Autoantibody Assessment in Clinical Routine

Cure Arthritis Naturally

Beat Arthritis Naturally

Get Instant Access

Patients exhibiting symptoms of suspected SLE should be screened for ANAs using indirect immunofluorescence on HEp-2 cells. Because ANAs are detectable in more than 95% of SLE patients, a negative result largely excludes this diagnosis. In extremely rare cases with clinical continuity of suspicion of SLE, a wide variety of autoantibody tests should be performed. The subsequent analysis of autoanti-bodies and their profile characteristic in SLE helps to consolidate the diagnosis and to predict lupus subsets with typical organ manifestations (Fig. 11.2).

Fig. 11.2 Decision tree of autoantibody testing in patients with clinical suspicion of SLE.

Some of them are included in the revised criteria of the American College of Rheumatology for the classification of SLE [22, 23]. A person is said to have SLE if four or more of the 11 criteria are present, either serially or simultaneously, during any interval or observation.

1. Malar rash

2. Discoid rash

3. Photosensitivity

4. Oral ulcers

5. Arthritis

6. Serositis a) Pleuritis or b) Pericarditis

7. Renal disorder a) Persistent proteinuria (>0.5 g/24 h or 3+) or b) Cellular casts

8. Neurologic disorder a) Seizures or b) Psychosis (having excluded other causes, e.g., drugs)

9. Hematologic disorder a) Hemolytic anemia or b) Leukopenia (<4/nl) or c) Lymphopenia (<1.5/nl) or d) Thrombocytopenia (< 100/nl)

10. Immunological disorders a) Raised anti-dsDNA antibody binding or b) Anti-Sm antibody or c) Positive finding of antiphospholipid antibodies based on:

i. IgG/M anticardiolipin antibodies ii. Lupus anticoagulant iii. False positive serological test for syphilis, present for at least 6 months

11. Antinuclear antibody in raised titer

The majority of autoantibodies do not correlate with disease activity. Therefore, it seems to be sufficient to control these antibodies in annual periods. Only antibodies to dsDNA, which may fluctuate with lupus activity in many patients but not in all, belong together with measurement of complement levels to the routine tools in monitoring disease activity.

It remains to be seen whether one or more other antibody tests such as anti-nucleosome, anti-ribosomal P, and anti-C1q will be accepted in routine parameters. Assumedly, future therapeutic options more selectively targeting the (auto)-immune system will require new biomarkers that include an extended palette of autoantibody tests [177-179].

References

1 Sherer Y, Gorstein A, Fritzler MJ, Shoen-feld Y. Autoantibody explosion in systemic lupus erythematosus: More than 100 different antibodies found in SLE patients. Semin Arthritis Rheum. 2004, 34:501-537.

2 Hargraves MM, Richmond H, Morton RJ. Presentation of two bone marrow elements: the "tart" cell and the "LE" cell. Proc Mayo Clin. 1948, 23:2558.

3 Haserick JR, Bortz DW. Normal bone marrow inclusion phenomena induced by lupus erythematosus plasma. J Invest Dermatol. 1949, 13:47-49.

4 Haserick JR, Lewis LA, Bortz DW. Blood factor in acute disseminated lupus er-ythematosus. I. Determination of y-glob-ulin as specific plasma fraction. Am J Med Sci. 1950, 219:660-663.

5 Miescher P, Fouconnet M. L'absorption du facteur "LE" par des noyaux cellulaires isolés. Experimentia. 1954, 10:252-254.

6 Ceppellini R, Polli E, Celada FA. DNA-reacting factor in serum of a patient with lupus erythematosus diffuses. Proc Soc Exp Biol. 1957, 96:572-574.

7 Holman HR, Kunkel HG. Affinity between the LE factor and cell nucleic acid nucleoprotein. Science. 1957, 126:162163.

8 Seligmann M. Mise en evidence dans le serum de malades atteints de lupus er-ythemateux dissemine diune substance determinant une reaction de precipitation avec liacide desoxyribonucleique. CR Acad Sci (Paris). 1957, 245: 243-245.

9 Miescher P, Straessle R. New serological methods for the detection of the LE factor. Vox Sang. 1957, 2:283-287.

10 Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, Harley JB. Development of autoantibod-ies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003, 349:1526-1533.

