Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy.
Unique autoantibody specificities are strongly associated with distinct clinical phenotypes, making autoantibodies useful for diagnosis and prognosis. To investigate the mechanisms underlying this striking association, we examined autoantigen expression in normal muscle and in muscle from patients with autoimmune myositis. Although myositis autoantigens are expressed at very low levels in control muscle, they are found at high levels in myositis muscle. Furthermore, increased autoantigen expression correlates with differentiation state, such that myositis autoantigen expression is increased in cells that have features of regenerating muscle cells. Consistent with this, we found that cultured myoblasts express high levels of autoantigens, which are strikingly down-regulated as cells differentiate into myotubes in vitro. These data strongly implicate regenerating muscle cells rather than mature myotubes as the source of ongoing antigen supply in autoimmune myositis. Myositis autoantigen expression is also markedly increased in several cancers known to be associated with autoimmune myositis, but not in their related normal tissues, demonstrating that tumor cells and undifferentiated myoblasts are antigenically similar. We propose that in cancer-associated myositis, an autoimmune response directed against cancer cross-reacts with regenerating muscle cells, enabling a feed-forward loop of tissue damage and antigen selection. Regulating pathways of antigen expression may provide unrecognized therapeutic opportunities in autoimmune diseases.
Casciola-Rosen
Livia
L
Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. lcr@jhmi.edu
Nagaraju
Kanneboyina
K
Plotz
Paul
P
Wang
Kondi
K
Levine
Stuart
S
Gabrielson
Edward
E
Corse
Andrea
A
Rosen
Antony
A
D001324:Autoantigens / Q000096:biosynthesis* / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D032342:Muscle Cells / Q000276:immunology* / Q000473:pathology; D009220:Myositis / Q000209:etiology / Q000276:immunology*
D001324:Autoantigens
J Rheumatol. 1981 Nov-Dec;8(6):925-30
6977032
J Rheumatol. 2000 Apr;27(4):940-8
10782820
Arthritis Rheum. 1983 May;26(5):604-11
6405755
Cancer Res. 1984 Oct;44(10):4679-87
6590117
J Cell Biol. 2000 May 1;149(3):603-12
10791974
J Immunol. 2000 May 15;164(10):5459-65
10799913
Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9209-14
10922072
Curr Opin Rheumatol. 2000 Nov;12(6):475-81
11092195
Lancet. 2001 Jan 13;357(9250):96-100
11197446
Ann Rheum Dis. 2001 Feb;60(2):116-23
11156543
Arthritis Rheum. 2001 Feb;44(2):389-96
11229471
Ann Intern Med. 2001 Jun 19;134(12):1087-95
11412048
J Immunol. 2001 Nov 1;167(9):5449-56
11673564
Curr Opin Rheumatol. 2001 Nov;13(6):476-82
11698723
Blood. 2002 Sep 15;100(6):2123-31
12200376
Rheum Dis Clin North Am. 2002 Nov;28(4):859-90, viii
12506776
Nat Rev Immunol. 2003 Jan;3(1):73-8
12511877
Arthritis Rheum. 2003 Feb 15;49(1):85-92
12579598
Cancer Immun. 2001 Mar 30;1:4
12747765
N Engl J Med. 2003 Oct 16;349(16):1526-33
14561795
Curr Opin Rheumatol. 2003 Nov;15(6):708-13
14569199
Nat Rev Cancer. 2004 Jan;4(1):36-44
14708025
Arthritis Rheum. 2004 Jan;50(1):233-41
14730621
Arch Neurol. 2004 Jan;61(1):30-2
14732616
Am J Pathol. 2004 Jul;165(1):53-61
15215161
J Exp Med. 1971 Jul 1;134(1):294-312
4997587
Br J Haematol. 1973 Oct;25(4):409-13
4137251
Proc Natl Acad Sci U S A. 1984 Sep;81(17):5435-9
6591199
J Rheumatol. 1984 Oct;11(5):663-5
6334746
Lancet. 1985 Feb 16;1(8425):361-3
2857418
Arthritis Rheum. 1985 Jul;28(7):796-803
2409985
J Neurol Sci. 1987 Oct;81(1):19-43
2445924
Arthritis Rheum. 1988 Mar;31(3):378-85
2833902
Hum Pathol. 1989 Mar;20(3):224-31
2470663
Arthritis Rheum. 1989 Sep;32(9):1165-9
2789047
Ann Neurol. 1991 Mar;29(3):241-51
2042940
Cell. 1991 Oct 18;67(2):325-33
1655278
N Engl J Med. 1991 Nov 21;325(21):1487-98
1658649
Neurology. 1991 Nov;41(11):1757-64
1944905
Medicine (Baltimore). 1991 Nov;70(6):360-74
1659647
N Engl J Med. 1992 Feb 6;326(6):363-7
1729618
Ann Neurol. 1992 Jan;31(1):46-52
1371910
Neurosci Lett. 1993 Feb 19;150(2):212-4
8469424
J Exp Med. 1994 Apr 1;179(4):1317-30
7511686
Semin Arthritis Rheum. 1995 Apr;24(5):323-58
7604300
Ann Neurol. 1995 Jul;38(1):102-10
7541976
J Exp Med. 1995 Dec 1;182(6):1625-34
7500007
Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11810-3
8524854
Arthritis Rheum. 1995 Dec;38(12):1837-44
8849357
J Neurosci. 1996 Feb 1;16(3):1114-22
8558240
J Clin Invest. 1996 Mar 15;97(6):1417-21
8617873
Arthritis Rheum. 1996 Feb;39(2):292-6
8849382
J Clin Invest. 1996 Jun 15;97(12):2905-10
8675705
Arthritis Rheum. 1996 Sep;39(9):1507-18
8814062
Science. 1997 Apr 25;276(5312):604-7
9110981
Immunity. 1998 Apr;8(4):451-60
9586635
Chest. 1998 Sep;114(3):801-7
9743170
Nature. 1982 Jul 15;298(5871):294-6
7045696