{"id":764,"date":"2025-11-05T11:00:00","date_gmt":"2025-11-05T11:00:00","guid":{"rendered":"https:\/\/wickedsister.evit.com.au\/index.php\/2025\/11\/05\/brutons-tyrosine-kinase-inhibitors\/"},"modified":"2025-11-05T11:00:00","modified_gmt":"2025-11-05T11:00:00","slug":"brutons-tyrosine-kinase-inhibitors","status":"publish","type":"post","link":"https:\/\/wickedsister.evit.com.au\/index.php\/2025\/11\/05\/brutons-tyrosine-kinase-inhibitors\/","title":{"rendered":"Bruton\u2019s Tyrosine Kinase Inhibitors"},"content":{"rendered":"
Tweet<\/a><\/div>\n

Bruton’s tyrosine kinase inhibitors rescue neuronal impairment caused by B cell-mediated lymphotoxin-\u03b1 release.<\/a><\/p>\n

Shin J, G\u00f6tz P, Sharif N, Sola-Sevilla N, Grasmuck C, Schraad M, Pape K, Muthuraman M, Fleischer V, Zandee SE, Bittner S, Vogelaar CF, Prat A, Hanuscheck N, Zipp F.Sci Transl Med. 2025;17(822):eadx2652.<\/p>\n

Although B cell depletion slows disability accrual in people with multiple sclerosis (pwMS), the role of B cells in MS-associated neuronal injury remains elusive<\/strong>. (So I think this sounds interesting we have been using B cell depleting agents increasingly over the past few years and on benefit we see this as good…<\/em>If we read the title is says Bruton Tyrosine kinase inhibitors to the rescue from the bad B cells….So it sounds like an advert for BTK manufacturers…so let’s see the conflicts..[There are none according to the paper! But have any of the authors received any support from Sanofi, Novartis, Roche that have active BTKi programmes, I have no doubt that they think they are not influenced by pharma, but you have to consider perceived conflicts, They used evobrutinib so check out Merck Serono too but this failed in relapsing MS].<\/em> The B cells release cytokines such as lymphotoxin-\u03b1 (LT\u03b1) (this is known to be involved in formation of lymphoid tissues like lymph glands<\/em>), and this proinflammatory protein is also present in the cerebrospinal fluid (CSF) and meninges of pwMS. B cell-specific ablation of LT\u03b1 alleviates disease severity in a preclinical model of MS.<\/strong> [[Schtopp…At this point I loose interest…there is a long history of tumour nectrosis factor inhibition and inhibition of EAE but likewise a long history of this worsening MS in some people<\/em>)…Importantly depletion of B cells using CD20 depleting antibodies has negligible to marginal influence and it is context dependent on when you deplete the B cells before disease induction and if may worsen disease in some peoples hands and so not sure it is a translational model for effects of B cell depletion in MS. Studies in EAE suggest that BTKi are affecting microglia]]. To further study the impact of B cell-derived cytokines on neuronal function [T cells produce lymphotoxin too<\/em>], we performed patch-clamp recordings on human iPSC-derived neurons [My interest perks up again<\/em>]. Coculture with proinflammatory human B cells led to depolarization and aberrant firing. Pretreatment of proinflammatory B cells (naive B cells activated with antigen receptor and costimulatory treatment and B cell proliferation and maturation support factors<\/em>) with a Bruton’s tyrosine kinase inhibitor (BTKi), reported in patients to beneficially affect disability progression even in the absence of inflammatory relapse activity, prevented neuronal impairment and inhibited LT\u03b1 release from B cells. [This is tolebrutinib a Sanofi drug<\/em>]. Blocking LT\u03b1, tumor necrosis factor receptor 1 (TNFR1), or receptor-interacting protein kinase 1 or 3 also prevented neuronal impairment, but blocking TNF\u03b1 or LT\u03b2 had no such effect [So lymphotoxin alpha is the beast, wonder if they dare do a trial with blockers?<\/em> . Neuronal impairment was reversible by BTKi or blockage of LT\u03b1, and this reversibility was dependent on the activity of acid sphingomyelinase. In pwMS, LT\u03b1 correlated with elevated neurofilament light chain (NfL) abundance in CSF, and anti-CD20 B cell-depletion therapy led to a reduction in circulating LT\u03b1, supporting the role of B cells as a regulator for LT\u03b1.<\/em> [So on balance B cells are the bad cells and it acts on excitatory nerves<\/em>]. These findings highlight the negative impact of B cell-derived LT\u03b1 on neurons and suggest potential treatment avenues for MS-associated neuronal injury.<\/p>\n

So it says B cell depletion should be a good thing for progression and limiting nerve loss.<\/em><\/p>\n

COI: Multiple<\/p>\n

Disclaimer: My views<\/em><\/p>\n<\/p>\n

Bruton\u2019s tyrosine kinase inhibitors (BTKis) suppress over-reactive B cell signaling and could potentially curtail disease progression in multiple sclerosis (MS). To investigate the signaling pathways involved in B cell\u2013mediated neuronal impairment… They demonstrated that lymphotoxin-\u03b1 (LT\u03b1) released from proinflammatory B cells triggered necroptotic signaling in neurons, leading to neuronal depolarization and silencing. BTKi mitigated these effects by inhibition of LT\u03b1 release. Patient data demonstrating that LT\u03b1 correlated with the neuronal injury marker NfL in cerebrospinal fluid suggest that the signaling pathways characterized in vitro could be relevant for the human condition.<\/p>\n

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

Tweet Bruton’s tyrosine kinase inhibitors rescue neuronal impairment caused by B cell-mediated lymphotoxin-\u03b1 release. Shin J, G\u00f6tz P, Sharif N, Sola-Sevilla N, Grasmuck C, Schraad M, Pape K, Muthuraman M, Fleischer V, Zandee SE, Bittner S, Vogelaar CF, Prat A, Hanuscheck N, Zipp F.Sci Transl Med. 2025;17(822):eadx2652. Although B cell depletion slows disability accrual in…<\/p>\n","protected":false},"author":0,"featured_media":0,"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-764","post","type-post","status-publish","format-standard","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\/764","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=764"}],"version-history":[{"count":0,"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/posts\/764\/revisions"}],"wp:attachment":[{"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/media?parent=764"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/categories?post=764"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/wickedsister.evit.com.au\/index.php\/wp-json\/wp\/v2\/tags?post=764"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}