomic motion patterns are evaluated against whole molecules as a reference, disregarding that such a reference is a dynamic entity by itself, thus degrading stability of the reference. As a remedy, we identify semi-rigid domains, lending themselves as more stable and reliable reference frames against which even minute differences in molecular motion can be quantified precisely. We propose an unsupervised three-step procedure. In previous work of our group and others, minute differences in motion patterns proved decisive for differences in function. Here, several highly reliable frames of reference are established for future investigations based on molecular motion.

Surgical management prospects for myasthenia gravis in Nigeria

Background: Myasthenia gravis (MG) is an acquired autoimmune neuromuscular disease characterized by fatigable and variable weakness of skeletal muscles as a result of autoimmune attack on postsynaptic antigenic targets. There is paucity of data on the outcome of treatment options available in resource-poor settings. Objective: The aim of this study was to determine the treatment outcome of surgical thymectomy for MG with regard to the local experience in Enugu, southeast Nigeria. Materials and Methods: It was a preliminary report of patients with MG seen at the Neurology Clinic of the University of Nigeria Teaching Hospital, Enugu, Nigeria, from February 2016 to October 2019. The treatment outcomes of the patients were analyzed following thymectomy to determine the effectiveness of the surgical management. Data obtained included patients’ age, response to treatment, intensive care unit (ICU) stay, and total hospital stay. Results: The mean age of the patients was 35.7 ± 15.1. The mean duration of stay at the ICU was 3.9 ± 4.6 days, while the mean total hospital stay was 12 ± 9.70 days. All the patients (100%) had symptomatic improvement following thymectomy and 40% had remission. Conclusion: The general outcome of MG patients following thymectomy was favorable. Thymectomy appears to improve the prognosis of MG in the local setting of Enugu, Nigeria.

Testicular Immunity and Its Connection with the Microbiota. Physiological and Clinical Implications in the Light of Personalized Medicine.

Reproduction is a complex process, which is based on the cooperation between the endocrine–immune system and the microbiota. Testicular immunity is characterized by the so-called immune privilege, a mechanism that avoids autoimmune attacks against proteins expressed by spermatozoa. Testicular microbiota is connected with the gut microbiota, the most prevalent site of commensals inthe body. Both microbiotas take part inthe development of the immune system and protection againstpathogen invasion. Dysbiosis is caused by concurrent pathologies, such as obesity, diabetes, infections and trauma. The substitution of beneficial bacteria with pathogens may lead to destruction of spermatozoa directly or indirectly and, ultimately, to male infertility. Novel therapeutic interventions, i.e., nutritional interventions and supplementation of natural products, such as, probiotics, prebiotics, antioxidants and polyphenols, may lead to the restoration of the otherwise-impaired male reproductive potential, even if experimental and clinical results are not always concordant. In this review, the structure and immune function of the testis will be described with special reference to the blood–testisbarrier. The regulatory role of both the gut and testicular microbiota will be illustrated in health and disease, also emphasizing therapeutic attempts with natural products for the correction of male infertility, in the era of personalized medicine.

