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DQB1*0602 rather than DRB1*1501 confers susceptibility to multiple sclerosis-like disease induced by proteolipid protein (PLP).

Kaushansky N, Altmann DM, David CS, Lassmann H, Ben-Nun A - J Neuroinflammation (2012)

Bottom Line: Due to strong linkage disequilibrium in HLA-II region, it has been hard to establish precisely whether the functionally relevant effect derives from the DRB1*1501, DQA1*0102-DQB1*0602, or DRB5*0101 loci of HLA-DR15 haplotype, their combinations, or their epistatic interactions.Moreover, that DQB1*0602, but not DRB1*1501, determines disease-susceptibility to PLP in HLA-transgenics, suggests a potential differential, functional role for DQB1*0602 as a predisposing allele in MS.This, together with previously demonstrated disease-susceptibility to MBP and MOG in DRB1*1501-transgenics, also suggests a differential role for DRB1*1501 and DQB1*0602 depending on target antigen and imply a potential complex 'genotype/target antigen/phenotype' relationship in MS heterogeneity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.

ABSTRACT

Background: Multiple sclerosis (MS) is associated with pathogenic autoimmunity primarily focused on major CNS-myelin target antigens including myelin basic protein (MBP), proteolipidprotein (PLP), myelin oligodendrocyte protein (MOG). MS is a complex trait whereby the HLA genes, particularly class-II genes of HLA-DR15 haplotype, dominate the genetic contribution to disease-risk. Due to strong linkage disequilibrium in HLA-II region, it has been hard to establish precisely whether the functionally relevant effect derives from the DRB1*1501, DQA1*0102-DQB1*0602, or DRB5*0101 loci of HLA-DR15 haplotype, their combinations, or their epistatic interactions. Nevertheless, most genetic studies have indicated DRB1*1501 as a primary risk factor in MS. Here, we used 'HLA-humanized' mice to discern the potential relative contribution of DRB1*1501 and DQB1*0602 alleles to susceptibility to "humanized" MS-like disease induced by PLP, one of the most prominent and encephalitogenic target-antigens implicated in human MS.

Methods: The HLA-DRB1*1501- and HLA-DQB1*0602-Tg mice (MHC-II(-/-)), and control non-HLA-DR15-relevant-Tg mice were immunized with a set of overlapping PLP peptides or with recombinant soluble PLP for induction of "humanized" MS-like disease, as well as for ex-vivo analysis of immunogenic/immunodominant HLA-restricted T-cell epitopes and associated cytokine secretion profile.

Results: PLP autoimmunity in both HLA-DR15-Tg mice was focused on 139-151 and 175-194 epitopes. Strikingly, however, the HLA-DRB1*1501-transgenics were refractory to disease induction by any of the overlapping PLP peptides, while HLA-DQB1*0602 transgenics were susceptible to disease induction by PLP139-151 and PLP175-194 peptides. Although both transgenics responded to both peptides, the PLP139-151- and PLP175-194-reactive T-cells were directed to Th1/Th17 phenotype in DQB1*0602-Tg mice and towards Th2 in DRB1*1501-Tg mice.

Conclusions: While genome studies map a strong MS susceptibility effect to the region of DRB1*1501, our findings offer a rationale for potential involvement of pathogenic DQ6-associated autoimmunity in MS. Moreover, that DQB1*0602, but not DRB1*1501, determines disease-susceptibility to PLP in HLA-transgenics, suggests a potential differential, functional role for DQB1*0602 as a predisposing allele in MS. This, together with previously demonstrated disease-susceptibility to MBP and MOG in DRB1*1501-transgenics, also suggests a differential role for DRB1*1501 and DQB1*0602 depending on target antigen and imply a potential complex 'genotype/target antigen/phenotype' relationship in MS heterogeneity.

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Histopathology of PLP-induced EAE in HLA DQB1*0602 Tg mouse. Samples were taken on day19 after immunization. Panel (A) shows the spinal cord, (B) the cerebellum and (C) the optic nerve. The sections were stained with hematoxylin & eosin (a), Luxol fast blue for myelin. (b) Bieschowsky silver impregnation for axons (c) and by immunocytochemistry for CD3 (d), and Mac-3 (e). Note the unusually profound inflammation in the cortex and optic nerve. Original magnifications: A and B: × 25; C: × 100.
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Figure 6: Histopathology of PLP-induced EAE in HLA DQB1*0602 Tg mouse. Samples were taken on day19 after immunization. Panel (A) shows the spinal cord, (B) the cerebellum and (C) the optic nerve. The sections were stained with hematoxylin & eosin (a), Luxol fast blue for myelin. (b) Bieschowsky silver impregnation for axons (c) and by immunocytochemistry for CD3 (d), and Mac-3 (e). Note the unusually profound inflammation in the cortex and optic nerve. Original magnifications: A and B: × 25; C: × 100.

