-Normal development:

stem cells (in bone marrow) Þ T- or B- lymphocytes.

T cells (mature via passage thru thymus) into:

(1) helper T cells; (aid and promote B-cell antibody production)

(2) suppressor T cells (modulate A/B prodn & responses mediated by T cells)

(3) cytotoxic T cells (capable of direct killing of cells expressing foreign antigens)

Collectively, responsible for; LK production, anti-viral cytotoxicity, graft-versus-host dis

delayed HS’ty responses, and graft rejection.

B cells (mature via passage thru fetal liver)

form IgM molecule that ultimately is incorporated into the cell membrane.

AUTOIMMUNITY

-autoimmune may result from reaction of antibodies or cells against self-constituents.

-disorders are considered:

- organ-specific (eg DM) or non-organ-specific diseases (eg SLE).

-3 primary mechanisms for autoimmune disorders:

1. autoantibodies against tissue antigens which attach to specific cell surface Ag’s, fix complement,

and result in tissue damage and organ dysfunction.

2. deposition of antigen-antibody immune complexes within tissues. (CIC’s)

3. destruction of tissue by specific activated cytotoxic T cells.

-role of genetic factors in the susceptibility and development of autoimmune disease;

eg; major histocompatibility genes (esp HLA-DR alleles)

EXPERIMENTAL IMMUNOLOGY OF INNER EAR

- immunoglobulin X’s blood-labyrinthine barrier & is found in perilymph at 1/1000 concentration found in serum ( analogous to BBB)

- inner ear has the property of concentrating immunoglobulins

- main immunoglobulins in perilymph are IgG, with lesser amounts of IgM and IgA

-endolymphatic sac

-secretory component and IgA have been found in epithelial cells (Arnold1984).

-has been suggested as site of host defenses within inner ear

-normal mouse has full complement of immunocompetent cells including macrophages, PMNs, IgM-

and IgG-plasma cells, and T-helper cells (Takahashi and Harris, 1988b).

-Examination of inner ears undergoing immune reactions reveals:

-many inflammatory cells in scala tympani, perisaccular connective tissue, endolymphatic sac lumen

-early in this response, PMN’s & macrophages predominate Ý IL-2levels; but over time, T-helper &

plasma cells predominate with gradual emergence of T-s cells by 3/52, to halt inflammation.

-cells enter inner ear via: spiral modiolar veins along a bony conduit into the scala tympani or

venules surrounding the endolymphatic duct and sac.

-Expt’s show endolymphatic sac provides an immunologic role for the inner ear in addition to its water-

resorptive role, analogous to gut.

-Expt’s have shown that cochlea is not a passive organ on exposure to a pathogen and that an immune

response can develop to protect and preserve cochlear function.

-Expt’s have shown that on the other hand, immune responses can be injurious to organ function if the inciting

antigen evokes a sufficiently vigorous response

(eg viruses may =>hydrops if they reach and replicate within sac epithelium)

-Exp’t of inoculating live CMV into immunosuppressed animals:

- two major findings:

1. a significant reduction in inflammatory response within cochlea following immunosuppression

2. immunosuppressed animals showed significantly preserved hearing compared to controls.

Þ the host's response to the invading organism causes the majority of damage rather than the

cytopathic effects of the virus itself

EXPERIMENTAL ALLERGIC LABYRINTHITIS

-Yoo 1983 developmed an animal model with inner ear injury secondary to type II collagen autoimmunity.

-their animals demonstrated spiral ganglion cell degeneration, atrophy of organ of Corti, arteritis of VIII & stria vascularis, endolymph hydrops with atrophy of surface epithelium of endolymph duct.

- Hearing loss and vestibular dysfunction.

-these studies => autoimmunity to type II collagen may underlie: ? otosclerosis, Meniere's disease, and SNHL nb: several studies done since that have& haven’t confirmed these findings.

-??Existence of other specific anticochlear autoantibody.

