Early Life Inflammation and the Developing Hematopoietic and Immune Systems: The Cochlea as a Sensitive Indicator of Disruption.

Emerging evidence indicates that perinatal infection and inflammation can influence the developing immune system and may ultimately affect long-term health and disease outcomes in offspring by perturbing tissue and immune homeostasis. We posit that perinatal inflammation influences immune outcomes in offspring by perturbing (1) the development and function of fetal-derived immune cells that regulate tissue development and homeostasis, and (2) the establishment and function of developing hematopoietic stem cells (HSCs) that continually generate immune cells across the lifespan. To disentangle the complexities of these interlinked systems, we propose the cochlea as an ideal model tissue to investigate how perinatal infection affects immune, tissue, and stem cell development. The cochlea contains complex tissue architecture and a rich immune milieu that is established during early life. A wide range of congenital infections cause cochlea dysfunction and sensorineural hearing loss (SNHL), likely attributable to early life inflammation. Furthermore, we show that both immune cells and bone marrow hematopoietic progenitors can be simultaneously analyzed within neonatal cochlear samples. Future work investigating the pathogenesis of SNHL in the context of congenital infection will therefore provide critical information on how perinatal inflammation drives disease susceptibility in offspring.

Virus-infection in cochlear supporting cells induces audiosensory receptor hair cell death by TRAIL-induced necroptosis.

Although sensorineural hearing loss (SHL) is relatively common, its cause has not been identified in most cases. Previous studies have suggested that viral infection is a major cause of SHL, especially sudden SHL, but the system that protects against pathogens in the inner ear, which is isolated by the blood-labyrinthine barrier, remains poorly understood. We recently showed that, as audiosensory receptor cells, cochlear hair cells (HCs) are protected by surrounding accessory supporting cells (SCs) and greater epithelial ridge (GER or Kölliker's organ) cells (GERCs) against viral infections. Here, we found that virus-infected SCs and GERCs induce HC death via production of the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Notably, the HCs expressed the TRAIL death receptors (DR) DR4 and DR5, and virus-induced HC death was suppressed by TRAIL-neutralizing antibodies. TRAIL-induced HC death was not caused by apoptosis, and was inhibited by necroptosis inhibitors. Moreover, corticosteroids, the only effective drug for SHL, inhibited the virus-induced transformation of SCs and GERCs into macrophage-like cells and HC death, while macrophage depletion also inhibited virus-induced HC death. These results reveal a novel mechanism underlying virus-induced HC death in the cochlear sensory epithelium and suggest a possible target for preventing virus-induced SHL.

Increased incidence of unilateral sudden sensorineural hearing loss in patients with hematological malignancies requiring hematopoietic stem cell transplantation.

Haematopoietic stem cell transplantation (HSCT) may dramatically alter the immunity of a recipient. Transient immunodeficiency that occurs before and after HSCT could be associated with the development of sudden sensorineural hearing loss (SSNHL), which is presumed to be often due to viral aetiology. We found an incidence of SSNHL of 29.4 per 10,000 person-years in patients receiving HSCT, 12-fold higher than reported for background population incidence. Development of SSNHL tended to cluster early after diagnosis of haematological malignancies, rather than around date of treatment with HSCT. Increased risk of unilateral SSNHL in patients with haematological malignancy may relate to underlying disease rather than treatment.

Long-term (16-26 years) follow-up outcome of steroid therapy in refractory autoimmune sensorineural hearing loss.