11 Hoffman IE, Peene I, Meheus L, Hui-zinga TW, Cebecauer L, Isenberg D, De Bosschere K, Hulstaert F, Veys EM, De Keyser F. Specific antinuclear antibodies are associated with clinical features in systemic lupus erythematosus. Ann Rheum Dis. 2004, 63:1155-1158.

12 Sawalha AH, Harley JB. Antinuclear autoantibodies in systemic lupus erythematosus. Curr Opin Rheumatol. 2004, 16:534-540.

13 Chan EKL, Pollard KM. Autoantibodies to ribonucleoprotein particles by immu-noblotting. In: Rose NR, de Macario EC, Fahey JL, Friedman H, Penn GM, eds. Manual of clinical laboratory immunology. Washington,D.C.: American Society for Microbiology, 1992:755-761.

14 Verheijen R, Salden M, van Venrooij WJ. Protein blotting. In: van Venrooij WJ, Maini RN, eds. Manual of Biological Markers of Disease. Kluwer Academic Publishers, 1993:A4-1-A4/25.

15 Lerner MR, Steitz JA. Antibodies to small nuclear RNAs complexed with proteins are produced by patients with systemic lupus erythematosus. Proc Natl Acad Sci USA. 1979, 76:5495-5499.

16 Pettersson I, Hinterberger M, Mimori T, Gottlieb E, Steitz JA. The structure of mammalian small nuclear ribonucleo-proteins. Identification of multiple protein components reactive with anti-(U1)ribo-nucleoprotein and anti-Sm autoantibodies. J Biol Chem. 1984, 259:5907-5914.

17 Hentschel Ch, Schoessler W, Schulte-Pelkum J, Kreutzberger J, Hiepe F. Development of a sensitive and reliable biochip for detection of autoantibodies in rheumatic diseases. In: Conrad K, Sack U, eds. Autoantigens, Autoanti-bodies, Autoimmunity. 4. Pabst, 2004: 484-489.

18 Robinson WH, DiGennaro C, Hueber W, Haab BB, Kamachi M, Dean EJ, Fournel S, Fong D, Genovese MC, de Vegvar HE, Skriner K, Hirschberg DL, Morris RI, Muller S, Pruijn GJ, van Venrooij WJ, Smolen JS, Brown PO, Steinman L, Utz PJ. Autoantigen microarrays for multiplex characterization of autoantibody responses. Nat Med. 2002, 8:295-301.

19 Joos TO, Schrenk M, Hopfl P, Kroger K, Chowdhury U, Stoll D, Schorner D, Durr M, Herick K, Rupp S, Sohn K, Hammerle H. A microarray enzyme-

linked immunosorbent assay for autoimmune diagnostics. Electrophoresis. 2000, 21:2641-2650.

20 Rouquette AM, Desgruelles C, Laroche P. Evaluation of the new multiplexed immunoassay, FIDIS, for simultaneous quantitative determination of antinuclear antibodies and comparison with conventional methods. Am J Clin Pathol. 2003, 120:676-681.

21 Buliard A, Fortenfant F, Ghillani-Dalbin P, Musset L, Oksman F, Olsson NO. Analysis of nine autoantibodies associated with systemic autoimmune diseases using the Luminex technology. Results of a multicenter study. Ann Biol Clin (Paris). 2005, 63:51-58.

22 Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997, 40:1725.

23 Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982, 25:1271-1277.

24 Hahn BH. Antibodies to DNA. N Engl J Med. 1998, 338:1359-1368.

25 Pisetsky DS. Anti-DNA and autoanti-bodies. Curr Opin Rheumatol. 2000, 12:364-368.

26 DeGiorgio LA, Konstantinov KN, Lee SC, Hardin JA, Volpe BT, Diamond B. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med. 2001, 7:1189-1193.

27 Omdal R, Brokstad K, Waterloo K, Koldingsnes W, Jonsson R, Mellgren SI. Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors. Eur J Neurol. 2005, 12:392-398.

28 Aarden LA, de Groot ER, Feltkamp TE. Immunology of DNA. III. Crithidia luci-liae, a simple substrate for the determination of anti-dsDNA with the immuno-fluorescence technique. Ann NY Acad Sci. 1975, 254:505-515.

29 Tan EM, Smolen JS, McDougal JS, Butcher BT, Conn D, Dawkins R, Fritzler

MJ, Gordon T, Hardin JA, Kalden JR, Lahita RG, Maini RN, Rothfield NF, Smeenk R, Takasaki Y, van Venrooij WJ, Wiik A, Wilson M, Koziol JA. A critical evaluation of enzyme immunoassays for detection of antinuclear autoantibodies of defined specificities. I. Precision, sensitivity, and specificity. Arthritis Rheum. 1999, 42:455-464.

