Review of immunology

The inner ear has little exposure to pathogens and few resident cells that are associated with immunologic function. In the past, this led to assumptions that it was immunologically privileged, similar to the brain. More recent research indicates that the inner ear is actually more immunoresponsive than the brain. The labyrinth exhibits a blood-labyrinthine barrier analogous to the blood-brain barrier, which maintains the cochlea’s unique ionic characteristics. There is no lymphatic drainage from the inner ear, and, although immunoglobulins are present in the perilymph, the amount is only one-thousandth of that in the serum.

The inner ear demonstrates cellular and humoral immunity. Most leukocytes enter the cochlea via the spiral modiolar vein. The innate immunity of the cochlea has been suggested to allow an adaptive local response to antigen challenge. Hashimoto and colleagues have suggested that the inner ear may be primed by lipopolysaccharides or other viral or bacterial antigens, resulting in the upregulation of interleukin (IL)-1C in the spiral ligament fibrocytes permitting leukocytes to enter. Subsequently, in those having lymphocytes primed to react against inner-ear antigens, an initiated immune response may result in local inflammation. Altermatt and colleagues have suggested that the seat of immunoactivity in the inner ear seems to be the endolymphatic sac (ES) and duct. Immunoglobulin (Ig) G, IgM, IgA, and secretory component are found in the ES, and numerous plasma cells and macrophages reside in the perisaccular connective tissue.

Additionally, the labyrinth exhibits active components of allergic reactivity. Mast cells have been identified in the perisaccular connective tissue. Following sensitization, IgE-mediated degranulation of mast cells has resulted in eosinophilic infiltration of the perisaccular connective tissue, and, clinically, the production of endolymphatic hydrops.

The ES is capable of processing antigen and producing its own local antibody response. Surgical destruction of the ES results in decreased antigen and antibody responses. The highly vascular subepithelial space of the ES contains numerous fenestrated blood vessels, with arterial branches of the posterior meningeal artery supplying the ES and duct. Although the labyrinth is protected by the blood-labyrinthine barrier, the posterior meningeal artery is fenestrated, offering a peripheral portal of circulation. Fenestrated vessels supplying organs involved in absorption (eg, kidney, choroid) are especially susceptible to damage by immune complex deposition.

Despite evidence of immune activity, only 30% of patients with MD show a true autoantibody response on Western blot assay to specific anticochlear antibody. Tests of abnormal cell-mediated immunity are either inconsistent or normal, even in patients with known causes of inner ear autoimmune dysfunction, including Cogan syndrome. Despite increased understanding of labyrinthine immunoreactivity, a reliable laboratory marker has not been developed to prove autoimmune or allergic causation in patients with suspected inflammatory hearing loss.

Possible mechanisms involving allergy

The first published report that MD was believed to be provoked by an allergic reaction was in 1923. Inhalant and food allergies have been linked with MD symptoms. Many of MD’s clinical characteristics suggest an underlying inflammatory, if not autoimmune, cause, such as its propensity to wax and wane with periods of remission. It is also bilateral in a significant number of cases.

There are different possible mechanisms by which an allergic reaction produces MD symptoms. First, the ES itself could be a target organ of the allergic reaction. The sac’s peripheral and fenestrated blood vessels could allow antigen entry, stimulating mast cell degranulation in the perisaccular connective tissue. The resulting inflammatory mediator release could affect the sac’s filtering capability, resulting in a toxic accumulation of metabolic products and interfering with hair cell function. Also, the fenestrated blood vessels to the ES could be pharmacologically vulnerable to the effects of vasoactive mediators such as histamine, which are released in a distal allergic reaction. The unique blood supply of the interosseus ES would serve as a portal for these mediators to exert a direct pharmacologic effect. The potent vasodilating effects of histamine or other mediators could affect the resorptive capacity of the ES. Yan and colleagues have shown that Waldeyer ring in the nasopharynx is the anatomic site of T-cell homing to the ES. In systemically sensitized rodents, intranasal antigen stimulation with keyhole limpet hemocyanin in Waldeyer ring resulted in an antigen-specific reaction in the ES and perilymphatic vessels, suggesting that viral or allergic antigen could be processed in the nasopharynx with the resulting specific immune reaction occurring at the ES.

