The capsule of human Meissner corpuscles: immunohistochemical evidence

Meissner corpuscles are cutaneous mechanoreceptors that are usually located in the dermal papillae of human glabrous skin. Structurally, these sensory corpuscles consist of a mechanoreceptive sensory neuron surrounded by non-myelinating lamellar Schwann-like cells. Some authors have described a partially developed fibroblastic capsule of endoneurial or perineurial origin around Meissner corpuscles; however, others have noted that these structures are non-encapsulated. As there is continuity between the periaxonic cells forming the sensory corpuscles and the cells of the nerve trunks, we used immunohistochemistry to examine the expression of endoneurial (CD34 antigen) or perineurial [Glucose transporter 1 (Glut1)] markers in human cutaneous Meissner corpuscles. We also investigated the immunohistochemical patterns of nestin and vimentin (the main intermediate filaments of the cytoskeleton of endoneurial and perineurial cells, respectively) in Meissner corpuscles. The most important finding from this study was that CD34-positive cells formed a partial/complete capsule of endoneurial origin around most Meissner corpuscles, without signs of other perineurial Glut1-positive elements. However, the cytoskeletal proteins of the capsular CD34-positive cells did not include either nestin or vimentin, so the cytoskeletal composition of these cells remains to be established. Finally, the intensity of the immunoreactivity for CD34 in the capsule decreased with ageing, sometimes becoming completely absent in the oldest individuals. In conclusion, we report the first immunohistochemical evidence of the capsule of Meissner corpuscles in humans and demonstrate the endoneurial origin of the capsule.     

Heparan sulfate in human cutaneous Meissner's and Pacinian corpuscles

Heparan sulfate proteoglycans are pericellular/cell surface molecules involved in somatosensory axon guidance in the peripheral nervous system. However, the distribution of heparan sulfate proteoglycans in the extracellular matrix of human cutaneous sensory corpuscles is unknown. Immunohistochemistry and immunofluorescence assays were performed to define the localization of heparan sulfate proteoglycans in human cutaneous Meissner's and Pacinian corpuscles using two anti-heparan sulfate antibodies together with anti-S100 protein, anti-PGP9.5, anti-CD34 (to immunolabel basement membranes, Schwann cells, axon and the intermediate endoneurial layer of Pacinian corpuscles, respectively), anti-Type IV collagen, and anti-chondroitin sulfate antibodies. Heparan sulfate proteoglycans were colocalized with Type IV collagen in Meissner's corpuscles and were located in the outer core lamellae and capsule, but not in the inner core or the intermediate layer, in Pacinian corpuscles. Chondroitin sulfate was observed in the intermediate layer of Pacinian corpuscles but was never colocalized with heparan sulfate proteoglycans. The present results strongly suggest that heparan sulfate proteoglycans are associated with the basement membranes of the lamellar cells in Meissner's corpuscles and with the complex outer core capsule in Pacinian corpuscles. The functional significance of these results, if any, remains to be elucidated.     

Myelin basic protein-positive nerve fibres in human Meissner corpuscles

Myelinated nerve fibres forming sensory corpuscles become amyelinic before entering the corpuscle. Interestingly, in Meissner corpuscles from monkey myelin basic protein (MBP), a specific component of myelin sheath co-localized with neuronal markers. To investigate whether or not this also occurs in human digital Meissner corpuscles, we used single and double immunohistochemistry to detect MBP associated with axonic (protein gene product (PGP) 9.5) or Schwann and Schwann-related cell (S100 protein) markers. We also studied these markers in Pacinian corpuscles. Nerve fibres immunoreactive for MBP were detected in about 25% of the Meissner corpuscles examined; however, MBP never co-localized with PGP 9.5 and MBP occasionally co-localized with S100 protein. MBP-immunoreactive fibres associated with Meissner corpuscles were observed at the periphery of the lamellar cells or within the corpuscle between the lamellar cells. These results describe the distribution of myelinated nerve fibres expressing MBP in human Meissner corpuscles, which is important when studying Meissner corpuscles in cutaneous biopsies used for the diagnosis of peripheral and degenerative neuropathies.     

