A human monoclonal IgG that binds aß assemblies and diverse amyloids exhibits anti-amyloid activities in vitro and in vivo.

Alzheimer's disease (AD) and familial Danish dementia (FDD) are degenerative neurological diseases characterized by amyloid pathology. Normal human sera contain IgG antibodies that specifically bind diverse preamyloid and amyloid proteins and have shown therapeutic potential in vitro and in vivo. We cloned one of these antibodies, 3H3, from memory B cells of a healthy individual using a hybridoma method. 3H3 is an affinity-matured IgG that binds a pan-amyloid epitope, recognizing both Aß and λ Ig light chain (LC) amyloids, which are associated with AD and primary amyloidosis, respectively. The pan-amyloid-binding properties of 3H3 were demonstrated using ELISA, immunohistochemical studies, and competition binding assays. Functional studies showed that 3H3 inhibits both Aß and LC amyloid formation in vitro and abrogates disruption of hippocampal synaptic plasticity by AD-patient-derived soluble Aß in vivo. A 3H3 single-chain variable fragment (scFv) retained the binding specificity of the 3H3 IgG and, when expressed in the brains of transgenic mice using an adeno-associated virus (AAV) vector, decreased parenchymal Aß amyloid deposition in TgCRND8 mice and ADan (Danish Amyloid) cerebral amyloid angiopathy in the mouse model of FDD. These data indicate that naturally occurring human IgGs can recognize a conformational, amyloid-specific epitope and have potent anti-amyloid activities, providing a rationale to test their potential as antibody therapeutics for diverse neurological and other amyloid diseases.

A detailed investigation of maternally inherited diabetes and deafness (MIDD) including clinical characteristics, C-peptide secretion, HLA-DR and -DQ status and autoantibody pattern.

BACKGROUND: This article presents a clinically characterization of the mitochondrial DNA mutation (A3243G) associated with maternally inherited diabetes and deafness (MIDD) syndrome in two families. METHODS: Six patients with MIDD and one mutation-positive relative with normal glucose tolerance (NGT) were examined. Fasting serum C-peptide was measured in all subjects and compared with controls having NGT (n = 14). C-peptide response to an intravenous glucose tolerance test (IVGTT) was investigated in the diabetic patients not treated with insulin (n = 3) and in the mutation-positive healthy individual and compared with the controls. RESULTS: The A3243G heteroplasmy value varied between 5 and 30%. All A3243G carriers had HLA-DR1-DQ5 haplotype, and either the -DQ5 or the -DQ6 allele. The fasting and the serum C-peptide levels at 120 min during the IVGTT did not differ between the A3243G carriers and the controls. A missing first phase and a decreased total C-peptide response was detected in the mutation-positive diabetics compared with controls (p < 0.0001). The same abnormality was found in the A3243G carrier with NGT. Circulating islet cell antibody (ICA) was present in three patients with MIDD. Glutamic acid decarboxylase (GAD), tyrosine phosphatase-like protein IA-2 (IA-2) and mitochondrial antibodies were missing. The diagnosis of MIDD was delayed in each case. CONCLUSIONS: A missing first phase and a decreased total C-peptide response during an IVGTT was characteristic for the A3243G mutation. The fasting C-peptide level of the carriers did not differ from the controls. Circulating ICA was present in some patients, but GAD, IA-2 and mitochondrial antibodies were absent. All subjects had HLA-DR1-DQ5 haplotype, and either -DQ5 or -DQ6 alleles.

An Immunological Perspective to Non-syndromic Sensorineural Hearing Loss.

Conventionally the etiology of congenital Non-Syndromic Hearing Loss has been attributed to mutations in the genes involved in ion homeostasis or the structural compartments of the inner ear. However, this contributes to only a part of the problem, as still the determinants for a large majority of the Non-Syndromic Hearing loss seems to be an enigma. Evidences indicate that pathogens like Rubella, Cytomegalovirus, and many other infections can also result in congenital hearing loss. Additionally, there are variety of factors other than the viral mediators, that can act as stressors to trigger an altered immune response, during the gestational period of the mother. It is also known that non-specific stimulation of the immune system can mimic an infection status. This indicates a strong role for environmental factors toward their contribution to the pathology, possibly by influencing the host immune response. These varieties of known or unknown environmental factors interact with the susceptible variants in immune response genes in defining the threshold for protection or infection in an individual. Considering this background we propose to present this perspective that threshold of the host immune response during the prenatal conditions, in response to environmental stimulus, might be determined by the susceptible variants in immune response genes. This in turn can directly or indirectly influence the genes involved in maintaining the structural components or ion homeostasis, resulting in hearing loss. The threshold of immune response alterations may be heavily dependent on the immunogenetic profile of the mother or the fetus.

