Sudden Hearing Loss Waves: The Effect of COVID-19 Infection and Vaccination on the Inner Ear.

Sudden sensorineural hearing loss (SSNHL) has emerged as a potential complication of COVID-19 infection and vaccination. Various mechanisms by which the SARS-CoV-2 virus can cause hearing loss have been reported, including direct viral invasion, neuroinflammation, blood flow disturbances, and immune-mediated response. However, the temporal relationship between COVID-19 infection and SSNHL remains unclear, with mixed findings and conflicting results reported in different studies. Similarly, while anecdotal reports have linked COVID-19 vaccination to SSNHL, evidence remains scarce. Establishing a correlation between COVID-19 vaccines and SSNHL implies a complex and multifactorial pathogenesis involving interactions between the immune system and the body's stress response. Nevertheless, it is important to consider the overwhelming evidence of the vaccines' safety and efficacy in limiting the spread of the disease and remains the primordial tool in reducing death.

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.

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.

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.

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.

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.

The Clinician Faced With Anticochlear Antibodies: What to Do With Them?

BACKGROUND: Autoimmune inner ear disease as a cause of sensorineural hearing loss is a poorly understood entity. Thus, the role of anticochlear antibodies (ACLAs) in clinical management is still not well established. OBJECTIVE: The aims of this study were to describe the use of ACLAs in our clinical setting and to understand the clinicians' therapeutic approach in these cases. We also analyzed the usefulness of these autoantibodies in clinical practice. METHODS: A retrospective study with nonprobabilistic convenience sampling of patients who were tested for ACLAs in the period from January 1, 2013, to December 31, 2015, was performed. The study was carried out in 2 stages: (1) medical records of all patients who were investigated for ACLAs were reviewed. The following variables were analyzed: age, sex, reason for requesting ACLAs, concomitant autoimmune disease, audiogram, immunosuppressive treatment, duration of treatment, and clinical response; (2) patients who received immunosuppressive therapy were contacted by telephone. A visual analog scale (VAS) (0-10) was applied to evaluate the therapeutic response. RESULTS: Thirty-nine patients who were investigated for ACLAs were identified. The mean age was 41 (SD, 16) years; there were 33 female patients. Of the 34 patients with ACLA-positive antibodies, 16 patients received immunosuppressive agents, of for management of their sensorineural hearing loss, corticosteroids was the most commonly used treatment. No clinical improvement was reported by patients after immunosuppressive treatment in this subgroup. CONCLUSIONS: The role of ACLAs in the diagnosis and management of sensorineural hearing loss remains unclear. In this small study at a single institution, ACLA testing may not have improved the outcome of sensorineural hearing loss.

Identification of evidence for autoimmune pathology of bilateral sudden sensorineural hearing loss using proteomic analysis.

Sudden sensorineural hearing loss (S-SNHL) is an inner ear disorder with an abrupt hearing loss occurring <3days. The pathologic mechanism of the disease remains unclear, although autoimmunity has been regarded as one of the suggested causes, especially in bilateral form. In this study, we aimed to provide evidence for the involvement of autoimmunity in bilateral S-SNHL using proteomic approaches such as ProtoArray®, western blotting, immunoprecipitation, and liquid column mass spectrometry for mass screening of candidate antigens and autoantibodies based on the hypothesis that multiple autoantibodies and target antigens must exist in order for autoimmune bilateral S-SNHL to develop. As the final outcome, we have proven the involvement of autoimmunity in the disease, and investigated the existence of circulating autoantibodies and candidate antigens. These findings could provide basic evidence necessary for the development of diagnostic biomarkers as well as the understanding of the pathological mechanisms underlying bilateral S-SNHL. S-SNHL: sudden sensorineural hearing loss; LC-MS: liquid chromatography-mass spectrometry; MS: mass spectrometry; autoAb: autoantibody; 1-DE: one-dimensional electrophoresis.

Congenital heart block and immune mediated sensorineural hearing loss: possible cross reactivity of immune response.

Immune-mediated sensorineural hearing loss may complicate systemic autoimmune diseases. We have previously reported the presence of antibodies directed against inner ear antigens in patients with Cogan syndrome, a disease characterized by sudden hearing loss and interstitial keratitis. Such autoantibodies cross-react with an epitope of SSA/Ro60 protein. Anti-Ro/SSA antibodies in pregnant women cross the placenta and reach the fetal tissues inducing an immune-mediated damage of the cardiac conduction system. We wanted to evaluate whether mothers with anti-Ro/SSA antibodies who gave birth to children with congenital heart block have antibodies directed against inner ear antigens and whether these antibodies are connected with the presence of immune-mediated sensorineural hearing loss. We did not find anti-inner ear antibodies in the majority of the mothers. On the contrary a 13-year-old boy with congenital heart block and sensorineural hearing loss was positive for the presence of anti-inner ear antigens antibodies. Moreover his serum was positive for the presence of anti-Ro60 peptide antibodies but did not recognize the entire protein Ro60 (TROVE2), a behaviour similar to that of sera from patients with Cogan syndrome. In conclusion the data obtained so far show that anti-inner ear antibodies do not recognize the entire protein TROVE2 and do not support the hypothesis that such antibodies may be involved in the pathogenesis of congenital heart block.