Merkel cells and Meissner's corpuscles in human digital skin display Piezo2 immunoreactivity

The transformation of mechanical energy into electrical signals is the first step in mechanotransduction in the peripheral sensory nervous system and relies on the presence of mechanically gated ion channels within specialized sensory organs called mechanoreceptors. Piezo2 is a vertebrate stretch‐gated ion channel necessary for mechanosensitive channels in mammalian cells. Functionally, it is related to light touch, which has been detected in murine cutaneous Merkel cell–neurite complexes, Meissner‐like corpuscles and lanceolate nerve endings. To the best of our knowledge, the occurrence of Piezo2 in human cutaneous mechanoreceptors has never been investigated. Here, we used simple and double immunohistochemistry to investigate the occurrence of Piezo2 in human digital glabrous skin. Piezo2 immunoreactivity was detected in approximately 80% of morphologically and immunohistochemically characterized (cytokeratin 20⁺, chromogranin A⁺ and synaptophisin⁺) Merkel cells. Most of them were in close contact with Piezo2⁻ nerve fibre profiles. Moreover, the axon, but not the lamellar cells, of Meissner's corpuscles was also Piezo2⁺, but other mechanoreceptors, i.e. Pacinian or Ruffini's corpuscles, were devoid of immunoreactivity. Piezo2 was also observed in non‐nervous tissue, especially the basal keratinocytes, endothelial cells and sweat glands. The present results demonstrate the occurrence of Piezo2 in cutaneous sensory nerve formations that functionally work as slowly adapting (Merkel cells) and rapidly adapting (Meissner's corpuscles) low‐threshold mechanoreceptors and are related to fine and discriminative touch but not to vibration or hard touch. These data offer additional insight into the molecular basis of mechanosensing in humans.     

Comparative analysis of Meissner's corpuscles in the fingertips of primates

Meissner's corpuscles (MCs) are tactile mechanoreceptors found in the glabrous skin of primates, including fingertips. These receptors are characterized by sensitivity to light touch, and therefore might be associated with the evolution of manipulative abilities of the hands in primates. We examined MCs in different primate species, including common marmoset (Callithrix jacchus, n = 5), baboon (Papio anubis, n = 2), rhesus macaque (Macaca mulatta, n = 3), chimpanzee (Pan troglodytes, n = 3), bonobo (Pan paniscus, n = 1) and human (Homo sapiens, n = 8). Fingertips of the first, second and fourth digits were collected from both hands of specimens, dissected and histologically stained using hematoxylin and eosin. The density (MCs per 1 mm²) and the size (cross‐sectional diameter of MCs) were quantified. Overall, there were no differences in the densities of MCs or their size among the digits or between the hands for any species examined. However, MCs varied across species. We found a trend for higher densities of MCs in macaques and humans compared with chimpanzees and bonobos; moreover, apes had larger MCs than monkeys. We further examined whether the density or size of MCs varied as a function of body mass, measures of dexterity and dietary frugivory. Among these variables, only body size accounted for a significant amount of variation in the size of MCs.     

Sensory innervation of the human palmar aponeurosis in healthy individuals and patients with palmar fibromatosis

The human palmar aponeurosis is involved in hand proprioception, and it contains different sensory corpuscle morphotypes that serve this role. In palmar fibromatosis (classically referred to as Dupuytren''s disease), the palmar aponeurosis undergoes fibrous structural changes that, presumably, also affect the nervous system, causing altered perception. We analysed the various sensory nerve formation morphotypes in the palmar aponeuroses of healthy subjects and patients with palmar fibromatosis. To do this, we used immunohistochemistry for corpuscular constituents and the putative mechanoproteins PIEZO2 and acid‐sensing ion channel 2. Free nerve endings and Golgi‐Mazzoni, Ruffini, paciniform and Pacinian corpuscles were identified in both the healthy and the pathological conditions. The densities of the free nerve endings and Golgi‐Mazzoni corpuscles were slightly increased in the pathological tissues. Furthermore, the Pacinian corpuscles were enlarged and displayed an altered shape. Finally, there was also morphological and immunohistochemical evidence of occasional denervation of the Pacinian corpuscles, although no increase in their number was observed. Both PIEZO2 and acid‐sensing ion channel 2 were absent from the altered corpuscles. These results indicate that the human palmar aponeurosis is richly innervated, and the free nerve endings and sensory corpuscles within the palmar aponeurosis undergo quantitative and qualitative changes in patients with palmar fibromatosis, which may explain the sensory alterations occasionally reported for this pathology.     

