{"id":2188,"date":"2026-06-12T09:05:00","date_gmt":"2026-06-12T09:05:00","guid":{"rendered":"https:\/\/wickedsister.evit.com.au\/index.php\/2026\/06\/12\/natalizumab-does-not-remove-all-inflammatory-activity-from-the-brain\/"},"modified":"2026-06-12T09:05:00","modified_gmt":"2026-06-12T09:05:00","slug":"natalizumab-does-not-remove-all-inflammatory-activity-from-the-brain","status":"publish","type":"post","link":"https:\/\/wickedsister.evit.com.au\/index.php\/2026\/06\/12\/natalizumab-does-not-remove-all-inflammatory-activity-from-the-brain\/","title":{"rendered":"Natalizumab does not remove all inflammatory activity from the Brain."},"content":{"rendered":"
Tweet<\/a><\/div>\n

The conclusion of the paper is that there is still residual inflammation in the MS brain despite treatment with natalizumab.<\/p>\n

Buhelt et al. Residual inflammation in the cerebrospinal fluid after short- and long-term natalizumab treatment in relapsing-remitting multiple sclerosis. Front. Immunol., 05 June 2026 Volume 17 – 2026 |\u00a0https:\/\/doi.org\/10.3389\/fimmu.2026.1817671<\/a><\/p>\n

Background and objectives:\u00a0<\/strong>Natalizumab (NTZ) is a high-efficacy therapy for relapsing-remitting multiple sclerosis (RRMS) that blocks peripheral immune cell migration into the central nervous system. While short-term NTZ treatment reduces cerebrospinal fluid (CSF) inflammation, the extent of residual intrathecal inflammation (inflammation within the spinal fluid<\/em>) after long-term NTZ treatment and its association with oligoclonal band (OCB) status remains unclear. In this study, we examined associations between NTZ treatment duration, OCB status and CSF inflammatory and tissue biomarkers as well as presence of residual intrathecal inflammation after more than five years of NTZ treatment.<\/p>\n

Discussion:\u00a0<\/strong>Natalizumab treatment reduces CSF inflammation biomarkers, but after more than five years of treatment levels of sCD27, sBCMA and IgG index remain significantly above control levels in OCB-positive NTZ-treated patients. This indicates residual intrathecal adaptive immune activation in OCB-positive NTZ-treated RRMS patients, suggesting that compartmentalized adaptive inflammation in RRMS is incompletely suppressed by NTZ.<\/p>\n

I have to laugh when I read the introduction preamble of papers when they say \u201cwe do the work because X or Y are unclear\u201d and I sometimes think \u201cThey should have gone to Spec Savers\u201d and done a bit more reading as they could get the answers. But I must admit, I like it when the work gives a bit more of the jigsaw to show that your ideas may not be so rubbish.<\/p>\n

You have seen this story before and the same idea was made when we looked at the influence of cladribine on oligoclonal bands, which represent antibodies made by antibody secreting cells in the central nervous system. There are long lived plasma cells that produce antibodies and we showed that that are not touched by cladribine and are likewise not touched by anti-CD20 antibodies and CD19 CAR-T therapy and as shown many times previously by natalizumab too….So whats the news. Long lived plasma cells do not express CD19, CD20, CD52 and deoxycytidine kinase and so are not touched by the MS drugs even if they could get into the CNS to kill the plasma cells. However, because antibodies are pretty poor at getting into the brain they don\u2019t even get there. This is the story of Natalizumab.<\/p>\n

We have suggested that oligoclonal bands are generated from short and long-lived antibody secreting cells. The short-lived cells could come from the blood but probably come from the memory B cells entering the CNS from the blood that differentiate into the short-lived plasma cells\/plasma blasts). Some of these may become long lived plasma cells and they live in the inflamed-brain because they get support from the inflammation  to stay alive. This support keeps plasma cells alive in your bone marrow to give you life-long protection from infections. Howevert in MS the plasma cells get sequestered in the brain and maintained sometimes for the duration of MS.<\/p>\n