Eosinophilic otitis media: a new middle ear disease entity.

Eosinophilic otitis media (EOM) is intractable otitis media characterized by the presence of a highly viscous yellow effusion containing eosinophils. It occurs mainly in patients with bronchial asthma and is resistant to conventional treatments for otitis media. Here we discuss the clinical features, pathogenesis, and management of EOM. EOM predominantly affects women and presents most often in patients in their 50s. The clinical features of the middle ear in EOM are roughly divided into the otitis media with effusion type and chronic otitis media type. The latter is further divided into two subtypes: simple perforation and granulation tissue formation. EOM is often complicated by rhinosinusitis (eosinophilic sinusitis). High-tone loss is more frequently found and more severe in EOM patients than in chronic otitis media control patients, and EOM patients sometimes become deaf suddenly. Systemic or topical steroid administration is the most effective treatment for patients with EOM. The instillation of triamcinolone acetonide, a suspension of steroids, into the middle ear is very effective for controlling eosinophilic inflammation. It is very important to explain to patients with EOM that the disease may last for a long period and that progressive and sudden hearing loss may occur.

The deafness of Ludwig van Beethoven: an immunopathy.

OBJECTIVE: To analyze and discuss the deafness of Ludwig van Beethoven (1770-1827) and to offer a logical theory for its etiology. METHOD: The study will carefully review the composer's symptoms as described in his letters to friends and acquaintances and also will review a large body of source material, particularly publications by his contemporaries, some of which were generously loaned by Beethoven-Haus, Bonn, Germany, where necessary translations were made directly from the original German. We will also study publications on Inflammatory Bowel Disease (IBD) and its associated extraintestinal manifestations and personal discussions with experienced gastroenterologists. RESULTS: Beethoven's abdominal symptoms that began in his teens are highly suggestive of IBD, which we believe to be a correct diagnosis. IBD is an umbrella term that includes a number of named entities such as ulcerative colitis and Crohn's Disease. IBD is now considered to be a problem of immune regulation with extra intestinal manifestations that include sensorineural hearing loss and primary sclerosing cholangitis (PSC). PSC eventually causes cirrhosis and failure of the liver. A diagnosis of IBD therefore provides a single entity that explains most of the composer's symptoms and was finally the cause of his death. Our conclusion is that Beethoven's sensorineural hearing loss was an immunopathy associated with IBD.

Low affinity antibody to rubella antigen in patients after rubella infection in utero.

As a measure of the affinity of antirubella antibody, the resistance of the antibody to elution was used by increasing concentration of ammonium thiocyanate. The term affinity index has been used to define the molarity of thiocyanate which leads to a reduction of 50% of the initial density. The serum from a group of patients with intrauterine rubella was compared with the serum from a group of deaf children, some of whom could have rubella, and a group of controls with antibody following natural infection. The results show that the affinity index of patients with rubella is significantly lower than that of controls. The other deaf patients span the range of indices of the rubella and control groups suggesting that a number of those children could have deafness caused by intrauterine rubella.

Sudden hearing loss following infectious mononucleosis: possible effect of altered immunoregulation.

Sudden, permanent hearing loss developed in three young patients. In an attempt to determine a viral etiology, their humoral and cell-mediated responses to a panel of seven viruses linked to deafness and altered immunity were measured. Although a specific viral cause was not determined, a mild Epstein-Barr virus infection was documented for each patient. It had preceded their hearing loss onset by 1 to 4 months. Evidence of altered cell-mediated responses to Epstein-Barr virus antigens was found in each patient. It is proposed that, in certain susceptible individuals, a temporary cellular immunosuppression, which accompanies normal recovery from Epstein-Barr virus infection, may provide an opportunity for a viral invasion of, or a latent viral reactivation in, the inner ear. This invasion or reactivation leads to deafness.

Persistently altered T cell immunity in high school students with the congenital rubella syndrome and profound hearing loss.

Because there are frequent progressive and autoimmune complications in children born with the congenital rubella syndrome, we evaluated immunoregulation in eight profoundly deaf adolescents with congenital rubella syndrome who lived in a state school. Serum antiviral antibodies, expressions of peripheral lymphocyte epitopes and serum soluble interleukin 2 receptor (IL-2R) content were compared with those of 16 classmates with profound hearing loss of unknown cause and of 24 age-matched, hearing students from this area. Both deaf groups showed activated but impaired T lymphocyte function compared with normals. Rubella virus alteration of T cell function was suggested in congenital rubella syndrome students by elevated numbers of both CD4+ helper and CD25+ IL-2R cells with unusually low released soluble IL-2R content. In contrast in deaf classmates elevated CD25+ and CD16+ natural killer cell groups and soluble IL-2R content with low numbers of CD4+ helper cells and CD4+ populations were of unknown etiology. Defective immunoregulation of the congenitally deaf to pathogens inherent in their environment may lead to autoimmune and other complications.