-etiology of autoimmunity is unknown, but one theory suggests that:

-tissues involved in this process are of either ectodermal or endodermal origin and are viewed as foreign by the immune system, which is mesodermal.

nb:entire membranous labyrinth is of ectodermal origin.

CLINICAL AUTOIMMUNE DISEASE OF THE INNER EAR

-autoimmune disease affecting ear may be either result of:

-organ-specific disease or

-result of a systemic disorder.

-Eg: Veldman 1984 reported autoimmune SNHL resulted from:

-immune complex-induced vasculitis,

-defect in PMN leukocytes,

-postvaccination serum sickness.

(A) Systemic disorders

Polyarteritis nodosa

-defn: systemic disorder affecting small- and medium-sized arteries throughout body,

-incid: only rarely associated with cochlear injury.

-clin: although this is a systemic disorder, hearing loss may be the sole presenting symptom (Bakaar, 1978)

-histopathology: -arteritis in internal auditory artery with wide-spread cochleovestibular ischemic changes, osteoneogenesis and fibrous tissue in the basilar turns.

-others: necrotizing vasculitis Þ disappearance of organ of Corti, atrophy of stria vascularis, collapse of Reissner's membr, distortion of tectorial membr, fibrosis of apical turn. ---Nb: search for such an etiology of vasculitis should be made in patients with profound unexplained deafness.

Cogan's syndrome

-defn: disorder of young adults cxtz’d by nonsyphilitic interstitial keratitis (IK)& vertibuloauditory dysfunction -aetiol: ?? hypersensitivity response to infectious agents associated with vasculitis (Cheson et al., 1976).

-clin: -IK develops suddenly with photophobia, lacrimination, and eye pain, gradually resolves

-vestib-audit sx are: acute episodes of vertigo, tinnitus, and hearing loss (Þ deafness over 1-3mnths)

-occasionally associated with systemic Sx’s, arthritis, PAN, GN, inflam bowel disease, splenomegaly

-atypical Cogan's syndrome

-vestibulo-auditory symptoms 1 to 6 months before or after the onset of IK

-vestibuloauditory symptoms plus episcleritis, uveitis, or conjunctivitis

-histo: endolymphatic hydrops, plasma cell & lymphocytic infiltration of spiral ligament

saccular rupture, osteoneogenesis of RW, spiral ganglion cell degeneration, degeneration of stria.

degeneration of organ of Corti, fibrosis and osteoneogenesis within perilymphatic space.

Vogt-Koyanagi-Harada syndrome (VKH).

-similarites to Cogan's syndrome

-characterized by SNHL, dizziness, granulomatous uveitis, depigmentation of hair and skin around eyes,

loss of eyelashes, and aseptic meningitis.

-etiopathogenesis is ?? autoimmunity to:

(1) melanocytes

(2) tissues containing these cells,( uvea, skin, meninges, and inner ear).

Wegener's granulomatosis

-classic triad consists of:

(1) necrotizing granulomas with vasculitis of upper and lower respiratory tracts,

(2) systemic vasculitis, and

(3) focal necrotizing glomerulitis

-ear manifestations occurred in 20% of patients

-most often serous otitis media associated with infection or obstruction of the nasopharynx.

-some patients had sensorineural losses, and some of these improved with prednisone therapy.

nb:may be the sole presenting symptom of these patients.

-etiology of the inner ear disease is unknown ???? necrotizing vasculitis.

-dx:. (cANCA: antineutrophil cytoplasmic antibody) test Þ (+’ve in 95% of pts with Wegener's: Schur 1991) -it recognizes antibodies to azurophilic granules in neutrophils.

Relapsing polychondritis

-defn: a rare disease ctzed by recurrent episodes of inflammatory necrosis affecting cartilaginous structures of

ears, nose, URT, & peripheral joints (McAdam, 1976).

-clin: -it destroys supporting cartilage, Þ auricular deformity or saddle nose deformity or tracheal collapse.