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Natalizumab doesn\u2019t work in the CNS it works on the blood vessels to stop memory B cells entering the CNS and so that stops relapsing MS and reduces the number of\u00a0 cells entering the NS and so stops lesion formation and relapses. \u00a0This is not going to directly affect the antibody secreting cells in the CNS and so when you look in many cases oligoclonal bands persist. This has been seen before with natalizumab, cladribine, ocrelizumab and HSCT and CD19 CAR-T therapy, etc. So, no surprises that they found what they found in today\u2019s paper.<\/p>\n

Here they looked for inflammatory mediators in the spinal fluid of people with and without MS and people with MS treated for different times with natalizumab. What was evident that natalizumab made a marked drop in a molecule called CXCL13 to background level. Yep this has totally been seen before and this is interesting because this molecule attracts circulating memory B cells into the CNS by a receptor called CXCR5 which is reduced on antibody secreting cells (Plasmablasts and plasma cells). So natalizumab stops memory B cells going into the CNS to inhibit MS.<\/p>\n

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So you block the recruitment of cells that become the short-lived plasma cells and the number of oligoclonal bands drop. They didn\u2019t report this here, but trust me I can\u00a0 reel off a few papers that so show this. They did however show that the level of antibody (IgG) dropped but persisted. However, the take home message is that oligoclonal bands persist and this is because the long-lived plasma cells are not being touched at least initially, or should I say not touch much, because some of the plasma cells formed from invading memory B cells will become long-lived cells.<\/p>\n

Again it is shown that soluble CD27 and soluble B cell maturation antigen drops but persists and these have some correlation with oligoclonal bands, which is not surprising because BCMA and CD27 are expressed by antibody secreting cells, CD27 is additionally expressed by memory B cells and T cells. There is loads of CD27 on the antibody secreting cells compared to memory B cells ans so not surprising the was an association with the oligoclonal bands<\/p>\n

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However because you are blocking immune cells from entering the CNS and you are inhibiting the amount of inflammation occurring in the brain, in some cases growth support that keeps the long-lived plasma cells alive is lost and we have suggested so in some individuals the oligoclonal bands will disappear with time.<\/p>\n

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This paper shows what we have already seen with cladribine and that is oligoclonal bands do not disappear quickly although some people will lose them within 12 months but it may take years for the number of oligoclonal band negative individuals to increase and with cladribine even at 10 years there are individuals with persistent long-lived plasma cells. The same happens with natalizumab and that is with time the number of people who become oligoclonal band negative increases.<\/p>\n

Now in this paper 20-30% of people lost their oligoclonal bands in 2-5 years. In previous studies with cladribine in year or two it was 10-20% as shown by from ProfK but after 10 years maybe 50% had lost the oligoclonal bands. So what we see is a common biology with different agents and this leads me to hope this maybe the reality.<\/p>\n

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The big question is what happens when BCMA CAR-T therapy is used. This should kill antibody secreting cells in the brain. Does it clear the oligoclonal bands<\/p>\n

Qin et al. Anti-BCMA CAR-T therapy in patients with progressive multiple sclerosis. Cell. 2025;188:6414-6423.e11. It says that there was plasma cell depletion…and reported reductions of immunoglobulin (antibody<\/em>) levels and kappa-free light-chain (antibody element<\/em>); but did not give news on positivity of oligoclonal bands \"🙁\"<\/p>\n

Source: multiple-sclerosis-research.org<\/a><\/em><\/p>\n","protected":false},"excerpt":{"rendered":"

Tweet The conclusion of the paper is that there is still residual inflammation in the MS brain despite treatment with natalizumab. Buhelt et al. Residual inflammation in the cerebrospinal fluid after short- and long-term natalizumab treatment in relapsing-remitting multiple sclerosis. Front. Immunol., 05 June 2026…<\/p>\n","protected":false},"author":0,"featured_media":2189,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4],"tags":[11,15,9,8,13,14,12,10],"class_list":["post-2188","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-multiple-sclerosis-research","tag-brain-repair","tag-marburg-type-ms","tag-ms","tag-multiple-sclerosis","tag-myelin","tag-neuroregeneration","tag-oligodendrocyte","tag-remyelination"],"_links":{"self":[{"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/posts\/2188","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/types\/post"}],"replies":[{"embeddable":true,"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/comments?post=2188"}],"version-history":[{"count":0,"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/posts\/2188\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/media\/2189"}],"wp:attachment":[{"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/media?parent=2188"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/categories?post=2188"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/tags?post=2188"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}