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Brief History Of Nebulous Connection Between Milk & MS (Multiple Sclerosis)

Sparse data on this subject consists of

  • An US epidemiological study that compared 1949 to 1967 MS mortality rates and food consumption data, and found high correlation (0.8 to 0.9) with milk consumption (1).
  • A couple of cross-sectional epidemiological studies from 1976 (2) and 1992 (3) that compared MS prevalence and dairy product consumption. The second one looked across 29 populations in 27 countries and suggested MS progression could be influenced by factors in liquid cow’s milk but not in processed milk.

The story then appeared to lie dormant for the next several years until revived by a 2000 rat EAE (Experimental autoimmune encephalomyelitis – Wikipedia) model study (4). This study mechanistically showed Butyrophilin – Wikipedia, a milk fat globule membrane protein expressed only by the lactating mammary gland,

Similar experiments in a mouse model (5) also showed Butyrophilin could prevent MOG-induced EAE, i.e., that this milk component could protect against EAE.

Problem is though originally developed in the 1950s to supposedly mimic human MS, these rodent (mainly rat and mouse) models simply don’t mimic human MS very well (6), haven’t yielded much insight or practical therapies and yet have taken over basic MS research and remain the mainstay in the field.

Meantime, a couple of small human studies from France (n=44 MS versus 30 controls, 7) and the US (n= 35 MS versus 25 controls, 8) yielded contradictory data

  • The French study (7) found MS patients with higher circulating antibody levels cross-reactive to MOG and Butyrophilin.
  • The US study (8) found MS patients and controls had similar levels of circulating antibodies cross-reactive to MOG and Butyrophilin. However, this US study also compared anti-MOG and -Butyrophilin antibody responses in blood as well as CSF (Cerebrospinal fluid – Wikipedia) of MS patients and found they were specific for different epitopes (parts) of Butyrophilin, the one dominating in the CSF also cross-reacting to a homologous MOG peptide in 34% of MS patients, i.e., possible Molecular mimicry – Wikipedia between MOG and Butyrophilin.

In addition to these two human studies contradicting each other, these purely observational studies examined circulating antibody levels, i.e., B cell – Wikipedia, not T, cell response as the animal model studies did. Apples and oranges.

While Butyrophilin’s plausible role in MS progression lies in its high sequence similarity to MOG (9), i.e., Molecular mimicry – Wikipedia, data from these two small human studies are inconclusive and so far there’s no other data on milk proteins’ role in MS prognosis or disease course (10).

How Milk Or Any Other Factor Might Trigger Or Flare MS (Multiple Sclerosis)

Though there are many suspects, confirmed triggers for MS are still unknown. Most convincing data exist not for dietary factors such as milk but for vitamin D levels and its receptor polymorphisms, history of Epstein-Barr virus infection including Infectious mononucleosis – Wikipedia and smoking (11, 12).

No matter the trigger though, how might MS disease cascade follow? Prime suspect is molecular mimicry, i.e., molecular level similarity between such triggers and the target of autoimmune attack in MS, typically proteins such as MOG expressed on Oligodendrocyte – Wikipedia, myelin sheath cells.

  • However, even this is insufficient. Consider milk for example. Many more people drink milk than get MS. If molecular mimicry alone sufficed, they should all have MS and they don’t.
  • Clearly other factors are also involved. No matter the degree of molecular mimicry, nothing can ensue if a person’s immune system can’t ‘see’ it.
    • An immunologically necessary condition would thus be the HLA (Human leukocyte antigen – Wikipedia) haplotype. However, HLA haplotype alone wouldn’t suffice because far more people share HLA haplotypes than develop MS.
    • Breakdown in T cell tolerance is also necessary. After all, during their development in the thymus, T cells with the capacity to recognize oligodendrocyte proteins should get deleted. Obviously that process seems to fall short in MS patients.
  • Thus target antigen (and molecular mimic)-specific T cells should be present and such target(s) of immune attack should be properly processed and presented to these T cells. However, though appropriate HLA haplotype and CNS (Central nervous system – Wikipedia) protein(s)-specific T cells are the necessary building blocks for MS autoimmune pathology, their presence alone doesn’t suffice either.
  • Context is also necessary, i.e., predisposing and/or conditioning factors necessary to drive the pathological immune response necessary for MS expression. Totality of such factors, sufficient to explain MS in each and every case, still remain undefined.

Bibliography

1. Agranoff, BernardW, and David Goldberg. “Diet and the geographical distribution of multiple sclerosis.” The Lancet 304.7888 (1974): 1061-1066. https://deepblue.lib.umich.edu/b…

2. Butcher, J. “The distribution of multiple sclerosis in relation to the dairy industry and milk consumption.” The New Zealand Medical Journal 83.566 (1976): 427-430)

3. Malosse, D., et al. “Correlation between milk and dairy product consumption and multiple sclerosis prevalence: a worldwide study.” Neuroepidemiology 11.4-6 (1993): 304-312.

4. Stefferl, Andreas, et al. “Butyrophilin, a milk protein, modulates the encephalitogenic T cell response to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis.” The Journal of Immunology 165.5 (2000): 2859-2865. http://www.jimmunol.org/content/…

5. Mañá, Paula, et al. “Tolerance induction by molecular mimicry: prevention and suppression of experimental autoimmune encephalomyelitis with the milk protein butyrophilin.” International immunology 16.3 (2004): 489-499. https://www.researchgate.net/pro…

6. Tirumalai Kamala’s answer to Why can chemicals that block the alpha tumour necrosis factor make multiple sclerosis worse? Do inhibiting cytokines make inflammation worse?

7. De March, A. Kennel, et al. “Anti-myelin oligodendrocyte glycoprotein B-cell responses in multiple sclerosis.” Journal of neuroimmunology 135.1 (2003): 117-125.

8. Guggenmos, Johannes, et al. “Antibody cross-reactivity between myelin oligodendrocyte glycoprotein and the milk protein butyrophilin in multiple sclerosis.” The Journal of Immunology 172.1 (2004): 661-668. http://www.jimmunol.org/content/…

9. Vojdani, Aristo. “Molecular mimicry as a mechanism for food immune reactivities and autoimmunity.” Altern Ther Health Med 21.Suppl 1 (2015): 34-45. http://bant.org.uk/wp-content/up…

10. Von Geldern, Gloria, and Ellen M. Mowry. “The influence of nutritional factors on the prognosis of multiple sclerosis.” Nature Reviews Neurology 8.12 (2012): 678-689.

11. Belbasis, Lazaros, et al. “Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses.” The Lancet Neurology 14.3 (2015): 263-273.

12. Tirumalai Kamala’s answer to Why does Colorado have the highest rate of multiple sclerosis?

https://www.quora.com/Does-processed-milk-cause-multiple-sclerosis-flare-up/answer/Tirumalai-Kamala

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