Inhibition of expansion and function of pathogenic age-associated b cells and use for the prevention and treatment of autoimmune disease

Abstract

This current invention provides methods and agents for preventing and treating autoimmune and lymphoproliferative disease by targeting pathogenic age-associated B cells as well as methods of detecting these pathogenic age-associated B cells as a method of diagnosing and predicting autoimmune disease and other lymphoproliferative and chronic inflammatory disorders. The current invention also provides targets for drug development and basic research for autoimmune diseases and other lymphoproliferative and chronic inflammatory disorders.

1 . A method of abolishing or decreasing pathogenic age-associated B cells in a subject in need thereof, comprising the administration of a therapeutically effective amount of an agent which stimulates, agonizes, and/or increases the expression and/or activity of at least one protein chosen from the group consisting of DEF6 and SWAP-70. 
     
     
         2 . The method of  claims 1 , wherein the agent is chosen from the group consisting of chemicals, pharmaceuticals, biologics, small organic molecules, antibodies, nucleic acids, peptides, and proteins. 
     
     
         3 . The method of  claim 2 , wherein the agent is chosen from the group consisting of nucleic acids which encode the SWAP-70 and DEF6 proteins, the entire SWAP-70 and DEF6 gene, a nucleic acid that is substantially homologous to the SWAP-70 and DEF6 genes, and variants, mutants, fragments, homologues or derivatives of the SWAP-70 and DEF6 genes that produces a protein that maintains or increases their function, a polypeptide of SWAP 70 and DEF6, and a variant of the polypeptide of SWAP70 and DEF6, 
     
     
         4 . The method of  claim 1 , wherein the agent is delivered directly to the pathogenic age-associated B cells in the subject. 
     
     
         5 . A method of treating and/or preventing an autoimmune or lymphoproliferative disease in a subject in need thereof, comprising the administration of a therapeutically effective amount of an agent which stimulates, agonizes, and/or increases the expression and/or activity of at least one protein chosen from the group consisting of DEF6 and SWAP-70, wherein the administration of the agent abolishes or decreases pathogenic age-associated B cells. 
     
     
         6 . The method of  claim 5 , wherein the autoimmune disease is chosen from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, myasthenia gravis, Graves disease, pernicious anemia, scleroderma, psoriasis, inflammatory bowel diseases, Hashimoto's disease, Addison's disease and Sjögren's syndrome. 
     
     
         7 . The method of  claim 5 , wherein the lymphoproliferative is chosen from the groups consisting of Hodgkin's lymphoma and Non-Hodgkin's lymphoma. 
     
     
         8 . The method of  claim 5 , wherein the agent is chosen from the group consisting of chemicals, pharmaceuticals, biologics, small organic molecules, antibodies, nucleic acids, peptides, and proteins. 
     
     
         9 . The method of  claim 8 , wherein the agent is chosen from the group consisting of nucleic acids which encode the SWAP-70 and DEF6 proteins, the entire SWAP-70 and DEF6 gene, a nucleic acid that is substantially homologous to the SWAP-70 and DEF6 genes, and variants, mutants, fragments, homologues or derivatives of the SWAP-70 and DEF6 genes that produces a protein that maintains or increases their function, a polypeptide of SWAP 70 and DEF6, and a variant of the polypeptide of SWAP70 and DEF6. 
     
     
         10 . The method of  claim 5 , wherein the agent is delivered directly to the pathogenic age-associated B cells in the subject. 
     
     
         11 . A method of abolishing or decreasing pathogenic age-associated B cells in a subject in need thereof, comprising the administration of a therapeutically effective amount of an agent which antagonizes, inhibits and/or reduces the expression and/or activity of interferon regulatory factor 5 (IRF5). 
     
     
         12 . The method of  claim 11 , wherein the agent is chosen from the group consisting of chemicals, pharmaceuticals, biologics, small organic molecules, antibodies, nucleic acids, peptides, and proteins. 
     
     
         13 . The method of  claim 11 , wherein the agent is chosen from the group consisting of a dominant-negative mutant of IRF5, IRF5-specific RNAi, IRF5-specific short RNA, IRF5-specific antisense oligonucleotides, IRF5-specific ribozymes, and IRF5-specific antibodies. 
     
     
         14 . The method of  claim 13 , wherein the short RNA is chosen from the group consisting of short interfering RNA (siRNA), small temporal RNAs (stRNAs), short hairpin RNA (shRNA), and micro-RNAs (miRNAs). 
     
     
         15 . The method of  claim 10 , wherein the agent is delivered directly to the pathogenic age-associated B cells in the subject. 
     
     
         16 . A method of treating and/or preventing an autoimmune or lymphoproliferative disease in a subject in need thereof, comprising the administration of a therapeutically effective amount of an agent which antagonizes, inhibits and/or reduces the expression and/or activity of interferon regulatory factor 5, wherein the administration of the agent abolishes or decreases pathogenic age-associated B cells. 
     
     
         17 . The method of  claim 16 , wherein the autoimmune disease is chosen from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, myasthenia gravis, Graves disease, pernicious anemia, scleroderma, psoriasis, inflammatory bowel diseases, Hashimoto's disease, Addison's disease and Sjogren's syndrome. 
     
     
         18 . The method of  claim 16 , wherein the lymphoproliferative is chosen from the groups consisting of Hodgkin's lymphoma and Non-Hodgkin's lymphoma. 
     
     
         19 . The method of  claim 16 , wherein the agent is chosen from the group consisting of chemicals, pharmaceuticals, biologics, small organic molecules, antibodies, nucleic acids, peptides, and proteins. 
     
     
         20 . The method of  claim 19 , wherein the agent is chosen from the group consisting of dominant-negative mutant of IRF5, IRF5-specific RNAi, IRF5-specific short RNA, IRF5-specific antisense oligonucleotides, IRF5-specific ribozymes, and IRF5-specific antibodies. 
     
     
         21 . The method of  claim 20 , wherein the short RNA is chosen from the group consisting of short interfering RNA (siRNA), small temporal RNAs (stRNAs), short hairpin RNA (shRNA), and micro-RNAs (miRNAs). 
     
     
         22 . The method of  claim 16 , wherein the agent is delivered directly to the pathogenic age-associated B cells in the subject. 
     
     
         23 .- 76 . (canceled)