JP6068362B2 - 腸および血液脳関門の透過性を検出する方法、およびその試験材料 - Google Patents
腸および血液脳関門の透過性を検出する方法、およびその試験材料 Download PDFInfo
- Publication number
- JP6068362B2 JP6068362B2 JP2013551330A JP2013551330A JP6068362B2 JP 6068362 B2 JP6068362 B2 JP 6068362B2 JP 2013551330 A JP2013551330 A JP 2013551330A JP 2013551330 A JP2013551330 A JP 2013551330A JP 6068362 B2 JP6068362 B2 JP 6068362B2
- Authority
- JP
- Japan
- Prior art keywords
- intestinal
- igg
- iga
- igm
- zonulin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000012360 testing method Methods 0.000 title claims description 51
- 230000007358 intestinal barrier function Effects 0.000 title claims description 37
- 238000000034 method Methods 0.000 title claims description 34
- 210000001218 blood-brain barrier Anatomy 0.000 title description 85
- 230000008499 blood brain barrier function Effects 0.000 title description 84
- 230000035699 permeability Effects 0.000 title description 28
- 239000000463 material Substances 0.000 title description 7
- 210000000936 intestine Anatomy 0.000 title description 3
- 239000000427 antigen Substances 0.000 claims description 99
- 102000036639 antigens Human genes 0.000 claims description 99
- 108091007433 antigens Proteins 0.000 claims description 99
- 239000002158 endotoxin Substances 0.000 claims description 78
- 229920006008 lipopolysaccharide Polymers 0.000 claims description 67
- 102100025255 Haptoglobin Human genes 0.000 claims description 48
- 108010027843 zonulin Proteins 0.000 claims description 48
- 230000000968 intestinal effect Effects 0.000 claims description 46
- 108090000623 proteins and genes Proteins 0.000 claims description 41
- 102000004169 proteins and genes Human genes 0.000 claims description 41
- 102000003940 Occludin Human genes 0.000 claims description 38
- 108090000304 Occludin Proteins 0.000 claims description 38
- 210000005027 intestinal barrier Anatomy 0.000 claims description 34
- 231100000699 Bacterial toxin Toxicity 0.000 claims description 28
- 239000000688 bacterial toxin Substances 0.000 claims description 28
- 102000000591 Tight Junction Proteins Human genes 0.000 claims description 26
- 108010002321 Tight Junction Proteins Proteins 0.000 claims description 26
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 24
- 108010043137 Actomyosin Proteins 0.000 claims description 23
- 230000003870 intestinal permeability Effects 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 230000001580 bacterial effect Effects 0.000 claims description 18
- 230000027455 binding Effects 0.000 claims description 18
- 210000004369 blood Anatomy 0.000 claims description 18
- 239000008280 blood Substances 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 17
- 108091008324 binding proteins Proteins 0.000 claims description 16
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 15
- 208000011580 syndromic disease Diseases 0.000 claims description 15
- 230000006378 damage Effects 0.000 claims description 10
- 230000037361 pathway Effects 0.000 claims description 10
- 108010053256 zonula occludens toxin receptor Proteins 0.000 claims description 10
- 238000004458 analytical method Methods 0.000 claims description 8
- 108010016160 Matrix Metalloproteinase 3 Proteins 0.000 claims description 7
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 claims description 7
- 102000005962 receptors Human genes 0.000 claims description 7
- 244000005709 gut microbiome Species 0.000 claims description 6
- 101710172711 Structural protein Proteins 0.000 claims description 5
- 210000003296 saliva Anatomy 0.000 claims description 4
- 239000003053 toxin Substances 0.000 claims description 4
- 231100000765 toxin Toxicity 0.000 claims description 4
- 108010085238 Actins Proteins 0.000 claims description 3
- 102000007469 Actins Human genes 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- 102000023732 binding proteins Human genes 0.000 claims 2
- 101150026046 iga gene Proteins 0.000 description 68
- 235000018102 proteins Nutrition 0.000 description 39
- 239000000523 sample Substances 0.000 description 24
- 208000015943 Coeliac disease Diseases 0.000 description 20
- 230000001537 neural effect Effects 0.000 description 20
- 206010061218 Inflammation Diseases 0.000 description 18
- 230000004054 inflammatory process Effects 0.000 description 18
- 201000006417 multiple sclerosis Diseases 0.000 description 18
- 230000005784 autoimmunity Effects 0.000 description 17
- 210000004556 brain Anatomy 0.000 description 16
- 238000003556 assay Methods 0.000 description 15
- 238000003745 diagnosis Methods 0.000 description 15
- 210000001578 tight junction Anatomy 0.000 description 15
- 102000014914 Carrier Proteins Human genes 0.000 description 14
- 230000004888 barrier function Effects 0.000 description 14
- 230000002496 gastric effect Effects 0.000 description 14
- 102000053171 Glial Fibrillary Acidic Human genes 0.000 description 12
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 12
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 12
- 208000023275 Autoimmune disease Diseases 0.000 description 11
- 210000004698 lymphocyte Anatomy 0.000 description 11
- 230000004770 neurodegeneration Effects 0.000 description 11
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 10
- 229920002521 macromolecule Polymers 0.000 description 10
- 230000003959 neuroinflammation Effects 0.000 description 10
- 108010068370 Glutens Proteins 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 230000007613 environmental effect Effects 0.000 description 9
- 235000021312 gluten Nutrition 0.000 description 9
- 235000006171 gluten free diet Nutrition 0.000 description 9
- 235000020884 gluten-free diet Nutrition 0.000 description 9
- 210000002966 serum Anatomy 0.000 description 9
- 108010061711 Gliadin Proteins 0.000 description 8
- 230000002159 abnormal effect Effects 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 210000000987 immune system Anatomy 0.000 description 8