863 Blocking the LFA-1 signaling pathway reverses alopecia areata in C3H/HeJ mice

Alopecia areata (AA) is caused by T cell-mediated autoimmune attack of the hair follicle. Therefore, inhibition of T lymphocyte migration and pathogenic activity represents an attractive therapeutic approach in the treatment of T lymphocyte-mediated autoimmune diseases, including AA. The lymphocyte function antigen-1 (LFA-1) receptor signaling pathway plays a crucial role in T cell activation, migration of T cells to target tissues and formation of the classical cytolytic immune synapse. We previously showed that the intercellular adhesion molecule 1(ICAM-1), one of the major ligands for LFA-1, is upregulated in lesional skin of both human patients and C3H/HeJ mice with AA. We observed that CD44+CD8+effector/memory T cell expressed high levels of LFA-1 within skin draining lymph nodes as well as within AA lesional skin. Here, we investigated the role of LFA-1 signaling pathway in AA using C3H/HeJ mice, and found that blockade of the LFA-1 signaling pathway using either anti-LFA-1 or anti-ICAM-1 mAbs prevented the development of AA in C3H/HeJ skin grafted mice. Immunohistochemical staining of skin biopsies show that anti-LFA-1- or anti-ICAM-1-treated mice have a striking decrease in skin T cell infiltration together with reduced expression of AA-associated markers (MHC-I and MHC-II). Furthermore, we observed that LFA-1 signaling blockade not only reduced CD44+CD8 +effector/memory T cell migration into the skin, but also led to enrichment of Tregs in skin draining lymph nodes. To limit systemic exposure, we topically treated C3H/HeJ AA mice with lifitegrast, a small molecule antagonist of LFA-1, and found that lifitegrast was effective in reversal of AA. Taken together, we demonstrated that LFA-1 plays a crucial role in T cell migration and activation in AA, and that reversal of AA was achieved by local LFA-1 signaling blockade using topical delivery. Our results invite further clinical investigation of LFA-1 pathway inhibition as a therapeutic target in AA treatment.

Effects of high-fat diet on thyroid autoimmunity in the female rat

BackgroundWhile contributions of dyslipidemia to autoimmune diseases have been described, its impact on thyroid autoimmunity (TA) is less clear. Programmed cell death 1(PD-1)/PD-ligand 1 (PD-L1) immune checkpoint is crucial in preventing autoimmune attack while its blockade exacerbates TA. We thus unveiled the effect of high-fat diet (HFD) on TA, focusing on the contribution of PD-1/PD-L1.MethodsFemale Sprague Dawley (SD) rats were randomly fed with a regular diet or HFD (60% calories from fat) for 24 weeks. Then, thyroid ultrasonography was performed and samples were collected for lipid and thyroid-related parameter measure.ResultsHFD rats exhibited hyperlipemia and abnormal biosynthesis of the unsaturated fatty acid in serum detected by lipidomics. These rats displayed a relatively lower echogenicity and increased inflammatory infiltration in thyroid accompanied by rising serum thyroid autoantibody levels and hypothyroidism, mimicking human Hashimoto’s thyroiditis. These alterations were concurrent with decreased mRNA and immunostaining of intrathyroidal PD-1 and also serum PD-1 levels but not the PD-L1 expression, suggesting a role of a PD-1 pathway. Meanwhile, the infiltration of B and T cell, a key cellular event inhibited by the PD-1 signals, was enhanced in the thyroid of HFD rats, along with thyroid fibrosis and apoptosis.ConclusionsOur data suggest that HFD triggers TA through a mechanism possibly involving downregulation of PD-1-related immunosuppression, providing a novel insight into the link between dyslipidemia and autoimmune toxicities.

Immune-Protective Formulations and Process Strategies for Improved Survival and Function of Transplanted Islets.

Type 1 diabetes (T1D) is an autoimmune disease caused by the immune system attacking and destroying insulin-producing β cells in the pancreas. Islet transplantation is becoming one of the most promising therapies for T1D patients. However, its clinical use is limited by substantial cell loss after islet infusion, closely related to immune reactions, including instant blood-mediated inflammatory responses, oxidative stress, and direct autoimmune attack. Especially the grafted islets are not only exposed to allogeneic immune rejection after transplantation but are also subjected to an autoimmune process that caused the original disease. Due to the development and convergence of expertise in biomaterials, nanotechnology, and immunology, protective strategies are being investigated to address this issue, including exploring novel immune protective agents, encapsulating islets with biomaterials, and searching for alternative implantation sites, or co-transplantation with functional cells. These methods have significantly increased the survival rate and function of the transplanted islets. However, most studies are still limited to animal experiments and need further studies. In this review, we introduced the immunological challenges for islet graft and summarized the recent developments in immune-protective strategies to improve the outcomes of islet transplantation.

Orally Administered Brain Protein Combined With Probiotics Increases Treg Differentiation to Reduce Secondary Inflammatory Damage Following Craniocerebral Trauma.