A second possible mechanism involves the production of a circulating immune complex, such as a food antigen, which is then deposited through the fenestrated blood vessels of the ES, producing inflammation. An increased incidence of circulating immune complexes in the serum has been described in MD and allergic rhinitis. The inflammatory response resulting from the deposition of immune complexes along vascular basement membranes is the hallmark of an immune complex disease. Although the binding of the complexes to the cell membranes facilitates their phagocytosis, it also results in the release of tissue-damaging enzymes. This is believed to be the mechanism of unexplained sensorineural hearing loss in patients with Wegener granulomatosis, a prototype immune-complex–mediated disease. On examining the temporal bones of patients with Wegener granulomatosis and unexplained sensorineural hearing loss, the cochlea is found to be normal; the pathology occurs in the ES.

Alternatively, circulating immune complexes may be deposited in the stria, causing the normally intact blood-labyrinthine barrier to leak as a result of increased vascular permeability. In addition to disrupting normal ionic and fluid balance in the extracapillary spaces, this could facilitate the entry of autoantibodies into the inner ear.

A third possible mechanism is a viral antigen-allergic interaction. A predisposing viral upper respiratory infection in childhood (eg, mumps, herpes) antigenically stimulates Waldeyer ring, with subsequent T-cell homing to the ES, resulting in a chronic low-grade inflammation. This is not enough initially to result in hearing loss or vertigo, but it does produce mild impairment of ES absorption. Later in adult life, something in the system stimulates excess fluid production. Several investigators have assumed that viral infections play a direct or indirect role in the cause of MD. Viruses are also capable of exacerbating allergic symptoms by several mechanisms. Live and ultraviolet light-inactivated viruses have been shown to enhance histamine release, an effect believed to be mediated by interferon. Viruses can also damage epithelial surfaces, thereby enhancing antigen entry and increasing the responsiveness of target organs to histamine. It has long been noted that patients with poorly controlled allergy are more likely than nonallergic persons to develop upper and lower respiratory viral infections.

Possible mechanisms involving allergy

The first published report that MD was believed to be provoked by an allergic reaction was in 1923. Inhalant and food allergies have been linked with MD symptoms. Many of MD’s clinical characteristics suggest an underlying inflammatory, if not autoimmune, cause, such as its propensity to wax and wane with periods of remission. It is also bilateral in a significant number of cases.

There are different possible mechanisms by which an allergic reaction produces MD symptoms. First, the ES itself could be a target organ of the allergic reaction. The sac’s peripheral and fenestrated blood vessels could allow antigen entry, stimulating mast cell degranulation in the perisaccular connective tissue. The resulting inflammatory mediator release could affect the sac’s filtering capability, resulting in a toxic accumulation of metabolic products and interfering with hair cell function. Also, the fenestrated blood vessels to the ES could be pharmacologically vulnerable to the effects of vasoactive mediators such as histamine, which are released in a distal allergic reaction. The unique blood supply of the interosseus ES would serve as a portal for these mediators to exert a direct pharmacologic effect. The potent vasodilating effects of histamine or other mediators could affect the resorptive capacity of the ES. Yan and colleagues have shown that Waldeyer ring in the nasopharynx is the anatomic site of T-cell homing to the ES. In systemically sensitized rodents, intranasal antigen stimulation with keyhole limpet hemocyanin in Waldeyer ring resulted in an antigen-specific reaction in the ES and perilymphatic vessels, suggesting that viral or allergic antigen could be processed in the nasopharynx with the resulting specific immune reaction occurring at the ES.

A second possible mechanism involves the production of a circulating immune complex, such as a food antigen, which is then deposited through the fenestrated blood vessels of the ES, producing inflammation. An increased incidence of circulating immune complexes in the serum has been described in MD and allergic rhinitis. The inflammatory response resulting from the deposition of immune complexes along vascular basement membranes is the hallmark of an immune complex disease. Although the binding of the complexes to the cell membranes facilitates their phagocytosis, it also results in the release of tissue-damaging enzymes. This is believed to be the mechanism of unexplained sensorineural hearing loss in patients with Wegener granulomatosis, a prototype immune-complex–mediated disease. On examining the temporal bones of patients with Wegener granulomatosis and unexplained sensorineural hearing loss, the cochlea is found to be normal; the pathology occurs in the ES.

Alternatively, circulating immune complexes may be deposited in the stria, causing the normally intact blood-labyrinthine barrier to leak as a result of increased vascular permeability. In addition to disrupting normal ionic and fluid balance in the extracapillary spaces, this could facilitate the entry of autoantibodies into the inner ear.