30 Kavanaugh AF, Solomon DH. Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-DNA antibody tests. Arthritis Rheum. 2002, 47:546-555.

31 Amoura Z, Piette JC, Bach JF, Koutou-zov S. The key role of nucleosomes in lupus. Arthritis Rheum. 1999, 42:833843.

32 Amoura Z, Koutouzov S, Piette JC. The role of nucleosomes in lupus. Curr Opin Rheumatol. 2000, 12:369-373.

33 Burlingame RW, Cervera R. Anti-chro-matin (anti-nucleosome) autoantibodies. Autoimmun Rev. 2002, 1:321-328.

34 Bavykin SG, Usachenko SI, Zalensky AO, Mirzabekov AD. Structure of nucleosomes and organization of inter-nucleosomal DNA in chromatin. J Mol Biol. 1990, 212:495-511.

35 Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature. 1997, 389:251-260.

36 Burlingame RW, Boey ML, Starkebaum G, Rubin RL. The central role of chro-matin in autoimmune responses to histones and DNA in systemic lupus erythematosus. J Clin Invest. 1994, 94:184-192.

37 Chabre H, Amoura Z, Piette JC, Godeau P, Bach JF, Koutouzov S. Presence of nucleosome-restricted antibodies in patients with systemic lupus erythematosus. Arthritis Rheum. 1995, 38:1485-1491.

38 Ghillani-Dalbin P, Amoura Z, Cacoub P, Charuel JL, Diemert MC, Piette JC, Musset L. Testing for anti-nucleosome antibodies in daily practice: a monocentric evaluation in 1696 patients. Lupus. 2003, 12:833-837.

39 Cervera R, Vinas O, Ramos-Casals M, Font J, Garcia-Carrasco M, Siso A, Ramirez F, Machuca Y, Vives J, Ingelmo

M, Burlingame RW. Anti-chromatin antibodies in systemic lupus erythematosus: a useful marker for lupus nephropathy Ann Rheum Dis. 2003, 62:431-434.

40 Lefkowith JB, Kiehl M, Rubenstein J, DiValerio R, Bernstein K, Kahl L, Rubin RL, Gourley M. Heterogeneity and clinical significance of glomerular-binding antibodies in systemic lupus erythemato-sus. J Clin Invest. 1996, 98:1373-1380.

41 Wallace DJ, Lin HC, Shen GQ, Peter JB. Antibodies to histone (H2A-H2B)-DNA complexes in the absence of antibodies to double-stranded DNA or to (H2A-H2B) complexes are more sensitive and specific for scleroderma-related disorders than for lupus. Arthritis Rheum. 1994, 37:1795-1797.

42 Bruns A, Bläss S, Hausdorf G, Burmes-ter GR, Hiepe F. Nucleosomes are major T and B cell autoantigens in systemic lupus erythematosus. Arthritis Rheum. 2000, 43:2307-2315.

43 Simon JA, Cabiedes J, Ortiz E, Alcocer-Varela J, Sanchez-Guerrero J. Anti-nucleosome antibodies in patients with systemic lupus erythematosus of recent onset. Potential utility as a diagnostic tool and disease activity marker. Rheumatology (Oxford). 2004, 43:220-224.

44 Min DJ, Kim SJ, Park SH, Seo YI, Kang HJ, Kim WU, Cho CS, Kim HY. Anti-nu-cleosome antibody: significance in lupus patients lacking anti-double-stranded DNA antibody. Clin Exp Rheumatol. 2002, 20:13-18.

45 Amoura Z, Koutouzov S, Chabre H, Cacoub P, Amoura I, Musset L, Bach JF, Piette JC. Presence of antinucleosome autoantibodies in a restricted set of connective tissue diseases: antinucleosome antibodies of the IgG3 subclass are markers of renal pathogenicity in systemic lupus erythematosus. Arthritis Rheum. 2000, 43:76-84.

46 Benucci M, Gobbi FL, Del Rosso A, Cesaretti S, Niccoli L, Cantini F. Disease activity and antinucleosome antibodies in systemic lupus erythematosus. Scand J Rheumatol. 2003, 32:42-45.

