Co-localization of the vanilloid capsaicin receptor and substance P in sensory nerve fibers innervating cochlear and vertebro-basilar arteries.

Evidence suggests that capsaicin-sensitive substance P (SP)-containing trigeminal ganglion neurons innervate the spiral modiolar artery (SMA), radiating arterioles, and the stria vascularis of the cochlea. Antidromic electrical or chemical stimulation of trigeminal sensory nerves results in neurogenic plasma extravasation in inner ear tissues. The primary aim of this study was to reveal the possible morphological basis of cochlear vascular changes mediated by capsaicin-sensitive sensory nerves. Therefore, the distribution of SP and capsaicin receptor (transient receptor potential vanilloid type 1-TRPV1) was investigated by double immunolabeling to demonstrate the anatomical relationships between the cochlear and vertebro-basilar blood vessels and the trigeminal sensory fiber system. Extensive TRPV1 and SP expression and co-localization were observed in axons within the adventitial layer of the basilar artery, the anterior inferior cerebellar artery, the SMA, and the radiating arterioles of the cochlea. There appears to be a functional relationship between the trigeminal ganglion and the cochlear blood vessels since electrical stimulation of the trigeminal ganglion induced significant plasma extravasation from the SMA and the radiating arterioles. The findings suggest that stimulation of paravascular afferent nerves may result in permeability changes in the basilar and cochlear vascular bed and may contribute to the mechanisms of vertebro-basilar type of headache through the release of SP and stimulation of TPVR1, respectively. We propose that vertigo, tinnitus, and hearing deficits associated with migraine may arise from perturbations of capsaicin-sensitive trigeminal sensory ganglion neurons projecting to the cochlea.

Decreased cochlear DNA receptor staining in MRL.MpJ-Fas(lpr) autoimmune mice with hearing loss.

OBJECTIVES: Previous studies of decreased cochlear DNA binding in autoimmune mice suggested that antibodies against a cochlear cell surface DNA receptor cause autoimmune hearing loss. However, the presence of a cochlear DNA receptor has not been determined. Therefore, immunohistochemistry with an anti-DNA receptor antibody was performed on MRL.MpJ-Fas(lpr) (MRL/lpr) autoimmune mice to determine 1) which inner ear structures contain DNA receptors and 2) whether the receptor staining pattern changes as autoimmune disease progresses and hearing thresholds increase. STUDY DESIGN: A prospective study of the progression of hearing loss in autoimmune mice and correlated alterations in immunostaining for the inner ear DNA receptor. METHODS: One group of MRL/lpr mice (n = 10) was allowed to develop autoimmune disease, and auditory brainstem response (ABR) audiometry was performed at 4, 6, and 9 months of age to measure the progression of hearing loss. A second group (n = 5) was tested for ABR thresholds at 2 months of age and immediately killed to assess receptor staining before the onset of autoimmune disease and hearing loss. The inner ears from all mice were immunohistochemically stained with an anti-DNA receptor antibody, and a qualitative analysis of the staining of cochlear structures was performed. RESULTS: Auditory brainstem response audiometry revealed a significant 20- to 30-dB elevation of thresholds as systemic disease progressed. Anti-DNA receptor staining was heaviest in the spiral ligament and less intense in the spiral ganglion and cochlear nerve. Both groups showed a similar pattern of staining in these structures. The stria vascularis and hair cells also stained in both groups. However, the stria cells of normal-hearing mice showed diffuse intracellular immunoreactivity, whereas older mice displayed less staining that was confined to the cell membranes. CONCLUSIONS: The inner ears of MRL/lpr mice contain DNA receptors. Autoimmune hearing loss was correlated with weaker overall intracellular staining in the stria vascularis and hair cells but increased staining of the cell membranes. This suggested DNA receptors have impaired endocytosis and more receptors remain on the cell membrane, possibly as a result of binding by circulating autoantibodies.

Noise-induced hearing loss: the effect of melanin in the stria vascularis.

