Peptides used in Experimental Encephalomyelitis Models

Encephalomyelitis (EAE), is a widely used animal model for studies of multiple sclerosis. EAE is induced by stimulating T-cell-mediated immunity to myelin antigens. Active induction of EAE is accomplished by immunization with myelin antigens emulsified in adjuvant. The most common EAE models currently studied use rats and mice. Mice are favored because of the abundance of transgenic and targeted gene-deletion models and the numerous antibodies and immunomodulatory reagents available in this species that can be used to dissect the pathogenic mechanisms in EAE.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Even thought all MS patients exhibit signs of neurological deficit, there is considerable variation in the clinical signs and disease course among individuals. The

pathology in the CNS is very heterogeneous, suggesting that MS may be more accurately described as a syndrome arising from multiple pathogenic pathways, rather than a single disease entity. Mechanistic insights into the complex pathogenesis of MS have relied extensively on animal models of CNS demyelination. Although several different models of demyelinating disease in the CNS exist, the most commonly used animal model for MS is EAE. EAE is induced by stimulating an immune response directed against CNS antigens. The origin of the model dates back to 1925 with the discovery that rabbits immunized with human spinal cord homogenate exhibited spinal cord inflammation and paralysis (referred to as active induction). In the 1930s, Rivers et al. showed that EAE could be induced in primates using multiple injections of emulsions of normal rabbit brain tissue. Subsequently, Paterson demonstrated that transfer of lymph node cells from rats immunized with spinal cord homogenate into naïve animals also induced EAE (referred to as passive induction).

Both multiple sclerosis and EAE are considered to be Th1-mediated autoimmune diseases in which neuroantigen-reactive lymphocytes infiltrate the CNS, mediate the development

of inflammatory lesions, and in some models, trigger the demyelination of axons leading to progressive paralysis. Elevated levels of IL-12 have been reported in humans with progressive multiple sclerosis. Increased frequencies of IL-12–secreting monocytes appear to correlate with active brain lesions detected by magnetic resonance imaging. IL-12 has been functionally implicated in the development of EAE by the observations that αIL-12 (αp70) blocks disease development in mice and IL-12 p40–/– mice are resistant to EAE induction.

Active Induction of EAE with PLP and MBP Protein or Peptide

Experimental autoimmune encephalomyelitis (EAE) can be induced in SJL mice by immunization with proteolipid protein (PLP), myelin basic protein (MBP), or peptides. Peptides used correspond to the immunodominant epitopes of MBP (MBP84-104), MOG (MOG92-106), or PLP (PLP139-151 and PLP178-191). In C57BL/6 mice the disease can be induced by immunization with the peptide corresponding to the immunodominant epitope of MOG (MOG35-55).

SJL Mice Info:  Inbr: F104 (J). Albino. Genet: c, p, rd. Origin: Swiss Webster outbred stock from three sources that were brought to The Jackson Laboratory between 1938 and 1943, and pen-bred until 1955, when sib-mating was started. Although the strain has been developed relatively recently, it has rapidly become widely used owing to the high incidence of reticulum cell sarcomas resembling Hodgkin's disease. General biological data on the strain have been reviewed by Crispens (1973). Carries the pink-eyed dilution gene, p, which is derived from Asian mice of the Mus musculus type (see also strains 129/J, P/J and FS/Ei) (Brilliant et al, 1994).

 Source: http://www.informatics.jax.org/external/festing/mouse/docs/SJL.shtml

TABLE 1:      Murine EAE models^a. Encephalitogenic Peptides of MBP, PLP, and MOG in Various Inbred Mouse Strains