包皮中人乳头瘤病毒基因的检测

了解人乳头瘤病毒（HPV）在正常包皮中的感染及感染型别，来分析HPV与阴茎癌的发生关系。采用PCR技术对48例包皮环切患者的包皮组织进行HPV感染相关性研究及分型。20／48例HPV阳性，阳性率为41．7％，其中HPV11、16、18型阳性率分别8．3％（4／48）、12．8％（6／48）、22．9％（11／48），未见HPV6型。包皮垢或包皮炎患者也有HPV11、16、18型感染。正常包皮中有HPVDNA存在且多为高危型，并伴有包皮垢或既往包皮炎等局部理化刺激因子，为HPV感染与阴茎癌的发生有密切关系提供了佐证。     

Glans clitoris innervation: PIEZO2 and sexual mechanosensitivity

The clitoris is a leading player in female sexual arousal, if not the main protagonist. Despite this role, studies performed on this structure with specific neuroanatomical techniques are few. This study focuses on glans clitoris innervation, with special emphasis on sensory corpuscles and the presence of the mechanotransducer protein PIEZO2 in these structures. Six glans clitoris samples were obtained at autopsy covering an age spectrum between 52 and 83 years old. Several types of nerve terminations including free nerve endings, genital endbulbs as well as Meissner-like corpuscles and Pacinian corpuscles, but not Ruffini corpuscles, were found. Although corpuscular morphology in the glans clitoris was subtly different from the cutaneous digital counterparts, their basic composition was comparable for both Pacinian and Meissner-like corpuscles. Genital endbulbs showed heterogeneous morphology, and the axons usually exhibited a typical “wool ball” or “yarn ball” aspect. Some of them were lobulated and variably encapsulated by endoneurial elements (65%); from the capsule originate septa that divides the genital endbulbs, suggesting that they are found in clusters rather than as single corpuscles. In addition, most corpuscles in the glans clitoris showed axonal PIEZO2 immunoreactivity, thus, suggesting a mechanical role and molecular mechanisms of mechanosensibility similar to those of digital Meissner's corpuscles. Our results demonstrate that sensory corpuscles of the glans clitoris are similar to those of other glabrous skin zones, as most genital organs are characterized by clusters of corpuscles and the occurrence of the mechanoprotein PIEZO2 in the axons. These findings strongly suggest that PIEZO2 participates in erotic and sexual mechanical sensing.     

Immunohistochemical localization of acid-sensing ion channel 2 (ASIC2) in cutaneous Meissner and Pacinian corpuscles of Macaca fascicularis

Acid-sensing ion channel 2 (ASIC2) is a member of the degenerin/epithelial sodium channel superfamily, presumably involved mechanosensation. Expression of ASIC2 has been detected in mechanosensory neurons as well as in both axons and Schwann-like cells of cutaneous mechanoreceptors. In these studies we analysed expression of ASIC2 in the cutaneous sensory corpuscles of Macaca fascicularis using immunohistochemistry and laser confocal-scanner microscopy. ASIC2 immunoreactivity was detected in both Meissner and Pacinian corpuscles. It was found to co-localize with neuron-specific enolase and RT-97, but not with S100 protein, demonstrating that ASIC2 expression is restricted to axons supplying mechanoreceptors. These results demonstrate for the first time the presence of the protein ASIC2 in cutaneous rapidly adapting low-threshold mechanoreceptors of monkey, suggesting a role of this ion channel in touch sense.     

