A Mixture of Five Bacterial Strains Attenuates Skin Inflammation in Mice.

BACKGROUND: There is a growing interest in the effects of probiotics for the prevention and treatment of skin diseases due to their immunomodulatory and antiinflammatory properties. OBJECTIVE: To assess a mixture of five bacterial strains in the prevention of chronic skin inflammation in mice. METHODS: Hairless SKH-1 mice received daily oral treatment with the probiotic mixture at the dose of 1x109 Colony-Forming Unit (CFU)/day (or vehicle) for three weeks. Chronic skin inflammation was induced by repeated applications of 12-O-tetradecanoylphorbol-13- acetate (TPA; control mice received acetone). Macroscopic and microscopic evaluations of skin lesions were performed and serum levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, IL-17, IL-22, IL-10 and IL-4 measured at the end of the study. RESULTS: Treatment with the probiotic mixture significantly limited the induced chronic skin inflammation at both the macroscopic and microscopic levels. This limitation was consistent with downregulated levels of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, IL- 17 and IL-22) and up-regulated levels of the anti-inflammatory cytokines, IL-10 and IL-4. CONCLUSION: The results suggest that the probiotic mixture tested could help in preserving skin integrity and homeostasis and that its use could be beneficial in dermatological conditions such as atopic dermatitis and psoriasis.

Lactobacillus salivarius LA307 and Lactobacillus rhamnosus LA305 attenuate skin inflammation in mice.

Oral probiotics potential for the management of dermatological diseases is vast. However, results of available studies in skin diseases, such as atopic dermatitis (AD), are inconsistent, partly because probiotic effects are strain specific. Careful selection of probiotic strains is therefore indispensable to ensure efficacy of treatment. In this study, Lactobacillus salivarius LA307, Lactobacillus rhamnosus LA305 and Bifidobacterium bifidum PI22, three strains that were previously identified for their interesting immunomodulatory properties in allergy and/or colitis models, were assessed in the prevention of chronic skin inflammation induced by repeated applications of 12-O-tetradecanoylphorbol-13-acetate in hairless SKH-1 mice. Macroscopic and microscopic evaluation of skin lesions was performed together with measurements of serum levels of interleukin (IL)-1ß, IL-6, tumour necrosis factor alpha (TNF-α), IL-17, IL-22, IL-10 and IL-4. Daily oral treatment with the three strains at the dose of 1×109 cfu/day for 3 weeks limited the development of chronic skin inflammation, the effects being strain dependent. Indeed the two Lactobacillus strains significantly limited the intensity of skin inflammation both at the macroscopic and microscopic levels. Macroscopic observations were correlated to the histological observations and the resulting microscopic score. This limitation of the development of AD-like skin lesions involved the modulation of cytokine production. Treatment with the two Lactobacillus strains induced a decrease in the serum levels of pro-inflammatory cytokines IL-1ß, IL-6, TNF-α, IL-17, IL-22 and at the opposite an increase in the production of the anti-inflammatory cytokine IL-10 and also of IL-4. Globally, B. bifidum PI22 had lower benefits. These results obtained in mice suggest that L. salivarius LA307 and L. rhamnosus LA305 could be good candidates for preserving skin integrity and homeostasis via the modulation of the gut microbiota and that their use could be beneficial in dermatological conditions such as AD.

Genetic, cytogenetic and physical refinement of the autosomal recessive CMT linked to 5q31-q33: exclusion of candidate genes including EGR1.

Charcot-Marie-Tooth disease is an heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked and autosomal recessive. By homozygosity mapping, we have identified, in the 5q23-q33 region, a third locus responsible for an autosomal recessive form of demyelinating CMT. Haplotype reconstruction and determination of the minimal region of homozygosity restricted the candidate region to a 4 cM interval. A physical map of the candidate region was established by screening YACs for microsatellites used for genetic analysis. Combined genetic, cytogenetic and physical mapping restricted the locus to a less than 2 Mb interval on chromosome 5q32. Seventeen consanguineous families with demyelinating ARCMT of various origins were screened for linkage to 5q31-q33. Three of these seventeen families are probably linked to this locus, indicating that the 5q locus accounts for about 20% of demyelinating ARCMT. Several candidate genes in the region were excluded by their position on the contig and/or by sequence analysis. The most obvious candidate gene, EGR1, expressed specifically in Schwann cells, mapped outside of the candidate region and no base changes were detected in two families by sequencing of the entire coding sequence.

A clinical, electrophysiologic, neuropathologic, and genetic study of two large Algerian families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease.

The hereditary sensory and motor neuropathies form a clinically heterogenous group of disorders, the most frequent of which is Charcot-Marie-Tooth disease (CMT). The autosomal dominant forms of CMT are well characterized, but the nosology of autosomal recessive CMT is still controversial. We report two large consanguineous Algerian families with an autosomal recessive demyelinating CMT and similar clinical manifestations. The clinical, electrophysiologic, and neuropathologic features resemble those of autosomal dominant CMT1, but the early onset and rapid progression of deformities are specific. We excluded by linkage analysis the three loci CMT1A (17p11.2), CMT1B (1q22-23), and CMT4A (8q11-21.1) responsible for demyelinating forms of CMT. These findings suggest a subtype of autosomal recessive neuropathy, the locus of which is undetermined.