Immune-mediated cochleovestibular disease.

OBJECTIVE: The aim of this study is to prove the involvement of the immune response in the etiopathogenesis of some cochleovestibular disorders by a demonstration of antibodies against inner ear antigens and identify the benefits of immunosuppressive therapy. BACKGROUND: McCabe in 1979 postulated the hypothesis of autoimmune inner ear disease. METHODS: Sodium dodecyl sulfate polyacrylamid gel electrophoresis and immunoblotting were used to examine the serum of 74 subjects for the presence of antibodies against inner ear antigens. The subjects were divided into three groups: A--subjects with idiopathic progressive sensorineural hearing loss, B--subjects with Menière´s disease, C--healthy subjects. Individuals with proven antibodies received immunosuppressive therapy. RESULTS: We detected antibodies against inner ear antigens with molecular weight of 30, 50, 60, 80, 100 kDa. In group A they were found in 52% of 25 subjects, in group B in 44% of 25 subjects and they were not detected in group C. An improvement of hearing was recorded in 69% of subjects in group A. An improvement of hearing was observed in 72%, significant relief of vertigo in 81% of subjects in group B. CONCLUSION: The present study supports the hypothesis of immune-mediated cochleovestibular disease (Tab. 3, Ref. 15).

Serum immunoglobulins in 28 adults with autoimmune sensorineural hearing loss: increased prevalence of subnormal immunoglobulin G1 and immunoglobulin G3.

BACKGROUND: Our informal observations suggested that some patients with acute sensorineural hearing loss (ASNHL) have subnormal serum immunoglobulin (Ig) levels. We evaluated 28 consecutive adults (18 men, 10 women) at ASNHL diagnosis using: antibodies to 68 kD protein, 30 kD protein, and type II collagen; and serum total IgG, IgG subclasses, total IgA, and IgM. Reference ranges for Ig levels were mean ± 2 SD. We compared prevalences of subnormal IgG subclasses to those in 275 healthy European adults in previous reports. We also reviewed charts of consecutive adult index patients with primary Ig deficiency (35 common variable immunodeficiency, 406 IgG subclass deficiency) to identify other patients with probable ASHNL. RESULTS: Mean age was 53 ± 10 (SD) y. Six patients (21.4%) had other autoimmunity manifestations. Antibodies to 68 kD protein, 30 kD protein, and type II collagen were detected in 21.4% (6/28), 21.1% (4/19) and 18.8% (3/16), respectively. Three patients (10.7%) had subnormal IgG1, six (21.4%) had subnormal IgG3, and four (14.3%) had subnormal IgG1 and IgG3. Some had subnormal IgG2, IgG4, IgA, and IgM (n = 1, 2, 3, and 1, respectively). Prevalences of subnormal IgG1 or IgG3 were greater in ASNHL patients (25.0% and 35.7%) than 275 controls (2.1% and 3.3%), respectively (p < 0.0001, each comparison). Relative risks of subnormal IgG1 and IgG3 in ASNHL were 11.5 [95% CI: 4.1, 31.7] and 10.9 [4.8, 25.6], respectively. Hearing improved after initial therapy in 17 patients (60.7%). Multiple regressions on Ig levels revealed no significant associations with other available variables. Logistic regressions on initial therapy response revealed a positive association with men (p = 0.0392) and a negative association with IgA (p = 0.0274). Our estimated prevalence of probable ASNHL in 35 patients with common variable immunodeficiency during a follow-up interval of 8 ± 4 y was 0% [95% CI: 0, 12.3]). Prevalence of probable ASNHL in 406 patients with IgG subclass deficiency during the same interval was 0.74% [0.19, 2.33]. CONCLUSIONS: Serum levels of IgG1 or IgG3 were subnormal in 46.4% of 28 patients with ASNHL. Among adults who present with primary Ig deficiency, some may have or later develop ASNHL.

A woman with warts, leg swelling, and deafness.

