This evidence suggests that the human
This evidence suggests that the human cochlea is equipped with antigen presenting macrophages as well as T lymphocytes that execute cytotoxic and immune mediation function. In an animal study, following acoustic overstimulation, Yang et al. (2015) found infiltration of macrophages into the region of the basilar membrane that displayed an increased expression of MHCII, and infiltration of CD4+ T cells into the same region. It is assumed that if out of normal range, the immune response could cause autoimmune injuries. Based on a study on cochlin-triggered autoimmune hearing loss (Solares et al., 2004; Baruah, 2014), T lymphocytes can be the cells responsible for autoimmune hearing loss (AIHL), because grafting of the peptide-activated T cells led to reduction in ABR. Among the potential autoimmune Azaserine that could induce hearing loss, collagen II and myelin basic protein have been thoroughly investigated in human cochleae (Liu et al., 2012, 2015). These two substances exist in human cochleae in a rather large quantity. Claudin-11 might be another important inner ear component that, after certain interaction with immune cells, could lead to autoimmune hearing loss. Claudin-11, also known as oligodendrocyte-specific protein (OSP/claudin-11) and a transmembrane protein intense in central nervous system myelin, is implicated as an autoantigen in the development of autoimmune demyelinating disease (Bronstein et al., 2000). Recent study shows an involvement of Claudin-11 in disruption of blood-brain, blood-spinal cord, and blood-arachnoid barriers in multiple sclerosis (Uchida et al., 2018), an immune-mediated disorder of the central nervous system. In the human cochlea, Claudin-11 forms a massive tight junction barrier between the type I fibrocytes of the spiral ligament, adjacent laterally to the stria vascularis (Liu et al., 2017); macrophages as well as CD4+/CD8+ lymphocytes were hardly seen between the type I fibrocytes in the human cochleae. This characteristic might be related to maintenance of the tight junction or/and prevention from autoimmunity. In other locations of the human cochleae, these two types of immune cells appeared not consistent in number indicating a diverse function of macrophages vs. lymphocytes in the cochlear tissues considered to be from normal hearing cochleae. Tissue lymphocytes and the circulating ones may exchange. Our study has demonstrated a remarkable organization of immune cells and their interaction in the cochlear tissue. T cells in the human cochlear tissue may include T memory cells that remember each specific pathogen encountered, and are able to mount a strong and rapid response if the same pathogen is detected again. In the study by Souter et al. (2012), when systemically increasing the immune reactivity by using Keyhole hemocyanin, the inner ear immunoreaction was enhanced. This was reflected in increased inflammatory activity after insertion of an electrode array into the cochlea, and the over-active inflammation led to hearing decline. The chemokine fractalkine (CX3CL1) was found in both inner and outer hair cells, as well as in the spiral ganglion neurons in human cochleae in our previous and present studies (Liu et al., 2018, Fig. 3). Its receptor CX3CR1 was seen in the macrophages among human spiral ganglion neurons (Fig. 3). This chemokine and its receptor in human cochleae as seen in our study lay the bases for interaction between macrophages and other important cell types (Kaur et al., 2015). Cluster of differentiation molecule 11B (CD11b) is one protein subunit that forms the heterodimeric integrin alpha-M beta-2 (αMβ2) molecule. AlphaMβ2 is expressed on the surface of many leukocytes involved in the innate immunity, such as macrophages and natural killer cells (Solovjov et al., 2005). It mediates inflammation by regulating cell adhesion and migration and has been implicated in several immune processes such as phagocytosis, cell-mediated cytotoxicity and chemotaxis (Solovjov et al., 2005). CD11b, IBA1, and MHCII are frequently used as markers for macrophages and microglia (Frick et al., 2013). However, human cochleae seemed to lack microglia since the markers for microglia, TMEM119 and P2Y12, were negative in human cochleae (detailed data not shown here). TMEM119 is a cell-surface protein and a specific microglial marker in humans. TMEM119 is not expressed by macrophages or other immune or neural cell types. P2Y12 was expressed in parenchymal microglia of the human brain but absent in perivascular or meningeal macrophages (Mildner et al., 2017).