Autoimmune sensorineural hearing loss (ASHL) is a rare disease of uncertain etiology, with no established treatment strategy. The duration of morbidity is increased in refractory cases; and therefore, the preservation of hearing and the prevention of adverse effects with steroid therapy are serious long term issues to consider. Long-term follow up of patients treated for ASHL was performed retrospectively in order to elucidate the pathogenesis of ASHL, evaluate the consequences of steroid therapy, and determine a promising treatment course. The cohort in this study consists of four female patients with refractory ASHL that were followed for 16-26 years. Three patients already had profound deafness on one side, probably due to ASHL, before the initiation of steroid treatment. ASHL was managed with steroid administration and the hearing was evaluated through regular audiometric tests (173-212 times). The relationship between pure tone threshold average and steroid dose was reviewed over a long-term follow-up period for each patient. During follow-up, hearing deficit progressed rapidly several times in all patients, as did responsiveness to steroid therapy. Long-term high-dose steroid therapy was not required for hearing maintenance. Hearing thresholds were nearly maintained in three patients during the 16- to 21- year follow-up, and gradually declined over a 26-year follow-up period in one patient. Considering the progress due to presbycusis, the maintenance of hearing was considered sufficient in all patients. No serious adverse effects were observed in any of the patients. Management of patients affected by ASHL with regular audiometry allowed for hearing maintenance without the morbidity of prolonged steroid therapy. The current observations give insight into the pathogenesis of ASHL pathogenesis and establish an efficient course of treatment.

High level of IgE in acute low-tone sensorineural hearing loss: A predictor for recurrence and Meniere Disease transformation.

BACKGROUND: Autoimmunity may play an important role in sudden onset sensorineural hearing loss. However, little is known about the relationship between immunoglobulin E (IgE) and acute low-tone sensorinerual hearing loss (ALHL). OBJECTIVES: To investigate the relationship between IgE level and endolymphatic hydrops and outcomes of ALHL. METHODS: A total of 242 subjects with sudden onset hearing loss, including 115 with ALHL and 127 with idiopathic sudden sensorineural hearing loss (ISSHL), were included in this study. Peripheral venous blood samples of 242 subjects were collected for detection. Clinical data, IgE level, and distribution of allergens were compared between the ALHL and ISSHL groups. The ALHL group received an electrocochleogram (ECochG) test and a follow-up in the outpatient unit or by telephone to evaluate outcomes. RESULTS: Compared to the values in the ISSHL group, a significantly younger onset age (42.30±14.33 years old), higher female onset proportion (72/115, 62.61%), increased total IgE level (median: 66.47, interquartile range: 24.56, 180.96, IU/mL) and specific IgE level (median: 9.42, interquartile range: 1.42, 22.23 IU/mL) were noted in the ALHL group. A clear difference in allergen distribution was noted between the ALHL and ISSHL groups (p=.001). Total IgE and specific IgE levels were factors that contributed to the SP/AP ratio in the electrocochleogram (ECochG) (R2=0.413) in ALHL group. Finally, during the follow-up (17.61±3.46 months) for the ALHL group, 37 subjects recurred, and 17 subjects developed Meniere Disease. In the ROC curve for ALHL recurrence, the area under the curve (AUC) of total IgE was 0.709 and that of specific IgE was 0.679. For MD transformation, the AUC of total IgE was 0.736 and that of specific IgE was 0.716. CONCLUSIONS: High IgE levels correlated with an enhanced SP/AP ratio in ALHL. High IgE levels could be used as a predictor of ALHL recurrence and MD transformation.

Blood genome expression profiles in infants with congenital cytomegalovirus infection.

Congenital CMV infection (cCMVi) affects 0.5-1% of all live births worldwide, making it the leading cause of sensorineural hearing loss (SNHL) in childhood. The majority of infants with cCMVi have normal hearing at birth, but are at risk of developing late-onset SNHL. Currently, we lack reliable biomarkers to predict the development of SNHL in these infants. Here, we evaluate blood transcriptional profiles in 80 infants with cCMVi (49 symptomatic, 31 asymptomatic), enrolled in the first 3 weeks of life, and followed for 3 years to assess emergence of late-onset SNHL. The biosignatures of symptomatic and asymptomatic cCMVi are indistinguishable, suggesting that immune responses of infants with asymptomatic and symptomatic cCMVi are not different. Random forest analyses of initial samples in infants with cCMVi, irrespective of their clinical classification, identify a 16-gene classifier signature associated with the development of SNHL with 92% accuracy, suggesting its potential value as a biomarker.

