Comparative analysis of macrophage migration inhibitory factors (MIFs) from the parasitic nematode Onchocerca volvulus and the free-living nematode Caenorhabditis elegans

The macrophage migration inhibitory factors (MIFs) from the filarial parasite Onchocerca volvulus (OvMIF) were compared to the MIFs from the free-living nematode Caenorhabditis elegans (CeMIF) with respect to molecular, biochemical and immunological properties. Except for CeMIF-4, all other MIFs demonstrated tautomerase activity. Surprisingly, OvMIF-1 displayed oxidoreductase activity. The strongest immunostaining for OvMIF-1 was observed in the outer cellular covering of the adult worm body, the syncytial hypodermis; moderate immunostaining was observed in the uterine wall. The generation of a strong humoral immune response towards OvMIF-1 and reduced reactivity to OvMIF-2 was indicated by high IgG levels in patients infected with O. volvulus and cows infected with the closely related Onchocerca ochengi, both MIFs revealing identical amino acid sequences. Using Litomosoides sigmodontis-infected mice, a laboratory model for filarial infection, MIFs derived from the tissue-dwelling O. volvulus, the rodent gut-dwelling Strongyloides ratti and from free-living C. elegans were recognized, suggesting that L. sigmodontis MIF-specific IgM and IgG1 were produced during L. sigmodontis infection of mice and cross-reacted with all MIF proteins tested. Thus, MIF apparently functions as a target of B cell response during nematode infection, but in the natural Onchocerca-specific human and bovine infection, the induced antibodies can discriminate between MIFs derived from parasitic or free-living nematodes.     

CD83 is a regulator of murine B cell function in vivo

The transmembrane glycoprotein CD83 has been described as a specific maturation marker for dendritic cells and several lines of evidence suggest that CD83 regulates thymic T cell maturation as well as peripheral T cell activation. Here we show for the first time that CD83 is involved also in the regulation of B cell function. CD83 is up-regulated on activated B cells in vivo, specifically in the draining lymph nodes of Leishmania major-infected mice. The ubiquitous transgenic (Tg) expression of CD83 interferes with Leishmania-specific T cell-dependent and with T cell-independent antibody production. This defect is restricted to the B cell population since the antigen-specific T cell response of CD83Tg mice to L. major infection is unchanged. The defective immunoglobulin (Ig) response is due to Tg expression of CD83 on the B cells because wild-type B cells display normal antigen-specific responses in CD83Tg hosts and CD83Tg B cells do not respond to immunization in a mixed wild-type/CD83Tg bone marrow chimera. Finally, the treatment of non-Tg C57BL/6 mice with anti-CD83 mAb induces a dramatic increase in the antigen-specific IgG response to immunization, thus demonstrating a regulatory role for naturally induced CD83 on wild-type B cells.     

Temporary threshold shift due to noise exposure in guinea pigs under emotional stress.

One of the factors which can affect the amount of temporary threshold shift (TTS) due to acoustic overstimulation is known to be the general metabolic state of the exposed subject. The present study was conducted to elucidate how preexisting intense emotional stress in awake guinea pigs could influence the TTS induced by exposure of 4 kHz at 120 dB SPL for 20 min. Considering the hypersympathetic activity in both 'stress' and 'noise' it was assumed that the two factors would act synergetically on the cochlear function. However, an unexpected result was obtained. The mean threshold for the stressed animals following noise exposure was significantly lower (better) than that of the controlled, sedated, guinea pigs.     

Basic metabolic rate in emotional stress: its potential influence on cochlear function

Using a model previously described, prolonged emotional stress was induced in guinea pigs. Under this condition, arterial blood gases, blood glucose level, PO2 and PCO2 in the expired air, and the heat irradiated by the animals were measured and compared to those of the anesthetized guinea pigs. From the present study, two important findings should be mentioned. First, the metabolic rate of the animals under stress was 30% higher than in the anesthetized group. Second, the arterial PO2 level of the animals under stress was significantly lower than that in the anesthetized ones. Evaluating the noxious effect of severe and/or prolonged emotional stress, one should not neglect the increased oxygen demand resulting from the high metabolic rate of the subject. This factor, together with the decreased arterial blood PO2 level, reinforce the hypoxic effects on the cochlear function, caused by the vasoconstriction of the labyrinthine vessels.     

Cochlear hypoxia and the compound action potentials

A relatively restricted area, including the ear, was perfused in guinea pigs with hypoxic blood having a pO2 of 10, 20, and 30 mm Hg, respectively. The changes induced to the cochlear action potentials were analyzed and the results compared with those obtained in a previous study in which the guinea pigs were rendered hypoxemic by ventilating them with air entrapped in a closed circuit from which the CO2 was continuously absorbed. The changes induced to the cochlear action potentials by both methods were very similar. However, while using the territorial model for inducing hypoxia, 75% of the animals showed a threshold shift at a blood pO2 of 20 mm Hg and with the general model all the animals showed a threshold shift at 25 mm Hg blood pO2. In other words, if the hypoxic condition affected the whole body, other factors such as a slight, but continuous tendency to acidosis with significant increase in blood lactic acid concentration could join the oxygen deficit in affecting cochlear function.     