Craniocerebral trauma is caused by external forces that can have detrimental effects on the vasculature and adjacent nerve cells at the site. After the mechanical and structural primary injury, a complex series of secondary cascades of injury exacerbates brain damage and cognitive dysfunction following mechanical and structural primary injury. Disruption of the blood-brain barrier and exposure of brain proteins following craniocerebral trauma, recognition by the immune system triggering autoimmune attack, and excessive secondary inflammatory responses causing malignant brain swelling, cerebral edema, and subsequent brain cell apoptosis provide a new direction for the suppression of brain inflammatory responses in the treatment of craniocerebral trauma. We observed that CD4+T/CD8+T in peripheral blood T cells of craniocerebral trauma rats were significantly higher than those of normal rats, and the ratio of CD4+CD25+Foxp3 (Foxp3)+Regulatory T cell (Treg) was significantly lower than that of normal rats and caused increased secondary inflammation. We constructed a rat model of post-surgical brain injury and orally administered brain protein combined with probiotics, which was observed to significantly reduce CD4+T/CD8+T and induce T-cell differentiation into CD4+CD25+Foxp3+Treg, thus, reducing secondary inflammatory responses following craniocerebral trauma. However, collecting intestinal stool and small intestinal tissues for broad target metabolomics, 16s rRNA bacteriomics, and the combined analysis of intestinal tissue proteomics revealed that oral administration of brain protein combined with probiotics activates glycerophospholipid and vitamin B6 metabolic pathways to promote the production of CD4+CD25+Foxp3+Treg. Therefore, we propose the novel idea that oral administration of brain protein combined with probiotics can induce immune tolerance by increasing Treg differentiation, thus, reducing secondary inflammatory injury following craniocerebral trauma.

COVID-19 vaccination antibody responses in patients with aplastic anaemia and paroxysmal nocturnal haemoglobinuria

COVID-19 vaccination antibody responses in patients with aplastic anaemia and paroxysmal nocturnal haemoglobinuria

Second-line immunotherapy and functional outcomes in autoimmune encephalitis: A systematic review and individual patient data meta-analysis.

Autoimmune encephalitis (AE) is a neurological disorder caused by autoimmune attack on cerebral proteins. Experts currently recommend staged immunotherapeutic management, with first-line immunotherapy followed by second-line immunotherapy if response to first-line therapy is inadequate. Meta-analysis of the evidence base may provide higher quality evidence to support this recommendation. We undertook a systematic review of observational cohort studies reporting AE patients treated with either second-line immunotherapy or first-line immunotherapy alone, and outcomes reported using the modified Rankin Scale (mRS; search date: April 22, 2020). We performed several one-stage multilevel individual patient data (IPD) meta-analyses to examine the association between second-line immunotherapy and final mRS scores (PROSPERO ID CRD42020181805). IPD were obtained for 356 patients from 25 studies. Most studies were rated as moderate to high risk of bias. Seventy-one patients (71/356, 19%) were treated with second-line immunotherapy. We did not find a statistically significant association between treatment with second-line immunotherapy and final mRS score for the cohort overall (odds ratio [OR] = 1.74, 95% confidence interval [CI] = .98-3.08, p= .057), or subgroups with anti-N-methyl-D-aspartate receptor encephalitis (OR=1.03, 95% CI = .45-2.38, p= .944) or severe AE (maximum mRS score > 2; OR=1.673, 95% CI = .93-3.00, p= .085). Treatment with second-line immunotherapy was associated with higher final mRS scores in subgroups with anti-leucine-rich glioma-inactivated 1 AE (OR=6.70, 95% CI=1.28-35.1, p= .024) and long-term (at least 12 months) follow-up (OR=3.94, 95% CI=1.67-9.27, p= .002). We did not observe an association between treatment with second-line immunotherapy and lower final mRS scores in patients with AE. This result should be interpreted with caution, given the risk of bias, limited adjustment for disease severity, and insensitivity of the mRS in estimating psychiatric and cognitive disability.