- 230000009885 systemic effect Effects 0.000 description 8
- 230000000890 antigenic effect Effects 0.000 description 7
- 230000004064 dysfunction Effects 0.000 description 7
- 230000006698 induction Effects 0.000 description 7
- 230000008595 infiltration Effects 0.000 description 7
- 238000001764 infiltration Methods 0.000 description 7
- 230000008506 pathogenesis Effects 0.000 description 7
- 206010003591 Ataxia Diseases 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 102000001109 Leukocyte L1 Antigen Complex Human genes 0.000 description 6
- 108010069316 Leukocyte L1 Antigen Complex Proteins 0.000 description 6
- 230000015556 catabolic process Effects 0.000 description 6
- 210000002889 endothelial cell Anatomy 0.000 description 6
- JCQLYHFGKNRPGE-FCVZTGTOSA-N lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 description 6
- 229960000511 lactulose Drugs 0.000 description 6
- PFCRQPBOOFTZGQ-UHFFFAOYSA-N lactulose keto form Natural products OCC(=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O PFCRQPBOOFTZGQ-UHFFFAOYSA-N 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 description 5
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 5
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 102000013691 Interleukin-17 Human genes 0.000 description 5
- 102100030703 Interleukin-22 Human genes 0.000 description 5
- 102000047918 Myelin Basic Human genes 0.000 description 5
- 101710107068 Myelin basic protein Proteins 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 108060008539 Transglutaminase Proteins 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 230000003960 inflammatory cascade Effects 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000005012 migration Effects 0.000 description 5
- 238000013508 migration Methods 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 102000003601 transglutaminase Human genes 0.000 description 5
- 206010003694 Atrophy Diseases 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 241000283707 Capra Species 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 102000005741 Metalloproteases Human genes 0.000 description 4
- 108010006035 Metalloproteases Proteins 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 102000013640 alpha-Crystallin B Chain Human genes 0.000 description 4
- 108010051585 alpha-Crystallin B Chain Proteins 0.000 description 4
- 230000037444 atrophy Effects 0.000 description 4
- 230000001363 autoimmune Effects 0.000 description 4
- 229940098773 bovine serum albumin Drugs 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 230000001703 neuroimmune Effects 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 239000006041 probiotic Substances 0.000 description 4
- 235000018291 probiotics Nutrition 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 230000008439 repair process Effects 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 208000018522 Gastrointestinal disease Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102000001398 Granzyme Human genes 0.000 description 3
- 108060005986 Granzyme Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 3
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 3
- 230000009102 absorption Effects 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 210000000133 brain stem Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 235000021245 dietary protein Nutrition 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000003018 immunoassay Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 108010027445 interleukin-22 receptor Proteins 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 208000030247 mild fever Diseases 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000000529 probiotic effect Effects 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 108700012359 toxins Proteins 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 230000032258 transport Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 102000002029 Claudin Human genes 0.000 description 2
- 108050009302 Claudin Proteins 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- SBJKKFFYIZUCET-JLAZNSOCSA-N Dehydro-L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(=O)C1=O SBJKKFFYIZUCET-JLAZNSOCSA-N 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 206010017914 Gastroenteritis salmonella Diseases 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 108010017525 Interleukin-17 Receptors Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 102000010445 Lactoferrin Human genes 0.000 description 2
- 108010063045 Lactoferrin Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 102000002233 Myelin-Oligodendrocyte Glycoprotein Human genes 0.000 description 2
- 108010000123 Myelin-Oligodendrocyte Glycoprotein Proteins 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229930003779 Vitamin B12 Natural products 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 206010000059 abdominal discomfort Diseases 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 229960004308 acetylcysteine Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 230000005549 barrier dysfunction Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 210000004970 cd4 cell Anatomy 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 208000037976 chronic inflammation Diseases 0.000 description 2
- 230000006020 chronic inflammation Effects 0.000 description 2
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 2
- 230000016396 cytokine production Effects 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000003748 differential diagnosis Methods 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 201000002491 encephalomyelitis Diseases 0.000 description 2
- 208000029182 enterotoxemia Diseases 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000002518 glial effect Effects 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 2