Mentions: We analyzed the histopathology associated with the development of EAE induced in DQB1*0602-Tg mice by phPLP175-194, as the more potent encephalitogenic peptide compared to phPLP139-151. The histopathological analysis of the spinal cord, brain and optic nerves show, gross pathological changes typical of classical EAE, consistent of inflammation (Figure 6a, d, e), demyelination (Figure 6b) and axonal loss (Figure 6c). Inflammatory infiltrates were composed mainly of CD3 positive T-cells (Figure 6Ad, Bd, Cd) and macrophages (Figure 6Ae, Be, Ce). In addition, profound microglia activation was seen in affected brain and spinal cord regions (Figure 6Ae, Be) and optic nerve (Figure 6Ce). An unusual finding was the profound involvement of the brain (shown here in the cerebellum and optic nerves) in comparison to the spinal cord. Generally, EAE induced by PLP or MOG in wild-type mice, the disease mainly affects the spinal cord, and with increasing disease severity there is an additional involvement of CNS region, but a gradient remains with the most severe lesions in the spinal cord compared to other regions of the CNS. Pathological analysis of phPLP175-194-induced EAE in DQ6-Tg mice (Figure 6) shows severe brain involvement [cerebellum (Figure 6B) and optic nerves (Figure 6C)] exceeding that of spinal cord involvement (Figure 6A). Inflammatory infiltrates were composed mainly of CD3 positive T-cells (Figure 6Ad, Bd, Cd) and macrophages Figure 6Ae, Be, Ce). In addition, profound microglia activation was seen in affected brain and spinal cord regions (Figure 6Ae, Be) and optic nerve (Figure 6Ce). Inflammation was also associated with a variably extent of demyelination and acute axonal injury (Figure 6a-c in A-C). Goverman and colleagues [42] have suggested that strong involvement of the cerebellum and brainstem is a feature of Th17-driven disease, which is in line with the high Th17 secretion by PLP175-194-primed LNC derived from DQB1*0602-Tg mice (Figure 5).


DQB1*0602 rather than DRB1*1501 confers susceptibility to multiple sclerosis-like disease induced by proteolipid protein (PLP).

Kaushansky N, Altmann DM, David CS, Lassmann H, Ben-Nun A - J Neuroinflammation (2012)

Histopathology of PLP-induced EAE in HLA DQB1*0602 Tg mouse. Samples were taken on day19 after immunization. Panel (A) shows the spinal cord, (B) the cerebellum and (C) the optic nerve. The sections were stained with hematoxylin & eosin (a), Luxol fast blue for myelin. (b) Bieschowsky silver impregnation for axons (c) and by immunocytochemistry for CD3 (d), and Mac-3 (e). Note the unusually profound inflammation in the cortex and optic nerve. Original magnifications: A and B: × 25; C: × 100.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3344688&req=5

Figure 6: Histopathology of PLP-induced EAE in HLA DQB1*0602 Tg mouse. Samples were taken on day19 after immunization. Panel (A) shows the spinal cord, (B) the cerebellum and (C) the optic nerve. The sections were stained with hematoxylin & eosin (a), Luxol fast blue for myelin. (b) Bieschowsky silver impregnation for axons (c) and by immunocytochemistry for CD3 (d), and Mac-3 (e). Note the unusually profound inflammation in the cortex and optic nerve. Original magnifications: A and B: × 25; C: × 100.
Mentions: We analyzed the histopathology associated with the development of EAE induced in DQB1*0602-Tg mice by phPLP175-194, as the more potent encephalitogenic peptide compared to phPLP139-151. The histopathological analysis of the spinal cord, brain and optic nerves show, gross pathological changes typical of classical EAE, consistent of inflammation (Figure 6a, d, e), demyelination (Figure 6b) and axonal loss (Figure 6c). Inflammatory infiltrates were composed mainly of CD3 positive T-cells (Figure 6Ad, Bd, Cd) and macrophages (Figure 6Ae, Be, Ce). In addition, profound microglia activation was seen in affected brain and spinal cord regions (Figure 6Ae, Be) and optic nerve (Figure 6Ce). An unusual finding was the profound involvement of the brain (shown here in the cerebellum and optic nerves) in comparison to the spinal cord. Generally, EAE induced by PLP or MOG in wild-type mice, the disease mainly affects the spinal cord, and with increasing disease severity there is an additional involvement of CNS region, but a gradient remains with the most severe lesions in the spinal cord compared to other regions of the CNS. Pathological analysis of phPLP175-194-induced EAE in DQ6-Tg mice (Figure 6) shows severe brain involvement [cerebellum (Figure 6B) and optic nerves (Figure 6C)] exceeding that of spinal cord involvement (Figure 6A). Inflammatory infiltrates were composed mainly of CD3 positive T-cells (Figure 6Ad, Bd, Cd) and macrophages Figure 6Ae, Be, Ce). In addition, profound microglia activation was seen in affected brain and spinal cord regions (Figure 6Ae, Be) and optic nerve (Figure 6Ce). Inflammation was also associated with a variably extent of demyelination and acute axonal injury (Figure 6a-c in A-C). Goverman and colleagues [42] have suggested that strong involvement of the cerebellum and brainstem is a feature of Th17-driven disease, which is in line with the high Th17 secretion by PLP175-194-primed LNC derived from DQB1*0602-Tg mice (Figure 5).