1443-P: Real-Time In Vivo Analysis of Beta-Cell Autophagy in Autoimmune Diabetes

Type 1 Diabetes (T1D) is an autoimmune disease caused by a combination of genetic and environmental factors. The onset of disease is associated with autoimmune attack against pancreatic beta-cells leading to a reduction of their number. While a role for the beta-cell in these events is widely hypothesized, a complete understanding of disease pathogenesis is still lacking. Our group recently found that beta-cell autophagy is defective in the context of human T1D as well as in the non-obese diabetic (NOD) mouse model of autoimmune diabetes. Importantly, our data suggested that defective autophagy is present prior to the onset of diabetes but stopped short of definitively demonstrating pre-existing defects. Therefore, here we evaluated autophagic flux in the pancreatic beta-cells of live mice using a fluorescent biosensor coupled to intravital microscopy. A custom beta-cell-selective autophagy biosensor (AAV8-INS-mCherry-EGFP-LC3B) was intraperitoneally (IP) injected into 7-week-old mice of three strains: wild type C57Bl/6J, NOD and NOD scid gamma (NSG) mice. Three weeks after biosensor injections, mice were placed under inhaled isoflurane anesthesia, then externalized pancreata were imaged using a LEICA SP8 DIVE two-photon microscope mounted with a 40x/1.1NA water objective. To evaluate autophagic flux, we assessed fluorescent signal over time in response to IP infusion of either saline or chloroquine, an autophagy inhibitor. Autophagic flux was assessed by quantifying the rate of change of the ph-sensitive GFP and the ph-insensitive RFP, as well as signal colocalization. In wild type mice, we observed clear evidence of autophagic flux over time that was altered in the presence of chloroquine. However, in contrast, in pre-diabetic NOD mice, islet autophagic flux did not respond effectively to chloroquine treatment. Collectively, these data support the conclusion that autophagy defects precede hyperglycemia and suggest a potential role for these defects in beta cell demise during T1D pathogenesis. Disclosure O.Melnyk: None. C.Muralidharan: None. M.M.Martinez irizarry: None. J.Crowder: None. A.K.Linnemann: Consultant; Janssen Research & Development, LLC. Funding National Institutes of Health (R01DK124380) . Startup funds to AKL from the Herman B Wells Center for Pediatric Research at Indiana University School of Medicine

The FVB mouse strain as a spontaneous model of degenerative mitral valve disease

Mitral valve disease is a complex entity with diverse origins, degeneration occurring following an extrinsic aggression (infection, autoimmune attack, drug), genetic malformation or being due to a hemodynamic abnormality (dilatation of the left ventricle, myocardial infarction). The aim is to present the main cardiovascular characteristics of the FVB mouse strain with a particular focus on spontaneous mitral valve degeneration and the serotonergic system in comparison with the C57BL/6 J, the usual background strain of many cardiovascular studies. Body weight, systolic blood pressure, heart rate, urinary 5-hydroxyindoleacetic acid (5-HIAA), whole blood and plasma serotonin, tail bleeding time, blood cell count, plasma TGF-β1 and plasma natriuretic peptide concentrations were measured in FVB/NJ and FVB/NRj mice strains (males and females) obtained from Janvier and Charles River Labs in comparison to the usual C57BL/6 background at different ages (12, 16, 20 and 24-week-old). To know if the mitral valve was remodeled, cardiac anatomy and function were assessed by echocardiography and mitral valves were finally characterized by histology. The expression of 5-HT2A and 5-HT2B receptors was measured by RTqPCR in the anterior leaflet of the valve. No significant difference in C57BL/6 J compared to FVB mice strains regarding body weight increase, arterial blood pressure and heart rate was observed. A progressive augmentation of plasma pro-ANP was observed in FVB mice. However, no cardiac hypertrophy or left-ventricular fibrosis were observed. Conversely, FVB mice demonstrated a high prevalence of fibromyxoid highly cellularized and enriched in glycosaminoglycans lesions, inducing major mitral leaflets thickening without increase in length (100% of 24-week-old FVB/NRj males). The increased thickness was correlated with urinary 5-HIAA and blood platelet count. Whole blood serotonin concentration was similar in the two strains but, in FVB, a reduction of plasma serotonin was observed together with an increase of the bleeding time. No difference regarding serotonergic receptors expression was observed. Finally, echocardiography identified left atrial and left ventricular remodeling associated with thickening of both mitral leaflets and mitral insufficient in 30% of FVB mice but no systolic protrusion of mitral leaflets towards the atrium meaning the absence of mitral valve prolapse. Spontaneous mitral myxomatous degeneration is highly prevalent in FVB mice. A contribution of the serotonergic system is suggested