KEY TEACHING POINTS • We describe a 45-year-old woman with GATA2 deficiency associated with verrucae, lymphedema, immunodeficiency, and a history of infections and skin cancer. • GATA2 deficiency has variable clinical expressivity with differing presentations, including infection, hematopoietic abnormalities, immunodeficiency, lymphedema, and cancer. • Cutaneous manifestations include verruca vulgaris, soft tissue infections, lymphedema, and panniculitis. • Patients may have verrucae that can progress to squamous cell carcinomas; dermatologists therefore play an important role in managing these patients as members of a multidisciplinary team.

Increased neutrophil-lymphocyte ratio in patients with idiopathic sudden sensorineural hearing loss.

OBJECTIVE: The aim of this study was to determine whether neutrophil-lymphocyte ratio (NLR) levels are elevated in patients with idiopathic sudden sensorineural hearing loss (ISSHL) compared with healthy controls. Moreover, we aimed to find out whether there is a correlation between NLR levels and the severity of hearing loss. MATERIALS AND METHODS: The study group consisted of 40 subjects with ISSHL and 40 control subjects with no evidence of ear pathology. Severity of hearing loss in the ISSHL patients was classified as mild (<40 dB loss for any frequency), moderate (up to 80 dB), and severe (profound, >80 dB). RESULTS: The mean ± SD NLR values were 5.53 ± 1.72 in the ISHHL patients and 2.73 ± 0.81 in the control group. The mean NLR values in the patients with ISHHL were significantly higher than in the control group (P = 0.0001). The mean ± SD NLR values in the patients with mild (group A), moderate (group B), and severe (group C) sensorineural hearing loss were 5.53 ± 1.72, 5.29 ± 1.81, and 5.82 ± 1.72, respectively. The mean NLR values in the patients with severe sensorineural hearing loss were significantly higher than in the other groups (P = 0.0001). Nevertheless, there was no correlation between NLR values and severity of hearing loss. CONCLUSIONS: There is no previous study that investigated the association between NLR and ISSHL in the literature. High NLR values in ISSHL patients may be a predictor of other ishemic conditions such as coronary or cerebral ischemia. Thus, the otorhinolaryngologist would then refer the patient to cardiology and then neurology specialists for the appropriate examinations.

[Cochlear implantation in immunocompromised patients].

This paper reports a clinical case that gives evidence of the possibility of cochlear implantation after liver transplantation. Patient K. aged 3 years 10 months was admitted to the Russian Research and Practical Centre of Audiology and Hearing Rehabilitation with the diagnosis of type IB glycogenosis after maternal liver transplantation associated with chronic neutropenia, chronic cutaneous and mucosal infection, partial symptomatic partial epilepsy, retarded psycho-motor development, and complaints of the absence of auditory response. The audiological examination provided materials for the diagnosis of grade IV bilateral sensorineural hearing loss tending toward deafness. Cochlear implantation recommended to the patient was performed on February 20, 2013 using the HiRes 90 K implant with the HiFocus Helix electrode (Advanced Bionics, USA). The surgical intervention and the postoperative period passed without complications. The speech processor was activated one month after surgery. The results of surdopedagogical testing gave evidence of successful rehabilitation promising the further improvement. It is concluded that immunosuppressive therapy is not an absolute contraindication for cochlear implantation, but this procedure requires detailed examination and thorough preparation for the forthcoming surgery.

T cell responses and clinical symptoms among infants with congenital cytomegalovirus infection.

BACKGROUNDCongenital cytomegalovirus (cCMV) infection can cause developmental impairment and sensorineural hearing loss (SNHL). To determine the relationship between immune responses to cCMV infection and neurologic sequelae, T cell responses were compared for their connection to clinical symptoms at birth and neurodevelopmental outcomes.METHODSThirty cCMV-infected and 15 uninfected infants were enrolled in a single-center prospective observational case-control study. T cell pp65-specific cytokine responses; CD57, CD28, and PD-1 expression; and memory subsets were compared.RESULTSInfected neonates (73% symptomatic at birth) lacked pp65-specific cytokine-secreting T cells, with elevated frequencies of CD57+, CD28-, and PD-1+CD8+ T cells and effector memory subsets. Though frequencies overlapped between cCMV symptom groups, asymptomatic infants had higher frequencies of CD57+PD-1+CD8+ T cells. Neonates with subsequent developmental delay lacked detectable CMV-specific T cell responses, with patterns resembling those of uninfected infants. Two children with progressive SNHL had high frequencies of PD-1+CD8+ T cells over the first year compared with children without progressive SNHL.CONCLUSIONSimilar to published reports, neonatal viral antigen-specific cytokine-secreting T cell responses were not detected, but overall patterns indicate that globally differentiated memory CD8+ T cell populations were induced by cCMV infection, with higher frequencies of terminally differentiated PD-1+CD8+ T cells potentially associated with asymptomatic infection. In this cohort, a lack of in utero T cell differentiation was associated with developmental delay, and high frequencies of PD-1+CD8+ T cells persisted only in children with progressive SNHL. Further work is needed to define the specificity of these T cells and their mechanistic connection to these outcomes.FUNDINGThis study was funded through an intramural research award at Nationwide Children's Hospital, the Pediatric Infectious Disease Society Fellowship Award funded by Stanley and Susan Plotkin and Sanofi Pasteur, the Abigail Wexner Research Institute at Nationwide Children's Hospital, and the Pichichero Family Foundation Vaccines for Children Initiative Research Award from the Pediatric Infectious Diseases Society Foundation.