Circadian elevation of IL-6 levels in Muckle-Wells syndrome: a disorder of the neuro-immune axis?

Muckle-Wells syndrome (MWS) is a rare autosomal dominant hereditary disorder characterized by chronic recurrent urticaria, arthralgia, sensorineural deafness, and in some cases nephropathy due to amyloidosis (AA type). We report a 21-year-old woman and her father, both suffering from this syndrome, in whom elevated serum levels of IL-6 could be documented during the flares of urticaria, and discuss the relevance of this finding for MWS.

Melatonin induces hyporeactivity caused by type II collagen in peripheral blood lymphocytes from patients with autoimmune hearing losses.

We have studied the behavior of peripheral blood lymphocytes in healthy controls and in patients with various hearing losses. These hearing losses were of an autoimmune origin in which type II collagen and melatonin were either present or absent, activated or not with concanavalin A (Con A). In patients with autoimmune hearing losses, the results showed lymphocytes that displayed hyporeactivity to type II collagen in terms of their proliferative activity in the presence of Con A. The hyporeactivity is specially relevant in those cells which are melatonin incubated. When different nosologic entities were studied, we observed similar lymphocyte hyporeactivity to type II collagen in bilateral sensorineural hearing loss, Ménière's disease and otosclerosis. We conclude that in the lymphocytes of patients with autoimmune hearing losses, there is hyporeactivity to type II collagen when compared to the hyporeactivity of lymphocytes in control groups. This hyporeactivity is revealed when the lymphocytes are activated in the presence of melatonin.

Immunologic aspects of otologic disease: an overview.

The immunologic explosion has now reached the field of otology. By having better techniques to measure the changes at cellular and molecular levels, it is now possible to devise experiments to show morphologic anatomic changes as well as functional changes. The demonstration in 1980 (M.S.) that tympanosclerosis could be induced immunologically represents a concrete advancement in immunologic thinking in conceptualization of otologic disease. In 1974, one of the authors (M.S.) published work dealing with the treatment of vasculitis of immunologic origin for sudden hearing loss. This was aimed at inhibiting the complement cascade from starting its destructive action. Recently, the immunologic challenge in animals demonstrated by changes in the inner ear was shown by one of the authors (T.J.Y.). Such changes were compatible with labyrinthine hydrops, or Meniere's disease, otosclerosis, and sensorineural hearing loss and vestibular dysfunction.

Autoimmune deafness is not related to hyperreactivity to type II collagen.

The pathogenic role of anti-type II collagen was analysed in a variety of hearing losses, in age-matched controls and in different autoimmune diseases. The immune reactivity of peripheral blood lymphocytes to type II collagen was studied by the degree of proliferation measured as the incorporation of bromodeoxyuridine in cultured lymphocytes. The anti-type II collagen antibodies showed a very low incidence in the hearing loss group. Lymphocytes of otosclerosis, Meniere's disease and other sensorineural deafness patients proliferated in response to concanavalin A and to type II collagen to a lower extent than peripheral blood lymphocytes from healthy controls. Nonetheless, these differences were not statistically significant. The immune hyperreactivity to type II collagen cannot explain the autoimmune mechanism of hearing losses. Humoral and cellular hyperreactivities to inner ear proteins different from type II collagen, could explain the autoimmune mechanism of deafness.

Cogan's Syndrome. High resolution MRI indicators of activity.

In the chronic-relapsing form of Cogan's syndrome, it can be difficult to evaluate the activity of the disease. In contrast to the initial stage, routine diagnostic techniques sometimes fail to indicate progression in the chronic stage. To determine whether high-resolution magnetic resonance imaging (HR-MRI) can be used to differentiate between active and inactive stages, we examined three patients with Cogan's syndrome (one during an acute relapse, two with chronic audiovestibular deficits), all of whom had antibodies to inner ear tissue (cochlea, vestibular labyrinth). Unenhanced T1-, T2, gadolinium-enhanced T1-weighted, and three-dimensional constructive interference in steady stage (CISS) images were used. Abnormal MRI signals of the inner ear were related to the activity of the disease. The patient studied during an acute exacerbation showed abnormal MRI signals in the vestibule, semicircular canals, vestibular nerve, and cochlea, which disappeared after the relapse. These abnormalities included high signal in the membranous labyrinth, the vestibule, and cochlea, with enhancement on T1-weighted images, indicating gadolinium leakage through the abnormal labyrinthine membrane into the perilymphatic spaces. In contrast, the other two patients with chronic audiovestibular deficits but no clinical signs of an acute relapse, had narrowing or occlusion of semicircular canals of the cochlea on the 3D-CISS images, but no high signal lesions (T1) and no enhancement. We conclude that sequential gadolinium-enhanced MRI can identify the active stage of Cogan's syndrome. The combination of HR-MRI and antibodies to inner ear antigens are helpful in the diagnosis of acute, sequential, bilateral audiovestibular impairment of autoimmune origin.

