Neuro-Behçet's disease: an update of clinical diagnosis, biomarkers, and immunopathogenesis

Abstract

Neuro-Behçet's disease (NBD) is a more severe but rare symptom of Behçet's disease, which is mainly divided into parenchymal NBD (p-NBD) involving brain stem, spinal cord, and cerebral cortex. Non-p-NBD manifests as intracranial aneurysm, cerebral venous thrombosis, peripheral nervous system injuries, and mixed parenchymal and non-parenchymal disease. p-NBD is pathologically characterized by perivasculitis presenting with cerebrospinal fluid (CSF) pleocytosis, elevated total protein, and central nervous system (CNS) infiltration of macrophages and neutrophils, which are subdivided into acute and chronic progressive stages according to relapsing-remitting courses and responses to steroids. The diagnosis of NBD depends heavily on clinical features and magnetic resonance imaging (MRI) findings. The lack of laboratory biomarkers has hindered standard diagnostics. CSF interleukin (IL)-6 is the most investigated dimension of NBD and correlates with NBD activity, therapeutic responses, and prognosis. Further investigations have focused on inflammatory biomarkers that reflect the activation of innate and adaptive immune responses. Higher levels of CSF migration inhibitory factor and immunosuppressive acidic protein indicated the activation of macrophages in the CNS; increased IL-17, IL-10, T-bet/GATA-3, and retinoic acid related orphan receptor (ROR)-γt/Foxp3 ratios, marking the disrupted scale of the Th1/Th2 and Th17/Treg axis; and elevated B-cell activating factor of the TNF family (BAFF) and IgA/IgM intrathecal synthesis, suggesting that B cells play a dominant role in NBD. CNS destruction and degeneration as a consequence of neuroinflammatory cascades were confirmed by elevated CSF levels of NFL, β2MG, and MBP. Autoantibodies, including anti-STIP-1, anti-Mtch1, anti-B-Crystallin, and anti-m-Hsp65, provide substantial evidence for autoimmune essence and underlying microbiological infections in NBD immunopathogenesis. We summarized opinions on the clinical diagnosis, biomarkers, and pathological findings of NBD.

Keywords: biomarkers; blood–brain barrier; cerebrospinal fluid; diagnosis; immunopathogenesis; neuro-Behçet’s disease.

Graphical Abstract

Figure 1:

CSF laboratory parameters for NBD patients during routine test of hospitalization in PUMCH. (A) Distribution of upregulated, normal, and downregulated CSF protein (Reference interval: 0.15–0.45 g/l), CSF chloride (Reference interval: 120–132 mmol/l), and CSF glucose (Reference interval: 2.5–4.5 mmol/l) among NBD patients (N = 314). (B) Positivity of OCBs using 70 CSF-serum paired samples of NBD. (C) CSF cytologic features among NBD patients based on morphology and May-Grunwald Giemsa (MGG) staining patterns discerned by two independent experienced lab scientists in PUMCH (N = 169)

Figure 2:

the hypothetic diagram of NBD immunopathogenesis. NBD pathogenesis first initiates from perivasculitis, with immunocytes (lymphocytes, neutrophils, foamy macrophages, etc.) and cytokines infiltrating in blood vessels, especially influencing CNS branches. The chronic autoinflammatory responses would further lead to the destruction of BBB, allowing more influx of immunopathogenic factors into brain parenchymal tissue, which gives rise to neuron demyelination or degradation events. In turn, the debris and fragments from neuronal damage caused by autoinflammation possess mitogenic and proliferative effects on B cells as well as T cells, promoting hyperfunction of humoral responses and autoimmunity episodes in terminal pathology among NBD patients (Created with BioRender.com)