Table 2. Association between endogenous expression of IFN-β-inducible genes in peripheral blood mononuclear cells with T-cell reactivity to myelin basic protein (MBP) and tetanus toxoid (TT) in untreated MS patients.
| Gene expression ratio (MBP responders/ non-responders) a | IFN-ß treatment induced changes in gene expression b | Gene expression ratio (TT proliferation high/ low) c | |||||
|---|---|---|---|---|---|---|---|
| Representative public ID | Gene symbol | Expression ratio | P-value | Gene expression | FDR | Gene expression | P-value |
| AA393940 | --- | 2,38983 | 0,00004 | 1,05436 | 0,71439 | 0,65885 | 0,07972 |
| AF127481 | --- | 0,66090 | 0,00568 | 0,80634 | 0,23709 | 1,72837 | 0,09079 |
| AL527773 | ABR | 0,60767 | 0,00796 | 0,94413 | 0,44159 | 0,79811 | 0,44018 |
| S69189 | ACOX1 | 0,60974 | 0,00695 | 0,85280 | 0,13347 | 0,73019 | 0,19905 |
| NM_006395 | ATG7 | 0,53188 | 0,00587 | 1,20249 | 0,00433 | 0,71277 | 0,30945 |
| U72937 | ATRX | 0,65347 | 0,00415 | 0,72367 | 0,00094 | 0,65718 | 0,12609 |
| AB035482 | C1orf38 | 0,65053 | 0,00801 | 1,63014 | 0,00000 | 0,80314 | 0,38388 |
| U62027 | C3AR1 | 0,59222 | 0,00348 | 2,64914 | 0,00001 | 0,68092 | 0,19756 |
| U47924 | CD4 | 0,62806 | 0,00558 | 0,92128 | 0,56399 | 0,74489 | 0,22181 |
| NM_001784 | CD97 | 0,64874 | 0,00816 | 1,35297 | 0,00026 | 0,78190 | 0,32496 |
| AL564683 | CEBPB | 0,63381 | 0,00476 | 1,50631 | 0,00014 | 0,77715 | 0,08505 |
| NM_005195 | CEBPD | 0,63337 | 0,00417 | 1,61098 | 0,00140 | 0,77148 | 0,30036 |
| NM_006090 | CEPT1 | 0,51559 | 0,00032 | 1,05430 | 0,64946 | 0,67176 | 0,16979 |
| NM_000760 | CSF3R | 0,56506 | 0,00785 | 1,56528 | 0,00008 | 0,76494 | 0,36178 |
| NM_004383 | CSK | 0,50162 | 0,00561 | 1,12576 | 0,18584 | 0,55615 | 0,14777 |
| N25915 | CUGBP1 | 0,49958 | 0,00484 | 0,74453 | 0,03732 | 0,55201 | 0,15624 |
| NM_004417 | DUSP1 | 0,44522 | 0,00398 | 1,52685 | 0,00020 | 0,56529 | 0,11542 |
| NM_001953 | ECGF1 | 0,51953 | 0,00732 | 4,53205 | 0,00002 | 1,12746 | 0,76894 |
| BC000533 | EIF3S8 | 0,63224 | 0,00664 | 0,79373 | 0,01835 | 0,74438 | 0,35954 |
| NM_012177 | FBXO5 | 0,66612 | 0,00629 | 0,85859 | 0,27780 | 0,58712 | 0,00558 |
| AW001443 | GGA1 | 0,49321 | 0,00502 | 0,70943 | 0,00408 | 0,64771 | 0,26468 |
| AW009695 | GGA1 | 0,48944 | 0,00551 | 0,70032 | 0,00746 | 0,60170 | 0,24124 |
| NM_004126 | GNG11 | 1,53490 | 0,00020 | 0,81936 | 0,01488 | 1,25208 | 0,25286 |
| BC000324 | GRN | 0,60910 | 0,00900 | 2,15801 | 0,00000 | 0,96352 | 0,88274 |
| NM_022460 | HS1BP3 | 0,61000 | 0,00873 | 1,09055 | 0,26549 | 0,78109 | 0,25038 |
| AF141870 | ILF3 | 0,46941 | 0,00869 | 0,73496 | 0,03630 | 0,52984 | 0,16518 |
| NM_002199 | IRF2 | 0,61305 | 0,00405 | 2,13032 | 0,00042 | 0,62974 | 0,12245 |
| NM_006084 | ISGF3G | 0,65931 | 0,00629 | 1,48177 | 0,00002 | 0,81538 | 0,35916 |
| NM_002229 | JUNB | 0,42768 | 0,00074 | 2,00080 | 0,00000 | 0,54768 | 0,06116 |