-associated with vestibuloauditory symtoms

-the erythema spares the lobula but involves the remainder of the pinna equally.

ddx: bacterial perichondritis and erysipelas.

-bacterial perichondritis exhibits fluctuation if the entire pinna is involved;

-erysipelas involves entire auricle, x’tnds onto periauricular skin with a well-demarcated margin.

-aetiol: immune-mediated rather than an infectious cause.

-mx: antiinflammatory agents good in reversing the inflammation and SNHL in this disorder.

Other rare systemic vasculitises:

-Takayasu's arteritis, postvaccination vasculitis, and serum sickness in which an occasional incidence

of vertibuloauditory dysfunction has been seen (Mair and Elverland, 1977; Rosen, 1949).

-basic underlying pathologic condition is vasculitis, Þ ischemic injury to inner ear.

Systemic lupus erythematosus

-defn: a multisystem disease that has protean manifestations.

-malar "butterfly rash" is pathognomonic but present in relatively few patients.

-Polyarthralgia, arthritis, pleuritis, pericarditis, pneumonitis, myocarditis, endocarditis, nephritis, cranial nerve

palsies, meningitis, cerebrovascular accidents, neuritis, scleritis, retinal degeneration secondary to vasculitis,

& inflammatory bowel disease are all part of the clinical spectrum of this disease (Steinberg1984; Tan 1982). -Otologic manifestations include:

chronic otitis media with necrotizing vasculitis and progressive SNHL or disequilibrium (McCabe,

-laboratory abnormalities include Ý ESR, circulating immune complexes,& multiple autoantibodies.

Rheumatoid arthritis

- chronic systemic inflammatory disease mainly affects joints.

- Extraarticular manifestations include: vasculitis, muscle atrophy, subcutaneous nodules, lymphadenopathy, splenomegaly, and leukopenia.

- Otologic manifestations Þ vestibuloauditory dysfunction.

(B) Organ-specific autoimmune inner ear disease

-cell-mediated immunity is implicated by studies of Hughes et al. (1986) and Berger et al. (1989).

-other studies: ??? autoantibodies (ANA, anticardiolipin, antismooth muscle, antiendoplasmic reticulum)

Ménière's disease

???? autoimmune etiology (Ryan, 1987).

-elevated circulating immune complexes and other immunologic abnormalities in patients with this disorder.

-Yoo reported an elevated type II collagen autoantibody level in patients with Ménière's disease & otosclerosis. Autoimmunity to type II collagen experimentally Þ wide-spread inner ear dysfunction

(that is, hearing loss, vestibular dysfunction, and endolymphatic hydrops).

TREATMENT

-Patients with clear-cut evidence of autoimmunity and whose deafness/disequilibrium are disabling:

Þ immunosuppressive regimen.

-Generally, 1-2 mg/kg/day (usual dose 60 mg) of prednisone for 4 weeks

Patients with a beneficial response Þ high dose for an additional 1-2 months, then taper down slowly.

-In nonresponsive but desperate cases, cyclophosphamide can then be added (2-5 mg/kg/day)

-taken each morning with liberal fluid intake to lessen the risks of urinary bladder toxicity.

-peripheral blood should be monitored so that total WCC does not drop below 3000 cells/mm3,

nor the neutrophil count below 1000 to 1500/mm3.

-McCabe's treatment regimen:

-patients are given an initial trial of high-dose steroids for 3 weeks,

-those who respond Þ escalated to a cyclophosphamide-prednisolone combination for 3-mnth period; cyclophosphamide is then discontinued, and the prednisolone is slowly tapered.

-any drop in hearing is followed by reinstitution of the full combination of drugs at original dosages

S/E’s of cyclophosphamide: hemorrhagic cystitis and malignancies of urinary tract, leukemogenic.

-In cases in which humoral immune mechanisms are more apparent:

-plasmapheresis can be considered (Luetje, 1989).

