Учебники / Auditory Trauma, Protection, and Repair Fay 2008

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no hearing loss with infusion of placebo into the cochlea (Nair et al. 1997). This monoclonal antibody binds a 68to 72-kDa protein antigen within the supporting cells of the guinea pig. This protein could very well be a choline transporter, most likely CTL-2 (Nair et al. 2004).

Finally, some of the animal models used to study other systemic autoimmune illnesses also display auditory and vestibular dysfunction. In particular, the MRL-Fas mouse model used for systemic lupus erythematosus develops significant degrees of sensorineural hearing loss. These MRL-Fas mice lose the ability to eliminate autoimmune T cells by apoptosis. As these autoimmune T cells accumulate, various endorgans are injured as occurs in systemic lupus erythematosus. Histopathologic studies of these mice reveal hydropic cellular degeneration isolated to the stria vascularis in the absence of any inflammatory infiltrate or immune complex deposition. However, significant antibody deposition within the capillaries of the stria vascularis has been identified. Whether these antibodies or other factors, such a uremia or genetic predisposition, lead to the sensorineural hearing loss found in these animals remains unclear (Ruckenstein 1999).

It is important to note that although the immune response of the inner ear can cause autoimmune damage, it more often serves a critical protective role against pathogens. Guinea pigs receiving live cytomegalovirus (CMV) injected into their inner ears developed progressive deafness within 1 week. If these guinea pigs were exposed systemically to CMV prior to having the live CMV injected into their inner ears, they quickly developed elevated levels of antibody within the perilymph against CMV. These antibodies prevented inner ear damage and the animals did not develop any degree of hearing loss (Woolf et al. 1985).

6. Mechanisms of Autoimmune Injury to the Inner Ear

Autoimmune injury in general can occur either via humoral or cell-mediated reactions. Injury to tissues can occur from direct damage by an antibody directed toward a specific antigen, by direct cell destruction from cytotoxic T cells, or by immune complex deposition into tissues. All three mechanisms of autoimmune injury can potentially damage inner ear tissues. However, confirmation of any of these mechanisms has proven difficult to obtain, and the exact mechanisms of autoimmune injury to the inner ear remain unknown.

It seems highly likely, however, that some subsets of patients with AIED do indeed develop organ-specific autoantibodies to a particular antigenic epitope within the inner ear. When inner ear proteins are injected into the inner ear of animals, hearing loss as well as inflammation within the cochlea develops along with antibodies specific to the inner ear tissues. Curiously, the hearing loss which is incurred by such measures is modest and transient. Also, control animals immunized with antigens that are not from the inner ear do not demonstrate any hearing loss or cochlear inflammation. The greatest degree of hearing loss and cochlear inflammation comes from a secondary immune response to purified

antigen used on animals with a high degree of preexisting immunity (Ryan et al. 2002). In addition, the mouse monoclonal antibody KHRI-3 binds to the inner ear supporting cells in guinea pigs and causes hearing loss that is not seen in control guinea pigs. This gives further evidence for antibody-mediated hearing loss in humans (Nair et al. 1997).

Evidence of antibody–antigen immune complex deposition is found in patients with certain systemic autoimmune diseases who go on to develop inner ear damage. Examples are collagen vascular diseases such as systemic lupus erythematosus, Wegener’s granulomatosis, and polyarteritis nodosum, all of which have immune complex deposition but only sporadically develop inner ear damage. Veldman et al. (1984) reported a case of a 14-year-old girl who presented with fatigue, arthralgias, and sensorineural hearing loss. She had circulating immune complexes and was diagnosed with juvenile arthritis. She was placed on prednisone and had a dramatic resolution of her symptoms including normalization of her hearing within 2 weeks. This case report is convincing for immune complex deposition as a possible etiology in some cases of autoimmune inner ear disease (Veldman et al. 1984). Immune complex disease has also been implicated as the mechanism of injury in patients who develop hearing loss, vertigo, and tinnitus in association with Cogan’s syndrome after vaccinations for small pox (Harris 1984).

