Mzb1, a novel b cell factor, and uses thereof

Abstract

The marginal zone (MZ) and B1 subsets of B cells, which differ from conventional follicular (FO) B cells both developmentally and functionally, are involved in early responses to infectious pathogens and the production of self-reactive antibodies. A novel gene, mzb1, is expressed at high levels in MZ and B1 B cells but at low level, if at all, in FOB cells. MZB1 is involved in the regulation of proliferation, BCR-mediated signal transduction, and antibody production in B cells. Inhibitors, activators and enhancers of MZB1 expression or activity can be used as immune modulators for research and therapeutic purposes.

1 .- 18 . (canceled) 
     
     
         19 . An inhibitor of the expression or at least one of the biological activities of a polypeptide comprising an amino acid sequence selected from the group consisting of:
 (a) the amino acid sequence as set forth in SEQ ID NO: 2 or 4,   (b) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 1 or 3,   (c) an amino acid sequence of (a) or (b) further comprising an amino-terminal methionine,   (d) an amino acid sequence which is an ortholog of any of (a)-(c), optionally further comprising an amino-terminal methionine,   (e) an amino acid sequence which is an allelic variant or a splice variant of any of (a)-(d), optionally further comprising an amino-terminal methionine,   (f) an amino acid sequence which is at least 72% identical to any of (a)-(e) over its entire length, optionally further comprising an amino-terminal methionine, and   (g) an amino acid sequence as set forth in SEQ ID NO: 2 or 4 with at least one amino acid modification selected from substitution, insertion, deletion, amino terminal turnction, carboxyl terminal truncation, or any combination thereof, optionally further comprising an amino-terminal methionine,   wherein (d)-(f) has at least one of the biological activities of the polypeptide having the amino acid sequence of any of (a)-(c), and   wherein the inhibitor is an antisense RNA, siRNA, shRNA, a ribozyme, a RNA or DNA aptamer, decoy RNA, a peptide aptamer, a small molecule, or an antibody.   
     
     
         20 . The inhibitor of  claim 19 , which is an antibody. 
     
     
         21 . The inhibitor of  claim 20 , which is an antibody specific for the polypeptide of any of (a)-(g). 
     
     
         22 . The inhibitor of  claim 21 , which is antibody specific for the polypeptide of any of (a)-(e). 
     
     
         23 . The inhibitor of  claim 22 , which is antibody specific for the polypeptide of any of (a)-(c). 
     
     
         24 . An activator or enhancer of the expression or at least one of the biological activities of a polypeptide comprising an amino acid sequence selected from the group consisting of:
 (a) the amino acid sequence as set forth in SEQ ID NO: 2 or 4,   (b) an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 1 or 3,   (c) an amino acid sequence of (a) or (b) further comprising an amino-terminal methionine,   (d) an amino acid sequence which is an ortholog of any of (a)-(c), optionally further comprising an amino-terminal methionine,   (e) an amino acid sequence which is an allelic variant or a splice variant of any of (a)-(d), optionally further comprising an amino-terminal methionine,   (f) an amino acid sequence which is at least 72% identical to any of (a)-(e) over its entire length, optionally further comprising an amino-terminal methionine, and   (g) an amino acid sequence as set forth in SEQ ID NO: 2 or 4 with at least one amino acid modification selected from substitution, insertion, deletion, amino terminal turnction, carboxyl terminal truncation, or any combination thereof, optionally further comprising an amino-terminal methionine,   wherein (d)-(f) has at least one of the biological activities of the polypeptide having the amino acid sequence of any of (a)-(c), and   wherein the activator or enhancer is a nucleic acid molecule or vector capable of driving the expression of a polypeptide of any one of (a) to (g), a transcription factor activating or enhancing the transcription of a nucleic acid sequence coding for a polypeptide of any one of (a) to (g), an agonistic antibody, or a small molecule agonist.   
     
     
         25 . A pharmaceutical composition comprising the inhibitor of  claim 19 . 
     
     
         26 . A pharmaceutical composition comprising the inhibitor of  claim 20 . 
     
     
         27 . A pharmaceutical composition comprising the inhibitor of  claim 21 . 
     
     
         28 . A pharmaceutical composition comprising the inhibitor of  claim 22 . 
     
     
         29 . A pharmaceutical composition comprising the inhibitor of  claim 23 . 
     
     
         30 . A pharmaceutical composition comprising the activator or enhancer of  claim 24 . 
     
     
         31 . A method of treating an autoimmune disease in a patient comprising administering an effective amount of the inhibitor of  claim 19  to a patient with an autoimmune disease, thereby treating the autoimmune disease in the patient. 
     
     
         32 . A method of treating an autoimmune disease in a patient comprising administering an effective amount of the inhibitor of  claim 20  to a patient with an autoimmune disease, thereby treating the autoimmune disease in the patient. 
     
     
         33 . A method of treating an autoimmune disease in a patient comprising administering an effective amount of the inhibitor of  claim 21  to a patient with an autoimmune disease, thereby treating the autoimmune disease in the patient. 
     
     
         34 . A method of treating an autoimmune disease in a patient comprising administering an effective amount of the inhibitor of  claim 22  to a patient with an autoimmune disease, thereby treating the autoimmune disease in the patient. 
     
     
         35 . A method of treating an autoimmune disease in a patient comprising administering an effective amount of the inhibitor of  claim 23  to a patient with an autoimmune disease, thereby treating the autoimmune disease in the patient. 
     
     
         36 . A method of treating an immunodeficiency in a patient comprising administering an effective amount of the activator or enhancer of  claim 24  to a patient with an immunodeficiency, thereby treating the immunodeficiency in the patient. 
     
     
         37 . An in vitro method for enhancing antibody production in a cell comprising the step of contacting a cell with an activator or enhancer of  claim 24 , wherein the cell is capable of producing an antibody, thereby enhancing antibody production in the cell. 
     
     
         38 . A method of screening for an inhibitor, activator, or enhancer of MZB 1 expression, which method comprises the steps of:
 (a) contacting a cell expression MZB1 or a variant thereof with candidate compounds;   (b) comparing the expression of MZB 1 in the presence and absence of the candidate compounds; and   (c) identifying compounds which increase or decrease MZB1 expression.   
     
     
         39 . A method of screening for an inhibitor, activator, or enhancer of MZB 1 activity, which method comprises the steps of:
 (a) contacting MZB1, a variant or a biologically active fragment thereof, or a cell expressing MZB1, a variant or biologically active fragment thereof with candidate compounds;   (b) comparing the activity of MZB 1 in the presence and absence of the candidate compounds; and   (c) identifying compounds which increase or decrease MZB1 activity.