Heat shock protein 60 is released in immune-mediated glomerulonephritis and aggravates disease: in vivo evidence for an immunologic danger signal

Heat shock proteins (Hsp) are ubiquitous intracellular proteins that can be released in various forms of cellular stress. Some Hsp, such as Hsp60, have been shown to stimulate directly T cell-mediated immune responses in vitro. Here, it is demonstrated that Hsp60 is released from the kidneys and excreted into the urine of mice with nephrotoxic nephritis (NTN), a model of rapidly progressive glomerulonephritis. For examining the functional relevance of Hsp60 release, this protein was injected into mice with subnephritogenic NTN, in which only transient proteinuria and minimal organ damage occur that do not progress to terminal kidney failure. Injection of Hsp60 strikingly aggravated disease, as evidenced by global glomerular necrosis, tubulointerstitial damage, and complete anuria after 10 to 12 d. This effect was mediated neither by endotoxin contaminations of Hsp60 nor by autologous antibodies. It was strictly T cell dependent but not associated with a systemic Th1/Th2 shift. Thus, Hsp60 is an endogenous mediator stimulating immune effector mechanisms that contribute to the progression of NTN. These findings demonstrate in vivo that Hsp60 fulfills criteria of immunologic danger signals and suggest that such signals may be involved in immune-mediated kidney disease.     

The R245X mutation of PCDH15 in Ashkenazi Jewish children diagnosed with nonsyndromic hearing loss foreshadows retinitis pigmentosa

Usher syndrome is a frequent cause of the combination of deafness and blindness due to retinitis pigmentosa (RP). Five genes are known to underlie different forms of Usher syndrome type I (USH1). In the Ashkenazi Jewish population, the R245X mutation of the PCDH15 gene may be the most common cause of USH1 (Ben-Yosef T, Ness SL, Madeo AC, Bar-Lev A, Wolfman JH, Ahmed ZM, Desnick RK, Willner JP, Avraham KB, Ostrer H, Oddoux C, Griffith AJ, Friedman TB N Engl J Med 348: 1664-1670, 2003). To estimate what percentage of Ashkenazi Jewish children born with profound hearing loss will develop RP due to R245X, we examined the prevalence of the R245X PCDH15 mutation and its carrier rate among Ashkenazi Jews in Israel. Among probands diagnosed with nonsyndromic hearing loss not due to mutations of connexin 26 (GJB2) and/or connexin 30 (GJB6), and below the age of 10, 2 of 20 (10%) were homozygous for the R245X mutation. Among older nonsyndromic deaf individuals, no homozygotes were detected, although one individual was heterozygous for R245X. The carrier rate of the R245X mutation among the normal hearing Ashkenazi population in Israel was estimated at 1%. Ashkenazi Jewish children with profound prelingual hearing loss should be evaluated for the R245X PCDH15 mutation and undergo ophthalmologic evaluation to determine whether they will develop RP. Rehabilitation can then begin before loss of vision. Early use of cochlear implants in such cases may rescue these individuals from a dual neurosensory deficit.     

Assessment of medial olivocochlear system function in pre-term and full-term newborns using a rapid test of transient otoacoustic emissions

This study was conducted to investigate maturation of the medial olivocochlear efferent system (MOCS) in pre- and full-term neonates using Quickscreen (Otodynamics Ltd) and to confirm previous findings on transient otoacoustic emission (TEOAE) suppression in neonates. MOCS maturation was investigated in 46 neonates born at the Chaim Sheba Medical Center, Tel Hashomer, Israel, using Quickscreen. All neonates were normal with no family history of general or auditory disease and no risk factors for hearing impairment. MOCS function appears gradually in human pre-term neonates and is considered to reach maturity shortly after term birth. The clinical value of MOCS testing in specific populations of newborns at risk for hearing and/or brainstem function can be legitimately raised as activation of the MOCS clearly alters cochlear output. The present results can be interpreted to support the testing of infants at risk of developing abnormal MOCS function using a commercially available rapid TEOAE measurement system.     

Reduced medial olivocochlear bundle system function in children with auditory processing disorders

A common complaint of children with auditory processing disorders (APD) is difficulty in understanding speech in the presence of background noise. Evidence from animal and human studies has suggested that the medial olivocochlear bundle (MOCB) may play a role in hearing in noise. The MOCB function can be evaluated by the suppression effect of the transient evoked otoacoustic emissions (TEOAE) in response to contralateral acoustic stimulation (CAS). The present study was conducted to investigate the suppression effect of TEOAE in APD children. The study groups comprised 15 APD children aged 8-13 years associated with learning disabilities and 15 controls matched for gender and age. The suppression effect of TEOAE was evaluated by comparing the TEOAE levels with and without CAS. A significantly reduced suppression effect of TEOAE was demonstrated in the APD group, when compared to the controls. In addition, higher TEOAE levels were found in the APD group, suggesting inherent reduced MOCB activity on the outer hair cells in APD children. These results imply that some APD children present low activity of the MOCB system, which may indicate a reduced auditory inhibitory function and affect their ability to hear in the presence of background noise.