Autoinflammation in addition to combined immunodeficiency: SLC29A3 gene defect.

INTRODUCTION: H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS). AIM: The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect. PATIENT AND METHODS: Mitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide. RESULTS: Patient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient's peripheral blood mononuclear cells secreted more IL-1ß and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient's monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient. CONCLUSION: Although autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases.

Intratympanic infliximab is a safe and effective rescue therapy for refractory immune-mediated hearing loss.

PURPOSE: To determine the efficacy and safety of the intratympanic infiltration of infliximab at the hearing threshold of patients in follow-up for refractory immune-mediated hearing loss. METHODS: 17 patients were collected with relapses, despite maintenance treatment with oral azathioprine associated or not with oral prednisone at low doses (between 5 and 7.5 ml/day) or refractory relapses to previous intratympanic corticoid treatment being 19 affected ears infiltrated. We measured the hearing threshold by Pure-Tone Average (PTA) 500-3000 Hz, 125-8000 Hz and 250-8000 Hz in pre-infiltration (baseline) and follow-up 3 weeks post-infiltration with auditory threshold at frequencies 125-8000 Hz. RESULTS: The average age was 50.68 years (±15.23 years). After the administration of intratympanic infliximab, an improvement of the hearing threshold was showed in the Pure-Tone Average (PTA) calculated at 500-3000 Hz (p = 0.004), 125-8000 Hz (p = 0.001) and 250-8000 Hz (p = 0.006). An immediate improvement in low frequencies also was observed: 125, 250 and 500 Hz (p = 0.009, p = 0.002 and p < 0.001 respectively) also at 1000 Hz (p = 0.004) and a persistence of the effect at 3 months in the low frequencies: 125 Hz (p = 0.020), 250 Hz (p = 0.006) and 500 Hz (p = 0.002). CONCLUSIONS: Infliximab intratympanic infiltration improves the hearing threshold in patients with immune-mediated hearing loss. The effect of improving the hearing threshold is higher in low frequencies and persists within 3 months of the infiltration. The administration of intratympanic infliximab is an effective and safe technique.

Demystifying autoimmune inner ear disease.

INTRODUCTION: Autoimmune inner disease (AIED) is an uncommon cause of sensorineural hearing loss and poses a diagnostic challenge. The present study aims to review the existing knowledge on the clinicopathological aspects, the diagnostic challenges, and therapeutic interventions in AIED. DISCUSSION: The incidence of AIED is less than five cases per 100,000 population. There are no definite seromarkers which make diagnosis of AIED difficult. Even though various markers have been studied, their sensitivity and specificity have not been replicated in the clinical scenario. The treatment of the condition is also an enigma. Corticosteroids are the drug of choice and require long-term use to prevent relapse. Various other therapeutic agents have been studied in a small cohort of patients, but the efficacy of these drugs needs to be validated in a large multicentric trial. CONCLUSION: Timely intervention can restore hearing loss in AIED patients, but the clinician has to find a delicate balance between the hearing outcome and the potential side effects resulting from long-term use of the drugs. Treatment of steroid resistant AIED is a challenge and there are no universal guidelines for the same. AIED being an uncommon diagnosis, multicentric trials and collaboration are required to formulate diagnostic criteria and therapeutic guidelines.

Does celiac disease cause autoimmune sensorineural hearing loss?