Autosomal recessive hereditary neuropathy with focally folded myelin sheaths and linked to chromosome 11q23: a distinct and homogeneous entity.

We describe a six generation Saudi kindred, with a recessive hereditary motor and sensory neuropathy (HMSN). Four individuals were affected including two children (a boy and a girl) and a 23-year-old man. The fourth (a female) died at the age of 14 years. Onset of the disease was early (< 2 years) and the clinical and neurophysiological features were, generally, quite similar to those of an Italian family linked to chromosome 11q23. The peculiar pathologic pattern was irregular and redundant loops associated with folding of the myelin sheaths. The genetic study confirmed linkage to chromosome 11q23 and refined the location of the gene between D11S1311 and D11S917, a 3.3 cM region. These findings support the existence of a homogeneous and distinct entity within the form of HMSN associated with focally folded myelin sheaths.

Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked, and autosomal recessive (AR) CMT. A locus responsible for the demyelinating form of ARCMT was assigned to the 5q23-q33 region (CMT4C) by homozygosity mapping. Recently, 11 mutations were identified in the SH3TC2 (KIAA1985) gene in 12 families with demyelinating ARCMT from Turkish, Iranian, Greek, Italian, or German origin. OBJECTIVE: To identify mutations in the SH3TC2 gene. METHODS: The authors searched for SH3TC2 gene mutations in 10 consanguineous CMT families putatively linked to the CMT4C locus on the basis of haplotype segregation and linkage analysis. RESULTS: Ten families had mutations, eight of which were new and one, R954X, recurrent. Six of the 10 mutations were in exon 11. Onset occurred between ages 2 and 10. Scoliosis or kyphoscoliosis and foot deformities were found in almost all patients and were often inaugural. The median motor nerve conduction velocity values (

The human neuregulin-2 (NRG2) gene: cloning, mapping and evaluation as a candidate for the autosomal recessive form of Charcot-Marie-Tooth disease linked to 5q.

Neuregulin-2 (NRG2) is a novel member of the neuregulin family of growth and differentiation factors. Through interaction with the ErbB family of receptors, neuregulin-2 induces the growth and differentiation of epithelial, neuronal, glial and other types of cells. In this study, we have cloned the human neuregulin-2 gene, and determined its genomic structure and alternative splicing patterns. By using radiation hybrid mapping panels, the human NRG2 gene was mapped to the D5S658-D5S402 region within 5q23-q33, close to an autosomal recessive form of demyelinating Charcot-Marie-Tooth (CMT) disease. The NRG2 gene was found to be on two yeast artificial chromosomes overlapping the candidate interval and was, thus, considered a good positional candidate for this form of CMT. When the entire neuregulin-2 coding sequence and splice junctions were explored, however, no mutation was identified in one CMT family linked to 5q23-q33. In addition, three intronic single nucleotide polymorphisms were identified in the NRG2 gene. Genotyping in two families localized the NRG2 gene outside of the revised candidate interval between D5S402-D5S210 and excluded NRG2 as the gene responsible for this form of CMT disease.

Homozygosity mapping of an autosomal recessive form of demyelinating Charcot-Marie-Tooth disease to chromosome 5q23-q33.

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited peripheral motor and sensory neuropathy characterised by chronic distal weakness with progressive muscular atrophy and sensory loss of the distal extremities. The dominant form of the disease is genetically heterogeneous but only one locus has been identified on chromosome 8q13-q21.1 for autosomal recessive CMT. By homozygosity mapping in a large Algerian kindred, we have assigned a second locus for autosomal recessive CMT to chromosome 5q23-33. Linkage analysis demonstrated that the same locus is involved in a second Algerian family with a demyelinating CMT. Haplotype reconstruction and determination of the minimal region of homozygosity restricts the candidate region to a 4 cM interval.

A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies characterized by chronic distal weakness with progressive muscular atrophy and sensory loss in the distal extremities. Inheritance can be autosomal dominant, X-linked or autosomal recessive (ARCMT). Recently, a locus responsible for a demyelinating form of ARCMT disease, named CMT4F, has been mapped on 19q13 in a large consanguineous Lebanese family. L- and S-periaxin are proteins of myelinating Schwann cells and homozygous periaxin-null mice display extensive demyelination of myelinated fibers in the peripheral nervous system, which suggests that the periaxin gene is a good candidate gene for an ARCMT disease. The human gene encoding the periaxins (PRX) was mapped to 19q13, in the CMT4F candidate interval. After characterizing the human PRX gene, we identified a nonsense R196X mutation in the Lebanese family which cosegregated with CMT. Histopathological and immunohistochemical analysis of a sural nerve biopsy of one patient revealed common features with the mouse mutant and the absence of L-periaxin from the myelin sheath. These data confirm the importance of the periaxin proteins to normal Schwann cell function and substantiate the utility of the periaxin-null mouse as a model of ARCMT disease.