Conflicting investigations regarding the potential protective effect of melanin against noise-induced sensorineural hearing loss have suggested that eumelanin and pheomelanin may have differing effects within the stria vascularis. Three strains of C57BL/6J mice, (+/+, a/a) wild-types (dark coats/black eyes), (c2j/c2j, a/a), albinos (white coats/pink eyes), and (+/+, Ay/Ay) yellow mice (yellow coats/black eyes), were subjected to five consecutive days of broad band noise exposure at 112 dB(A) SPL for 3 h/day. Cochlear function was evaluated with auditory brainstem response audiometry to pure tones immediately pre-exposure, 5-6 h postexposure, and 14 days post-exposure. No significant difference in the degree of sensorineural hearing loss induced in the three strains of mice was identified. The eumelanin and pheomelanin content of each stria vascularis and amount of protein per stria for both mouse and guinea pig (2/NCR) were determined via high performance liquid chromatography. No pheomelanin was found in the stria of yellow mice, suggesting that coat color is not an accurate predictor of strial melanin content. The melanin content per mg of strial protein was higher in mice than in guinea pigs. A species-specific difference in melanin content does not explain the absence of a protective effect in mice.

Aldosterone and prednisolone control of cochlear function in MRL/MpJ-Fas(lpr) autoimmune mice.

Recently this laboratory showed aldosterone, a mineralocorticoid that only enhances sodium transport, was as effective as the glucocorticoid prednisolone in restoring cochlear function in autoimmune mice. To further test this relationship between sodium transport and autoimmune hearing loss, dosage comparisons were made of prednisolone and aldosterone control of the auditory dysfunction in autoimmune MRL/MpJ-Fas(lpr) mice. Mice were tested at 2 months of age to establish baseline auditory brainstem response (ABR) thresholds, hematocrit, serum immune complexes, and anti-nuclear antibodies. Mice were then given different doses of prednisolone or aldosterone in their drinking water for 2 months. After the treatment period, most untreated water controls showed elevation of ABR thresholds due to the ongoing autoimmune disease. However, the steroid groups had significantly more mice with improved or unchanged thresholds. Both steroids improved stria vascularis morphology, although aldosterone appeared to be more effective. The immune suppressive prednisolone caused a dose-related improvement in levels of serum immune complexes and hematocrit, hallmarks of systemic autoimmune disease. Aldosterone, which has no immune suppressive function, did not alter systemic disease. The comparable efficacy of prednisolone and aldosterone in restoring auditory function suggests steroid reversal of autoimmune hearing loss in mice is due to increasing stria vascularis sodium transport and not suppression of systemic autoimmune reactions.

Co-existence of tyrosine hydroxylase and calcitonin gene-related peptide in cochlear spiral modiolar artery of guinea pigs.

The distribution of tyrosine hydroxylase (TH) and calcitonin gene-related peptide (CGRP) on the cochlear spiral modiolar artery (SMA) was investigated in the guinea pig. The SMA was dissected from the modiolus so that the entire length of the vessel and many of its branches could be observed. Immunohistochemical labeling and double immunofluorescence were employed to localize each compound and to determine whether the TH and CGRP co-exist in neurons of the SMA. Microscopic examination of whole vessel preparations revealed numerous TH- and CGRP-positive neural networks innervating the SMA and its branches. The labeled neurons showed distinct arborization, varicosities and overlap, and were of different diameters. Confocal immunofluorescence microscopy of double-labeled TH and CGRP neurons showed that a number of the TH- and CGRP-positive neurons were co-labeled. Thus, TH and CGRP partially co-exist within the neuronal innervation of SMA. These findings support a hypothesis that specific neuropeptide and adrenergic neurons regulate cochlear blood flow.

Capsaicin stimulation of the cochlea and electric stimulation of the trigeminal ganglion mediate vascular permeability in cochlear and vertebro-basilar arteries: a potential cause of inner ear dysfunction in headache.

Trigeminal neurogenic inflammation is one explanation for the development of vascular migraine. The triggers for this inflammation and pain are not well understood, but are probably vasoactive components acting on the blood vessel wall. Migraine-related inner ear symptoms like phonophobia, tinnitus, fluctuation in hearing perception and increased noise sensitivity provide indirect evidence that cochlear blood vessels are also affected by basilar artery migraine. The purpose of this investigation was to determine if a functional connection exists between the cochlea and the basilar artery. Neuronally mediated permeability changes in the cochlea and basilar artery were measured by colloidal silver and Evans Blue extravasation, following orthodromic and antidromic stimulation of the trigeminal ganglion innervating the cochlea. Capsaicin and electrical stimulation induced both dose- and time-dependent plasma extravasation of colloidal silver and Evans Blue from the basilar artery and anterior inferior cerebellar artery. Both orthodromic and antidromic activation of trigeminal sensory fibers also induced cochlear vascular permeability changes and significant quantitative differences between the treated and control groups in spectrophotometric assays. These results characterize a vasoactive connection between the cochlea and vertebro-basilar system through the trigeminal sensory neurons. We propose that vertigo, tinnitus and hearing deficits associated with basilar migraine could arise by excitation of the trigeminal nerve fibers in the cochlea, resulting in local plasma extravasation. In addition, cochlear "dysfunction" may also trigger basilar and cluster headache by afferent input to the trigeminal system.