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 description 2
- 229940078795 lactoferrin Drugs 0.000 description 2
- 235000021242 lactoferrin Nutrition 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 208000024714 major depressive disease Diseases 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 238000010984 neurological examination Methods 0.000 description 2
- 230000007310 pathophysiology Effects 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- -1 respectively Proteins 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 235000019163 vitamin B12 Nutrition 0.000 description 2
- 239000011715 vitamin B12 Substances 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 239000011710 vitamin D Substances 0.000 description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 2
- 229940046008 vitamin d Drugs 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- HZWWPUTXBJEENE-UHFFFAOYSA-N 5-amino-2-[[1-[5-amino-2-[[1-[2-amino-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoic acid Chemical compound C1CCC(C(=O)NC(CCC(N)=O)C(=O)N2C(CCC2)C(=O)NC(CCC(N)=O)C(O)=O)N1C(=O)C(N)CC1=CC=C(O)C=C1 HZWWPUTXBJEENE-UHFFFAOYSA-N 0.000 description 1
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 1
- 240000007241 Agrostis stolonifera Species 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000023345 Autoimmune Diseases of the Nervous System Diseases 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 241000589968 Borrelia Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108010074051 C-Reactive Protein Proteins 0.000 description 1
- 102100032752 C-reactive protein Human genes 0.000 description 1
- 102000005701 Calcium-Binding Proteins Human genes 0.000 description 1
- 108010045403 Calcium-Binding Proteins Proteins 0.000 description 1
- 206010051288 Central nervous system inflammation Diseases 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 241000588923 Citrobacter Species 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 241000305071 Enterobacterales Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 241000588731 Hafnia Species 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- 241000714259 Human T-lymphotropic virus 2 Species 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 201000008225 Klebsiella pneumonia Diseases 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 208000016604 Lyme disease Diseases 0.000 description 1
- 208000036696 Microcytic anaemia Diseases 0.000 description 1
- 241000588771 Morganella <proteobacterium> Species 0.000 description 1
- 208000010428 Muscle Weakness Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000282376 Panthera tigris Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010035717 Pneumonia klebsiella Diseases 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 108700039882 Protein Glutamine gamma Glutamyltransferase 2 Proteins 0.000 description 1
- 102100038095 Protein-glutamine gamma-glutamyltransferase 2 Human genes 0.000 description 1
- 102000016202 Proteolipids Human genes 0.000 description 1
- 108010010974 Proteolipids Proteins 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 208000020764 Sensation disease Diseases 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 230000001977 ataxic effect Effects 0.000 description 1
- 208000035362 autoimmune disorder of the nervous system Diseases 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000005978 brain dysfunction Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 238000002052 colonoscopy Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 101150054175 cro gene Proteins 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000009841 epithelial lesion Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000003492 excitotoxic effect Effects 0.000 description 1
- 231100000063 excitotoxicity Toxicity 0.000 description 1
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000004424 eye movement Effects 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 210000004837 gut-associated lymphoid tissue Anatomy 0.000 description 1
- CJNBYAVZURUTKZ-UHFFFAOYSA-N hafnium(IV) oxide Inorganic materials O=[Hf]=O CJNBYAVZURUTKZ-UHFFFAOYSA-N 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 108040001304 interleukin-17 receptor activity proteins Proteins 0.000 description 1
- 102000053460 interleukin-17 receptor activity proteins Human genes 0.000 description 1
- 102000009548 interleukin-22 receptor activity proteins Human genes 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 210000005026 intestinal epithelial barrier Anatomy 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 208000027905 limb weakness Diseases 0.000 description 1
- 231100000861 limb weakness Toxicity 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 244000005706 microflora Species 0.000 description 1
- 210000004925 microvascular endothelial cell Anatomy 0.000 description 1
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000004682 mucosal barrier function Effects 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000000955 neuroendocrine Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000007557 neuronal destruction Effects 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000013610 patient sample Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000005451 protein repair Effects 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 231100000617 superantigen Toxicity 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000031068 symbiosis, encompassing mutualism through parasitism Effects 0.000 description 1
- 208000006379 syphilis Diseases 0.000 description 1
- 210000004876 tela submucosa Anatomy 0.000 description 1
- 238000009601 thyroid function test Methods 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000007279 water homeostasis Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/06—Gastro-intestinal diseases