| NM_005354 | JUND | 0,58269 | 0,00860 | 1,34615 | 0,01096 | 0,63146 | 0,21424 |
| NM_007054 | KIF3A | 0,62358 | 0,00228 | 0,62132 | 0,00137 | 0,64832 | 0,01398 |
| NM_016285 | KLF12 | 0,60366 | 0,00182 | 0,67407 | 0,00478 | 0,63583 | 0,06954 |
| BF514079 | KLF4 | 0,59463 | 0,00091 | 1,32022 | 0,00059 | 0,71383 | 0,12362 |
| NM_005461 | MAFB | 0,60432 | 0,00356 | 3,03565 | 0,00000 | 0,72817 | 0,20138 |
| NM_002406 | MGAT1 | 0,55525 | 0,00223 | 1,45918 | 0,00004 | 0,70792 | 0,19953 |
| NM_005931 | MICB | 0,62026 | 0,00773 | 1,05054 | 0,69661 | 0,62686 | 0,12993 |
| NM_014381 | MLH3 | 1,55617 | 0,00037 | 0,98685 | 0,89715 | 1,30512 | 0,22600 |
| NM_012331 | MSRA | 0,66622 | 0,00478 | 0,95432 | 0,51950 | 0,74943 | 0,08485 |
| NM_017458 | MVP | 0,55557 | 0,00277 | 1,89293 | 0,00000 | 0,73133 | 0,26680 |
| U70451 | MYD88 | 0,57903 | 0,00055 | 1,91913 | 0,00000 | 0,73916 | 0,17010 |
| NM_002505 | NFYA | 0,49007 | 0,00928 | 0,92316 | 0,55970 | 0,48639 | 0,13324 |
| NM_013392 | NRBP1 | 0,52913 | 0,00542 | 1,05099 | 0,58002 | 0,70485 | 0,30052 |
| AI824012 | NRIP1 | 0,53985 | 0,00219 | 1,67004 | 0,00233 | 0,60243 | 0,08224 |
| NM_002534 | OAS1 | 0,40953 | 0,00229 | 6,83506 | 0,00000 | 0,62769 | 0,25810 |
| NM_016817 | OAS2 | 0,54858 | 0,00293 | 4,85365 | 0,00000 | 0,77768 | 0,43984 |
| NM_006187 | OAS3 | 0,56192 | 0,00701 | 7,09851 | 0,00000 | 0,79581 | 0,45168 |
| AF242521 | OAZ2 | 0,62811 | 0,00292 | 1,11296 | 0,05416 | 0,78569 | 0,35423 |
| NM_023914 | P2RY13 | 0,53025 | 0,00107 | 1,61084 | 0,00057 | 0,74296 | 0,25271 |
| NM_002656 | PLAGL1 | 0,71437 | 0,01698 | 1,23990 | 0,07508 | 0,59712 | 0,00765 |
| NM_018444 | PPM2C | 0,55737 | 0,00865 | 0,89289 | 0,33921 | 0,67981 | 0,24250 |
| NM_007318 | PSEN1 | 0,61678 | 0,00925 | 1,05178 | 0,46844 | 0,66741 | 0,15644 |
| NM_002806 | PSMC6 | 0,79988 | 0,16321 | 0,79397 | 0,00226 | 0,66459 | 0,00427 |
| NM_002872 | RAC2 | 0,66609 | 0,00465 | 0,96417 | 0,69396 | 0,68330 | 0,08692 |
| NM_002902 | RCN2 | 0,81450 | 0,11315 | 0,50180 | 0,00001 | 0,60390 | 0,00465 |
| AI263909 | RHOB | 0,37747 | 0,00029 | 3,49399 | 0,00001 | 0,55096 | 0,10617 |
| NM_012249 | RHOQ | 0,59453 | 0,00037 | 1,13092 | 0,19030 | 0,71506 | 0,14372 |
| BE897886 | RHOQ | 0,54734 | 0,00163 | 1,06784 | 0,42048 | 0,56116 | 0,07599 |
| NM_002939 | RNH1 | 0,52587 | 0,00221 | 1,44191 | 0,00004 | 0,92825 | 0,81932 |
| NM_000979 | RPL18 | 1,50894 | 0,00011 | 0,69713 | 0,00006 | 1,33955 | 0,02902 |
| NM_003942 | RPS6KA4 | 0,58647 | 0,00545 | 1,30240 | 0,05970 | 0,71857 | 0,34645 |
| AI871457 | SFRS8 | 0,77329 | 0,02205 | 0,74400 | 0,00536 | 0,64223 | 0,00582 |
| NM_005627 | SGK | 0,56251 | 0,00198 | 0,67001 | 0,00243 | 0,73625 | 0,28065 |
| NM_020979 | SH2B2 | 0,62734 | 0,00053 | 1,65552 | 0,00000 | 0,80701 | 0,28688 |
| AI025519 | SLC26A2 | 0,58834 | 0,00438 | 0,62356 | 0,00097 | 0,62053 | 0,13411 |