[Sudden deafness and cytomegaly virus infection (author's transl)]. / Hörsturz bei Zytomegalievirusinfektion

A 49-year old patient complained of sudden deafness in his right ear. With the exception of a rising titre level of the complement-fixing antibodies there were no positive findings for the cytomegaly virus. However, the eight-fold rise in the titre level after a latent period made it appear likely that the sudden deafness was caused by a cytomegaly virus infection. This assumption was also supported by the lack of vestibular symptoms, which, according to literature, is quite frequent in virus diseases of the inner ear. The usual therapy led to an improvement in the patient's hearing, which was also accompanied by a drop in the titre level of the antibodies. No prognosis can be made, since similar observations have not yet been recorded.

Immunological and virological study of sudden deafness.

Thirty-three patients with sudden deafness and 11 controls were selected from the patients admitted to the Department of Otolaryngology, Tokai University Hospital from November 1990 to October 1991. Viral titers were measured for mumps, adenovirus, rubella, measles, herpes simplex virus (HSV), varicella zoster virus (VZV), rhinosyncytial virus, cytomegalo-virus (CMV), and mycoplasma pneumoniae in 33 sudden deafness patients and 11 controls at a 2-week interval. In 20 of 33 sudden deafness patients and 5 of 11 controls, autoantibodies of rheumatoid factor (RF), anti-mitochondrial antibody (AMA), anti-nuclear antibody (ANA), anti-parietal cell antibody (APA), anti-smooth muscle antibody (ASA), and anti-type II collagen antibody were studied. Viral titer study did not reveal any significant change either in the patients or in the controls, whereas autoantibody study revealed a relatively high incidence for ASA in the patients as compared with the controls. The relatively high incidence for ASA suggests that immune-mediated processes may be involved in the etiology of sudden deafness.

Autoimmune sensorineural deafness: case report.

Rapidly progressive binaural sensorineural deafness responding to steroid therapy has recently been recognised. Clinical and laboratory findings indicate an autoimmune aetiology. The scant literature is discussed, and a case report presented. The importance of this entity is stressed because of the beneficial effects of therapy.

[Primary sclerosing cholangitis and autoimmune cochlear deafness: a new syndrome?]. / Cholangite sclérosante primitive et surdité endocochléaire auto-immune: nouveau syndrome?

Association of autoimmune cochlear hearing loss with primary sclerosing cholangitis is reported in two patients. Endocochlear sensorineural hearing loss was associated with the presence of anti-cochlear antibodies in the serum directed against the walls of vessels in the stria vascularis. The hearing loss appeared at the same time or shortly after the diagnosis of cholangitis. This association, which has never been described, may reinforce the theory of the role of immunologic factors in the pathogenesis of primary sclerosing cholangitis, possibly linked to or initiated by vasculitis.

Immune complex-associated deafness: preliminary communication.

During the last year patients presenting with progressive bilateral or sudden sensorineural deafness of unknown aetiology have been investigated for possible abnormal immune activity. Twenty-six cases are reported in which significantly raised circulating immune complexes were present, together with 2 cases of clinical autoimmune deafness where the complexes were normal. Thirty-six control subjects were also studied. Following a review of the clinical features, the pathogenesis of this new association with sensorineural deafness is discussed. In some cases the aetiology is probably autoimmune, and in others related to infection. In certain patients the deafness has been partly reversed by medical treatment with systemic steroids or plasma exchange. It is hypothesized that circulating immune complexes may reflect a previously unrecognized final common pathophysiological pathway in a variety of cochleovestibular disorders.

In search of the aetiology of deafness in Nigeria--the probable role of rubella infection.

The present study attempts to establish a relationship between maternal rubella and congenital deafness in Nigeria. For the purpose of the survey, the immunological status with respect to rubella infection of 179 healthy but deaf school children (study group) and 248 school children with normal hearing (control group) was determined. The serological technique employed was the haemagglutination inhibition (HI) test. The percentage of immunized persons ranged from 48.6 to 74.2% in the study group and 55.3 to 68.3% in the control group. Furthermore, the HI antibody titres for the study group were not significantly different from those of the control group although both groups were found to exhibit low HI antibody titres. The presence of low titres of HI antibodies in both groups and the absence of any significant correlation between the state of hearing and HI antibody levels seem to indicate that intrauterine rubella is not an important cause of congenital deafness in Nigeria.