BACKGROUND/AIMS: The primary aim of this study is to identify whether an autoimmune sensorineural hearing loss is an extraintestinal neurological manifestation in adult CD patients. The secondary aim is to identify whether the duration of a gluten-free diet has an effect on the hearing levels of CD patients. MATERIALS AND METHODS: This prospective study consisting of 103 adult CD patients and 79 healthy controls between May 2012 and August 2018 at the University of Gaziantep Gastroenterology and Otorhinolaryngology Departments. CD patients were divided into two groups as remission or active, according to their gluten-free diet duration and serum levels of anti-t-TG. The control group was checked both for CD symptoms and anti-t-TG serum levels. Both participants performed a pure tone audiometry after detailed ear nose and throat examination. RESULTS: Only 4 of 103 CD patients showed sensorineural hearing loss. There was no statistically significant difference between hearing levels of the CD patients and the control group in both measurements of air and bone conductions. The hearing levels comparing the remission and active CD patients did not show any difference in air and bone conduction frequencies. CONCLUSION: In this study with a higher number of CD patients when compared with the previous studies, it has been shown that CD does not appear to cause autoimmune sensorineural hearing loss. In addition, the status of the patients regarding the activeness or the remission of CD did not display a differ between the CD patients in terms of hearing levels.

Virus-induced cochlear inflammation in newborn mice alters auditory function.

Although human cytomegalovirus (HCMV) is a known cause of sensorineural hearing loss in infants with congenital HCMV (cCMV) infections, mechanisms that contribute to sensorineural hearing loss (SNHL) in infants with cCMV infection are not well defined. Using a murine model of CMV infection during auditory development, we have shown that peripheral infection of newborn mice with murine CMV (MCMV) results in focal infection of the cochlea and virus-induced cochlear inflammation. Approximately 50%-60% of infected mice exhibited increased auditory brainstem response (ABR) thresholds across a range of sound frequencies. Histological analyses of the cochlea in MCMV-infected mice with elevated ABR thresholds revealed preservation of hair cell (HC) number and morphology in the organ of Corti. In contrast, the number of spiral ganglion neurons (SGN), synapses, and neurites connecting the cochlear HC and SGN nerve terminals were decreased. Decreasing cochlear inflammation by corticosteroid treatment of MCMV-infected mice resulted in preservation of SGN and improved auditory function. These findings show that virus-induced cochlear inflammation during early auditory development, rather than direct virus-mediated damage, could contribute to histopathology in the cochlea and altered auditory function without significant loss of HCs in the sensory epithelium.

l-Thyroxine does not prevent immunemediated sensorineural hearing loss in autoimmune thyroid diseases / l-Tiroxina no previene la hipoacusia neurosensorial inmuno-mediada en enfermedades tiroideas autoinmunes

Objective: This is the first report dealing with immune-mediated inner ear disease (IMIED) hearing loss in a group of patients affected with autoimmune thyroid disease (AITD), whose treatment required corticosteroids, despite being treated with levothyroxine. Immunopathology linking the inner ear and the thyroid gland is also presented. Patients: A total of 220 patients were selected with sensorineural hearing loss (SNHL) of causes other than presbycusis. Audiometry was performed and pure tone average was calculated before and after treatment with corticosteroids. Results: Eighty-four (84) patients had SNHL of autoimmune origin, and 15 patients were diagnosed with AITD (Hashimoto's disease). Bilateral hearing loss was observed in 10 patients (66.5%). Sudden sensorineural hearing loss was the most frequent clinical form of presentation. Nine patients showed a hearing recovery greater than 10 dB after corticosteroid treatment. Conclusions: Acquired hypothyroidism is thought to affect hearing due to different mechanisms. Although specific hormonal therapy may improve peripheral or central auditory disorders associated with hypothyroidism, the presence of IMIED in AITD patients requires another approach. Altered immune regulatory mechanisms involving Treg cells and CD4+CD45RO cells have been suggested in patients with AITD and IMIED. In the present study, although all the patients with hypothyroidism and subclinical hypothyroidism were being treated with levothyroxine, immune-mediated hearing loss was observed. Therapy with corticosteroids could achieve hearing recovery. Since inner ear and thyroid gland share possible antigen targets, we highlight the existence of IMIED in AITD patients and the importance of implementing appropriate therapy with corticosteroids