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/70—Mechanisms involved in disease identification
- G01N2800/709—Toxin induced
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Analytical Chemistry (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Cell Biology (AREA)
- Biotechnology (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Food Science & Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Chemistry (AREA)
- Rehabilitation Therapy (AREA)
- Rheumatology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本願は、2011年1月28日出願の米国仮出願第61/437,244号の利益を請求し、これは、参照によりその全体が本明細書に組み込まれる。
消化管関連リンパ系組織および神経内分泌ネットワークと共に、細胞間のタイトジャンクションを伴う腸上皮のバリアは、非自己抗原に対する寛容と免疫の均衡を制御する。
血液脳関門(BBB)は、中枢神経系の内部環境と安定性を維持する。BBBへの構造的および機能的変化は、自己免疫疾患をもたらすことがあり、特に、多発性硬化症(28)のような神経系の自己免疫疾患である。
腸管透過性を評価するための現在の方法論は、ラクツロースとマンニトールを使用する。過去40年間にわたって、それは便利な臨床ツールだった。ラクツロース吸収は、腸バリアにおける涙液を示唆しており、したがって、腸管透過性である。俗説に対し、この小分子の吸収は、涙液というより微小リークを実際には示している。ラクツロースは、比較的低い分子サイズを有し、腸管膜を介したこの物質の転移は、食品または他のタンパク質の転移およびそれらに対する免疫応答のための状況を反映しない。さらに、ラクツロース/マンニトール検査は、経細胞経路ではなく傍細胞経路のみを介した小分子の転移を測定する。
A.材料および方法―プレートおよび試料調製:
E.coli 055:85由来のリポ多糖類;E.coli K−235、緑膿菌、シュードモナス、サルモネラ腸炎、ネズミチフス菌、クレブシエラ肺炎、モルガネラ、ハフニアーアルベイ、シトロバクター・コセリ、アクチン、アクトミオシン、ミエリン塩基性タンパク質とa−Bクリスタリンは、Sigma−Aldrich社(ST.Louis、MO)から購入された。グリア原線維酸性タンパク質(GFAP)は、Boehringer Mannheim社(Indianapolis、IN)から購入された。また、ゾヌリンペプチド1、2、3、腸ZOT受容体、ミエリン塩基性タンパク質87−106、ペプチド87−106、細胞間結合タンパク質、マトリックスメタロプロテアーゼ−3、本研究で命名されたS100−Bのカルシウム結合領域、BBB−1 MSELEKAMVA LIDVFHQYSG REGDKHKLKK、BBB−2 SELKELINNE LSHFLEEIKE QEVVDKVMET、BBB−3 LDNDGDGECD FQEFMAFVAM VTTACHEFFE HE、脳ZOT結合タンパク質−1、−2、カルプロテクチン(MRP−8)、および脳ZOTレセプターも使用された。
LPS、腸管および/またはBBBタンパク質に対するIgG、IgMおよび/またはIgA抗体のための分析手順について、これから説明する。いくつかの態様において、検査アッセイを開始する前に、全ての試薬を室温に戻した。この検査アッセイ手順には、所望の数および所望の種類の抗原ならびに/またはペプチドでコーティングした所望の数のウェルもしくはプレートの準備が含まれる。マイクロタイターウェルを準備した後、1:100で希釈された対照標準物質約100μlは、マルチチャネルピペッターを用いて行うことができ、図7に示すように、マイクロタイタープレートのA列およびB列に添加された。図7に示すように、1:100で希釈された患者の検査試料(ここでは血清)約100μlは、第1臨床検体のC列およびD列、第2臨床検体のE列およびF列、ならびに第3臨床検体のG列およびH列の2つ組のウェルに添加された。
405nmでプレートの読み取りを行い、光学密度値(OD405)を得た後、列AおよびBにおいて、陰性対照の平均OD、陽性対照の平均ODおよび各臨床検体の平均ODを標準物質の平均ODで除し、各指標値(IV)を得た。
指標=患者の平均OD/標準物質の平均OD
i.セリアック病、グルテン免疫反応性および感受性ならびにクローン病患者におけるIgG/IgM/IgA抗体のパターン
9名の健常対象者(表1から3)のIgG、IgMおよびIgA抗体パターンの例およびセリアック病および腸管透過性のある3名の患者(表4)、グルテン運動失調のある3名の患者(表5)および多発性硬化症の3名の患者(表6)とのそれらの比較をそれぞれ表1−6で示す。
指標の計算に基づき、9名の健常対照者(表1から3)、セリアック病および腸管透過性のある3名の患者(表4)、グルテン運動失調のある3名の患者(表5)および多発性硬化症の3名の患者(表6)のIgG、IgMおよびIgA抗体のパターンをそれぞれ表1−6で示す。健常対象全員において、抗体指標が1.5より高いかもしれないが、2.0よりも著しく大きくはないであろうLPSおよびMBPを除き、他の抗原に対する抗体指標は、1.5よりも小さいかまたはきわめて小さいことに留意されたい(表1−3)。
腸管透過性は胃腸自己免疫疾患で顕著である(4)。図9は、健常対照および消化管自己免疫がある患者における、細菌エンドトキシン(リポ多糖)およびタイトジャンクションの構造(オクルジン/ゾヌリン)に対する抗体の上昇を比較する図表を示す。
2つの異なる症例報告、第一にセリアック病患者および第二に多発性硬化症患者の症例を次のとおり与える。
身長5’4”、体重106lbsで、線維筋痛様の症候群および体重減少(過去6ヶ月中、月に1から2lbs)を伴い、便秘、下痢および全身にわたる疼痛を含むGI障害のある38歳女性を内科医が診察した。実験室研究から、CBCが異常であり、ヘモグロビン9.9g/dL、MCVが77fL、赤血球沈降速度54mm/1sthrであり、葉酸およびビタミンB12濃度は低いが、肝臓酵素レベルおよび高感度C−反応性タンパク質が高いことが明らかとなった。ANA、リウマチ因子、T3、T4およびTSHレベルを含む詳細な生化学および免疫学的プロファイルを調べたところ、全ての試験が正常範囲内であった。胃腸の不快感、軽度の発熱および頭痛について繰り返し訴えた後、GI検査のために患者を専門機関に紹介した。
身長5’8”、体重182lbsの38歳男性は、四肢脱力を伴う3週間の進行性の頸部、背部および筋肉痛という病歴後、神経科医を紹介された。紹介前日、本患者は、刺痛を伴う排尿困難ならびに階段を昇ることができないほどの胴部および肢の知覚障害を発症した。入院の僅か2年前、本患者には家族の問題があり、非常に落ち込んでいたが、それに対して何ら助けを求めなかった。本患者の全体的な既往歴は、他に、ビタミンB12および鉄サプリメントで治療を受けた原因不明の軽度の小球性貧血を除き、特になかった。
1.Walker WA,Sanderson IR.Epithelial barrier function to antigens.Ann NY Acad Sci.664:10−17,1992.
2.Walker WA,Isselbacher KJ.Uptake and transfer of macromolecules by the intestine.Gastroenterol.67:531−550,1974.
3.Arrieta MC,Bistritz L,Meddings JB.Alterations in intestinal permeability.Gut.55:1512−1520,2006.
4.Fasano A,Shea−Donohue T.Mechanisms of disease:the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases.Nat Clin Prac Gastroenterol Hepatol.2(9):416−422,2005.
5.Sapone A,Lammers KM,Mazzarella G,et al.Differential mucosal IL−17 expression in two gliadin−induced disorders:gluten sensitivity and the autoimmune enteropathy celiac disease.Int Arch Allergy Immunol.152:75−80,2010.
6.Sapone A,Lammers KM,Casolaro V,et al.Divergence of gut permeability and mucosal immune gene expression in two gluten−associated conditions:celiac disease and gluten sensitivity.BMC Med.9:23,2011.
7.Fasano A.Zonulin and its regulation of intestinal barrier function:the biological door to inflammation,autoimmunity and cancer.Physiol Rev,91:151−175,2011.
8.Shor DB,Barzilai O,Ram M,et al.Gluten sensitivity in multiple sclerosis:experimental myth or clinical truth? Ann NY Acad Sci,1173:343−349,2009.
9.Vojdani A,O’Bryan T,Green JA,et al.Immune response to dietary proteins,gliadin and cerebellar peptides in children with autism.Nutr Neurosci.7(3):151−161,2004.
10.Correale J,Villa A.The blood−brain−barrier in multiple sclerosis:functional roles and therapeutic targeting.Autoimmunity.40:148−160,2007.
11.Morgan L,Shah B,Rivers LE,et al.Inflammation and dephosphorylation of the tight junction protein occludin in an experimental model of multiple sclerosis.Neurosci.147:664−673,2007.
12.Skardelly M,Armbruster FP,Meixensberger J,et al.Expression of zonulin,c−kit,glial fibrillary acidic protein in human gliomas.Transl Oncol.2:117−120,2009.
13.Yacyshyn B,Meddings J,Sadowski D,et al.Multiple sclerosis patients have peripheral blood CD45RO+B cells and increased intestinal permeability.Dig Dis Sci.41(12):2493−2498,1996.
14.Garate I,Garcia−Bueno B,Madrigal,JLM et al.Origin and consequences of brain toll−like receptor 4 pathway stimulation in an experimental model of depression.J Neuroinflamm.8:151,1−31,2011.
15.Al−Sadi RM,Ma TY.IL−1β causes an increase in intestinal epithelial tight junction permeability.J Immunol.178:4641−4649,2007.
16.Matysiak−Budnik T,Thomas−Collignon A,Megraud F,Heyman M.Alterations of epithelial permeability by Helicobacter and IL−1beta in vitro:protective effect of rebamipide.Dig Dis Sci,2001;46:1558−1566.
