Bridging the gap from genetic association to functional understanding: the next generation of mouse models of multiple sclerosis

Abstract

Summary: Multiple sclerosis (MS) is a disabling autoimmune disease of the central nervous system, which affects approximately 0.1% of the population with variable degrees of severity. Disease susceptibility is jointly determined by genetic predisposition and environmental contribution. However, as only a handful of genetic risk factors have been investigated beyond initial genome‐wide association studies and environmental factors are largely unidentified, the exact mechanism of how these associations interact remains speculative. Our current understanding of this complex and heterogeneous disease has been advanced by experimental data obtained from animal modeling, with particular focus on the mouse MS model, experimental autoimmune encephalomyelitis. Manipulation of the mouse genome to study genetic risk factors has largely proved informative, but it also has limitations. Integration effects of transgene insertion, gene copy number, and expression variation, as well as differences in regulatory elements between mouse and human, are some of the hurdles faced when using such models to understand human gene variants in mice. Furthermore, as the list of MS disease‐associated genetic variants continues to increase, so does the demand to find new approaches to study them. A new generation of humanized mice aims to tighten the gap between mouse and human, such that MS‐associated genetic variants can be modeled more physiologically and systematically.

The HLA-DRB1*15

“…11 DRB1*15:01 Tg mice were immunized with a1(IV)NC1, a3(IV)NC1, or the E A chimera (containing ha3 [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] or the E B chimera (containing ha3 127-141 overlapping the restricted T cell epitope), and lymphocytes were then re-stimulated with either murine a3 9-28 or a3 129-148 . Mice immunized with a1(IV)NC1 or the E A chimera responded to neither peptide ( Figure 4A), whereas mice immunized with the E B chimera or full-length a3(IV)NC1 responded to a3 129-148 but not a3 [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] . Further groups of mice were immunized with a3(IV)NC1, the E A chimera, or the E B chimera and re-stimulated with chimeric and whole proteins.…”

“…12 However, in the Wistar Kyoto (WKY) rat, T cell reactivity occurs in several different areas. [13][14][15] T cell-mediated disease can be induced by a3 [14][15][16][17][18][19][20][21][22][23][24][25][26] and a3 11-25 15-17 and there is evidence of epitope spreading to involve B cell epitopes. 16,18 Our hypothesis was based on studies in humans with anti-GBM GN showing strong MHC II association and suggesting key epitopes.…”

“…We studied mice that were entirely deficient in mouse MHC II, 19,20 but that coexpressed the essentially nonpolymorphic HLA-DRA1*01:01, with either HLA-DRB1*15:01 or DRB1*01:01. HLA transgenic mice, especially those lacking all murine MHC II elements, 19 have been powerful tools in studying the pathogenesis of autoimmune disease, 20,21 because their CD4 + T cell repertoire is shaped by the presence of human (but not mouse) MHC II molecules. We found that in anti-GBM GN, a3 136-146 is an immunodominant and nephritogenic CD4 + T epitope in DRB1*15:01 Tg mice, but not in DRB1*01:01 Tg or C57BL/6 mice.…”

“…Autoantibodies bind to the conformational a3(IV) NC1 epitopes "E A " a3 [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] and "E B " a3 127-141 (all amino acid numbering, including other cited epitopes, follows Netzer et al). 11 Studies examining T cell epitopes in human anti-GBM disease are less common, although an important study showed reactivity to two peptides, a3 68-89 and a3 [129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148] (close to the E B autoantibody epitope), in all six patients studied.…”

Preferential Recruitment of Neutrophils into the Cerebellum and Brainstem Contributes to the Atypical Experimental Autoimmune Encephalomyelitis Phenotype

“…However, no single model can recapitulate the complexity of MS in humans, indicating a clear need for developing and characterizing new animal models (52,53). We recently demonstrated that deletion of SOCS3 in myeloid cells was associated with a particularly severe form of atypical EAE, characterized by prominent macrophage and neutrophil infiltration into the CRB, enhanced STAT3 signaling, and ataxia and tremors (3).…”