A third possible mechanism is a viral antigen-allergic interaction. A predisposing viral upper respiratory infection in childhood (eg, mumps, herpes) antigenically stimulates Waldeyer ring, with subsequent T-cell homing to the ES, resulting in a chronic low-grade inflammation. This is not enough initially to result in hearing loss or vertigo, but it does produce mild impairment of ES absorption. Later in adult life, something in the system stimulates excess fluid production. Several investigators have assumed that viral infections play a direct or indirect role in the cause of MD. Viruses are also capable of exacerbating allergic symptoms by several mechanisms. Live and ultraviolet light-inactivated viruses have been shown to enhance histamine release, an effect believed to be mediated by interferon. Viruses can also damage epithelial surfaces, thereby enhancing antigen entry and increasing the responsiveness of target organs to histamine. It has long been noted that patients with poorly controlled allergy are more likely than nonallergic persons to develop upper and lower respiratory viral infections.

Epidemiology

In a survey the authors performed of 734 patients with MD, the prevalence of skin test-confirmed concurrent allergic disease was 41%. Although the prevalence of allergic rhinitis is often quoted as 20% or more, the recent Allergies in America report, the largest survey to date regarding prevalence and disease burden of allergic rhinitis, found that physician-diagnosed allergic rhinitis in patients with rhinitic symptoms is 14%. Hence, the prevalence of physician-diagnosed allergy in American patients diagnosed with MD is almost 3 times that of the general population. In a more recent survey of patients with MD, the authors found that patients reported a 58% rate of allergy history, and again, a 41% rate of positive skin or in vitro test.

In his original description, Prosper Ménière suggested an association between migraine and MD. Many authors have subsequently noted paroxysmal headache independently occurring in many patients with MD. Radtke and colleagues published a well-designed prospective trial based on strict diagnostic criteria, which established an increased lifetime prevalence of migraine in patients diagnosed with MD.

A recent study reported an increased incidence of self-reported migraine and allergic rhinitis in patients with MD, as compared with a control group of age- and sex-matched patients without MD attending an otolaryngology clinic. Sen and colleagues used a Web-based questionnaire to recruit 108 patients with MD and a control group of 100 patients attending the otolaryngology clinic for other problems. The migraine prevalence in MD sufferers was 39% compared with 18% in the control group, whereas the prevalence of allergy in those with MD was 51.9% compared with 23% in the control group. In the MD group, a history of allergy was significantly more prevalent in patients with migraine (71%) than in those without migraine (39%). There was no such link between allergy and migraine in the control group, with the combination of allergy and migraine 9 times more prevalent in the MD group (adds ratio 9.23; 95% confidence interval 3.11–27.32).

The study by Sen and colleagues is interesting because it suggests that in that large subset of patients with MD who also have migraine, the vast majority report an additional diagnosis of allergy. One weakness of their Web-based questionnaire is that the allergy history is obtained by asking subjects whether they or their family members suffer from any allergy, without confirmatory skin or in vitro testing. However, all patients—control and MD groups—were asked the same question and gave such differing responses as to add credence to the supposition that there is a much higher incidence of allergy and migraine in patients with M.D.

More recently, Ibekwe and colleagues reported that 32% of patients presenting to a clinic in Nigeria and diagnosed by an otolaryngologist with MD also had associated features of migraine, compared with 5.3% of the overall population. Migraine without aura (“common migraine”) was the most common presentation, occurring in approximately 62.5% of patients. This study shows that a history of allergy is much more common in patients with MD and migraine than in those without migraine. The investigators suggest that the vasodilatory effects of allergy or possible extravasations of immune complexes may serve as a common pathway for migraine and MD.Although a weakness of this paper is the small number of patients reported, there is a striking similarity in the prevalence of migraine in this study and that reported by Sen.

Although the list of causes for migraine is extensive, it has long been noted that allergic reactions were a common trigger in many sufferers. There are striking similarities in symptom presentation and vascular changes between MD, allergy, and migraines. All 3 tend to recur cyclically, and sufferers are often able to note a cause and effect between a particular suspected “exposure” or event and the subsequent development of symptoms. All the entities also show similar vascular changes during the course of symptom production: vasoconstriction, vasodilatation, and plasma extravasations. There is an elevation in IgG-containing immune complexes in the meningeal vessels of patients with migraine and in the subepithelial layer of the ES in patients with MD. The elevated level of circulating immune complexes in MD has already been mentioned.

Ibekwe hypothesized that there may be a common defective ion channel in both disease states, with the predominant expression in the inner ear and brain, resulting in a local increase in extracellular potassium and the production of symptoms.