17.Turner JR.”Putting the squeeze” on the tight junction:understanding cytoskeletal regulation.Semin Cell Dev Biol,2000;11:301−308.
18.Ma TY,Hoa NT,Tran DD,Bui V,Pedram A,Mills S,Merryfield M.Cytochalasin B modulation of Caco−2 tight junction barrier:role of myosin light chain kinase.Am J Physiol,2000;279:G875−G885.
19.Ma TY,Tran D,Hoa N,Nguyen D,Merryfield M,Tarnawski A.Mechanism of extracellular calcium regulation of intestinal epithelial tight junction permeability:role of cytoskeletal involvement.Microsc Res Tech,2000;51:156−168.
20.Al−Sadi R,Ye D,Dokladny K,Ma TY.Mechanism of IL−1β−induced increase in intestinal epithelial tight junction permeability.J Immunol.2008;180:5653−5661.
21.Shen L,Black ED,Witkowski ED,Lencer WI,Guerriero V,Schneebrger EE,Turner JR.Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structure.J Cell Sci,2006;119:2095−2106.
22.Hecht G,Pestic L,Nikcevic G,Koutsouris A,Tripuraneni J,Lorimer Dd,Nowak G,Guerriero,Jr V,Elson El,Lanerolle PD.Expression of the catalytic domain of myosin light chain kinase increases paracellular permeability.Am J Physiol,1996;271:C1678−1684.
23.Ma TY,Boivin MA,Ye E,Pedram A,Said HM.Mechanism of TNF−α modulation of Caco−2 intestinal epithelial tight junction barrier:role of myosin light−chain kinase protein expression.Am J Physiol,2005;288:G422−G430.
24.Mae M,Kudera M,Leunis JC.The gut−brain barrier in major depression:intestinal mucosal dysfunction with an increased translocation of LPS from gram negative bacteria(leaky gut)plays a role in the inflammatory pathophysiology of depression.Euro Endocrinol Lett,2008;29:117−124.
25.Mae M,Coucke F,Ategis JC.Normalization of the increased translocation of endotoxin from gram negative enterobacteria(leaky gut)is accompanied by a remission of chronic fatigue syndrome.Neuro Endocrinol Lett,2007;28(6):101−116.
26.Walker−Smith JA,Ford RP,Phillips AD.The spectrum of gastrointestinal allergies to food.Ann Allergy,1984;53:629−636.
27.Juvonen P,Jakobsson I,Lindberg T.Macromolecular absorption and cow’s milk allergy.Arch Dis Child,1990;65:300−303.
28.Huang XN,FuJ,Wang WZ.The effects of Fasudil on the permeability of the rat blood−brain barrier and blood−spinal cord barrier following experimental autoimmune encephalomyelitis.J Neuroimmunol.239:61−67,2011.
29.Lassmann H,Zimprich F,Vass K,Hickey WF.Microglial cells are a component of the perivascular glia limitans.J Neurosci Res,1991;28:236−243.
30.Schneeberger EE,Lynch RD.The tight junction:a multifunctional complex.Am J Physiol Cell Physiol,2004;286:C1213−C1228.
31.Chen ML,et al.Disruption of tight junctions and induction of proinflammatory cytokine responses in colonic epithelial cells by Campylobacter jejuni.Infect Immun,2006;74:6581−6589.
32.LaPierre LA.The molecular structure of the tight junction.Adv Drug Deliv,2000;41:255−264.
33.Wong V,Gumbiner BM.A synthetic peptide corresponding to the extracellular domain of occludin perturbs the tight junction permeability barrier.J Cell Biol,1997;136(2):399−409.
34.Engelhardt B,Rasohoff RM.The ins and outs of the T−lymphocyte trafficking to the CNS:anatomical sites and molecular mechanisms.Trends Immunol,2005;26(9):485−495.
35.Aloisi F,Ria F,Adorini L.Regulation of T−cell responses by CNS antigen−presenting cells:different roles for microglia and astrocytes.Immunol Today,2000;21(3):141−147.
36.Ghirnikar RS,Lee YL,Eng LF.Inflammation in traumatic brain injury:role of cytokines and chemokines.Neurochem Res,1998;23(3):329−340.
37.Kebir H,Kreymborg K,Ifergan I,Dodelet−Devillers A,Cayrol R,Bernard M,Biuliani F,Arbour N,Becher B,Prat A.Human TH17 lymphocytes promote blood−brain barrier disruption and central nervous system inflammation.Nat Med,2007;13:1173−1176.
38.Sospedra M,Martin R.Immunology of multiple sclerosis.Annu Rev Immunol,2005;23:683−747.
39.Biernacki K,Prat A,Blain M,Antel JP.Regulation of Th1 and Th2 lymphocyte migration by human adult brain endothelial cells.J Neuropathol Exp Neurol,2001;60(12):1127−1136.
40.Wosik K,Cayrol R,Dodelet−Devillers A,Berthelet F,Bernard M,Moumdjian R,Bouthillier A,Reudelhuber TL,Prat A.Angiotensin II controls occluding function and is required for blood−brain barrier maintenance:relevance to multiple sclerosis.J Neurosci,2007;27(34):9032−9042.
41.Kawanokuchi J,Shimizu K,Nitta A,Yamada K,Mizuno T,Takeuchi H,Suzumura A.Production and function of IL−17 in microglia.J Neuroimmunol,2008;194:54−61.
42.Ganor Y,Teichberg VI,Levite M.TCR activation eliminate glutamate receptor GLUR3 from the cell surface of normal human T cells via an autocrine/paracrine granzyme B−mediated proteolytic cleavage.J Immunol,2007;178:683−692.
43.Vojdani A,Lambert J.A gut feeling for immune dysregulation and neuroinflammation.The Autism File USA,2009;31:56−64.
