Systems and methods to diagnose sarcoidosis and identify markers of the condition

Abstract

Systems and methods to diagnose sarcoidosis are described. In addition to diagnosing sarcoidosis, the systems and methods can distinguish sarcoidosis from tuberculosis. Further disclosed is a cDNA library and methods of its use for reliably identifying sarcoidosis markers.

What is claimed is: 
     
         1 . A kit comprising:
 a protein that binds Small inducible cytokine A21 precursor (CCL21); Methionine aminopeptidase 1 (Metap1); Activated RNA polymerase II transcription cofactor variant 4 (PC4); RNA methyltransferase (CLI_3190); Tumor necrosis factor receptor superfamily member 21 precursor (TNFRSF21); Monocyte differentiation antigen CD14 (CD14); DnaJ (Hsp40) homolog subfamily C member 1 precursor (DNAJC1); Amyloid β A4 precursor protein binding family B member 1-interacting protein (APBB1); Fibroblast growth factor binding protein 2 precursor (FGFBP-2); or SH3 domain-containing YSC84 like protein 1 (SH3YL1) and a detectable label;   a nucleic acid that binds a gene encoding CCL21; Metap1; PC4; CLI_3190; TNFRSF21; DNAJC1; APBB1; FGFBP-2; or SH3YL 1 and a detectable label;   a protein that binds Ferredoxin (Fed A); WDFY3 protein (WDFY3); Membrane protein (MFS); Leucine rich PPR-motif containing protein (LRPPRC); HLA-DR alpha (HLA-DR); Transketolase (TKT); Dihydroxy acid dehydratase (Rv0189C); Chain A  Mycobacterium tuberculosis  (BfrA); Disabled homolog 2 isoform 2 (DAB2); or Transcription elongation factor B polypeptide 2 isoform ( Homo sapiens ) (TCEB2) and a detectable label; or   a nucleic acid that binds a gene encoding Fed A; WDFY3; MFS; LRPPRC; HLA-DR; TKT; Rv0189C; BfrA; DAB2; or TCEB2 and a detectable label.   
     
     
         2 . The kit according  claim 1 , wherein the kit comprises more than one protein, and the proteins comprise antibodies, epitopes or mimotopes. 
     
     
         3 . The kit according to  claim 1 , wherein the detectable label comprises a radioactive isotope, enzyme, dye, fluorescent dye, magnetic bead, or biotin. 
     
     
         4 . The kit according  claim 1 , wherein the kit comprises reagents to perform an enzyme-linked immunosorbent assay (ELISA), a radioimmunoassay (RIA), a Western blot, an immunoprecipitation, an immunohistochemical staining, flow cytometry, fluorescence-activated cell sorting (FACS), an enzyme substrate color method, and/or an antigen-antibody agglutination. 
     
     
         5 . A microarray comprising:
 a protein that binds cytokine A21 precursor (CCL21); Methionine aminopeptidase 1 (Metap1); Activated RNA polymerase II transcription cofactor variant 4 (PC4); RNA methyltransferase (CLI_3190); Tumor necrosis factor receptor superfamily member 21 precursor (TNFRSF21); Monocyte differentiation antigen CD14 (CD14); DnaJ (Hsp40) homolog subfamily C member 1 precursor (DNAJC1); Amyloid β A4 precursor protein binding family B member 1-interacting protein (APBB1); Fibroblast growth factor binding protein 2 precursor (FGFBP-2); or SH3 domain-containing YSC84 like protein 1 (SH3YL1);   a protein that binds Ferredoxin (Fed A); WDFY3 protein (WDFY3); Membrane protein (MFS); Leucine rich PPR-motif containing protein (LRPPRC); HLA-DR alpha (HLA-DR); Transketolase (TKT); Dihydroxy acid dehydratase (Rv0189C); Chain A  Mycobacterium tuberculosis  (BfrA); Disabled homolog 2 isoform 2 (DAB2); or Transcription elongation factor B polypeptide 2 isoform ( Homo sapiens ) (TCEB2);   a nucleic acid that binds to a gene encoding CCL21; Metap1; PC4; CLI_3190; TNFRSF21; CD14; DNAJC1; APBB1; FGFBP-2; or SH3YL1;   a nucleic acid that binds a gene encoding Fed A; WDFY3; MFS; LRPPRC; HLA-DR; TKT; Rv0189C; BfrA; DAB2; or TCEB2;   one or more of CCL21; Metap1; PC4; CLI_3190; TNFRSF21; CD14; DNAJC1; APBB1; FGFBP-2; or SH3YL1; or   one or more of Fed A; WDFY3; MFS; LRPPRC; HLA-DR; TKT; Rv0189C; BfrA; DAB2; or TCEB2.   
     
     
         6 . A method, comprising
 obtaining a sample from the subject;   assaying the sample for:
 one or more markers selected from cytokine A21 precursor (CCL21); Methionine aminopeptidase 1 (Metap1); Activated RNA polymerase II transcription cofactor variant 4 (PC4); RNA methyltransferase (CLI_3190); Tumor necrosis factor receptor superfamily member 21 precursor (TNFRSF21); Monocyte differentiation antigen CD14 (CD14); DnaJ (Hsp40) homolog subfamily C member 1 precursor (DNAJC1); Amyloid β A4 precursor protein binding family B member 1-interacting protein (APBB1); Fibroblast growth factor binding protein 2 precursor (FGFBP-2); or SH3 domain-containing YSC84 like protein 1 (SH3YL1); or 
 one or markers selected from WDFY3 protein (WDFY3); Membrane protein (MFS); Leucine rich PPR-motif containing protein (LRPPRC); HLA-DR alpha (HLA-DR); Chain A  Mycobacterium tuberculosis  (BfrA); Disabled homolog 2 isoform 2 (DAB2); or Transcription elongation factor B polypeptide 2 isoform ( Homo sapiens ) (TCEB2). 
   