Objetivo: Este es el primer trabajo que trata la hipoacusia por enfermedad inmune-mediada del oído interno (IMIED) en un grupo de pacientes afectados de tiroiditis autoinmune (AITD), cuyo tratamiento requirió corticosteroides, a pesar de haber sido tratados con levotiroxina. También se presenta la inmunopatología que vincula el oído interno y la glándula tiroides. Pacientes: Se seleccionó un total de 220 pacientes con hipoacusia neurosensorial (SNHL) por causas diferentes a presbiacusia. A todos los pacientes se les realizó una audiometría, calculándose la media de tonos puros antes y después del tratamiento con corticosteroides. Resultados: Ochenta y cuatro (84) pacientes tenían SNHL de origen autoinmune, y 15 pacientes fueron diagnosticados de AITD (Enfermedad de Hashimoto). Se observó hipoacusia bilateral en 10 pacientes (66,5%). La sordera súbita fue la forma de presentación clínica más frecuente. Nueve pacientes presentaron una recuperación auditiva superior a 10 dB tras el tratamiento con corticosteroides. Conclusiones: Se piensa que el hipotiroidismo adquirido afecta a la audición por diferentes mecanismos. Aunque la terapia hormonal específica puede mejorar los trastornos auditivos periféricos o centrales asociados al hipotiroidismo, la presencia de IMIED en los pacientes de AITD requiere otro abordaje. Se ha sugerido una alteración de los mecanismos reguladores de la respuesta inmune que implica a las células de Treg y a las células CD4+CD45RO en los pacientes con AITD e IMIED. En el presente estudio, a pesar de que todos los pacientes con hipotiroidismo e hipotiroidismo subclínico estaban siendo tratados con levotiroxina, se observó hipoacusia inmuno-mediada. La terapia con corticosteroides podría lograr una recuperación auditiva. Dado que el oído interno y la glándula tiroides comparten posibles antígenos diana, destacamos la existencia de IMIED en los pacientes de AITD, y la instauración de una terapia adecuada con corticosteroides

Congenital Hypopigmentary Disorders with Multiorgan Impairment: A Case Report and an Overview on Gray Hair Syndromes.

The term congenital hypopigmentary disorders refers to a wide group of heterogeneous hereditary diseases, clinically characterized by inborn pigmentary defects of the iris, hair, and/or skin. They include Gray Hair Syndromes (GHSs), a rare group of autosomal recessive genodermatosis hallmarked by inborn silvery gray hair. GHSs encompass Griscelli, Chediak⁻Higashi, Elejalde, and Cross syndromes, which are all characterized by a broad spectrum of severe multisystem disorders, including neurological, ocular, skeletal, and immune system impairment. In this manuscript, we describe in detail the clinical, trichoscopic, and genetic features of a rare case of Griscelli syndrome; moreover, we provide an overview of all the GHSs known to date. Our report highlights how an accurate clinical examination with noninvasive methods, like trichoscopy, may play a crucial rule in diagnosis of rare and potentially lethal genetic syndromes such as Griscelli syndrome, in which timely diagnosis and therapy may modify the clinical course, quality of life, and likelihood of survival.

Prestin autoantibodies screening in idiopathic sudden sensorineural hearing loss.

OBJECTIVES: To define the clinical association of serum prestin autoantibodies and their impact on prognosis, as specific serum diagnostic markers in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). DESIGN: Sera from 63 patients with ISSNHL were screened prospectively for the presence of prestin autoantibodies by an enzyme-linked immunosorbent assay (Elisa) test. Serum was assayed for anti-prestin IgG antibodies using recombinant human prestin (SLC26 A5). Demographic, clinical, and audiometric variables were analyzed. RESULTS: Two patients (3.17%) had demonstrable anti-prestin antibodies in serum (exact 95% CI: -1.16% to 7.5%). No statistically significant association was found between prestin autoantibodies and demographic or audiologic parameters. CONCLUSIONS: This preliminary and novel study does not support the presence of an active humoral immune reaction against prestin in ISSNHL.

