Effects of Bacille Calmette-Gu?rin after the first demyelinating event in the CNS
RobertLisak, Neurology, Wayne State University Medicalrlisak@med.wayne.edu
Submitted February 24, 2014
Ristori et al. studied the effect of vaccination with BCG on patients with
a first-ever multiple sclerosis (MS) event. [1] The mechanisms involved in
disease reduction by BCG vaccination raises interesting questions as
discussed in the accompanying editorial [2] about types of infection and
exposure to infectious agents and MS. Viral infections seem to increase
the chances of a relapse [3] and concomitant parasitic infections have the
opposite effect. [4]
Why disease activity is reduced by vaccination with BCG is unclear.
[2] It is not known if active infection with a Mycobacterium is required
to obtain this therapeutic effect. The relationship between Mycobacteria
and other bacteria in the induction and prevention of experimental
autoimmune ('allergic') encephalomyelitis (EAE) is complex with
interactions dependent on the nature and dose of the bacterial agent and
timing of exposure. [5] While active infection with Mycobacteria can
inhibit EAE, active infection with mycobacteria is not always necessary
for this effect. [5,6].
Animals pre-treated with heat killed M. tuberculosis as part of
Complete Freund's Adjuvant (CFA) or some components of M. tuberculosis [7]
inhibited actively-induced EAE but the mechanisms are unclear. This
inhibition is associated with reduced cell-mediated reactivity to the
inducing antigen, myelin basic protein (MBP), manifested by delayed
hypersensitivity skin tests [5] and two in vitro assays that measured cell
-mediated reactivity to antigens without reduction in response to PPD skin
tests or tuberculin in vitro. [7,8]
The 12-kDa protein in PPD that protected mice from induction of EAE
did not share epitopes with MBP. [7] Pre-treatment of recipient animals
with CFA inhibited the development of EAE and skin test reactivity to MBP
in recipient animals receiving sensitized cells from EAE donor animals vs
other recipient animals not pretreated with CFA but receiving sensitized
cells from EAE donor animals. [9] The mechanism/s for the reduction of
reactivity to the inducing autoantigen is unclear [1] but possibilities
include regulatory cells, induction of clonal anergy or-- less likely--
clonal deletion of the antigen-specific autoimmune cells. More than one
mechanism may be involved in the protection in EAE and in MS.
1. Ristori, G, Romano, S, Cannoni, S, et al. Effects of Bacille
Calmette-Guerin after the first demyelianting event in the CNS. Neurology
2014; 82:41-48.
2. Bourdette, D, Naismith, RT. BCG vaccine for clinically isolated
syndrome and MS. Infections and protective immunity. Neurology 2014;
82:15-16.
3. Sibley, WA, Foley, JM. Infection and immunization in multiple
sclerosis. Ann NY Acad Sci 1965; 122:457-468.
4. Correale, J, Farez, Z. Association between parasite infection and
immune response in multiple sclerosis. Ann Neurol 2007; 61:97-108.
5. Lisak, RP, Kies, MW. Mycobacterial suppression of delayed
hypersensitivity in experimental allergic encephalomyelitis. Proc Soc Exp
Biol Med 1968; 28:214-218.
6. Lehmann, D, Ben-Nun, A. Bacterial agents protect against
autoimmune disease. I. Mice pre-exposed to Bordetella pertussis or
mycobacterim tuberculosis are highly refractory to induction of
experimental autoimmune encephalomyelitis. J Autoimmun 1992; 5:675-690.
7. Ben-Nun, A, Mendel, I, Sappler, G et al. A 12-kDa protein of
Mycobacterium tuberculosis protects mice against experimental autoimmune
encephalomyelitis. Protection in the absence of shared T cell epitopes
with encephalitogenic proteins. J Immunol 1995; 154:2939-2948.
8. Lisak, RP, Zweiman, B. Immune responses to myelin basic protein in
mycobacterial-induced suppression of experimental allergic
encephalomyelitis. (1974), Cell Immunol 14; 242-254.
9. Falk, GA, Kies, MW, Alvord, EC, Jr. Passive transfer of
experimental allergic encephalomyelitis: mechanisms of suppression. J
Immunol 1969; 103:1248-1253.