Aldosterone (mineralocorticoid) equivalent to prednisolone (glucocorticoid) in reversing hearing loss in MRL/MpJ-Fas1pr autoimmune mice.

HYPOTHESIS: Although the glucocorticoid prednisone is the standard therapy for autoimmune sensorineural hearing loss, what this hormone does in the ear to restore hearing is not known. MRL/MpJ-Fas(lPr) autoimmune mice consistently have shown only stria vascularis disease, implying that abnormal ion balances in the endolymph underlie cochlear dysfunction. Previously we have shown that hearing loss in these mice is reversed with prednisolone treatment. This, coupled with the complete lack of cochlear inflammation, suggests that the restoration of hearing with prednisolone is due to its sodium transport function and not to its anti-inflammatory or immune suppression effects. Therefore the hypothesis of this study was that the mineralocorticoid aldosterone, which only increases sodium transport, would be as effective as prednisolone in reversing autoimmune hearing loss. STUDY DESIGN: MRL/MpJ-Fas(lPr) autoimmune mice were treated with either prednisolone or aldosterone to compare steroid effects on auditory brainstem response (ABR) thresholds and stria morphology. METHODS: After baseline ABR audiometry, autoimmune mice were given prednisolone (5 mg/kg per day), aldosterone (15 microg/kg per day), or water in their drinking bottles. After 2 months of treatment the ABR thresholds were remeasured, and ears collected for histological examination. RESULTS: The untreated controls showed continued elevation of ABR thresholds and edematous stria. However, thresholds in most steroid mice were improved or unchanged and their stria morphology improved, particularly with aldosterone treatment. CONCLUSIONS: Restoration of hearing with steroid treatment is due to increased sodium transport to re-establish cochlear ionic balances. Aldosterone therapy may offer advantages over prednisone for long-term management of not only autoimmune hearing loss, but also other forms of nonimmune-related deafness for which steroids are currently prescribed.

Abnormal cochlear connective tissue mineralization in the palmerston north autoimmune mouse.

Inner ear fibrosis and osteogenesis are common features of human autoimmune disease, although the cellular mechanisms are unknown. The Palmerston North (PN) autoimmune strain mouse has been shown to develop modiolar sclerotic lesions with progression of its systemic disease. Therefore, lesion development was studied in the cochleas of PN mice to gain insight into potential autoimmune osteogenic processes in the human ear. Cochleas from PN mice were examined with electron microscopy to characterize the cellular and extracellular matrix changes that lead to abnormal mineralization. Initially, activated fibroblasts produced extracellular matrix fibers, ranging in size from fine fibrils to larger collagen-like fibers. These proliferating fibers appeared to 'seed' the mineralizing lesions by serving as the framework for mineral deposition. As mineralization continued, the foci grew in size and fused to form large sclerotic masses within the connective tissue. However, the lesions never invaded nor degraded the normal modiolar bone. These observations of abnormal mineralization of cochlear connective tissue fibers show some parallels with human cochlear autoimmune osteogenesis, suggesting similar molecular processes may be involved.

Twenty-stimulus train for rapid acquisition of auditory brainstem responses in humans.

