Recovery of Otoacoustic Emission Function in Luetic Endolymphatic Hydrops: A Possible Measure of Improvement in Cochlear Function

Syphilis is a preventable and curable multi-organ disease caused by Treponema pallidum that may also affect the inner ear. First reported in 1887 by Adam Politzer, luetic endolymphatic hydrops (LEH) is a treatable complication of syphilis which causes a potentially reversible sensorineural hearing loss. Symptoms of LEH include fluctuating hearing loss (often low frequency), tinnitus, and vertigo. Though audiometric parameters have been examined in patients with otosyphilis, few studies have examined the use of otoacoustic emissions (OAEs) as a tool to measure improvement in cochlear function. Here we report an improvement in hearing loss, speech discrimination, and OAEs following treatment of LEH

Histamine H(3) receptor integrates peripheral inflammatory signals in the neurogenic control of immune responses and autoimmune disease susceptibility.

Histamine H(3) receptor (Hrh3/H(3)R) is primarily expressed by neurons in the central nervous system (CNS) where it functions as a presynaptic inhibitory autoreceptor and heteroreceptor. Previously, we identified an H(3)R-mediated central component in susceptibility to experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS), related to neurogenic control of blood brain barrier permeability and peripheral T cell effector responses. Furthermore, we identified Hrh3 as a positional candidate for the EAE susceptibility locus Eae8. Here, we characterize Hrh3 polymorphisms between EAE-susceptible and resistant SJL and B10.S mice, respectively, and show that Hrh3 isoform expression in the CNS is differentially regulated by acute peripheral inflammatory stimuli in an allele-specific fashion. Next, we show that Hrh3 is not expressed in any subpopulations of the immune compartment, and that secondary lymphoid tissue is anatomically poised to be regulated by central H(3)R signaling. Accordingly, using transcriptome analysis, we show that, inflammatory stimuli elicit unique transcriptional profiles in the lymph nodes of H(3)RKO mice compared to WT mice, which is indicative of negative regulation of peripheral immune responses by central H(3)R signaling. These results further support a functional link between the neurogenic control of T cell responses and susceptibility to CNS autoimmune disease coincident with acute and/or chronic peripheral inflammation. Pharmacological targeting of H(3)R may therefore be useful in preventing the development and formation of new lesions in MS, thereby limiting disease progression

Differential <i>Hrh3</i> isoform expression in B10.S and SJL mice in response to peripheral inflammatory stimuli.

<p>(<b>A</b>) <i>Hrh3a</i> expression in the forebrain of B10.S and SJL mice (n = 20), as determined by qRT-PCR (see Materials and Methods), either untreated, or D1 and D10 post-treatment. (<b>B</b>) <i>Hrh3c</i> expression in the forebrain of B10.S and SJL mice, untreated, or D1 and D10 post-treatment. Data were analyzed by two-way ANOVA for effect of treatment and strain.</p

Predicted effects on inflammatory response function in H₃RKO vs. WT LN after CFA+PTX treatment.

<p>Molecules differentially expressed in the pathway with the highest Z-score in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062743#pone-0062743-t004" target="_blank">Table 4</a>, showing gene expression changes for individual molecules and the predicted impact on the associated annotated function (inflammatory response).</p

Genes differentially expressed in WT vs. H₃RKO LN after CFA treatment.

<p>Gene expression was determined by microarray analysis. The criterion for differential expression was set at p<0.05 and signed fold change >2. Fold change indicates the change in expression in H₃RKO LN relative to WT.</p

<i>Hrh3</i> isoform expression is influenced primarily by strain.

<p>Expression levels were determined by real time PCR using mRNA isolated from perfused forebrains on D1 (A) and (C) and D10 (B) and (D) post-injection with either CFA, PTX, CFA+PTX or PLP_139–151+CFA+PTX, as described in Materials in Methods (n = 4–8). Data were analyzed by two-way ANOVA for effect of treatment and strain.</p

Murine <i>Hrh3</i> demonstrates a single nucleotide polymorphism.

<p>(<b>A</b>) Sequence alignment of <i>Hrh3</i> alleles from B10.S and SJL mice, and rat. <i>Hrh3</i> cDNAs from the B10.S and SJL mice were amplified, subcloned, and sequenced, as described in the Materials and Methods. (<b>B</b>) The strain distribution of the SNP at position 293 in <i>Hrh3</i>. The presence of the SNP in the indicated strains of mice was determined using restriction typing, as described in the Materials and Methods.</p

Genes differentially expressed in WT vs. H₃RKO LN after CFA+PTX treatment.

<p>Gene expression was determined by microarray analysis. The criterion for differential expression was set at p<0.05 and signed fold change >2. Fold change indicates the change in expression in H₃RKO LN relative to WT.</p