44.Vojdani A,Vojdani E,Cooper EL.Antibodies to myelin basic protein,myelin oligodendrocytes peptides,α−β−crystallin,lymphocyte activation and cytokine production in patients with multiple sclerosis.J Internal Med,2003;254:363−74.
45.Kirk J,Plumb J,Mirakhur M,et al.Tight junctional abnormality in multiple sclerosis white matter affects all calibers of vessel and is associated with blood−brain barrier leakage and active demyelination.J Pathol.2003;201:319−327.
46.Hawkins BT,Davis TP.The blood−brain barrier/neurovascular unit in health and disease.Pharmacol Rev,2005;57:173−185.
47.Leech S,Kirk J,Plumb J,et al.Persistent endothelial abnormalities and blood−brain barrier leak in primary and secondary progressive multiple sclerosis.Neuropathol Appl Neurobiol,2007;33:86−98.
48.Persidsky Y,Ramirez SH,Haorah J,et al.Bllod−brain barrier:structural components and function under physiologic and pathologic conditions.J Neuroimmune Pharmacol,2006,1:223−236.
49.Reijerkerk A,Kooij G,van der Pol SM,et al.Tissue−type plasminogen activator is a regulator of monocyte diapedesis through the brain endothelial barrier.J Immunol,2008;181:3567−3574.
50.Wosik K,Cayrol R,Dodelet−Devillers A,et al.Angiotension II controls occluding function and is required for blood−brain barrier maintenance:relevance to multiple sclerosis.J Neurosci,2007;27:9032−9042.
51.El Asmar,Panigrahi P,Bamford P,et al.Host−dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure.Gastroenterol,2002;123:1607−1615.
52.Balkovetz DF,Katz J.Bacterial invasion of paracellular route:divide and conquer.Microbes Infect,2003;5:613−619.
53.Kuula H et al.Local systemic responses in matrix metalloproteinase 8−deficient mice during Porphyromonas gingivalis−induced periodontitis.Infect Immun,2009;77(2):850−859.
54.Cywes C,Wessels M.R.Group A Streptococcus tissue invasion by CD44−mediated cell signalling.Nature,2001;414:648−652.
55.Y Xu,Q Yu.E−cadherin negatively regulated CD44−hyaluronan interaction and CD44−mediated tumor invasion and branching morphogenesis.J Biol Chem,2003;278:8661−8668.
56.Garrote J,Gomez−Gonzalez E,Bernardo D,Arranz E,Chirdo F.Celiac disease pathogenesis:the proinflammatory cytokine network.J Pediatr Gastroenterol Nutr,2008;47(Suppl 1).
57.Maldonado Galdeano C,Perdigon G.The probiotic bacillum Lactobacillus casei induces activation of the mucosal immune system through innate immunity.Clin Vaccine Immunol,2006,13(2):219−226.
58.Wakabayashi H,Takakura N,Yamauchi K,et al.Modulation of immunity−related gene expression in small intestine of mice by oral administration of lactoferrin.Clin Vaccine Immunol,2006;13(2):239−245.
59.Han S,Jeong SY,Nam YJ,et al.Xylitol inhibits inflammatory cytokine expression induced by lipopolysaccharides from Porphyromonas gingivalis.Clin Diag Lab Immunol,2005;12(11):1285−1291.
60.Chevrier MR,Ryan AE,Lee DY−W,et al.Boswellia carterii extract in hibits the cytokines and promotes Th2 cytokines in vitro.Clin Diag Lab Immunol,2005;575−580.
61.Syrovets T,Buchele B,Krauss C,et al.Acetyl−boswellic acids inhibit lipopolysaccharide−mediated TNF−alpha induction in monocytes by direct interaction with ΙκΒ kinases.J Immunol,2005;174:498−506.
Claims (17)
- 巨大抗原分子に対する腸管の透過性を測定するために、ヒト試料を試験する方法であって、
リポ多糖を含む細菌毒素に対する、前記ヒト試料の第一の分画中のIgG、IgMおよび/またはIgAの結合についてのシグナルを含む、第一のシグナルを測定すること;および
ネイティブ腸関連抗原に対する、前記ヒト試料の第二の分画中のIgG、IgMおよび/またはIgAの結合についてのシグナルを含む、第二のシグナルを測定すること、
を含む、前記方法。 - 前記ネイティブ腸関連抗原が、(1)腸管構造タンパク質;(2)タイトジャンクションタンパク質;(3)タイトジャンクションタンパク質に対する結合受容体;および(4)細胞間結合タンパク質からなる一覧から選択される、請求項1に記載の方法。
- 前記腸管構造タンパク質がアクチンおよび/またはアクトミオシンを含む、請求項2に記載の方法。
- 前記タイトジャンクションタンパク質がオクルジンおよびゾヌリンからなる群から選択される、請求項2に記載の方法。
- 前記タイトジャンクションタンパク質に対する結合受容体が、腸管ZOT受容体を含む、請求項2に記載の方法。
- 前記腸管構造タンパク質が、マトリクスメタロプロテイナーゼ−3(MMP−3)を含む、請求項2に記載の方法。
- 前記ヒト試料が、血液試料である、請求項1〜6のいずれか1項に記載の方法。
- 前記ヒト試料が、唾液試料である、請求項1〜6のいずれか1項に記載の方法。
- 巨大抗原分子に対する腸管の透過性を測定するために、ヒト試料を試験する方法に用いる試験プレートであって、
前記試験プレートが、
(1)リポ多糖を含む細菌毒素、および(2)ネイティブ腸関連抗原を、結合ペプチドとして有し、
ならびに、
前記ヒト試料を試験する方法が、
前記リポ多糖を含む細菌毒素に対する、前記ヒト試料の第一の分画中のIgG、IgMおよび/またはIgAの結合についてのシグナルを含む、第一のシグナルを測定すること;および
前記ネイティブ腸関連抗原に対する、前記ヒト試料の第二の分画中のIgG、IgMおよび/またはIgAの結合についてのシグナルを含む、第二のシグナルを測定すること、
を含む、
前記試験プレート。 - 前記ネイティブ腸関連抗原が、(1)腸管構造タンパク質;(2)タイトジャンクションタンパク質;および(3)タイトジャンクションタンパク質に対する結合受容体;および(4)細胞間結合タンパク質からなる群から選択される、請求項9に記載の試験プレート。
