title: Expression of extra trinucleotide in CD44 variant of rheumatoid arthritis patients allows generation of disease-specific monoclonal antibody.
abstract: Selective targeting of cells engaged in pathological activities is a major challenge for medical research. We generated monoclonal antibodies (mAbs) that exclusively bind, at concentrations ranging from 2 to 100 microg/ml, to a modified CD44 variant (designated CD44vRA) expressed on synovial fluid cells from joints of rheumatoid arthritis (RA) patients. These mAbs cross-reacted with keratinocytes expressing wild type CD44vRA (CD44v3-v10) only at a relatively high concentration (200 microg/ml). Sequence analysis of CD44vRA cDNA revealed, in 33 out of 43 RA and psoriatic arthritis patients, an extra intron-derived trinucleotide, CAG, which allows translation of an extra alanine. This insertion imposes a configurational change on the cell surface CD44 of RA synovial fluid cells, creating an immunogenic epitope and potentiating the ability to produce disease-specific antibodies. Indeed, the anti-CD44vRA mAbs (designated F8:33) were able to induce apoptosis in synovial fluid cells from RA patients, but not in peripheral blood leukocytes from the same patients, in keratinocytes from normal donors or in synovial fluid cells from osteoarthritis patients. Furthermore, injection of anti-CD44vRA mAbs reduced joint inflammation in DBA/1 mice with collagen-induced arthritis. These findings show that anti-CD44vRA mAbs are both bioactive and RA-specific.
authors: The Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Itshak
authors: I
authors: Golan
authors: Shlomo
authors: S
authors: Nedvetzki
authors: Ira
authors: I
authors: Golan
authors: Lora
authors: L
authors: Eshkar-Sebban
authors: David
authors: D
authors: Levartovsky
authors: Ori
authors: O
authors: Elkayam
authors: Dan
authors: D
authors: Caspi
authors: Suhail
authors: S
authors: Aamar
authors: Howard
authors: H
authors: Amital
authors: Alan
authors: A
authors: Rubinow
authors: David
authors: D
authors: Naor
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology* / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D015535:Arthritis, Psoriatic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D015153:Blotting, Western; D003001:Cloning, Molecular; D000939:Epitopes; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D008969:Molecular Sequence Data; D013582:Synovial Fluid / Q000276:immunology; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D018960:Hyaluronan Receptors