This study addressed the clinical need to obtain frequency-specific auditory brainstem responses (ABRs) more rapidly than is currently possible. ABRs were obtained from 20 subjects using two different methods: a conventional method with tone bursts presented singly and a multiple-stimulus method using a train of 20 tone bursts. For both methods, tone bursts were presented at frequencies 1, 2, 4, and 8 kHz, shaped with a Blackman-Harris window and having intensity levels up to 105 dB peak equivalent sound pressure level (peSPL). The single tone bursts were presented at a 17.2/sec repetition rate. The 20 tone-burst train used the four frequencies at five intensities each and a repetition rate of 3.7/sec (separations between tone bursts of 9-12 msec, with 77 msec off-time between trains). Mean latencies and mean amplitudes for wave V were compared using t-tests for each of 12 conditions (four frequencies, each at the three highest output levels). For latency, only one comparison was significantly different (2 kHz, 77 dB peSPL). Similarly, only one comparison was significant for amplitude (2 kHz, 97 dB peSPL). There was, however, a trend for the tone bursts presented in trains to have longer latencies and reduced amplitudes compared to the respective responses for the single tone-burst condition. These results indicate the presence of some response adaptation when tone bursts are presented in a train. The use of a properly designed stimulus train can result in a significant time savings for obtaining frequency-specific ABRs as compared with single tone-burst presentations.

Steroid treatment improves cochlear function in the MRL.MpJ-Fas(lpr) autoimmune mouse.

Corticosteroid therapy is used to reverse autoimmune sensorineural hearing loss, although little is known of the mechanism by which this occurs. This has been due to the lack of a suitable animal model with spontaneous hearing loss that is steroid responsive. The present study examined the effects of prednisolone treatment on auditory thresholds in the MRL.MpJ-Fas(lpr) autoimmune mouse to determine its suitability as such a model. Autoimmune mice at 3.5-4. 5 months of age were evaluated by pure-tone auditory brainstem response (ABR) to establish threshold elevations due to the disease. The steroid treatment group was then given prednisolone in their drinking water for 2.5 months, while untreated controls were given tap water. Significantly more steroid treated mice survived to the time of post-treatment ABR evaluation. Half of the steroid treated ears demonstrated either improvement or no change in cochlear function compared to only 25% in the untreated controls. Overall, cochlear thresholds in the untreated controls increased by 14.7 dB, whereas no significant threshold increase was seen in the steroid treated group (4.3 dB) over the treatment period. No qualitative anatomical differences were seen in the ears of those mice surviving to the end of the study. These findings establish the autoimmune mouse as a model for studies of steroid responsive mechanisms within the ear. This could apply to autoimmune sensorineural hearing loss, as well as any hearing disorder for which steroid therapy is recommended.

Steroid treatment in young MRL.MpJ-Fas(lpr) autoimmune mice prevents cochlear dysfunction.

Corticosteroid therapy reverses clinical autoimmune sensorineural hearing loss, although little is known of how steroids restore normal auditory function. If suppression of systemic autoimmune processes underlies hearing restoration, then preventing autoimmune symptoms from developing should prevent cochlear dysfunction. MRL. MpJ-Fas(lpr) autoimmune mice were used to test this potential mechanism by initiating oral prednisolone treatment at 6 weeks of age, prior to autoimmune disease and hearing loss onset. The steroid treatment group was given prednisolone in their drinking water, while untreated controls were given tap water. Treatment continued for 7 months with periodic evaluations of cochlear function with auditory brainstem response (ABR) audiometry. Autoimmune mice given the steroid lived longer and did not develop levels of serum immune complexes seen in their untreated controls. Also, their ABR thresholds remained near normal throughout the 7 months of treatment, while untreated controls showed progressive threshold elevations typical for autoimmune disease. This correlation of suppressed systemic autoimmune activity and maintenance of normal cochlear function identifies one potential mechanism for autoimmune hearing loss and hearing restoration with steroid therapy. The autoimmune mouse should serve as a valuable model for future studies of the cochlear mechanisms responsive to steroid treatment in autoimmune hearing loss.

Steroid-responsive cochlear dysfunction in the MRL/lpr autoimmune mouse.

Corticosteroids historically have been used to treat autoimmune sensorineural hearing loss, although little is known of how steroids restore normal inner ear function. Therefore, to identify a potential model for this field of research, this study examined the effects of prednisolone on auditory brain stem response thresholds in the MRL/lpr mouse model of autoimmune sensorineural hearing loss. Mice treated with prednisolone after auditory threshold elevations demonstrated significant improvement and stabilization of thresholds compared with untreated controls. MRL/lpr mice treated with steroids before the onset of autoimmune disease and cochlear dysfunction demonstrated decreased serum immune complexes, higher survival rates, and lower auditory thresholds compared with untreated controls. These positive results suggest the autoimmune mouse may be useful for studies of steroid-responsive mechanisms of the cochlea in autoimmune sensorineural hearing loss, as well as any hearing disorder in which steroid therapy is currently used.