Evidence of cytotoxic T cell damage to inner ear tissues comes from the lymphocyte transformation test, a test designed to identify cytotoxic T cell injury. The lymphocyte transformation test involves taking lymphocytes and exposing them to an antigen with subsequent evaluation of their activity. In a study performed on 68 patients with bilateral progressive sensorineural hearing loss of unknown etiology using type II collagen as an antigen, Berger and coworkers found 34 out of 68 patients had a strong stimulation in the transformation test as compared to only 4 of 68 control patients (Berger 1991).

Although definitive evidence is lacking for either humoral or cell-mediated mechanisms of injury, one can gain some insight into the mechanism of damage from autoimmune inner ear disease through the histopathologic examination of inner ear tissue from affected patients. In temporal bones evaluated from patients suffering from autoimmune inner ear disease, damage to both the organ of Corti and the stria vascularis has been found. Similarly, animal models of autoimmune inner ear disease also demonstrate damage to both the organ of Corti and stria vascularis. Further, the degree of damage to the organ of Corti and stria vascularis is closely correlated to the severity of inflammation in secondary immune responses. The most damage occurs to the organ of Corti in the cochlear turns with the highest amount of inflammatory response. Typically, the amount of inflammation is most severe in the basal turns with the apical cochlear turns often displaying much less inflammation and damage to the organ of Corti and stria vascularis. In human tissue and animal models, both the inner and outer hair cells as well as supporting cells undergo apoptosis. The stria vascularis also demonstrates signs of injury with cell protrusion, hyperplasia, thinning, and even total degeneration. Although the inflammatory response does not involve Rosenthal’s

142 Q. Gopen and J.P. Harris

canal at any point, the spiral ganglion neurons demonstrate significant loss and degeneration at roughly 6 weeks after the initial immune response, suggesting their retrograde degeneration after hair cell loss. However, the mechanisms behind the spiral ganglion cell loss are not well understood. When the inflammatory response is vigorous and goes unchecked, the cochlea often develops an inflammatory matrix. This matrix is often quite difficult for the inner ear to clear, which ultimately leads to ossification within the cochlea (Ma et al. 2000).

The mechanisms of how the hair cells, the supporting cells, and the cells of the stria vascularis are damaged in the immune response remain unclear. Perhaps clues can be taken from other pathologies such as presbycusis, noise trauma, or ototoxicity in which oxidant stress may be a factor initiating apoptotic or necrotic cell death (see Chapters 6, 7, and 8 on these topics) but substantial research efforts will be required to elucidate these undoubtedly complex mechanisms.

7. Summary

The inner ear can participate as the afferent limb of the immune response with the endolymphatic sac and perisaccular tissue functioning as the primary antigen processing site of the inner ear. Systemic cells are then recruited into the inner ear via the spiral modiolar vein. It remains unclear whether autoimmune damage to the inner ear occurs via cell-mediated, humoral, or a combined mechanism. Patients typically present with fluctuating sensorineural hearing loss progressing over weeks to months. Although one third of patients suffer from a concurrent systemic autoimmune illness, two thirds of patients present with isolated autoimmune inner ear damage. High-dose corticosteroids remain the treatment of choice for patients with AIED, but more specific medications including TNFantagonists such as Remicade, Enbrel, and Humira as well as the anti-B cell agent Rituxan show promise in preliminary studies.

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2. History and Epidemiology

Historical accounts of research in ARHL are given by Gilad (1979a,b), by Schuknecht (1993), and more recently by Schacht and Hawkins (2005). The first presentation of ARHL as a distinct pathology at a scientific meeting may have been by S.J. Roosa to the American Otological Society in 1885, where he introduced the term presbycusis. It was not until the 1930s that Guild, and also Crowe and colleagues, associated hearing loss in aging with specific cochlear structures. von Fieandt and Saxen (1937), (cited in Schacht and Hawkins [2005]) coined the terms senile atrophy of auditory neurons and angiosclerotic degeneration, the latter term foreshadowing decades of speculation about the role of microvascular pathology in ARHL. Crowe (1934) and Saxen (1937) are credited with the initial division of ARHL into forms emphasizing pathology of organ of Corti versus afferent neurons. Glorig and Davis (1961) and later Nixon and Glorig (1962) argued for nondegenerative pathology of the mechanical structures of the inner ear, later supported by Schuknecht as inner ear conductive ARHL. Schuknecht, in a series of papers beginning in 1953, expanded the number of posited forms to include ARHL characterized by pathology of stria vascularis, and began evaluating temporal bones in terms of putatively independent pathology of organ of Corti, afferent neurons, stria, and spiral ligament. To the present day, there is no clearly superior competing paradigm for understanding ARHL.

