Immune cascades in human intervertebral disc: the pros and cons

Abstract

The unique structural hallmark of the intervertebral disc has made its central composition, the nucleus pulposus (NP), excluded from the immunologic tolerance. Consequently, the intervertebral disc is identified as an immune-privileged organ. Traditionally, local detrimental immune activities caused by NP at the lesion sites of the disc are noted as a significant factor contributing to disc degeneration. However, given the beneficial activities of immune cells in other immune-privileged sites on basis of current evidence, the degenerate disc might need the assistance of a subpopulation of immune cells to restore its structure and lessen inflammation. In addition, the beneficial impact of immune cells can be seen in the absorption of the herniated NP, which is an important factor causes the mechanical compression of nerve roots. Consequently, a modulated immune network in degenerate disc is essential for the restoration of this immune-privileged organ. Until now, the understandings of immune response in disc degeneration still rest on the harmful aspect. Further studies are needed to explore its beneficial influence. Accordingly, there are no absolutely the pros and cons in terms of immune reactions caused by NP.

Introduction

Intervertebral disc degeneration (IDD) is a significant cause of low back pain which accounts for not only greatly individual suffering, but global socioeconomic burden [1-3]. By leading to instability, IDD is also a trigger for a variety of spinal diseases and can cause secondary spinal deformity and spinal canal stenosis [4,5]. The intervertebral disc plays an important role in the support, durability, and flexibility of the spine. It is composed of three parts: the nucleus pulposus (NP), the annulus fibrosus (AF) and cartilaginous endplates. The central NP is surrounded by concentrically arranged collagen fibrils of the AF and sandwiched between two cartilaginous endplates adjoining the vertebra body [6]. Moreover, it is the largest avascular organ of the body. This unique structural hallmark has made the NP excluded from the development of immunologic tolerance and the intervertebral disc has been identified as an immune-privileged organ with no access to systemic circulation. Accumulating evidence indicates that herniated NP is capable of inducing a specific autoimmune response and plays a role in the pathophysiology of IDD [7-10]. However, studies addressing the immune reactions to NP are still in an early stage, mainly focusing on their detrimental aspect.

Intervertebral disc as an immune-privileged organ

Immune-privileged organs were operationally defined as sites in the body where foreign tissue grafts can survive for extended, often indefinite periods of time, whereas similar grafts placed at regular sites in the body are acutely rejected [11]. Well studied organs include the eye and the brain, as well as the pregnant uterus and testis. It is noteworthy that the intervertebral disc remains less explored [12,13]. These immune-privileged organs are immune-cell-forbidden sites maintained by specialized physical barriers and various molecular mechanisms. In the case of intervertebral disc, the blood-tissue barrier makes the central NP isolated from the immune system of the host, which includes the avascular collagen fibrils of the AF and the adjacent cartilaginous endplates. Meanwhile, FasL, which predominantly expresses in activated T lymphocytes and stromal cells of immune-privileged sites, has also been noted in normal NP cells and plays an important role in the maintenance of immune privilege of the NP [14-16]. As a type II membrane protein of 40 kDa, FasL belongs to the tumor necrosis factor family. Once binding to its receptor Fas, it will kill the infiltrating Fas-bearing immune cells within hours [17-19]. Several lines of evidence imply a decreasing expression of FasL in degenerate NP and indicate close relationship between disc degeneration and immune privilege destruction [20-23].

Traditionally, immune cascades caused by NP have long been renowned ever since its discovery. Local detrimental immune activities seen at the lesion site of the intervertebral disc is thought to be a significant factor contributing to disc degeneration [24,25]. During the pathological process of IDD, both the passive and active immune privilege barriers are damaged through various mechanisms [26]. Briefly, the tear of AF and the diminishing amounts of fibrocartilage expose the NP to the immune system. Once the NP extrudes from the AF to host circulation, the immune system recognizes it as a foreign body, which may induce the antigen capture. The autoimmune reactions proceed with activation of B cells with the production of auto-antibodies and T cells with cytotoxicity. On the other hand, the decreasing FasL expression weakens the NP cells’ ability to clear the invading Fas-positive activated cytotoxic T-lymphocytes (CTLs). Taken together, these mechanisms destroy the immune balance of the microenvironment of the disc. The multiple amplification of the downstream cascades from the immune system attract various specific and nonspecific immune cells to the region, together with the cytokines they secret, aggravate the condition, hinder the recovery and cause pain. Meanwhile, with an increasing expression of growth factors and inflammatory agents, neovascularization and neurogenesis occur in the autoimmune region [27,28]. These views have been well established that are supported by many lines of evidence. In fact, Anti-TNF therapy has been used as a treatment option for sciatica [29]. However, whether the immune reactions in IDD caused by NP are totally harmful still remains unknown.

Immune reactions in other immune-privileged organs

Inflammation is the body’s adaptive response to any mechanical, biochemical, or immune-mediated insult. However, it could be beneficial only under the circumstance that it ends in an active resolution [30]. Studies on injury healing out-side immune privilege organs indicate the distinct subpopulation of macrophages that infiltrate the site of wound and exhibit different functions corresponding to the changing needs of the tissue along with the course of healing [31-33]. Inflammation consists of the elimination of dead cells and tissue debris at the first stage, and the secretion of anti-inflammatory cytokines and growth factors at the later stage [34]. This physiological process can aid tissue regeneration and finally lead to restoration of immune homeostasis [35,36].

