You may have heard of the blood-brain barrier, how about the blood-nucleus pulposus barrier?

immune senstive border

Intervertebral Disc Degeneration

IVD (Intervertebral Disc) is the biggest avascular structure in the human body. Intervertebral discs consist of 3 parts known as the NP (Nucleus Pulposus), AF (Annulus Fibrosus), and CEP (Cartilaginous endplate (CEP). The nucleus is the center surrounded by the annulus and finally has two end plates.

The IVD structure is unique and isolates the nucleus from the immune system. It also inhibits cytokine filtration and immune cell effects. Due to this, the intervertebral disc is considered an immune-privileged organ and aids in the balanced homeostasis of the organ. 

The CEP and AF combined are known as BNB (blood-nucleus pulposus barrier) that protects the nucleus. If the blood-nucleus pulposus barrier is damaged, the barrier is compromised, which leads to complications and disc degeneration. Diseases arising from barrier damage include hernia, sciatica, and nucleus regression. 

A better understanding of IVD function and immune privilege can aid the discovery of better treatments for symptomatic disc diseases. The mechanism of IVD is still not fully understood even though several studies to find out more about the IVD privilege have already been conducted.1

What Is IVD Degeneration?

IVD degeneration is a major cause of disc degeneration, leading to disability, chronic/acute pain, and psychological issues. Current treatment methods include surgery and conservative treatment. New treatment methods, like cell translation, genetic modification, and biomaterials application, have proven beneficial. 

The bad news is that the pathology of disc degeneration is still not completely understood. An intervertebral disc between the vertebrae is necessary for spinal support, flexibility, and durability. The nucleus of the IVD is gel-like due to several proteoglycan-collagen clusters embedded together. This cell structure is also known as the ECM (Extracellular Matrix). 

The composition of the nucleus is the reason behind auto-immune chain reactions when the host is suffering from disc degeneration. This led the IVD to be referred to as the immune privilege organ.

This function of the IVD has been observed several times, and the status was awarded to the organ as it is essential for normal function and disc homeostasis. However, there have been zero past studies that clarify the function of IVD in great depth.

How does the IVD develop?

IVD Development 

Developing vertebrae have embryonic tissue in their center, known as the notochord and sclerotome. The sclerotome surrounds the notochord to form the annulus and vertebrae. The notochordal expands into the future area where the nucleus will be formed. Later, it is compressed to form a dense ring of sclerotome connective tissue. In its early stages, the notochordal forms the nucleus, which grows rapidly in its later stages and the sclerotome forms the annulus with ECF that is full of glycoproteins and various collagens.

While the above formation is occurring, endochondral bone tissue formation and chondrocyte differentiation start to happen in the vertebral structure. At this stage, high levels of BMP (Bone Morphogenetic Protein) activity occur. With the bony structure in place, hyaline cartilage next to the intervertebral disc forms the CEP at the ends.

During its infancy, the nucleus of the IVD is a huge vacuolated notochordal cell cluster with tiny chondrocyte cells. In the later stages, the notochordal cells vanish, and the nucleus transforms into a notochordal form with small chondrocyte tissue. Disc degeneration is known to occur when the notochordal cells disappear. Note that the nucleus has been isolated from the immune system since the beginning.

What Is The BNB?

BNB (Blood-nucleus pulposus barrier) allows the IVD to be considered an immune privileged organ. It forms a protective barrier and is  known as a region that accepts foreign tissue grafting and implants to allows it to stay in the human body for a long period.

The body can reject implants, but studies on the eye, brain, testis and pregnant uterus have been conducted as these also act as barriers between the external and internal tissues. However, the NP mechanism and its isolation are still pretty undefined.

What Have Studies On The IVD Shown?

Research conducted has helped deduce the following:

  • The BNB prevents immune mediators and immunocytes from entering the NP tissue inside an IVD.
  • The blood-NP barrier is a complex formation of molecules.
  • The BNB comprises the AF and CEP.
  • The annulus has several collagen layers with proteoglycans that resist pressure and tensile stress from being placed on the nucleus.
  • The cartilage layer is around 0.5 mm to 1 mm thick and contains collagens, ECM, and chondrocytes. The CEP protects the nucleus and the bone.
  • Great physical pressure and high proteoglycan levels stop the growth of blood vessels, which leads to immunocyte filtration.
  • The FasL (Fas ligand) is an important constituent of immune privilege organs in the nucleus tissue.
  • A healthy annulus has substances that inhibit VEGF (vascular endothelial growth factor) tumor, cell angiogenesis, (TNF)-α (necrosis factor), (IL)-1β (interleukin), C-C motif (chemokine), and (CCL2/MCP-1) ligand 2.
  • Notochordal cells exhibit a protective effect by stopping endothelial invasion and VEGF tumor formation.

blood-nucleus pulposus barrier model

Study Findings On Notochordal Cells

The notochordal cells in the IVD were found to contain glycosaminoglycans that stop neurite formation and balance neuronal viability, according to one study. Another study did not find any anti-neurogenic/anti-angiogenic effects in notochordal cells.

Authors have derived that these differences were found due to different life stages of the specimens, cell culture conditions, and animal breeds. However, evidence is still very limited, and IVD being an immune-privileged organ, still requires extensive research. It is also believed that miRNAs and exosomes might inhibit immune cells. 

Auto-Immune Response Of The Nucleus Pulposus

Disc degeneration and blood-NP damage, including tears and fissures, are known to change the CEP and AF pathology. Annulus damage leads to blood vessel ingrowth that further channels an auto-immune response. Studies conducted in the 1960s have proven that radicular pain due to disc hernia arises from the nucleus being exposed to chemicals released in an auto-immune trigger.

Macrophages and monocytes are present in extruded disc material which are released due to a disc’s autoimmune reaction. IgGs were identified against collagen type I, II, and V in degenerated disc samples that show inflammation and can vary due to cell culture and degeneration degrees.

Are All IVD Degenerations A Result Of Blood-Nucleus Pulposus Barrier (BNB) Failure?

No, not all disc degeneration is a result of blood-nucleus pulposus failure. Annulus tearing can cause abnormalities in mechanical distribution, nucleus leakage, and even ingrown nerves.

Endplate micro-fractures due to EP calcification in aging or trauma can cause the nucleus to get exposed to the blood supply. Disc herniation is a major reason behind radicular pain, and research has also shown that random regression may happen due to an auto-immune response.


The immune privilege state is essential for normal IVD function and homeostasis. The blood-nucleus pulposus barrier is a complex structure comprising the nucleus and annulus that limits the infiltration of immune system chemicals and cells.

Blood-NP breakdown leads to an IVD auto-immune reaction and often leads to disc degeneration. IVD studies are limited, and discovering the function of underlying mechanisms, IVD breakdown, and structure is still needed.

Dynamic Disc Designs

At ddd, we create models demonstrating disc dynamics to educate the patients on the principles of how a disc protrusion can differ from a disc extrusion and disc bulge. These different types of disc pathologies can make a difference in how care is structured. For example, the immune system can identify an extruded disc that exposes the nucleus pulposus. At the same time, a protrusion is not so well recognized and may be trickier to treat and absorb. Having a patient understand the difference sets up realistic expectations for low back care. Explore.