Prognostic Marker For Cryoglobulinemic Vasculitis And B Cell Malignancies In HCV Infected Patients

Abstract

The invention provides methods and compositions for early diagnosis and treatment of a disease associated with a specific antibody by employing the detection of a cross-idiotypic epitope on the specific antibody to detect the cells that produce the antibody before the development of clinical symptoms of the disease.

What is claimed is: 
     
         1 . A method of identifying a subject who is at the risk of developing cryoglobulinemic vasculitis and B cell malignancy associated with hepatitis C virus (HCV) comprising:
 providing a sample from a subject infected with HCV;   detecting in said sample WA cross-idiotype (Xid)+ B cells;   thereby identifying a subject who is at the risk of developing cryoglobulinemic vasculitis and B cell malignancy associated with HCV.   
     
     
         2 . The method of  claim 1 , wherein said WA Xid+B cells are detected by identifying an immunoglobulin nucleic acid sequence from a clonally expanded B cell population, wherein said immunoglobulin nucleic acid sequence is associated with WA Xid. 
     
     
         3 . The method of  claim 1 , wherein said WA Xid+B cells are detected with an isolated anti-WA Xid antibody. 
     
     
         4 . The method of  claim 1 , wherein said subject is identified early. 
     
     
         5 . The method of  claim 4 , wherein said early-identified subject is identified after initial HCV infection, but prior to the manifestation of symptoms associated with cryoglobulinemic vasculitis or B cell lymphoma. 
     
     
         6 . The method of  claim 1 , wherein said sample is a biological fluid comprising whole blood. 
     
     
         7 . The method of  claim 2 , wherein said immunoglobulin nucleic acid sequence associated with WA Xid comprises IgH V1-69 or IgHV V 3-7 or related germ line genes, VK325 or VK 328, JH4 or JH3, Jk1, and a D region consensus sequence comprising SEQ ID NO: 1 (consensus 1) or SEQ ID NO: 2 (consensus 2). 
     
     
         8 . The method of  claim 7 , wherein said SEQ ID NO: 1 (consensus 1) comprises the amino acid sequence EG-------NP. 
     
     
         9 . The method of  claim 7 , wherein said SEQ ID NO: 2 (consensus 2) comprises the amino acid sequence GDYYD-S-G-YIDA. 
     
     
         10 . The method of  claim 3 , wherein said isolated anti-WA Xid antibody is attached to a label selected from the group consisting of a fluorescein isothiocyanate (FITC) label and a phycoerythrin (PE) label. 
     
     
         11 . The method of  claim 3 , wherein said WA Xid+B cell is detected via flow cytometric analysis. 
     
     
         12 . The method of  claim 3 , wherein said method further comprises detecting in said sample a CD 11C +  cell with an anti-CD 11c antibody. 
     
     
         13 . A method for identifying a subject who is at risk of developing cryoglobulinemic vasculitis or B Cell malignancy associated with hepatitis C virus infection (HCV) comprising:
 providing a nucleic acid sample from clonally expanded B cells of an HCV-infected patient;   detecting in said sample sequences comprising immunoglobulin nucleic acid sequence associated with WA Xid, wherein said sequences comprise IgH V1-69 or IgHV V 3-7 or related germ line genes, VK325 or VK 328, JH4 or JH3, Jk1, and a D region consensus sequence comprising SEQ ID NO: 1 (consensus 1) or SEQ ID NO: 2 (consensus 2); and   prognosing the development of an HCV-infection associated cryoglobulinemic vasculitis or B Cell malignancy if said WA Xid sequence and said SEQ ID NO:1(consensus 1) or SEQ ID NO: 2 (consensus 2) are present in said HCV-infected patient-derived nucleic acid.   
     
     
         14 . A method of treating cryoglobulinemic vasculitis and B cell malignancy associated with HCV in a subject comprising:
 providing a sample from a subject infected with hepatitis C virus (HCV);   administering an anti-WA antibody to said subject if WA Xid+B cells-are detected in said sample,   thereby treating said cryoglobulinemic vasculitis or B Cell malignancy in said subject.   
     
     
         15 . The method of  claim 14 , wherein said patient lacks a clinical symptom of cryoglobulinemic vasculitis or B Cell malignancy. 
     
     
         16 . A method of identifying a subject who is at the risk of developing malignancy associated with hepatitis C virus (HCV), comprising:
 providing a sample from a subject infected with HCV;   detecting in said sample non-WA cross-idiotype positive (non-WA Xid+) B cells; thereby identifying a subject who is at the risk of developing malignancy associated with hepatitis C virus (HCV).   
     
     
         17 . The method of  claim 16 , wherein said non-WA Xid+B cells are detected by identifying an immunoglobulin nucleic acid sequence from a clonally expanded B cell population, wherein said immunoglobulin nucleic acid sequence is associated with specific non-WA Xid. 
     
     
         18 . The method of  claim 17 , wherein said specific non-WA Xid+B cells are detected with an isolated anti-non-WA Xid antibody. 
     
     
         19 . The method of  claim 16 , wherein said diagnosis is an early diagnosis. 
     
     
         20 . The method of  claim 19 , wherein said early diagnosis is after initial HCV infection, but prior to the manifestation of sign or symptoms associated B cell malignancies. 
     
     
         21 . The method of  claim 16 , wherein said sample is a biological fluid comprising whole blood. 
     
     
         22 . A kit comprising a set of first primers and second primers, and instructions for prognosis of cryoglobulinemic vasculitis and B cell malignancy associated with HCV-infection based on the detection of the immunoglobulin nucleic acid sequences associated with WA Xid comprising IgH V1-69 or IgH V 3-7 or related germ line genes, VK325 or VK 328, JH4 or JH3, Jk1, and SEQ ID NO: 1 (consensus 1) or SEQ ID NO: 2 (consensus 2), wherein said set of first primers and second primers comprises a first primer and a second primer that flank the complementary determining region 3 (CDR3) sequence, a first primer and a second primer that flank the VH-D-JH sequence and a first primer and a second primer that flank VK-JK sequence in Ig-encoding transcripts.