Immunolocalization of the mitogen-activated protein kinase signaling pathway in Hassall's corpuscles of the human thymus

In the present study, we investigated the immunohistochemical localization of mitogen-activated protein kinase (MAPK) signaling pathway in the human thymus. Three members of MAPK, the extracellular signal-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK) and the p38 kinase, showed differential expression patterns in the thymus medulla. The phosphorylated form of ERK (p-ERK) was abundantly present in the outer layer of Hassall's corpuscles, and the phosphorylated form of p38 kinase (p-p38 kinase) was present in the entire Hassall's corpuscles. The phosphorylated form of JNK (p-JNK) was expressed in medullary thymocytes. We also examined localization of MAPK kinases (MAPKK or MEK) which specifically activate MAPK. MEK1, an activator of ERK, was found in the outer layer of Hassall's corpuscles where p-ERK was expressed. MEK3, an activator of p38 kinase, was also expressed in the outer layer. MEK4 and MEK7, which are activators of JNK, were present in the entire Hassall's corpuscles. Thus, differential expression of MAPK in the thymus supports the concept that the MAPK signaling pathway controls the specificity of functional thymic responses to extracellular stimuli. Furthermore, the abundant expression of various elements of the pathway in Hassall's corpuscles suggests that the pathway is involved in thymic medullary epithelial maturation.     

Immunohistochemical characteristics of human paraganglion cells and sensory corpuscles associated with the urinary bladder. A developmental study in the male fetus, neonate and infant

Triple label immunohistochemistry was used to study the coexistence of the catecholamine-synthesising enzymes dopamine beta-hydroxylase (DBH) and tyrosine hydroxylase (TH) and several neuropeptides including neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), somatostatin (SOM) and galanin (GAL) as well as nitric oxide synthase (NOS) in developing pelvic paraganglion cells in a series of human male fetal, neonatal and infant specimens ranging in age from 13 wk of gestation to 3 y postnatal. 13–20 wk old fetal specimens possessed large clusters of paraganglion cells lying lateral to the urinary bladder and prostate gland which were intensely DBH-immunoreactive (-IR) but lacked TH, NOS and the neuropeptides investigated. With increasing fetal age small clusters of paraganglion cells were observed in the muscle coat of the urinary bladder. At 23 wk of gestation occasional paraganglion cells were NOS or NPY-IR while at 26 wk of gestation the majority of paraganglion cells were TH-IR and a few were SOM or GAL-IR. Some postnatal paraganglia within the bladder musculature contained cells which were all VIP, SP or CGRP-IR while others displayed coexistence of NOS and NPY, SP and CGRP, or NPY and VIP. The presence of NOS in certain paraganglion cells indicates their capacity to generate nitric oxide (NO). These results show that human paraganglion cells develop different phenotypes possibly dependent upon their location within the bladder wall. A delicate plexus of branching varicose nerves was observed in the fetal paraganglia which increased in density with increasing gestational age. The majority of these nerves were VIP-IR while others were CGRP, SP, NPY, NOS or GAL-IR. The presence of nerve terminals adjacent to the paraganglion cells implies a neural influence on the functional activity of the paraganglia. Some paraganglia in the late fetal and early postnatal specimens contained Timofeew's sensory corpuscles, resembling pacinian corpuscles in their morphology. The central nerve fibre of these corpuscles displayed immunoreactivity for SP, CGRP and NOS, the latter indicating a possible role for NO in afferent transmission from the urinary bladder. In addition, a few corpuscles were penetrated by a noradrenergic nerve fibre immunoreactive for NPY and TH, which may have a modulatory role on the sensory receptor.     

男子不育症相关的Y染色体基因组学

由于Y染色体存在性别决定基因和精子发生相关基因,男子不育相关的Y染色体基因组学逐步形成,对男子不育症有了全新的诠释。研究发现:缺乏基因重组的Y染色体不但不会逐渐丢失其重要基因,更不会逐渐消亡,而且也处于不断进化中;人类Y染色体有独特的短串重复序列-微卫星DNA和中度Alu家族重复序列,可能与男子不育症的发生有关;Y染色体上约有107个基因列在基因库,在MSY区域约有156个转录单位,其中78个编码蛋白质有27个蛋白质家族已被确认,11个蛋白质仅在睾丸组织中表达,与调节精子的发生相关;Y染色体所特有的基因不但调节着睾丸的生精功能,可能对前列腺、大脑等人体组织器官也有重要作用。     