| AA524345 | SNX4 | 0,65104 | 0,00840 | 0,87639 | 0,20487 | 0,61664 | 0,07937 |
| X15132 | SOD2 | 0,67714 | 0,03673 | 1,60177 | 0,00032 | 0,56143 | 0,00801 |
| AL442077 | SPFH2 | 0,62805 | 0,00197 | 0,88592 | 0,12560 | 0,69761 | 0,07905 |
| M97935 | STAT1 | 0,54867 | 0,00826 | 2,23157 | 0,00000 | 0,69476 | 0,32416 |
| NM_005131 | THOC1 | 0,64186 | 0,00742 | 0,56570 | 0,00006 | 0,61169 | 0,06322 |
| NM_003266 | TLR4 | 0,61293 | 0,00465 | 1,45846 | 0,00045 | 0,68766 | 0,14945 |
| NM_016610 | TLR8 | 0,51446 | 0,00730 | 1,18074 | 0,08572 | 0,63275 | 0,25378 |
| NM_001243 | TNFRSF8 | 0,59619 | 0,00229 | 0,94210 | 0,62315 | 0,70852 | 0,17841 |
| NM_025195 | TRIB1 | 0,57316 | 0,00247 | 1,77640 | 0,00045 | 0,61108 | 0,07589 |
| AI363270 | TRIM38 | 0,61895 | 0,00611 | 1,45895 | 0,00016 | 0,65750 | 0,16616 |
| NM_030912 | TRIM8 | 0,64113 | 0,00047 | 1,11388 | 0,23857 | 0,76183 | 0,12478 |
| NM_007124 | UTRN | 0,55447 | 0,00563 | 1,07708 | 0,47925 | 0,57623 | 0,09694 |
| NM_004184 | WARS | 0,55612 | 0,00991 | 3,98419 | 0,00000 | 0,92506 | 0,81254 |
| NM_014795 | ZFHX1B | 0,56386 | 0,00468 | 1,16480 | 0,31749 | 0,52589 | 0,06223 |
| NM_003407 | ZFP36 | 0,54741 | 0,00230 | 1,42917 | 0,00657 | 0,59914 | 0,09480 |
| BG250310 | ZFP36L1 | 0,62283 | 0,00140 | 1,05199 | 0,61205 | 0,65364 | 0,10535 |
(a) In a previous study, 4 out of 17 patients responded to MBP with CD4+ T-cell proliferation ex vivo [21]. By DNA array analysis of gene expression [18], we found that 75 out of 3284 genes were more than 1.5-fold differentially expressed (p<0.01) in the 4 patients who had CD4+ T-cell reactivity to MBP as compared to the 13 patients who did not show CD4+ T-cell reactivity to MBP (differentially expressed genes are highlighted with bold letters). Data were obtained from the substudy-1 population and are given as ratio of the mean gene expression in both groups.
(b) We compared these results with data on IFN-β treatment-induced gene-expression levels in 23 patients from a recent study from our group [22]: 23 out of the 75 (31%) genes differentially expressed in patients with MBP-induced T-cell proliferation were induced at least 1.5-fold in patients treated with IFN-β (false discovery rate< 1% for all genes). Out of the remaining 3209 genes 171 (5.3%) were similarly induced after treatment with IFN-β (X2 = 84.64, df = 1, p<0.001).
(c) Data on TT reactivity were available from 12 patients from the sub-study 1 population [21]. Dividing the patients into two groups according to the level of TT reactivity (6 TT high responders vs. 6 TT low responders), we calculated the gene-expression ratio and identified 6 genes that were more than 1.5-fold differentially expressed (p<0.01; bold letters). (b) 4 out of these 6 genes were also significantly regulated by treatment with IFN-β, although only one of these genes was induced more than 1.5-fold.