     
     
         7 . The method of  claim 6 , wherein:
 the sample is a tissue sample, a cell sample, a whole blood sample, a serum sample, a plasma sample, a saliva sample, a sputum sample, or a urine sample; and/or   assaying the sample for one or more markers comprises contacting the sample with a probe comprising a detectable label and that binds the one or more markers; and/or   obtaining a value based on the assay comprises quantitating the amount of the marker in the sample; and/or   the value is a score or a weighted score.   
     
     
         8 . The method according to  claim 6 , wherein assaying the sample for one or more markers comprises contacting the sample with a probe comprising a detectable label and that binds the one or more markers. 
     
     
         9 . The method according to  claim 6 , wherein obtaining a value based on the assay comprises quantitating the amount of the marker in the sample. 
     
     
         10 . The method according to  claim 9 , wherein the value is a score. 
     
     
         11 . The method according to  claim 10 , wherein the score is a weighted score. 
     
     
         12 . The method of  claim 6 , wherein the sample is assayed for two or more markers selected from CCL21, Metap1, PC4, CLI_3190, TNFRSF21, CD14, DNAJC1, APBB1, FGFBP-2, or SH3YL1. 
     
     
         13 . The method of  claim 6 , further comprising:
 obtaining a value based on the assay;   comparing the value to a reference level;   diagnosing the subject as having sarcoidosis based on the up- or downregulation of the one or more markers as demonstrated by the value and the reference level; and   treating the subject diagnosed with having sarcoidosis with a sarcoidosis treatment comprising one or more of lifestyle and behavioral interventions, corticosteroids, methotrexate or azathioprine, hydroxychloroquine or chloroquine, cyclophosphamide or chlorambucil, pentoxifylline and thalidomide, infliximab or adalimumab, colchicine, various nonsteroidal anti-inflammatory drugs (NSAIDs), and/or organ transplantation.   
     
     
         14 . The method of  claim 6 , wherein the sample is assayed for one or markers selected from WDFY3, MFS, LRPPRC, HLA-DR, BfrA, DAB2, or TCEB2. 
     
     
         15 . The method of  claim 6 , further comprising:
 obtaining a value based on the assay;   comparing the value to a reference level; and   diagnosing the subject as having tuberculosis based on the upregulation of one or more of WDFY3, MFS, LRPPRC, and/or HLA-DR, or the downregulation of the one or more of BfrA, DAB2, and/or TCEB2, as demonstrated by the value and the reference level; and   treating the subject diagnosed as having tuberculosis with a tuberculosis treatment comprising one or more of isoniazid (INH), rifampin (RIF), ethambutol (EMB), or pyrazinamide (PZA).   
     
     
         16 . A method of diagnosis a subject as having sarcoidosis rather than tuberculosis and treating sarcoidosis in the subject, the method comprising:
 obtaining a sample derived from the subject;   assaying the sample for HLA-DR alpha (HLA-DR) and Membrane protein (MFS);   obtaining a value based on the assay;   comparing the value to a reference level;   diagnosing the subject as having sarcoidosis rather than tuberculosis based on the up- or down-regulation of the one or more markers as demonstrated by the value and the reference level; and   treating the subject diagnosed as having sarcoidosis with a sarcoidosis treatment comprising one or more of a corticosteroid, methotrexate, azathioprine, hydroxychloroquine, chloroquine, cyclophosphamide, chlorambucil, pentoxifylline and thalidomide, infliximab, adalimumab, colchicine, a nonsteroidal anti-inflammatory drug (NSAID), and/or organ transplantation.   
     
     
         17 . The method of  claim 16 , comprising further assaying the sample for one or more markers selected from WDFY3 protein (WDFY3); Leucine rich PPR-motif containing protein (LRPPRC); Chain A  Mycobacterium tuberculosis  (BfrA); Disabled homolog 2 isoform 2 (DAB2); Transcription elongation factor B polypeptide 2 isoform ( Homo sapiens ) (TCEB2); Small inducible cytokine A21 precursor (CCL21); Methionine aminopeptidase 1 (Metap1); Activated RNA polymerase II transcription cofactor variant 4 (PC4); RNA methyltransferase (CLI_3190); Tumor necrosis factor receptor superfamily member 21 precursor (TNFRSF21); Monocyte differentiation antigen CD14 (CD14); DnaJ (Hsp40) homolog subfamily C member 1 precursor (DNAJC1); Amyloid β A4 precursor protein-binding family B member 1-interacting protein (APBB1); Fibroblast growth factor binding protein 2 precursor (FGFBP-2); or SH3 domain-containing YSC84 like protein 1 (SH3YL1). 
     
     
         18 . The method of  claim 17 , comprising diagnosing the subject as having tuberculosis based on the upregulation of one or more of WDFY3, MFS, LRPPRC, and/or HLA-DR, or the downregulation of the one or more of BfrA, DAB2, and/or TCEB2, as demonstrated by the value and the reference level.