You ask if this paper is interesting

James Bates RE, Browne E, Schalks R, Jacobs H, Tan L, Parekh P, Magliozzi R, Calabrese M, Mazarakis ND, Reynolds R. Lymphotoxinalpha expression in the meninges causes lymphoid tissue formation and neurodegeneration. Brain. 2022 Jul 1:awac232. doi: 10.1093/brain/awac232.

Yes, but I would say NSS wasn’t this obvious 30 thirty yearss ago?

Lymphotoxin is also known as tumour necrosis factor (TNF) beta and many years ago we made the case that blocking TNF in the brain may be beneficial. I was working with Sir Marc Feldmann who introduced me to a bright young neurologist from South Africa, and he did the studies of blocking Tumour necrosis factor in arthritis and filed the patent for rheumatoid arthritis. This was the first example where a scientist had taken the idea from bench to bedside to treat autoimmunity and as a result, Sir Marc became minted as this led to the licensing of anti-TNF for arthritis and other conditions worth billions.

When I was homeless at Christmas, Sir Marc would let me stay at his 5 floor house in West London when he took a holiday to US/Australia. Anyway we did the work for MS for Sir Marc and we filed a patent for blocking TNF in the brain

Baker D, Butler D, Scallon BJ, O’Neill JK, Turk JL, Feldmann M. Control of established experimental allergic encephalomyelitis by inhibition of tumor necrosis factor (TNF) activity within the central nervous system using monoclonal antibodies and TNF receptor-immunoglobulin fusion proteins. Eur J Immunol. 1994; 24:2040-8.

Only problem, before we could do a study others took the arthritis drug and put it in MS to block TNF outside the brain and it seem to make MS worse. So rather than a 5 storey swanky house in West London….I got zilch:-(.

No one was interested in blocking TNF in the brain anymore.

Now why do I say NSS and again we go back 30 years and the development of a lymphotoxin knockout mouse and guess they had no lymph nodes, so it is clear that lymphotixin is important in development of these tissues .

De Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A, Mariathasan S, Smith SC, Carlson R, Shornick LP, Strauss-Schoenberger J, et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science. 1994; 264:703-7

There are two main types of lymphotixin called alpha (previously known as TNF beta) and Beta and lymphotoxin alpha is particularly important in lymph node development

Koni PA, Sacca R, Lawton P, Browning JL, Ruddle NH, Flavell RA. Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Immunity. 1997 Apr;6(4):491-500.

Fu YX, Huang G, Wang Y, Chaplin DD. Lymphotoxin-alpha-dependent spleen microenvironment supports the generation of memory B cells and is required for their subsequent antigen-induced activation. J Immunol. 2000;164:2508-14.

Wang Y, Wang J, Sun Y, Wu Q, Fu YX. Complementary effects of TNF and lymphotoxin on the formation of germinal center and follicular dendritic cells. J Immunol. 2001; 166:330-7.

We did a piece on this

Baker D, Hadjicharalambous C, Gnanapavan S, Giovannoni G.Mult Scler Relat Disord. 2021;53:103057. doi: 10.1016/j.msard.2021.103057 Can rheumatologists stop causing demyelinating disease?

In the new paper the authors did the work rather than us pontificating. So what does the new paper say?..

Abstract Bates et al. 2022

Organised meningeal immune cell infiltrates (aggregates of white blood cells on the outside of the brain) are suggested to play an important role in cortical grey matter pathology (damage to the outside layers of the brain containing nerve cell heads) in the multiple sclerosis brain, but the mechanisms involved are as yet unresolved. Lymphotoxin-alpha plays a key role in lymphoid organ development and cellular cytotoxicity in the immune system and its expression is increased in the cerebrospinal fluid of naïve and progressive multiple sclerosis patients and post-mortem meningeal tissue (See above). Here we show that persistently increased levels of lymphotoxin alpha in the cerebral meninges can give rise to lymphoid-like structures and underlying multiple sclerosis-like cortical pathology.

Injections of lymphotoxin-alpha into the rat meninges led to acute meningeal inflammation and demyelination that resolved after 28 days, with demyelination being dependent on prior sub-clinical immunisation with myelin oligodendrocyte glycoprotein. Injection of a lymphotoxin-alpha lentiviral vector into the cortical meningeal space, to produce chronic localised over-expression of the cytokine, induced extensive lymphoid-like immune cell aggregates, maintained over 3 months, including T-cell…and B-cell rich zones with a network of follicular dendritic cells (cell central to formation and maintainence of B cell follicles)…..Extensive microglial and astroglial activation, demyelination and marked neuronal loss occurred in the underlying brain tissue……LTα treated microglia was able to induce a reactive phenotype in astrocytes. Our results show that chronic lymphotoxin-alpha overexpression alone is sufficient to induce formation of meningeal lymphoid-like structures and subsequent neurodegeneration, similar to that seen in the progressive multiple sclerosis brain.

So we have to block lymphotoxin in the brain and hope that it can block the neurodegeneration, but the idea was patented and the intellectual property is long gone, but let’s hope the model can be used to show us how to get rid of the follicles.

CoI: None Now

Disclaimer: These are the ideas of the authour

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