The ultrastructure of sensory nerve endings in the human knee joint capsule

Summary The ultrastructure of sensory nerve endings in the human knee joint capsule was studied. Three types of nerve endings were found: free nerve endings (FNE), Ruffini corpuscles and Pacini corpuscles.In the joint capsule, FNE are located below the synovial layer and within the fibrous layer near blood vessels. These nerve terminals derive from myelinated A-fibres or from unmyelinated C-fibres. Their structure is almost identical to FNE in human hairy and non-hairy skin.Ruffini corpuscles are present within the fibrous layer and the ligaments of the capsule in three variations: small Ruffini corpuscles without a capsule, small with a connective tissue capsule, and large Ruffini corpuscles with an incomplete perineural capsule. Their afferent axons are myelinated and measure 3–5 m in diameter. Inside the corpuscle, nerve terminals are anchored in the connective tissue belonging to the fibrous layer or to the ligaments respectively. The presence of an incomplete perineural capsule depends on the structure of the surrounding connective tissue. In ligaments with collagenous fibrils oriented in a parallel fashion, the perineural capsule is well-developed and the Ruffini corpuscle resembles a Golgi tendon organ; in areas where the fibrils show no predominant orientation, Ruffini corpuscles lack a capsule.Small Pacini corpuscles are situated within the fibrous layer near the capsular insertion at the meniscus articularis or at the periost. They consist of one or several inner cores and a perineural capsule of 1–2 layers. Larger Pacini corpuscles with one or several inner cores and a perineural capsule consisting of 20–30 layers are found on the outer surface of the fibrous layer.The ultrastructure of these nerve endings is compared with the ultrastructure of articular receptors of various animals and with the ultrastructure of sensory nerve endings in the skin of several mammalian species including man.Supported by the Verein zur Förderung der Erforschung und Bekämpfung rheumatischer Krankheiten e.V. in Bad Bramstedt andby the Deutsche Forschungsgemeinschaft (Sch 587/1-4)     

Nerve growth factor receptor immunoreactivity in Meissner and Pacinian corpuscles of the human digital skin

The presence of nerve growth factor receptors (NGFr) in sensory nerve corpuscles of human digital skin, primarily Meissner and Pacinian corpuscles, was investigated immunohistochemically using two monoclonal antibodies directed against human-NGFr. To ensure the localization of NGFr immunoreactivity (IR) alternative sections to that processed for NGFr detection were assayed for neurofilament protein (NFP) and S-100 protein which selectively label the axon and the periaxonic specialized cells (lamellar cells of Meissner's corpuscles; inner-core cells of Pacinian corpuscles), respectively. Occurrence of NGFr IR was observed in both types of sensory corpuscles. In Meissner's corpuscles NGFr-IR was found in the lamellar cells, whereas in the Pacinian corpuscles the lamellae of the inner core, outer core, and capsule displayed NGFr IR. Moreover, a positive IR was observed in the central axon of some Pacinian corpuscles. However, remarkable differences were encountered among Pacinian corpuscles in the pattern of NGFr IR distribution. Present results demonstrate puscles in the pattern of NGFr IR distribution. Present results demonstrate the presence of NGFr IR in sensory nerve corpuscles of the human digital skin, suggesting that NGFr could be involved in the concentration of NGF and in the conveying of this molecule from the cutaneous sources to the cell body of NGF-dependent primary sensory neurons. However, the mechanisms involved in this process remain to be clarified. © 1993 Wiley-Liss, Inc.     

Localization of CuZn-superoxide dismutase in the human male genital organs.

We performed an immunohistochemical analysis using a polyclonal antibody to determine the localization of CuZn-superoxide dismutase (SOD), a scavenger of superoxide anion radicals, in the human male genital organs. In the testis, intense immunoreactivity of CuZn-SOD was shown in both the cytoplasm and nucleus of the spermatogonia of the seminiferous tubules. Spermatocytes, further differentiated germ cells and Sertoli cells showed no or weak immunoreactivity. In the ductus epididymis, the principal cells showed no or weak immunoreactivity except for the stereocilial region, while the basal cells showed relatively intense immunoreactivity. In the ductus deferens, the prostate and the seminal vesicles, columnar and cuboidal epithelia showed CuZn-SOD immunoreactivity. The immunoreactivity was more intense in the epithelia of the ductus deferens than in the prostate or the seminal vesicles. Basal cells in the prostate also showed intense immunoreactivity. Collectively, the present immunohistochemical results suggest that CuZn-SOD in the male genital organs is localized where it could play an important role in cell differentiation, including spermatogenesis. The CuZn-SOD could also play a role in local defence mechanisms against tissue damage mediated through superoxide anion radicals, as well as in providing SOD to the seminal plasma.     