Indeed, in other immune-privileged organs, a subset of monocyte-derived macrophages can exert an immune-resolving function. They are crucial for the resolution of inflammation following sterile insults in models of spinal cord injury and retinal glutamate intoxication [37,38]. These macrophages are essential for healing on the basis of the measure by a functional motor scale after spinal cord injury and the cell survival in the retina. Despite these organs are classified as immune privilege sites, they benefit from the regulated recruitment of innate immune cells from the outside circulation to assist in their healing.

Beneficial aspects of modulated immune cascades on the intervertebral disc

When it comes to the case of the intervertebral disc, harmful factors such as hyper-physiological loading or overload, low nutrition and oxygen, contribute to an increased number and extent of clefts and tears of the intervertebral disc [3,39,40]. These micro lesions might expose antigenic substances of the NP to the immune system and cause an initial immune response. Similar to the aforementioned immune-privileged organs, these wounds might need the assistance of a subpopulation of immune cells to restore structure and reduce inflammation. Although the relevant infiltration of massive inflammatory cells, growth factors and cytokines might be harmful and aggravate the degeneration, at least some groups of immune cells might be beneficial to the regrowth of the intervertebral disc wounds and the immune privilege maintenance in the early stage. The involved immune cells with various phenotypes and function could be necessary factors in the elimination of cell debris as well as the secretion of anti-inflammatory cytokines. Peng et al noted abundant macrophages and mast cells in the granulation tissue zones of painful discs and indicated the key roles in the repair of the injured AF and subsequent disc degeneration [41]. In an experimental study in pig, Geiss et al found a subpopulation of immune cells were elevated in subcutaneous NP chambers [42] These cells include activated T cells (CD4, CD8 and CD45RC) as well as activated B cells expressing immunoglobulin kappa (Ig). Moreover, Murai et al reported natural killer (NK) cells and macrophages may have an immunological function in the early phase of disc herniation [9]. Consequently, a controlled immune reaction involved by some specific immune cells might be helpful (Figure 1).

Figure 1.

Schematic summary demonstrates immune cascades in human intervertebral disc. Immune reaction of the intervertebral disc is induced by the micro wound of the disc, which exposes the NP to the host immune system. Whereas the downstream of the inflammatory reactions can cause immune destruction, the beneficial aspects of immune cascades might play an important role in the restoration of disc immune balance. AF, annulus fibrosus; NP, nucleus pulposus.

On the other hand, while the other immune-privileged organs contain their own population of immune cells, there have been no studies addressing the resident immune cells in the intervertebral disc. Although phagocytic activity was observed in NP by a subset of cells [43], the mission of clearing dead cell and noxious substance may not be fulfilled without the assistance of extraneous immune cells. Meanwhile, as some inflammatory agents could be secreted by degenerate NP cells, the infiltrating blood-derived macrophages are essential for anti-inflammatory activities in IDD [44-46]. Therefore, we assumed that the infiltrating cells might fulfill specialized functions in the healing and anti-inflammatory process of the disc, which the local phagocytic-associated cells either fail to manifest at sufficient levels or at the right time.

In addition, the beneficial influence of immune cells can also be seen in the absorption of the herniated NP, which is an important factor contributing to the compression of nerve roots. Using a co-culture system of herniated lumbar disc specimens and peripheral blood mononuclear cells, Doita et al implicated immune cells, with enhanced production of matrix metalloproteinases, play an essential role in spontaneous regression of disc materials [47]. Ikeda et al investigated infiltrated cells consisting of macrophages and a small number of T cells, and proposed that extruded or sequestrated disc material has the potential to be absorbed by phagocytes [48]. Indeed, one of the initial purposes of inflammatory is to eliminate dead cells and tissue debris, which in the case of herniation absorption, exert a beneficial function in the nerve root decompression at least in some degree. However, the downstream inflammatory reactions of this uncontrolled process might lead to the detrimental effect, which is so notable that covers its primal impact.

Summary

Available evidence indicates that a modulated immune response in degenerate disc is essential for the recovery of this immune-privileged organ. A suitable time point, duration, and cell phenotype are vital in this restoration. Although the downstream amplified inflammatory reactions are detrimental, the immune response might be re-judged for their beneficial involvement. Accordingly, there are no absolutely the pros and cons in terms of immune reactions caused by NP. It is all a matter of their control and coordination. Actually, an acute autoimmune response caused by the NP tissue and the chronic immune related restoration, might be confused by current studies. Until now, the understandings of immune response in IDD still rest on the harmful aspect. Further studies are needed to explore its beneficial influence. In conclusion, comprehensive understandings of the immune reactions of NP will definitely deepen our knowledge in the immune aspects of IDD and laid a foundation for its treatment.

Conflicts of interest statement

The authors declare no competing financial interests.