Autoimmune sensorineural hearing loss: the otology-rheumatology interface.

Autoimmune sensorineural hearing loss (SNHL) is a rare clinical entity characterized by a progressive fluctuating bilateral asymmetric SNHL that develops over several weeks to months. Vestibular symptoms, tinnitus and aural fullness are present in up to 50% of patients. Due to the lack of specific diagnostic tests, both clinical suspicion and responsiveness to corticosteroids are the pillars for the diagnosis of autoimmune SNHL. The evaluation of patients in whom this condition is suspected should include a detailed history and physical examination, an audiogram, an MRI and a limited laboratory workup to exclude secondary causes of hearing loss. The low frequency of this condition, the heterogeneity in the designs of the available studies and the absence of randomized trials comparing treatment responses and assessing long-term outcomes are some of the factors accounting for the limited evidence to guide the clinician in the approach to the diagnosis and treatment of autoimmune SNHL.

Phosphorylation of the myosin IIA tailpiece regulates single myosin IIA molecule association with lytic granules to promote NK-cell cytotoxicity.

Natural killer (NK) cells are innate immune lymphocytes that provide critical defense against virally infected and transformed cells. NK-cell cytotoxicity requires the formation of an F-actin rich immunologic synapse (IS), as well as the polarization of perforin-containing lytic granules to the IS and secretion of their contents at the IS. It was reported previously that NK-cell cytotoxicity requires nonmuscle myosin IIA function and that granule-associated myosin IIA mediates the interaction of granules with F-actin at the IS. In the present study, we evaluate the nature of the association of myosin IIA with lytic granules. Using NK cells from patients with mutations in myosin IIA, we found that the nonhelical tailpiece is required for NK-cell cytotoxicity and for the phosphorylation of granule-associated myosin IIA. Ultra-resolution imaging techniques demonstrated that single myosin IIA molecules associate with NK-cell lytic granules via the nonhelical tailpiece. Phosphorylation of myosin IIA at residue serine 1943 (S1943) in the tailpiece is needed for this linkage. This defines a novel mechanism for myosin II function, in which myosin IIA can act as a single-molecule actin motor, claiming granules as cargo through tail-dependent phosphorylation for the execution of a pre-final step in human NK-cell cytotoxicity.

IL-1ß is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease.

Autoimmune inner ear disease is an enigmatic disorder characterized by recurring episodes of sudden or progressive sensorineural hearing loss. Hearing loss can be improved by timely corticosteroid administration, but only half of those treated respond, and for many responders, that response is lost over time. The mechanisms that control corticosteroid responsiveness in this disorder are largely uncharacterized. We have previously identified that the induction by dexamethasone of IL-1R type II (IL-1R2) expression in PBMC predicts corticosteroid responsiveness in this disorder. In this study, we asked whether IL-1ß was overexpressed, and whether clinical corticosteroid responders differentially regulated IL-1ß expression or release in response to dexamethasone, as compared with nonresponders. IL-1ß has been reported to induce matrix metalloproteinase-9 (MMP-9) expression. Given that metalloproteinases can cleave IL-1R2, we also asked whether MMP-9 expression was altered in this disorder. In this study, we demonstrate that corticosteroid nonresponders have elevated plasma levels of IL-1ß and MMP-9 as compared with clinically responsive patients (p = 0.0008 and p = 0.037, respectively). Increasing MMP-9 expression correlated with increasing IL-1ß concentration, suggesting that IL-1ß expression regulates MMP-9 expression. As expected, monocytes were the predominant producers of IL-1ß. In vitro exposure of PBMC to dexamethasone from clinical corticosteroid responders suppressed IL-1ß release. PBMC of corticosteroid nonresponders have substantially higher release of IL-1ß into the conditioned media, and when exposed to dexamethasone, failed to repress IL-1ß release (p = 0.05). Treatment of PBMC from clinical corticosteroid nonresponders with anakinra resulted in repression of IL-1ß release, suggesting that IL-1ß blockade may be a viable therapy for these patients.