Surrounding the nerve bundle is a sheath of unique connective tissue cells that constitutes the perineurium. The perineurium serves as a metabolically active diffusion barrier that contributes to the formation of a blood–nerve barrier. This barrier maintains the ionic milieu of the ensheathed nerve fibers. In a manner similar to the properties exhibited by the endothelial cells of brain capillaries forming the blood–brain barrier (see page 385), perineurial cells possess receptors, transporters, and enzymes that provide for the active transport of substances across perineurial cells. The perineurium may be one or more cell layers thick, depending on the nerve diameter. The cells that compose this layer are squamous; each layer exhibits an external (basal) lamina on both surfaces (Fig. 12.23b and Plate 27, page 390). The cells are contractile and contain an appreciable number of actin filaments, a characteristic of smooth muscle cells and other contractile cells. Moreover, when there are two or more perineurial cell layers (as many as five of six layers may be present in larger nerves), collagen fibrils are present between the perineurial cell layers, but fibroblasts are absent. Tight junctions provide the basis for the blood–nerve barrier and are present between the cells located within the same layer of the perineurium. In effect, the arrangement of these cells as a barrier—the presence of tight junctions and external (basal) lamina material—liken them to an epithelioid tissue. On the other hand, their contractile nature and their apparent ability to produce collagen fibrils also liken them to smooth muscle cells and fibroblasts.
The limited number of connective tissue cell types within the endoneurium (page 375) undoubtedly reflects the protective role that the perineurium plays. Typical immune system cells (i.e., lymphocytes, plasma cells) are not found within the endoneurial and perineurial compartments. This absence of immune cells (other than the mast cells and macrophages) is accounted for by the protective barrier created by the perineurial cells. Typically only  fibroblasts, a small number of resident macrophages, and occasional mast cells are present within the nerve  compartment.
Epine.urium consists of dense irregular connective tissue that surrounds and binds nerve fascicles into a common bundle.