1295-P: Learning from Immune Privileged Tissue Stem Cells to Generate Hypoimmunogenic Islets

The ultimate goal to accomplish a definitive cure for Type 1 Diabetes (T1D) is to replace the lost beta-cell mass while ensuring its long-lasting survival. This could be done by transplantation of pancreatic islets or stem cell-derived insulin-producing cells. However, any replacement will irrevocably succumb to the same autoimmune attack that killed the original beta-cells. Moreover, a mismatch between donor cells and recipient patients adds an allo-graft rejection. Thus, it is of the utmost importance to develop strategies to protect transplanted pancreatic islets from immune attack. Unfortunately, many approaches aiming at restoring tolerance by manipulating immune cells have been tested and, although safe, have shown only limited efficacy. Inflammatory processes, infections or major lifestyle changes can easily alter the balance again towards immune activation. We recently discovered the existence of immune privileged stem cells in the skin and muscle, and found that their ability to resist direct attack by T cells was not dependent on a physical barrier. Instead, it is a cell-autonomous process that allows independent cloaking from immune cells. Here we propose to exploit the molecular circuits controlling this striking phenomenon (that already naturally occurs in our bodies) to provide similar protection to islets for transplantation. We identified a molecular pathway that reduces antigen presentation allowing protection from T cells while preserving enough MHC class I to not trigger a Natural Killer (NK) cell response. Since this mechanism of protection is cell intrinsic, changes in overall immune function should not alter the ability of engineered islets to hide from immune rejection allowing for long-lasting survival. Disclosure J.Agudo: None. Funding American Diabetes Association (1-20-ACE-08)

Antigen receptor‐engineered Tregs inhibit CNS autoimmunity in cell therapy using nonredundant immune mechanisms in mice

CD4+FOXP3+ Tregs are currently explored to develop cell therapies against immune‐mediated disorders, with an increasing focus on antigen receptor‐engineered Tregs. Deciphering their mode of action is necessary to identify the strengths and limits of this approach. Here, we addressed this issue in an autoimmune disease of the CNS, EAE. Following disease induction, autoreactive Tregs upregulated LAG‐3 and CTLA‐4 in LNs, while IL‐10 and amphiregulin (AREG) were increased in CNS Tregs. Using genetic approaches, we demonstrated that IL‐10, CTLA‐4, and LAG‐3 were nonredundantly required for the protective function of antigen receptor‐engineered Tregs against EAE in cell therapy whereas AREG was dispensable. Treg‐derived IL‐10 and CTLA‐4 were both required to suppress acute autoreactive CD4+ T‐cell activation, which correlated with disease control. These molecules also affected the accumulation in the recipients of engineered Tregs themselves, underlying complex roles for these molecules. Noteworthy, despite the persistence of the transferred Tregs and their protective effect, autoreactive T cells eventually accumulated in the spleen of treated mice. In conclusion, this study highlights the remarkable power of antigen receptor‐engineered Tregs to appropriately provide multiple suppressive factors nonredundantly necessary to prevent autoimmune attacks.

A Global Regulatory Network for Dysregulated Gene Expression and Abnormal Metabolic Signaling in Immune Cells in the Microenvironment of Graves' Disease and Hashimoto's Thyroiditis.

