Effects of Natalizumab Therapy on Intrathecal Immunoglobulin G Production Indicate Targeting of Plasmablasts

Abstract

ObjectivesTo evaluate the long-term effects of natalizumab (NTZ) on different features of intrathecal immunoglobulin (Ig) synthesis in patients with multiple sclerosis (MS) and to quantify the expression of α4-integrin in stages of B-cell maturation.MethodsWe combined a cross-sectional (49 NTZ-treated MS patients, mean treatment duration 5.1 years, and 47 untreated MS patients) and a longitudinal study (33 patients with MS before and during NTZ, mean treatment duration: 4.8 years), analyzing paired serum and CSF samples for IgG, IgA, and IgM levels, reactivity against selected viruses (measles virus, rubella virus, and varicella zoster virus [MRZ] reaction), and oligoclonal bands (OCBs). Banding patterns before and after therapy were directly compared by isoelectric focusing in 1 patient. In addition, we determined the expression of α4-integrin by FACS analysis on blood-derived B-cell subsets (plasmablasts, memory B cells, and naive B cells) of healthy controls.ResultsIn serum, NTZ decreased IgM and IgG, but not IgA, levels. IgM hypogammaglobulinemia occurred in 28% of NTZ-treated patients. In CSF, NTZ treatment resulted in a strong reduction of intrathecally produced IgG and, to a lesser extent, IgA, whereas IgM indices [(Ig CSF/Serum)/(Albumin CSF/Serum)] remained largely unchanged. Reduction of the IgG index correlated with NTZ treatment duration, as did serum IgM and IgA levels. MRZ reaction was unchanged and OCB persisted. Direct comparison of OCB pattern before and after NTZ revealed the persistence of individual bands. α4-Integrin expression was highest on plasmablasts (CD19+CD38+CD27+).ConclusionOur data indicate that NTZ reduces short-lived plasmablasts in the CNS compartment but has little effect on locally persisting long-lived plasma cells.

Natalizumab Induces Changes of Cerebrospinal Fluid Measures in Multiple Sclerosis

“…Although the number of OCBs reduced after NTZ treatment, OCBs disappeared completely only in 9 patients (9.7%) and OCBs positivity dropped from 94.6% to 86.0%. This was consistent with previous studies reporting a decrease in OCB positivity from a 100% positivity at the baseline to an 84% positivity at the follow-up (n = 73) [14], from an 86% positivity at the baseline to a 76% positivity at the follow-up (n = 33 before and 49 after NTZ treatment) [13] and a 93.3% positivity at the baseline to an 80% positivity at the follow-up (n = 15) [15]. Only one study by Mancuso et al observed a complete disappearance of OCBs in the majority of patients on NTZ with a decrease in the OCB positivity from 92% at the baseline to 42% at the follow-up (n = 24) [17].…”

“…This was consistent with recent research showing a negative correlation between a younger age and higher CSF leukocytes [30] but also with a number of studies documenting a higher inflammatory activity in young patients and in early disease stages [25,31,32]. Reductions in the IgG and IgM indices and quotients following NTZ have also been reported previously [13,15,16]. However, only the study by Schluter et al found that NTZ induced a reduction of the IgG index but not the IgM indices in RRMS patients [13].…”

“…Additionally, NTZ normalizes the levels of B cells, monocytes, natural killer cells and dendritic cells in the CSF [ 5 ]. NTZ treatment is also associated with a reduction of CSF plasmablasts [ 12 ], especially in short-lived cells of the CNS compartment and, to a lesser extent, locally persisting long-lived plasma cells [ 13 ]. NTZ decreases the total CSF IgG [ 14 , 15 , 16 ] and IgM levels [ 15 , 16 ] as well as the IgG index [ 16 ] and intrathecally produced IgG [ 14 ].…”

“…NTZ decreases the total CSF IgG [ 14 , 15 , 16 ] and IgM levels [ 15 , 16 ] as well as the IgG index [ 16 ] and intrathecally produced IgG [ 14 ]. Despite several studies that have reported the disappearance of CSF-restricted oligoclonal bands (OCBs) in a great proportion of patients [ 17 ], more recent research has found a persistence of OCBs in the vast majority of patients and a disappearance in only a few patients [ 13 , 14 , 15 ]. Interestingly, a direct comparison of OCB patterns before and after NTZ showed the persistence of individual bands in the CSF [ 13 ].…”

Cerebrospinal Fluid IgM and Oligoclonal IgG Bands in Multiple Sclerosis: A Meta-Analysis of Prevalence and Prognosis

“…From the clinical point of view, emerging evidence shows that disease-modifying treatments (DMTs) may alter intrathecal immunoglobulins production and that intrathecal immunoglobulins may modulate DMT response. For example, natalizumab decreased serum IgM and IgG levels but, in CSF, only IgG indices [ 49 ]. Furthermore, it has been demonstrated that autologous hematopoietic stem cell transplantation (aHSCT) lowered intrathecal immunoglobulin indices and suppressed both IgG and IgM oligoclonal bands, thus challenging the notion that OCBs are unaffected by therapeutic intervention in MS [ 50 ].…”