Immune-Mediated Inner Ear Disease: Diagnostic and therapeutic approaches.

INTRODUCTION: Immune Mediated Inner Ear Disease (IMIED) is a rare form of sensorineural bilateral hearing loss, usually progressing in weeks to months and responsive to immunosuppressive treatment. Despite recent advances, there is no consensus on diagnosis and optimal treatment. METHODS: A review of articles on IMIED from the last 10 years was conducted using PubMed® database. RESULTS: IMIED is a rare disease, mostly affecting middle aged women. It may be a primary ear disease or secondary to autoimmune systemic disease. A dual immune response (both cellular and humoral) seems to be involved. Cochlin may be the inner ear protein targeted in this disease. Distinction from other (core common) forms of neurosensory hearing loss is a challenge. Physical examination is mandatory for exclusion of other causes of hearing loss; audiometry identifies characteristic hearing curves. Laboratory and imaging studies are controversial since no diagnostic marker is available. CONCLUSION: Despite recent research, IMIED diagnosis remains exclusive. Steroids are the mainstay treatment; other therapies need further investigation. For refractory cases, cochlear implantation is an option and with good relative outcome.

l-Thyroxine does not prevent immunemediated sensorineural hearing loss in autoimmune thyroid diseases.

OBJECTIVE: This is the first report dealing with immune-mediated inner ear disease (IMIED) hearing loss in a group of patients affected with autoimmune thyroid disease (AITD), whose treatment required corticosteroids, despite being treated with levothyroxine. Immunopathology linking the inner ear and the thyroid gland is also presented. PATIENTS: A total of 220 patients were selected with sensorineural hearing loss (SNHL) of causes other than presbycusis. Audiometry was performed and pure tone average was calculated before and after treatment with corticosteroids. RESULTS: Eighty-four (84) patients had SNHL of autoimmune origin, and 15 patients were diagnosed with AITD (Hashimoto's disease). Bilateral hearing loss was observed in 10 patients (66.5%). Sudden sensorineural hearing loss was the most frequent clinical form of presentation. Nine patients showed a hearing recovery greater than 10dB after corticosteroid treatment. CONCLUSIONS: Acquired hypothyroidism is thought to affect hearing due to different mechanisms. Although specific hormonal therapy may improve peripheral or central auditory disorders associated with hypothyroidism, the presence of IMIED in AITD patients requires another approach. Altered immune regulatory mechanisms involving Treg cells and CD4+CD45RO cells have been suggested in patients with AITD and IMIED. In the present study, although all the patients with hypothyroidism and subclinical hypothyroidism were being treated with levothyroxine, immune-mediated hearing loss was observed. Therapy with corticosteroids could achieve hearing recovery. Since inner ear and thyroid gland share possible antigen targets, we highlight the existence of IMIED in AITD patients and the importance of implementing appropriate therapy with corticosteroids.

Cogan syndrome: An autoimmune eye and ear disease with systemic manifestations.

Cogan syndrome (CS) is a rare vasculitis seen primarily in young adults. It predominantly affects eyes, ears and the heart with characteristic findings of interstitial keratitis, sensorineural hearing loss and vestibular dysfunction. A high index of suspicion is required to diagnose this rare disorder. It is one of the few vasculitis which can involve vessels of all sizes: small, medium and large. Coexistence of inflammatory bowel disease (IBD) in Cogan syndrome has been described in the literature. Immunosuppressive agents such as corticosteroids with or without steroid sparing agents are the standard of care. Early diagnosis and treatment are the cornerstone of treatment to prevent permanent damage to the ears and eyes. We describe a patient with Cogan syndrome with large vessel vasculitis and IBD. Our patient was treated with glucocorticoids and methotrexate.