Sunday, 19 March 2017

Viral Infections can be a problem

Clerico M, De Mercanti S, Artusi CA, Durelli L, Naismith RT. Active CMV infection in two patients with multiple sclerosis treated with alemtuzumab. Mult Scler. 2017 Feb 1:1352458516688350. doi: 10.1177/1352458516688350. [Epub ahead of print]
Alemtuzumab is a humanized monoclonal antibody targeting the surface molecule CD52, resulting in a rapid depletion of innate and adaptive immune cells. Infection rates in multiple sclerosis (MS) treatment trials were higher in alemtuzumab than in interferon beta-treated patients. We report two MS patients who developed cytomegalovirus disease within 1 month after the first 5-day cycle of alemtuzumab. Upon identification and appropriate treatment of the infection, each recovered completely. Neurologists should be aware of this serious but treatable complication.

So there you are warned. CMV is a common virus in humans and is a problem if you are immunosuppressed. It appears it can be a problem in mice too

Murine Cytomegalovirus Infection Induces Susceptibility to EAE in Resistant BALB/c Mice.Milovanovic J, Popovic B, Milovanovic M, Kvestak D, Arsenijevic A, Stojanovic B, Tanaskovic I, Krmpotic A, Arsenijevic N, Jonjic S, Lukic ML.Front Immunol. 2017;8:192. doi: 10.3389/fimmu.2017.00192.

In contrast to C57BL/6 mice, BALB/c mice are relatively resistant to the induction of experimental autoimmune encephalomyelitis (EAE) after challenge with MOG35-55 peptide. Here, we provide the first evidence that infection with murine cytomegalovirus (MCMV) in adulthood abrogates this resistance. Infected BALB/c mice developed clinical and histological signs similar to those seen in susceptible C57BL/6 mice. In addition to CD4+ cells, large proportion of cells in the infiltrate of diseased BALB/c mice was CD8+, similar with findings in multiple sclerosis. CD8+ cells that responded to ex vivo restimulation with MOG35-55 were not specific for viral epitopes pp89 and m164. MCMV infection favors proinflammatory type of dendritic cells (CD86+CD40+CD11c+) in the peripheral lymph organs, M1 type of microglia in central nervous system, and increases development of Th1/Th17 encephalitogenic cells. This study indicates that MCMV may enhance autoimmune neuropathology and abrogate inherent resistance to EAE in mouse strain by enhancing proinflammatory phenotype of antigen-presenting cells, Th1/Th17, and CD8 response to MOG35-55.

How times change when I first started with EAE, we had the SJL and the PL mouse and BALB/c and notably C57BL/6 were classed as the most genetically resistant mouse strains on the planet. 

This is becuase people were using myelin basic protein or proteolipid protein to induce EAE. We first showed that myelinoligodendrocyte glycoprotein (MOG) in mice.

Amor S, Groome N, Linington C, Morris MM, Dornmair K, Gardinier MV, Matthieu JM, Baker D. Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice.J Immunol. 1994;153:4349-56.

Then it was shown shortly after that C57BL/6 mice could get MOG induced EAE, using the MOG35-55 that we showed induced disease in ABH (H-2g7= Kd, Ag7, E-, Dq transplantation antigen type that determines which peptides they respond to) mice.
This opened up the use of knockout mice which were typically made on the C57BL/6 (H-2b) or 129 (H-2b) mouse background.

We showed also that the MOG35-55 peptide commonly used may not have been the best peptide in C57BL/6 (H-2Ab) mice
Delarasse C, Smith P, Baker D, Amor S.Novel pathogenic epitopes of myelin oligodendrocyte glycoprotein induce experimental autoimmune encephalomyelitis in C57BL/6 mice. Immunology. 2013;140(4):456-64. doi: 10.1111/imm.12155.

This was repeated a year later, by a group from West Coast USA that forgot not to acknowledge the existence of the early discovery (Bad Science)-
 I'm not bitter:-)

This is great and bad because C57BL/6 is still a weak susceptibility background and shows gene related differences that disappear as unimportant once you do the same experiment in a high susceptibility strain

Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis.
Sisay S, Pryce G, Jackson SJ, Tanner C, Ross RA, Michael GJ, Selwood DL, Giovannoni G, Baker D.PLoS One. 2013 Oct 9;8(10):e76907. 

We also showed that BALB/c mice were other low susceptiblity strain can be induced to develop disease.

Croxford JL, O'Neill JK, Baker D.Polygenic control of experimental allergic encephalomyelitis in Biozzi ABH and BALB/c mice.J Neuroimmunol. 1997;74(1-2):205-11

So in this study they find that infection of BALB/c (H-2d) mice with CMV makes them susceptible to EAE with MOG35-55.
They get alot of CD8 to respond ,so that will be by Kd or Dd molecule by which they are restricted, and it is interesting in ABH mice (Kd, dq) get disease and we have noticed more CD8 cells in the CNS when mice are immunised with this peptide. 

It also induced monophasic chronic disease that becomes progressive from first attack in ABH and C57BL/6 mice whereas MOG8-22 (residues 8-22 in the MOG molecule) get relapsing disease. So saying that genetics does not necessarily dictate disease course.

It also says that viral infection can influence susceptibility, which is known too and this was how PL/J were found to EAE susceptible after infection with mouse hepatitis virus.

Cross AH, McCarron R, McFarlin DE, Raine CS.Adoptively transferred acute and chronic relapsing autoimmune encephalomyelitis in the PL/J mouse and observations on altered pathology by intercurrent virus infection. Lab Invest. 1987; 57:499-512.

8 comments:

  1. Mouse Doctor ... this is getting really interesting as things are starting to look more like the disease in humans.
    Or are we trying to interpret things in mice so that they fit with waht we observe in the clinic? I hope we are not.

    so what is in those MOG residues? ( don't tell me it is something to do with galactose or I'll faint :-)

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  2. One of our patients with CNS vasculitis developed CMV reactivation disease. He was quite immunocompromised having previously failed cyclophosphamide and was on high dose steroids.

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  3. Any heavy immmunosuppression is going to put the patients at risk of CMV reactivation, there is no way around it. We live with viruses in us, "put the shields down" and trouble can brew.
    But in all the years of SoluMedrol I cannot remember a single patient that had a CMV reactivation on just SoluMedrol. But there were several that got into trouble after SaluMedrol in combination with other immunosuppressives.
    Prof G, I think the last data on alemtuzumab in the real world is not that impressive and I expect that we will probably swing to more benign treatment choices as the time goes.

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  4. MD forgive me if I do not understand, but then did CMV end up inducing EAE in mice immunosuppressed with alemtuzumab?
    Can viruses such as CMV lead to autoimmunity?

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  5. No the CMV didnt induce EAE, the infection appearred to enhance the capacity to develop autoimmunity perhaps because the immune system is juiced up.

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    1. And I have always thought that my MS gets triggered by HSV-1 reactivation, maybe viruses are just amplifiers of some process that is going on in the background.

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  6. MD, you mentioned earlier that you could reverse the disease in mice. Can you elaborate on this:
    1. Is there some "window of opportunity", that is a certain time frame from induction when the process can be stopped/reversed and the mice are still healthy, seem to enjoyed life as much as caged mice can and have a normal lifespan?

    2. Likewise, if there is a "point of no return"(permanent irreversible disability) in the induced disease model, when is it?

    Does it depend on time from induction to therapeutic intervention or does it dpend on how old the mice are when the induction happens ?

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