- リポ多糖を含む細菌毒素に対する、ヒト試料の第一の分画中のIgG、IgMおよび/またはIgAの結合についてのシグナルを含む第一のシグナル;および
ネイティブ腸関連抗原に対する、前記ヒト試料の第二の分画中のIgG、IgMおよび/またはIgAの結合についてのシグナルを含むの第二のシグナル
を生成させる抗体試験パネルから試験結果を得ること、
ならびに
前記試験結果を解析すること、
を含む、
ヒト患者における腸管壁浸漏症候群に関連する疾患の可能性の判断に使用するための、試験結果の解析方法(ただし、医師による診断行為を除く)。 - 前記ヒト試料が血液試料である、請求項11に記載の方法。
- 前記ヒト試料が唾液試料である、請求項11に記載の方法。
- 前記ネイティブ腸関連抗原が、オクルジン、ゾヌリンおよびアクトミオシンを含み、
前記試験結果が、前記細菌毒素に対するIgA、IgMまたはIgGの陽性結果、前記オクルジンおよびゾヌリンに対する前記IgA、IgMおよびIgGの陰性結果、および、アクトミオシンに対するIgGの陰性結果を含むとき、
前記ヒト患者に、腸内微生物叢腸内毒素症に関連する疾患の可能性があると判断することに使用するための、
請求項11〜13のいずれか一項に記載の解析方法。 - 前記ネイティブ腸関連抗原が、オクルジンもしくはゾヌリン、およびアクトミオシンを含み、
前記試験結果が、前記細菌毒素に対するIgA、IgMまたはIgGの陽性結果、前記オクルジンもしくはゾヌリンに対するIgA、IgMまたはIgGの陽性結果、および、前記アクトミオシンに対するIgGの陰性結果を含むとき、
前記ヒト患者に、傍細胞経路を介する細菌性抗原による腸管バリアの破壊に関連する疾患の可能性があると判断することに使用するための、
請求項11〜13のいずれか一項に記載の解析方法。 - 前記ネイティブ腸関連抗原が、オクルジンもしくはゾヌリン、およびアクトミオシンを含み、
前記試験結果が、前記細菌毒素に対するIgA、IgMおよびIgGの陰性結果、前記オクルジンもしくはゾヌリンに対するIgA、IgMまたはIgGの陽性結果、および、前記アクトミオシンに対するIgAの陰性結果を含むとき、
前記ヒト患者に、傍細胞経路を介する細菌性抗原以外による腸管バリアの破壊に関連する疾患の可能性があると判断することに使用するための、
請求項11〜13のいずれか一項に記載の解析方法。 - 前記ネイティブ腸関連抗原が、オクルジン、ゾヌリンおよびアクトミオシンを含み、
前記試験結果が、前記細菌毒素に対するIgA、IgMまたはIgGの陽性結果、前記オクルジンおよびゾヌリンに対するIgA、IgMおよびIgGの陰性結果、および、前記アクトミオシンに対するIgAの陽性結果を含むとき、
前記ヒト患者に、経細胞経路を介する細菌性抗原による腸管バリアの破壊に関連する疾患の可能性があると判断することに使用するための、
請求項11〜13のいずれか一項に記載の解析方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161437244P | 2011-01-28 | 2011-01-28 | |
US61/437,244 | 2011-01-28 | ||
PCT/US2012/022706 WO2012103324A2 (en) | 2011-01-28 | 2012-01-26 | Method for detection of intestinal, and blood-brain barrier permeability and testing materials thereto |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2014503829A JP2014503829A (ja) | 2014-02-13 |
JP2014503829A5 JP2014503829A5 (ja) | 2016-02-04 |
JP6068362B2 true JP6068362B2 (ja) | 2017-01-25 |
Family
ID=46577669
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2013551330A Active JP6068362B2 (ja) | 2011-01-28 | 2012-01-26 | 腸および血液脳関門の透過性を検出する方法、およびその試験材料 |
Country Status (13)
Country | Link |
---|---|
US (2) | US8663911B2 (ja) |
EP (1) | EP2668498B1 (ja) |
JP (1) | JP6068362B2 (ja) |
KR (1) | KR101941308B1 (ja) |
CN (2) | CN103460044B (ja) |
AU (3) | AU2012211328A1 (ja) |
BR (1) | BR112013019380A2 (ja) |
CA (2) | CA2964555C (ja) |
HK (1) | HK1189938A1 (ja) |
IL (2) | IL227676A (ja) |
MX (1) | MX2013008746A (ja) |
RU (2) | RU2607479C2 (ja) |
WO (1) | WO2012103324A2 (ja) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012051519A2 (en) | 2010-10-14 | 2012-04-19 | The Johns Hopkins University | Biomarkers of brain injury |
EP2825893A4 (en) | 2012-03-13 | 2016-03-16 | Univ Johns Hopkins | BRAINED CEREBRAL AND NEUROLOGIC PROTEINS AS BIOMARKERS OF BRAIN INJURIES OR NEURODEGENERESCENCE |
US20140147856A1 (en) * | 2012-11-29 | 2014-05-29 | Rush University Medical Center | Intestinal Permeability Assay for Neurodegenerative Diseases |
US10534003B2 (en) | 2013-07-17 | 2020-01-14 | The Johns Hopkins University | Multi-protein biomarker assay for brain injury detection and outcome |
US20180024145A1 (en) | 2015-02-05 | 2018-01-25 | Immunarray USA, Inc. | Methods and compositions for diagnosing brain injury or neurodegeneration |
WO2017147378A1 (en) * | 2016-02-25 | 2017-08-31 | The Trustees Of Columbia University In The City Of New York | Systemic immune activation and biomarkers of nonceliac wheat/gluten sensitivity |
CN105974105A (zh) * | 2016-05-16 | 2016-09-28 | 河北艾驰生物科技有限公司 | 基质金属蛋白酶-3(mmp3)检测试剂盒 |
CN110312937B (zh) * | 2017-01-19 | 2023-01-10 | 和田孝一郎 | 诊断肠黏膜通透性的诊断药、诊断方法及诊断装置 |
CN108191977B (zh) * | 2017-12-25 | 2018-12-18 | 首都医科大学宣武医院 | 用于检测缺血性脑卒中血脑屏障早期损伤的抗体及其应用 |
CN108152492B (zh) * | 2017-12-25 | 2019-03-08 | 首都医科大学宣武医院 | 用于检测缺血性脑卒中血脑屏障早期损伤的抗体及其应用 |
KR102341906B1 (ko) * | 2018-10-26 | 2021-12-22 | 가천대학교 산학협력단 | 청년기 우울증 동물모델의 제조방법 |
CN112958172B (zh) * | 2021-02-24 | 2021-12-28 | 北京航空航天大学 | 一种模拟体内微生物-肠-脑轴信号传导过程的仿生微流控芯片 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020028215A1 (en) * | 1999-08-09 | 2002-03-07 | Jagath L. Kadurugamuwa | Novel vaccines and pharmaceutical compositions using membrane vesicles of microorganisms, and methods for preparing same |