BackgroundAlthough the pathogenetic mechanisms of Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) have been elucidated, the molecular mechanisms by which the abnormal immune function of cellular subpopulations trigger an autoimmune attack on thyroid tissue largely remains unexplained.MethodsThe study included 2 HT patients, 2 GD patients, and 1 control donor. The thyroid samples were extracted for single-cell RNA sequencing, whole transcriptome, full-length transcriptome (Oxford Nanopore Technologies), and metabolome sequencing. Identification of immune cells with dysregulated gene expression and abnormal metabolic signaling was performed in the microenvironment, both at the bulk and single-cell levels. Based on functional enrichment analysis, the biological processes and pathways involved in abnormal immune cells were further explored. Finally, according to cell communication analysis, the global regulatory network of immune cells was constructed.ResultsCD4+ T cells, CD8+ T cells, and macrophages were abnormally increased in patients with HT and GD. The differentially expressed genes of these cells were significantly involved in signaling pathways, including Th1 and Th2 cell differentiation, Th17 cell differentiation, cytokine–cytokine receptor interaction, and NF-kappa B signaling pathway. Moreover, in HT, CD4+ T cells interact with macrophages via the IL16-CCR5/FGF10-FGFR1/CXCL13-CXCR3 axis, and macrophages interact with CD8+ T cells via the CD70-CD27 axis, thereby activating the T-cell receptor signaling pathway and NF-kappa B signaling pathway. In GD, CD4+ T cells interact with macrophages via the CXCR3-CXCL10/PKM-CD44/MHCII-NFKBIE axis, and macrophages interact with CD8+ T cells via the IFNG-IFNGR1/CCR7-CCL21 axis, thereby activating T-cell receptor signaling pathway, Th1 and Th2 cell differentiation, and chemokine signaling pathway.ConclusionIn HT and GD, immune dysregulated cells interact and activate relevant immune pathways and further aggravate the immune response. This may trigger the immune cells to target the thyroid tissue and influence the development of the disease.

Achalasia.

Achalasia is a rare disorder of the oesophageal smooth muscle characterized by impaired relaxation of the lower oesophageal sphincter (LES) and absent or spastic contractions in the oesophageal body. The key pathophysiological mechanism is loss of inhibitory nerve function that probably results from an autoimmune attack targeting oesophageal myenteric nerves through cell-mediated and, possibly, antibody-mediated mechanisms. Achalasia incidence and prevalence increase with age, but the disorder can affect all ages and both sexes. Cardinal symptoms consist of dysphagia, regurgitation, chest pain and weight loss. Several years can pass between symptom onset and an achalasia diagnosis. Evaluation starts with endoscopy to rule out structural causes, followed by high-resolution manometry and/or barium radiography. Functional lumen imaging probe can provide complementary evidence. Achalasia subtypes have management and prognostic implications. Although symptom questionnaires are not useful for diagnosis, the Eckardt score is a simple symptom scoring scale that helps to quantify symptom response to therapy. Oral pharmacotherapy is not particularly effective. Botulinum toxin injection into the LES can temporize symptoms and function as a bridge to definitive therapy. Pneumatic dilation, per-oral endoscopic myotomy and laparoscopic Heller myotomy can provide durable symptom benefit. End-stage achalasia with a dilated, non-functioning oesophagus may require oesophagectomy or enteral feeding into the stomach. Long-term complications can, rarely, include oesophageal cancer, but surveillance recommendations have not been established.

Thyroid Cancer and COVID-19: Prospects for Therapeutic Approaches and Drug Development.

Thyroid cancer is the most prevalent endocrine malignancy and the reported incidence of thyroid cancer has continued to increase in recent years. Since 2019, coronavirus disease 2019 (COVID-19) has been spreading worldwide in a global pandemic. COVID-19 aggravates primary illnesses and affects disease management; relevant changes include delayed diagnosis and treatment. The thyroid is an endocrine organ that is susceptible to autoimmune attack; thus, thyroid cancer after COVID-19 has gradually attracted attention. Whether COVID-19 affects the diagnosis and treatment of thyroid cancer has also attracted the attention of many researchers. This review examines the literature regarding the influence of COVID-19 on the pathogenesis, diagnosis, and treatment of thyroid cancer; it also focuses on drug therapies to promote research into strategies for improving therapy and management in thyroid cancer patients with COVID-19.