-during plasmapheresis, cyclophosphamide and steroids should be continued.

Nb: in Wegener's granulomatosis and Cogan's syndrome, aggressive immunosuppressive therapy for 1 year

after the disappearance of active disease (Fauci and Wolfe, 1973; Fauci et al., 1978).

IMMUNOASSAYS

Lymphocyte transformation

-phytohemagglutinin (PHA), a lectin from kidney beans, caused the transformation of small lymphocytes into proliferating lymphocytes when cocultured in vitro (Nowell, 1960).

-assesses lymphocyte responsiveness to antigens or allogeneic cells.

Lymphokine assays

-various lymphokines are released from lymphocytes following stimulation by antigens, mitogens, surface immunoglobulins, and various membrane receptors.

Macrophage migration inhibitory factor

-production of macrophage migration inhibitory factor (MIF) is correlated with development of delayed hypersensitivity responses on skin testing.

Leukocyte migration inhibitory factor (LMIF)

-produced by either T or B lymphocytes.

Serum protein electrophoresis

-provides an overview of more than 100 serum proteins

-good screening test for the presence or absence of normal blood constituents.

-identification of abnormal spikes Þ gammopathies such as Waldenstrom's macroglobulinemia or myeloma.

Immunoelectrophoresis

-combines electrophoretic separation of serum proteins with immunodiffusion using monospecific antisera.

Erythrocyte sedimentation rate

-a simple means of serially monitoring patients with a diverse range of inflammatory disorders.

-major disadvantages are its nonspecificity and relative insensitivity.

-determined by the serum viscosity; \ substances such as fibrinogen, acute-phase reactants, macroglobulins,

which are often associated with chronic inflammatory states, have a significant effect on elevating the ESR.

Cryoglobulins

-systemic diseases associated with presence of serum immunoglobulins have the property of forming

precipitates in the cold.

-Autoimmune, neoplastic, and infectious diseases have cryoglobulins at some point in their clinical course.

eg: lupus nephritis, rheumatoid vasculitis, Sjögren's syndrome, and polyarteritis nodosa.

occult infections, (eg chronic hepatitis B or bacterial endocarditis, lymphoproliferative disorders)

Quantitative immunoglobulins

-Normally in adults the distribution is:

85% IgG, 10-15% IgA, 5-10% IgM.

Antinuclear antibody

-these have an overlap region in which normal patients and diseased patients both show positive responses. Here one must use additional clinical criteria to confirm the suspected diagnosis.

-patients in whom ANA is strikingly positive at high dilution, Þ is diagnostic of an autoimmune state.

-In general, ANA is positive in 50% of pts with scleroderma; 30% of pts with rh arthritis & 7% of normal pts.

Anti-DNA antibodies

-are measured in patients with collagen vascular diseases,

the specific ANA is classified as: -native double-stranded DNA (nDNA) or

-single-stranded DNA (ssDNA).

-anti-nDNA is highly associated with SLE, and its presence parallels the activity of the disease.

-anti-ssDNA is less specific, found in many types of collagen vascular disease.

C1Q-binding assay

-Ý C1Q binding provide Þ strong evidence for circulating immune complexes of the type that interact with the classic pathway of complement activation (IgG and IgM).

Raji cell assay

-detects soluble IC’s in serum & is based on binding of IC’s to Raji cells via complement receptors.

-unreliable in SLE and other diseases where antilymphocyte antibodies.

Summary

The following tests are most often helpful in screening for immune-mediated deafness:

1. ANA

2. Sedimentation rate

3. C1Q binding

4. Raji cell assay

5. Rheumatoid factor

6. Cryoglobulins

7. Urinalysis

8. FTA-ABS

Bibliography:

Cummings, C. Otolaryngology.  chapter 164

Gates Current Therapeutics

Scott Brown, , Otolaryngology

Schucknect, Pathology of the Ear