Normal cochlear function in mdx and mdx(Cv3) Duchenne muscular dystrophy mouse models.

OBJECTIVES/HYPOTHESIS: Sensorineural hearing loss has been found in association with inherited muscular dystrophies in humans and in mouse models. An increased brainstem auditory evoked response threshold has been previously reported in the dystrophin-deficient mdx mouse model for Duchenne muscular dystrophy, suggesting that full-length dystrophin (Dp427) is involved in hearing. The objective of the present study was to confirm cochlear dysfunction with this gene defect and determine whether the shorter carboxyl terminus isoforms of dystrophin are also critical in maintaining normal hearing. STUDY DESIGN: Case controlled. Animal model. METHODS: Auditory brainstem response (ABR) audiometry to pure tones was used to evaluate cochlear function. Fourteen mdx, 4 mdx(Cv3), and 13 age-matched control (C57BL/6J and C57BL/10ScSn) male mice were tested at 5 weeks and 11 weeks of age. The ABR thresholds to tone-burst stimuli at 4, 8, 16, and 32 kHz were obtained for each ear and statistically compared (ANOVA) for potential group differences. RESULTS: Both mdx and mdx(Cv3) mice demonstrated normal ABR thresholds when compared with controls. CONCLUSIONS: Both mdx and mdx(Cv3) mouse models have normal hearing by ABR. The authors' data suggest that dystrophin and its carboxyl terminus isoforms do not play a critical role in hearing in the mouse. This was unexpected, as previous studies using the brainstem auditory evoked response method suggested that the mdx mouse has an increased threshold for hearing.

The use of a 56-stimulus train for the rapid acquisition of auditory brainstem responses.

To further develop a multiple stimulus method for the rapid acquisition of auditory brainstem responses (ABRs), a 56-stimulus train was tested in mice. Stimuli in the train were tone bursts spaced at 0.5-octave intervals from 4 to 32 kHz. ABR thresholds, latency-intensity and amplitude-intensity functions were obtained using stimuli presented singly (one at a time) and using the 56-stimulus train. Responses from stimuli presented singly and those obtained using the 56-stimulus train were compared. There were no significant differences in thresholds (0.01 level) and very small differences in response latencies and amplitudes. These findings demonstrate the feasibility of multiple stimulus trains for the rapid acquisition of ABRs.

Submandibular and lacrimal gland immunoglobulin in the C3H.MRL-Faslpr autoimmune mouse model of Sjögren's syndrome.

OBJECTIVE: To distinguish potential autoimmune and nonautoimmune mechanisms underlying the salivary gland inflammation seen in Sjögren's syndrome and normal aging. STUDY DESIGN: Immunohistochemical studies were conducted on the lacrimal and salivary glands of 2- and 5-month-old C3H.MRL-Faslpr autoimmune strain mice and age-matched C3H/HeJ nonautoimmune controls. METHODS: Glandular inflammatory foci, interstitial areas, and vasculature were stained for immunoglobulin G (IgG), immunoglobulin A (IgA), and complement to determine differences in their local immune parameter. Differences between the two strains were compared for immune changes attributable to autoimmune disease and between the two normal groups for normal aging changes. RESULTS: Greater staining of IgG, IgA, and complement occurred in the inflammatory foci and interstitial areas of 5-month-old C3H.MRL-Faslpr lacrimal and submandibular glands compared with 5-month-old controls. Normal mice showed some increased immunoglobulin staining with aging, but little or no complement in any glands. CONCLUSIONS: These differential findings suggest that the systemic autoimmune disease plays a more direct role in focal glandular inflammation in Sjögren's syndrome, whereas less severe immune mechanisms are involved in the inflammation of normal glands.

Failure of elevated heat shock protein 70 antibodies to alter cochlear function in mice.