Bottom Line: Due to strong linkage disequilibrium in HLA-II region, it has been hard to establish precisely whether the functionally relevant effect derives from the DRB1*1501, DQA1*0102-DQB1*0602, or DRB5*0101 loci of HLA-DR15 haplotype, their combinations, or their epistatic interactions.Moreover, that DQB1*0602, but not DRB1*1501, determines disease-susceptibility to PLP in HLA-transgenics, suggests a potential differential, functional role for DQB1*0602 as a predisposing allele in MS.This, together with previously demonstrated disease-susceptibility to MBP and MOG in DRB1*1501-transgenics, also suggests a differential role for DRB1*1501 and DQB1*0602 depending on target antigen and imply a potential complex 'genotype/target antigen/phenotype' relationship in MS heterogeneity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.

ABSTRACT

Background: Multiple sclerosis (MS) is associated with pathogenic autoimmunity primarily focused on major CNS-myelin target antigens including myelin basic protein (MBP), proteolipidprotein (PLP), myelin oligodendrocyte protein (MOG). MS is a complex trait whereby the HLA genes, particularly class-II genes of HLA-DR15 haplotype, dominate the genetic contribution to disease-risk. Due to strong linkage disequilibrium in HLA-II region, it has been hard to establish precisely whether the functionally relevant effect derives from the DRB1*1501, DQA1*0102-DQB1*0602, or DRB5*0101 loci of HLA-DR15 haplotype, their combinations, or their epistatic interactions. Nevertheless, most genetic studies have indicated DRB1*1501 as a primary risk factor in MS. Here, we used 'HLA-humanized' mice to discern the potential relative contribution of DRB1*1501 and DQB1*0602 alleles to susceptibility to "humanized" MS-like disease induced by PLP, one of the most prominent and encephalitogenic target-antigens implicated in human MS.

Methods: The HLA-DRB1*1501- and HLA-DQB1*0602-Tg mice (MHC-II(-/-)), and control non-HLA-DR15-relevant-Tg mice were immunized with a set of overlapping PLP peptides or with recombinant soluble PLP for induction of "humanized" MS-like disease, as well as for ex-vivo analysis of immunogenic/immunodominant HLA-restricted T-cell epitopes and associated cytokine secretion profile.

Results: PLP autoimmunity in both HLA-DR15-Tg mice was focused on 139-151 and 175-194 epitopes. Strikingly, however, the HLA-DRB1*1501-transgenics were refractory to disease induction by any of the overlapping PLP peptides, while HLA-DQB1*0602 transgenics were susceptible to disease induction by PLP139-151 and PLP175-194 peptides. Although both transgenics responded to both peptides, the PLP139-151- and PLP175-194-reactive T-cells were directed to Th1/Th17 phenotype in DQB1*0602-Tg mice and towards Th2 in DRB1*1501-Tg mice.

Conclusions: While genome studies map a strong MS susceptibility effect to the region of DRB1*1501, our findings offer a rationale for potential involvement of pathogenic DQ6-associated autoimmunity in MS. Moreover, that DQB1*0602, but not DRB1*1501, determines disease-susceptibility to PLP in HLA-transgenics, suggests a potential differential, functional role for DQB1*0602 as a predisposing allele in MS. This, together with previously demonstrated disease-susceptibility to MBP and MOG in DRB1*1501-transgenics, also suggests a differential role for DRB1*1501 and DQB1*0602 depending on target antigen and imply a potential complex 'genotype/target antigen/phenotype' relationship in MS heterogeneity.

Show MeSH
Related in: MedlinePlus