Figure 6.1 shows the average progression of ARHL across the span of life (Glorig et al. 1957). The common pattern is one of progressive loss of sensitivity to high frequencies, with relatively little change below 2 kHz to about age 40. Ages 40–60 are characterized by further erosion of high-frequency hearing, typically accompanied by flat losses at low frequencies. After age 60, the entire audiogram may indicate increased hearing loss, such that more than 40% show a clinically significant hearing loss (generally taken to be greater than 25 dB at any frequency) by age 60. Between ages 70 and 80, the prevalence of ARHL exceeds 50%. Nevertheless, the tendencies graphed in Fig. 6.1 obscure a highly skewed character of the underlying distributions, particularly at advanced ages. The rate of hearing decline is quite individualized, so that among those 60 years of age or older will be people with near-normal hearing, sometimes referred to as “golden ears.” Debilitating hearing loss is not an inevitable part of aging, and if understood well enough, may be avoidable. Interindividual differences must reflect different environments and experiences, as well as differences in genetic makeup, predisposing some people to cellular damage from health habits or events that would be benign to others. Also not evident in Fig. 6.1 is the fact that different cochlear cells and structures are affected in different people, so that an unknown number of distinct conditions have been combined.

The pattern of sound frequencies affected by ARHL depends on gender, albeit in a complex manner. Figure 6.2, based on a summary of USPHS surveys by Jerger et al. (1993), shows that men and women have comparable hearing thresholds at 0.5 kHz up to about age 50. After that, thresholds in women deteriorate more rapidly than in men at this frequency. By contrast, above

impacts hearing. Separating peripheral and central pathology is therefore appropriate, and one of the organizing principles of this chapter.

3. Peripheral Aspects of ARHL in Humans

In attempting to impose some kind of typology on ARHL, one might take one of the following approaches: classifying ARHL by its clinical characteristics, by cause, or by the cell type(s) affected. Clinical measures of age-at-onset, severity, laterality, stability, and audiogram shape (see later) are not reliably diagnostic of any particular ARHL type. They are, of course, quite useful for distinguishing other forms of inner ear dysfunction from ARHL, as it is generally symmetrical and nonfluctuating. An elevated “notch” in the audiogram at 4–6 kHz may be useful in separating hearing loss that is principally noise-related from ARHL (e.g., McBride and Williams 2001). Absent any clear indications of causes other than aging, the “cause” of ARHL is the very goal of much current basic research, not a clinical tool. The single current diagnostic for a particular type of ARHL (noted later) is that speech perception in noise may be impacted, even when hearing sensitivity remains normal. To approach the cell biology of ARHL, it has proven more useful to classify cases according to the pattern of cells affected. Classifications made this way unfortunately arrive too late to help the donors of temporal bones, but thus far so have any real cures.

3.1 Classification by Affected Cochlear Structure and Cell Type

The presently dominant framework for classifying of ARHL using histopathology is one championed by Schuknecht in a series of papers written over 40 years, and in his classic book Pathology of the Ear (Schuknecht 1953, 1964, 1993; Schuknecht et al. 1974; Schuknecht and Gacek 1993). From his studies of a modest collection of human temporal bones, Schuknecht was struck by cases of relatively isolated degeneration of organ of Corti, afferent neurons, and stria vascularis. He proposed that these represent distinct types of ARHL: sensory ARHL (hearing loss due principally to organ of Corti pathology), neural ARHL (hearing loss reflecting primary loss of neurons despite the presence of inner hair cells), and strial ARHL (hearing loss due mainly to strial degeneration and reduction of the endocochlear potential). Other forms proposed included mixed ARHL (multiple apparent contributors), cochlear conductive ARHL (possible nondegenerative changes in passive mechanics), and indeterminate. Isolated occurrences of delimited pathology of organ of Corti, afferent neurons, and stria were taken to demonstrate the potential for independent degeneration of these structures, and for the existence of environmental and genetic risk factors specific to each. Dysfunction of any one structure/population was further posited to impact independently hearing ability and the shape of the audiogram.