Heat shock protein 70 (HSP70) has been suggested as the putative cochlear antigen underlying a proposed autoimmune etiology in certain cases of Meniere's disease and idiopathic hearing loss. To determine if antibodies to this cellular protein are capable of altering cochlear function, BALB/c (N= 3) and CBA/J (N= 9) mice were inoculated with bovine HSP70 by intraperitoneal injections (10 microg in saline) every 10 days for 7 or 10 months, respectively. An equal number of control mice were injected with PBS according to the same schedule. ABR thresholds at 4, 8, 16, and 32 kHz in the HSP70-inoculated mice did not change over the 10 month period and were similar to saline controls. Furthermore, serum immune complexes and antinuclear antibodies did not increase over the inoculation period. ELISA analysis demonstrated the mice created antibodies to the foreign HSP70, but these apparently caused no abnormalities in the auditory or immune systems. It was concluded that foreign HSP70 is antigenic and inoculation with it will raise antibodies, but these antibodies were neither immunopathogenic nor cochleopathic. Therefore, these findings do not support current theories that elevated anti-HSP70 antibodies are the underlying cause of hearing loss in patients with such antibodies present.

Craniofacial and otic capsule abnormalities in a transgenic mouse strain with a Col2a1 mutation.

Abnormal craniofacial features of a transgenic mouse model of chondrodysplasia with a type II collagen mutation (Gly574Ser) are described in this report. In addition to a shortened mandible and cleft palate, a misshapen otic capsule was observed. Interestingly, hearing impairment is often a component of the chondrodysplasia phenotype that results from mutations in COL2A1. To identify a potential mechanism in the hearing loss associated with type II collagen mutations, we examined the development of the otic capsule in the transgenic mice. It appeared to be smaller overall, relative to the skull proportions, and rather than the normal rounded dimensions, the transgenic capsule was flattened and elongated. We speculate that the cartilage of the developing otic capsule was less able to resist the mechanical forces from the developing brain and other tissues within the cranium and thus became deformed under pressure. We further speculate that the hearing loss associated with the chondrodysplasia phenotype is at least partially due to these defects in the developing cartilage matrix of the otic capsule.

Otitis media incidence and impact on the auditory brain stem response in lipopolysaccharide-nonresponsive C3H/HeJ mice.

Although mice of the C3H strain normally respond to bacterial lipopolysaccharide with appropriate immune system activation, mice of the C3H/HeJ substrain do not because of a gene defect. This suggests they may be more susceptible to opportunistic bacterial infections and more likely to have otitis media than a normally responding substrain, such as the C3H/HeSnJ. Therefore these two substrains were evaluated for incidence of spontaneous middle ear disease at 2, 4, 6, 10, 12, 15, and 18 months of age. Auditory brain stem response audiometry to pure tones of 4, 8, 16, 24, and 32 kHz was performed to establish the impact of middle ear disease on auditory function. None of the lipopolysaccharide-responsive C3H/HeSnJ mice demonstrated middle ear disease. However, middle ear disease was present in 33% of the C3H/HeJ mice. The conductive loss caused by the otitis media resulted in auditory brain stem response threshold shifts of 15 to 40 dB SPL, lowered peak amplitudes, and increased latencies. Reduced lipopolysaccharide responsiveness by C3H/HeJ mice makes them less capable of reacting immunologically to bacterial infection and presumably underlies the failure to clear middle ear disease. The C3H/HeJ mouse may provide a valuable model in which to study lipopolysaccharide biologic activity and related middle ear inflammatory or immune mechanisms.

Cochlear immunoglobulin in the C3H/lpr mouse model for autoimmune hearing loss.

Immunoglobulin staining was conducted in cochlear tissue from the C3H/lpr autoimmune strain mouse to better understand the local immune processes underlying autoimmune inner ear disease. This mouse is a model for spontaneous systemic lupus erythematosus with coincident elevated cochlear thresholds. Cochleas were examined from C3H/lpr mice at 2 months of age, before disease onset, and at 8 months of age, when systemic disease and hearing loss are manifested. Sections of these cochleas, along with cochlear sections from age-matched C3H/HeJ nonautoimmune controls, were immunocytochemically stained for IgG and IgM to identify areas of abnormal immunoglobulin activity. IgM immunoreactivity was similar in control and autoimmune cochlear tissue and did not appear to vary with disease progression. Staining was limited to the inside of capillaries in the stria vascularis and other areas within the cochlea. Similar staining patterns were seen in control animals stained for IgG. However, C3H/lpr mice with autoimmune disease showed extensive IgG immunoreactivity spreading out from the stria vascularis capillaries into the extracapillary spaces. This increased permeability suggested that breakdown of the blood labyrinth barrier was coincident with systemic autoimmune disease.