Innervation of the Skin

fingertip skin biopsy

Fingertip skin biopsy

Full width confocal microscopy1 image of a punch skin biopsy from the fingertip by double immunofluorescence labelling for a) the pan-axonal marker PGP9.5 (red fibers) to visualize small unmyelinated nerve fibers within (white arrow) and below (pink arrow) the epidermis, as well as within myelin sheaths (yellow arrow); and for b) the compact-myelin marker MBP (green fibers) to detect myelinated nerves (yellow arrow). Also visible are Meissner's corpuscles (blue arrow) in the dermal papillae, the basement membrane (white arrowhead) between the epidermis and dermis below, and spiral-like sweat ducts (green arrow) to the surface of the skin.
myelinated nerves

Myelinated dermal nerve fibers (Click for 3-D video)

Myelinated and unmyelinated axons of nerve cells in a 60 μm thick section of a skin punch biopsy. Axons are detected by immunofluorescence staining for the axonal marker, PGP9.5 (red). The myelin sheath around some axons is visualized by co-staining for myelin basic protein, MBP (green). Examples of nodes of Ranvier (arrows) and branching myelinated axons (arrowheads) are shown.
meissners corpuscle

Meissner's corpuscle (Click for 3-D video)

Meissner's corpuscle in a 60 μm thick section of a human skin punch biopsy from the fingertip. Meissner's corpuscles are located in the dermal papillae beneath the epidermis and detect light touch. They are innervated by 1 or more myelinated nerve axons which become unmyelinated within the corpuscle, as well as by other unmyelinated axons. The axons are detected by immunofluorescence staining for the axonal marker, PGP9.5 (red) and the myelin sheath by co-staining for myelin basic protein, MBP (green).

The skin provides a barrier that protects the body from pathogens, mediates sensations, and helps maintain the body's internal environment. Its functions are subserved by specialized structures or receptors that are connected to the spinal cord and brain via the peripheral nerves. Damage to the peripheral nerves can disrupt the skin's normal functions.

The skin consists of 3 layers; the outer layer or epidermis, a middle layer called the dermis that is separated from the epidermis by the basal lamina, and a third layer called the subcutaneous tissue. Specialized organs in the skin, including Merkel cells, Meissner's corpuscles and Pacinian corpuscles, are stimulated by touch, pressure or vibration. Free nerve endings in the epidermis can detect painful stimuli or temperature changes. Sweat glands help maintain temperature, hydration, and salt concentrations.

Nerve processes, or axons, may be myelinated (ie, covered by a myelin sheath that provides insulation) or remain unmyelinated. Both types of fibers course their way through the subcutaneous tissue into the dermis, but all nerve endings that reach into the epidermis are unmyelinated, including those which are unmyelinated extensions of myelinated fibers below the epidermis. The intraepidermal nerve fiber density (IENFD) is determined by counting the number of small, unmyelinated nerve fibers that cross the basal lamina from the dermis to the epidermis. Reduction of the IENFD is often an early sign of peripheral neuropathy.

There is ongoing research into pathological changes in the skin that are associated with neuropathy. The number of Meissner's corpuscles has been reported to be reduced in several different types of neuropathy (Dyck et al 1966, Saporta et al 2009), and NT3, a neurotrophic peptide, was reported to increase the number of Merkel cells in diabetic mice (Christianson et al, 2007). Innervation of sweat glands has also been reported to be decreased in conditions such as Friedreich's ataxia and diabetic neuropathy (Nolano et al 2001, Gibbons et al 2009).

Specific ultrastructural and immunocytochemical findings have also been described in skin of patients with particular types of neuropathy. In addition to the characteristic changes seen in vasculitis or amyloidosis, abnormalities of myelin have been reported in Charcot-Marie-Tooth disease type I (CMT-I) or chronic inflammatory demyelinating polyneuropathy (CIDP) (Saporta et al, 2009), and IgM deposits on myelin sheaths have been described in anti-MAG neuropathy (Lombardi et al 2005). Accumulation of lipids in lysosomes is characteristic of Fabry disease (Askari et al, 2007), intracellular bodies that contain alpha synuclein are seen in Lewy body disease (Shishido et al, 2010), and granular accumulations of mutated Notch-3 protein in blood vessels is diagnostic of CADASIL (Ishiko et al, 2006).

These are all areas of active investigation. Increasingly, skin biopsy analyses promises to be a valuable technique to aid in the diagnosis of neuropathy and help elucidate the underlying pathophysiology.

1All images and videos of immunofluorescence labeled biopsy tissue shown on this site were obtained with the Olympus Fluoview FV10i confocal laser scanning microscope.

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