Mouse strain	MHC	Peptide	Peptide sequence	Peptide origin	Clinical course
PL/J	H-2u	MBPAc1-11	Ac-ASQKRPSQRHG	rat	Classic
B10.PL	H-2u	MBPAc1-9 PLP178-191 MBP35-47 PLP43-64	Ac-ASQKRPSQR NTWTTCQSIAFPSK TGILDSIGRFFSG EKLIETYFSKNYQDYEYLINVI	rat/mouse mouse rat/mouse mouse	Classic Classic Classic Classic
SJL/J	H-2s	PLP139-151 PLP139-151b PLP178-191 MBP84-104b MBP89-101 MOG92-106d PLP57-70 PLP104-117	HCLGKWLGHPDKF HSLGKWLGHPDKF NTWTTCQSIAFPSK VHFFKNIVTPRTPPPSQGKGR VHFFKNIVTPRTP DEGGYTCFFRDHSYQ YEYLINVIHAFQYV KTTICGKGLSATVT	human/mouse human/mouse mouse rat rat ? mouse mouse mouse	Classicc Classicc Classicc Classicc Classic Classic Classic Classic
C57BL/6	H-2b	MOG35-55 MOG35-55 PLP178-191	MEVGWYRSPFSRVVHLYRNGK MEVGWYRPPFSRVVHLYRNGK NTWTTCQSIAFPSK	rat/mouse human mouse	Classic Classic Classic
NOD	H-2g7	MOG35-55 PLP48-70 PLP56-70	MEVGWYRSPFSRVVHLYRNGK TYFSKNYQDYEYLINIHAFQYV DYEYLINVIHAFQYV	rat/mouse human/mouse	Classic Classic
C3H.SW C3H	H-2b H-2k	MOG35-55 PLP103-116	MEVGWYRSPFSRVVHLYRNGK YKTTICGKGLSATV	rat/mouse	Classic
ABH (Biozzi)	H-2dq1	PLP56-70 MOG8-22	DYEYLINVIHAFQYV PGYPIRALVGDEQED	mouse rat	Classic Classic
A.SW	H-2s	MOG92-106d	DEGGYTCFFRDHSYQ	rat	Atypical
C3H/HeJ	H-2k	PLP190-209 PLP215-232	SKTSASIGSLCADARMYGVL PGKVCGSNLLSICKTAEFQ	human/mouse human/mouse	Classic or Atypical Classic or Atypical
CBA/J	H-2k	PLP190-209 PLP215-232	SKTSASIGSLCADARMYGVL PGKVCGSNLLSICKTAEFQ	human/mouse human/mouse	Atypical Atypical
DBA/1	H-2q	MOG79-96d	GKVALRIONVRFSDHGGY	rat	Classic
BALB/cPt	H-2d	PLP178-191	NTWTTCQSIAFPSK	mouse	na
(SJLX C3H/HeJ)F1	H-2s/k	PLP190-209 PLP215-232	SKTSASIGSLCADARMYGVL PGKVCGSNLLSICKTAEFQ	mouse	na
(SJL X B10.PL) F1	H-2s/q	PLP139-151 PLP178-191 MBPAc1-11	HSLGKWLGHPDKF NTWTTCQSIAFPSK Ac-ASQKRPQRHG	mouse mouse rat/mouse	na
SWR	H-2q	PLP215-232	PGKVCGSNLLSICKTAEF	na	na
(PL/J X SJL) F1	H-2s/u	MBPAc1-11 PLP43-64 PLP139-151	Ac-ASQKRPQRHG EKLIETYFSKNYQDYEYLINVI HSLGKWLGHPDKF	na	na

This table summarizes a variety of murine EAE models that can be actively induced with emphasis on the dominant encephalitogenic epitopes that have been described. This list is not inclusive of all EAE murine models reported in the literature. Strains that are in bold are the most commonly used.

^bMultiple peptides within this region are encephalitogenic.

^cReported to exhibit relapsing-remitting clinical course.

^dPertussis toxin is not required for EAE induction with this strain/antigen combination, but influences the clinical course in A.SW mice.

MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein.

Note 1:  The EAE observed in some of these mice is nonclassical. In (SJL X C3H/HeJ)F1 mice, the disease causes imbalance and axial rotary movement (rotary EAE). In BALB/cPt, mice show lack of balance and forelimb paralysis in the absence of hindlimb paralysis.

Note 2:  Sequences for MBP peptides are based on different species variants of MBP, which have different numbering systems; sequences for PLP and MOG peptides are based on the mouse sequence. The reader is urged to consult the indicated references for more detailed information.

References

Burkhard Becher, Brigit G. Durell, and Randolph J. Noelle; Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12 J. Clin. Invest. 110:493–497 (2002).

Brilliant M. H., Ching A., Nakatsu Y., and Eicher E. M. (1994) The original pink-eyed dilution mutation (p) arose in asiatic mice: Implications for the H4 minor histocompatibility antigen, Myod1 regulation and the origin of inbred strains. Genetics 138, 203-211. \par
Crispens C. G. (1973) Some characteristics of strain SJL/JDg mice. Lab. Animal Scie.  23, 408-413. \par

Ingunn M Stromnes & Joan M Goverman; Active induction of experimental allergic encephalomyelitis Nature Protocols 1, 1810 - 1819 (2006)

Stephen D. Miller, William J. Karpus, and Todd Scott Davidson; Experimental Autoimmune Encephalomyelitis in the Mouse Curr Protoc Immunol. 2007 May ; CHAPTER: Unit–15.1. doi:10.1002/0471142735.im1501s77