Immunohistochemical Detection of the Putative Mechanoproteins ASIC2 and TRPV4 in Avian Herbst Sensory Corpuscles

The avian Herbst corpuscles are the equivalent of the Pacinian corpuscles in mammals, and detect vibration and the movement of joints and feathers. Therefore, they can be regarded as rapidly adapting low‐threshold mechanoreceptors. In recent years, it has been establish that some ion channels are involved in mechanosensation and are present in both mechanosensory neurons and mechanoreceptors. Here we have used immunohistochemistry to localize some putative mechanoproteins in the Herbst corpuscles from the rictus of Columba livia. The proteins investigated were the subunits of the epithelial Na⁺ channel (ENaC), the transient‐receptor potential vanilloid 4 (TRPV4), and the acid‐sensing ion channel 2 (ASIC2). Immunoreactivity for ENaC subunits was never found in Herbst corpuscles, while the axon expressed ASIC2 and TRPV4 immunoreactivity. Moreover, TRPV4 was also detected in the cell forming the inner core. The present results demonstrate for the first time the occurrence of mechanoproteins in avian low‐threshold mechanoreceptors and provide further evidence for a possible role of the ion channels in mechanosensation. Anat Rec, 2013. © 2012 Wiley Periodicals, Inc.     

S100α and S100β proteins in human cutaneous sensory corpuscles: Effects of nerve and spinal cord injury

S100 protein in the vertebrate peripheral nervous system consists of homo- or heterodimers of S100α and S100β proteins, the first predominating in neurons and the second in glial cells. Recently, however, occurrence of S100β protein in neurons has been reported. The expression of S100 protein by Schwann cells, as well as their derivatives in sensory corpuscles, depends on the sensory axon (i.e., the Schwann cell–axon contact). The present study analyzed the distribution of S100α and S100β proteins in human cutaneous sensory corpuscles and the effects of peripheral or central sensory axon severance in the expression of these proteins. Simple or double immunohistochemistry was carried out using a panel of antibodies against S100α, S100β or S100α+β proteins, and the sections were examined by light or laser confocal scanning microscopy. Skin samples were obtained from normal subjects and patients with spinal cord injury, nerve entrapment, and nerve sections plus graft. The lamellar cells of Meissner corpuscles as well as the inner-core lamellae of the Pacinian corpuscles displayed strong immunoreactivity (IR) for all antigens examined, the most intense labeling being obtained for S100β protein. The pattern of immunostaining was unchanged after spinal cord injury, whereas the number of stained corpuscles as well as the intensity of IR for each antigen decreased in cutaneous sensory corpuscles after nerve injury, both entrapment and section plus graft. No evidence was found of axonal labeling. The present results provide evidence that Schwann-related cells in human cutaneous sensory corpuscles contain both S100α and S100β and that the expression of these proteins is dependent on the functional and structural integrity of sensory fibers. Anat. Rec. 251:351–359, 1998. © 1998 Wiley-Liss, Inc.     

The highly conserved NANOS2 protein: testis-specific expression and significance for the human male reproduction

The highly conserved Nanos gene was found to encode a translationalrepressor necessary for germ-cell development in lower organisms.The mammalian homologue, Nanos2, was recently found to be expressedin the mouse germ cells. Since its disruption caused infertilityexclusively in males, we sought to study the significance ofthis gene in human male reproduction. Here, we describe forthe first time the expression pattern of the NANOS2 gene inhuman tissues and show that it is testis specific. We foundthat NANOS2 protein is present in prenatal germ cells and atlater stages in spermatogenesis. To elucidate the role of NANOS2in human germ-line development, we screened this gene for mutationsin 214 males with isolated sterility and spermatogenic abnormalities.We identified two heterozygous variants, each in a differentoligospermic patient, the second allele being the wild-type.The influence of the first variant, a missense mutation H68Qon the sterility phenotype, was not obvious since it was accompaniedby a microdeletion within the AZF region of the Y chromosome.The second variant contained a silent mutation, H109H. Althoughboth mutations were situated within the most conserved RNA-bindingdomain and were absent in 400 fertile males, it is not obviousthat they cause male infertility.