DE19842609C2 (de) * | 1998-09-17 | 2000-09-21 | Diagnostik Gmbh Leipzig Lab | Salmonellenantigengemisch und Kit zur Bestimmung von Antikörpern gegen Salmonellen |
US6958324B2 (en) * | 1998-12-02 | 2005-10-25 | Inotek Pharmaceuticals Corporation | Inosine compounds and their use for treating or preventing an inflamation or a reperfusion disease |
US6884591B2 (en) * | 2001-06-25 | 2005-04-26 | The Cleveland Clinic Foundation | Peripheral marker of blood brain barrier permeability |
CN1788017B (zh) * | 2003-02-10 | 2013-04-24 | to-BBB控股股份有限公司 | 炎症状态下在血脑屏障中差异表达的核酸 |
US20080038843A1 (en) * | 2006-08-11 | 2008-02-14 | University Of Maryland - Baltimore | Method of diagnosing celiac disease |
RU2007145635A (ru) * | 2005-05-13 | 2009-06-20 | Юниверсити Оф Мэриленд, Балтимор (Us) | Способ оценки эффективности режима лечения |
WO2006130697A1 (en) * | 2005-06-01 | 2006-12-07 | Cytokine Pharmasciences, Inc. | Hmgb1 expression and protective role of semapimod in nec |
EP1757940A1 (en) * | 2005-08-26 | 2007-02-28 | Cézanne S.A.S. | In vitro method for diagnosing and monitoring renal cell carcinoma (RCC) using MMP-7 as humoral biomarker for RCC |
JP4791866B2 (ja) * | 2006-03-24 | 2011-10-12 | 国立大学法人秋田大学 | 下痢原性大腸菌感染症の判別に用いられる固相等 |
US7892763B2 (en) * | 2009-01-26 | 2011-02-22 | Dodds W Jean | Multi-stage nutrigenomic diagnostic food sensitivity testing in animals |
-
2012
- 2012-01-26 KR KR1020137022644A patent/KR101941308B1/ko active IP Right Grant
- 2012-01-26 AU AU2012211328A patent/AU2012211328A1/en not_active Abandoned
- 2012-01-26 EP EP12739704.0A patent/EP2668498B1/en active Active
- 2012-01-26 RU RU2013139476A patent/RU2607479C2/ru active
- 2012-01-26 MX MX2013008746A patent/MX2013008746A/es unknown
- 2012-01-26 WO PCT/US2012/022706 patent/WO2012103324A2/en active Application Filing
- 2012-01-26 BR BR112013019380A patent/BR112013019380A2/pt not_active Application Discontinuation
- 2012-01-26 CN CN201280015809.0A patent/CN103460044B/zh active Active
- 2012-01-26 CN CN201610171077.4A patent/CN105823887B/zh active Active
- 2012-01-26 US US13/359,007 patent/US8663911B2/en active Active
- 2012-01-26 RU RU2016149216A patent/RU2016149216A/ru not_active Application Discontinuation
- 2012-01-26 CA CA2964555A patent/CA2964555C/en active Active
- 2012-01-26 CA CA2828194A patent/CA2828194A1/en active Pending
- 2012-01-26 JP JP2013551330A patent/JP6068362B2/ja active Active
-
2013
- 2013-07-28 IL IL227676A patent/IL227676A/en active IP Right Grant
-
2014
- 2014-03-04 US US14/196,972 patent/US9194867B2/en active Active
- 2014-03-21 HK HK14102850.9A patent/HK1189938A1/zh unknown
-
2016
- 2016-11-18 AU AU2016259430A patent/AU2016259430B2/en active Active
- 2016-11-24 AU AU2016262726A patent/AU2016262726B2/en active Active
-
2017
- 2017-03-01 IL IL250871A patent/IL250871B/en active IP Right Grant
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6068362B2 (ja) | 腸および血液脳関門の透過性を検出する方法、およびその試験材料 | |
JP6239685B2 (ja) | グルテン感受性の検出およびグルテン感受性とセリアック病を鑑別するための方法ならびに装置 | |
NZ614707B2 (en) | Method for detection of intestinal, and blood-brain barrier permeability and testing materials thereto | |
LINNELL et al. | RETRACTED: Ileal-Lymphoid-Nodular Hyperplasia, Non-Specific Colitis, and Pervasive Developmental Disorder in Children |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20141202 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20150114 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150119 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150406 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20150903 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150908 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20151203 |
|
A524 | Written submission of copy of amendment under article 19 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A524 Effective date: 20151203 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20160517 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20160816 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160929 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20161206 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20161222 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6068362 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |