B Cell, Th17, and Neutrophil Related Cerebrospinal Fluid Cytokine/Chemokines Are Elevated in MOG Antibody Associated Demyelination

Abstract

Background: Myelin oligodendrocyte glycoprotein antibody (MOG Ab) associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination.

Aim: To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS) and -negative (NEG) groups.

Methods: We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM = 8), transverse myelitis (TM = 2) n = 10] and serum MOG Ab NEG (ADEM = 5, TM = 4, n = 9) demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls.

Results: The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19) as well as some of Th17 related cytokines (IL-6 AND G-CSF) compared to MOG Ab NEG group (all p<0.01). In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies.

Conclusion: Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets.

Fig 1. Comparison of MRI brain radiological features in serum MOG Ab POS vs MOG Ab NEG demyelination group.

A) MOG Ab POS group: (a) T2 axial and (b) T2 FLAIR coronal views of case 1 show large subcortical demyelinating lesions. Case 2 shows confluent bilateral thalamic lesions and subcortical diffuse demyelinating lesions with hazy margins. B) MOG Ab NEG group: (a) T2 axial and (b) T2 FLAIR coronal views of case 3 show small multiple hyperintensities in putamina, head of caudate nuclei, thalami, midbrain, posterior pons, and medulla. Case 4 shows small well-defined demyelinating lesions in left subcortical white matter.

Fig 2. CSF cytokine/ chemokine concentrations in serum MOG Ab POS, serum MOG Ab NEG demyelination groups and controls according to T and B cell subsets.

Th17 (IL-6 & G-CSF), B cell related (CXCL13, CCL19, APRIL & BAFF) and other cytokines and chemokines (TNF-α, IL1ra and IL-10) were elevated in serum MOG Ab POS patients compared to serum MOG Ab NEG group (p<0.05). Dotted lines represent medians. The statistical analysis was performed using Kruskal Wallis test.

Fig 3. CSF cytokine/chemokine concentrations in serum MOG Ab POS, serum MOG Ab NEG demyelination groups and controls, according to T and B cell subsets.

Cytokines and chemokines within Th1, Th2 and other CSF cytokine subgroups were not elevated in serum MOG Ab POS compared to serum MOG Ab NEG group. Dotted lines represent medians. The statistical analysis was performed using Kruskal Wallis test.

Fig 4. CSF cytokine/ chemokine concentrations in CSF MOG Ab POS patients and CSF MOG Ab NEG patients.

B cell (CXCL13, CCL19, CXCL12,) and Th17 (G-CSF, IL-17A) cytokines/chemokines were elevated in CSF MOG Ab POS patients when compared to CSF MOG Ab NEG patients (P<0.05). Dotted lines represent medians. The statistical analysis was performed using Man Whitney’s test.

Fig 5. Correlation between CSF cytokine and chemokine levels in patients with MOG Ab POS demyelination.

This figure shows that the majority of B cell cyto/chemokines correlate with each other and with Th17 molecules (IL-17A, IL-6 and G-CSF) and IL-10, but do not show any association with Th1 (except TNF-α) and Th2 related cytokines/chemokines. The above heat map is graded based on Spearman rank correlation* 0.0 to 0.03, negligible correlation; 0.3 to 0.5, low positive correlation; 0.50 to 0.70, moderate correlation; 0.70 to 0.90, high correlation; 0.9 to 1, very high correlation). *The negative correlations were all moderate or weaker so have been coded the same as the “negligible” correlations.