ST8Sia6 expression in beta cells mitigates onset of autoimmune diabetes in the murine NOD model

Abstract In this study, we harnessed immunomodulatory Siglec-sialic acid interactions to mitigate autoimmune rejection of beta cells in Type 1 Diabetes (T1D). Mice engineered to express the sialyltransferase ST8Sia6 in beta cells (βST mice) were backcrossed to the non-obese diabetic mouse model of T1D and followed for disease; 60% of female littermates spontaneously developed diabetes by 300 days, compared to minimal occurrence (5%) in female βST mice. Histologic analysis of pancreas sections from non-diabetic βST and littermate mice suggested a similar degree of immune infiltration at 4 and 8 weeks of age, but the severity of insulitis was drastically reduced in βST mice beyond 20 weeks of age as compared to littermates. IHC for various immune populations suggested no difference in composition of insulitis at 8 weeks between βST and littermate mice. ELISA for serum anti-insulin antibodies demonstrated no difference in concentration between female βST and littermate mice. After female euglycemic βST and littermate mice at 16 weeks of age were challenged with anti-PD-L1 monoclonal antibodies, both groups resulted in similarly rapid induction of disease, suggesting that ST8Sia6 dependent protection occurs peripherally. Shut-off of ST8Sia6 expression in euglycemic βST mice at 20 weeks of age did not abrogate protection from disease, supporting persistent immune tolerance beyond this time. Flow analysis of islet infiltrating immune cells at 300 days confirmed reduced number of infiltrating immune cells in βST mice. Thus, induced expression of ST8Sia6 has been shown to mitigate autoimmune attack in the NOD mouse and presents a novel path forward for improving the success of curative islet transplant into T1D patients. Supported by funding from the Mayo Clinic (Mayo Clinic Center for Biomedical Discovery, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic MSTP) and the NIH (5R21AI135858-02, 1F30DK127564). Supported by funding from the Mayo Clinic (Mayo Clinic Center for Biomedical Discovery, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic MSTP) and the NIH (5R21AI135858-02, 1F30DK127564).

Three Cases of Encephalopathy / Disseminated Encephalomyelitis in SARS-COV-2 Infection

Abstract Аs many other viral pandemics, the current SARS-CoV-2 is also characterized by nervous system involvement, mainly in elderly patients with comorbidities. Recent scientific reports indicate that involvement of the nervous system is manifested by a variety of clinical symptoms related to the severity and extent of brain damage. Encephalopathy, encephalitis and polyneuritis are among the complications reported in patients with SARSCoV- 2. These complications have been morphologically proven. As an immune-privileged structure, neural tissue is particularly vulnerable to autoimmune attacks. Therefore, various neurological diseases such as MS, Guillain-Barre syndrome, as well as autoimmune encephalitis and psychosis have also been reported in patients with SARS-CoV-2 infection. Herein, we present three cases of patients who died after infection with the SARS-CoV-2 virus. We emphasize on the pathomorphological changes found in a detailed study of the brain and cervical spine. The analysis of the inflammatory findings, mainly manifested by perivenous lymphocytic infiltrates, serodiapedesis and erythrocyte depots around the vessels, showed a presence of initial demyelination (in two of the cases). The blood supply of most venous vessels with different size and a pronounced “sludge” phenomenon were the most impressive findings, as in some sections these changes were demonstrated by a presence of thrombosis. Inflammatory manifestations were also observed in the brainstem near to the stem nuclei. The SARS-CoV-2 virus induces a variety of immune system responses. In some patients there is a negligible or no reaction, while in others there is a “cytokine storm” with a system damage of multiple organs – often including the brain.