For disclosures, contact the editorial office at journal@neurology.org.
Ristori et al. studied the effect of vaccination with BCG on patients with a first-ever multiple sclerosis (MS) event. [1] The mechanisms involved in disease reduction by BCG vaccination raises interesting questions as discussed in the accompanying editorial [2] about types of infection and exposure to infectious agents and MS. Viral infections seem to increase the chances of a relapse [3] and concomitant parasitic infections have the opposite effect. [4]
Why disease activity is reduced by vaccination with BCG is unclear. [2] It is not known if active infection with a Mycobacterium is required to obtain this therapeutic effect. The relationship between Mycobacteria and other bacteria in the induction and prevention of experimental autoimmune ('allergic') encephalomyelitis (EAE) is complex with interactions dependent on the nature and dose of the bacterial agent and timing of exposure. [5] While active infection with Mycobacteria can inhibit EAE, active infection with mycobacteria is not always necessary for this effect. [5,6].
Animals pre-treated with heat killed M. tuberculosis as part of Complete Freund's Adjuvant (CFA) or some components of M. tuberculosis [7] inhibited actively-induced EAE but the mechanisms are unclear. This inhibition is associated with reduced cell-mediated reactivity to the inducing antigen, myelin basic protein (MBP), manifested by delayed hypersensitivity skin tests [5] and two in vitro assays that measured cell -mediated reactivity to antigens without reduction in response to PPD skin tests or tuberculin in vitro. [7,8]
The 12-kDa protein in PPD that protected mice from induction of EAE did not share epitopes with MBP. [7] Pre-treatment of recipient animals with CFA inhibited the development of EAE and skin test reactivity to MBP in recipient animals receiving sensitized cells from EAE donor animals vs other recipient animals not pretreated with CFA but receiving sensitized cells from EAE donor animals. [9] The mechanism/s for the reduction of reactivity to the inducing autoantigen is unclear [1] but possibilities include regulatory cells, induction of clonal anergy or-- less likely-- clonal deletion of the antigen-specific autoimmune cells. More than one mechanism may be involved in the protection in EAE and in MS.
1. Ristori, G, Romano, S, Cannoni, S, et al. Effects of Bacille Calmette-Guerin after the first demyelianting event in the CNS. Neurology 2014; 82:41-48.
2. Bourdette, D, Naismith, RT. BCG vaccine for clinically isolated syndrome and MS. Infections and protective immunity. Neurology 2014; 82:15-16.
3. Sibley, WA, Foley, JM. Infection and immunization in multiple sclerosis. Ann NY Acad Sci 1965; 122:457-468.
4. Correale, J, Farez, Z. Association between parasite infection and immune response in multiple sclerosis. Ann Neurol 2007; 61:97-108.
5. Lisak, RP, Kies, MW. Mycobacterial suppression of delayed hypersensitivity in experimental allergic encephalomyelitis. Proc Soc Exp Biol Med 1968; 28:214-218.
6. Lehmann, D, Ben-Nun, A. Bacterial agents protect against autoimmune disease. I. Mice pre-exposed to Bordetella pertussis or mycobacterim tuberculosis are highly refractory to induction of experimental autoimmune encephalomyelitis. J Autoimmun 1992; 5:675-690.
7. Ben-Nun, A, Mendel, I, Sappler, G et al. A 12-kDa protein of Mycobacterium tuberculosis protects mice against experimental autoimmune encephalomyelitis. Protection in the absence of shared T cell epitopes with encephalitogenic proteins. J Immunol 1995; 154:2939-2948.
8. Lisak, RP, Zweiman, B. Immune responses to myelin basic protein in mycobacterial-induced suppression of experimental allergic encephalomyelitis. (1974), Cell Immunol 14; 242-254.
9. Falk, GA, Kies, MW, Alvord, EC, Jr. Passive transfer of experimental allergic encephalomyelitis: mechanisms of suppression. J Immunol 1969; 103:1248-1253.
For disclosures, contact the editorial office at journal@neurology.org.