47 Berden JH, Licht R, van Bruggen MC, Tax WJ. Role of nucleosomes for induction and glomerular binding of autoanti-

bodies in lupus nephritis. Curr Opin Nephrol Hypertens. 1999, 8:299-306.

48 Berden JH, van Bruggen MC. Nucleo-somes and the pathogenesis of lupus nephritis. Kidney Blood Press Res. 1997, 20:198-200.

49 van Bruggen MC, Kramers C, Walgreen B, Elema JD, Kallenberg CG, van den BJ, Smeenk RJ, Assmann KJ, Muller S, Monestier M, Berden JH. Nucleosomes and histones are present in glomerular deposits in human lupus nephritis. Nephrol Dial Transplant. 1997, 12:57-66.

50 Koutouzov S, Jeronimo AL, Campos H, Amoura Z. Nucleosomes in the patho-genesis of systemic lupus erythemato-sus. Rheum Dis Clin North Am. 2004, 30:529-558.

51 Abraham SJ, Rojas-Serrano J, Cabiedes J, Alcocer-Varela J. Antinucleosome antibodies may help predict development of systemic lupus erythematosus in patients with primary antiphospholipid syndrome. Lupus. 2004, 13:177-181.

52 Burlingame RW, Rubin RL. Drug-induced anti-histone autoantibodies display two patterns of reactivity with substructures of chromatin. J Clin Invest. 1991, 88:680-690.

53 Burlingame RW. The clinical utility of antihistone antibodies. Autoantibodies reactive with chromatin in systemic lupus erythematosus and drug-induced lupus. Clin Lab Med. 1997, 17:367-378.

54 Hmida Y, Schmit P, Gilson G, Humbel RL. Failure to detect antinucleosome antibodies in scleroderma: comment on the article by Amoura et al. Arthritis Rheum. 2002, 46:280-282.

55 Suer W, Dahnrich C, Schlumberger W, Stocker W. Autoantibodies in SLE but not in scleroderma react with protein-stripped nucleosomes. J Autoimmun. 2004, 22:325-334.

56 Li L, Chen M, Huang DY, Nishioka M. Frequency and significance of antibodies to chromatin in autoimmune hepatitis type I. J Gastroenterol Hepatol. 2000, 15:1176-1182.

57 Zieve GW, Khusial PR. The anti-Sm immune response in autoimmunity and cell biology. Autoimmun Rev. 2003, 2:235-240.

58 Tan EM, Kunkel HG. Characteristics of a soluble nuclear antigen precipitating with sera of patients with systemic lupus erythematosus. J Immunol. 1966, 96:464-471.

59 Arnett FC, Hamilton RG, Roebber MG, Harley JB, Reichlin M. Increased frequencies of Sm and nRNP autoantibod-ies in American blacks compared to whites with systemic lupus erythemato-sus. J Rheumatol. 1988, 15:1773-1776.

60 Ignat GP, Rat AC, Sychra JJ, Vo J, Varga J, Teodorescu M. Information on diagnosis and management of systemic lupus erythematosus derived from the routine measurement of 8 nuclear autoantibod-ies. J Rheumatol. 2003, 30:1761-1769.

61 Yasuma M, Takasaki Y, Matsumoto K, Kodama A, Hashimoto H, Hirose S. Clinical significance of IgG anti-Sm antibodies in patients with systemic lupus erythematosus. J Rheumatol. 1990, 17:469-475.

62 Cervera R, Khamashta MA, Font J, Se-bastiani GD, Gil A, Lavilla P, Domenech I, Aydintug AO, Jedryka-Goral A, de Ramon E. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1000 patients. The European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore). 1993, 72:113-124.

63 ter Borg EJ, Groen H, Horst G, Limburg PC, Wouda AA, Kallenberg CG. Clinical associations of antiribonucleoprotein antibodies in patients with systemic lupus erythematosus. Semin Arthritis Rheum. 1990, 20:164-173.

64 Vlachoyiannopoulos PG, Karassa FB, Karakostas KX, Drosos AA, Moutsopou-los HM. Systemic lupus erythematosus in Greece. Clinical features, evolution and outcome: a descriptive analysis of 292 patients. Lupus. 1993, 2:303-312.

65 Riemekasten G, Marell J, Trebeljahr G, Klein R, Hausdorf G, Haupl T, Schnei-der-Mergener J, Burmester GR, Hiepe F. A novel epitope on the C-terminus of SmD1 is recognized by the majority of sera from patients with systemic lupus erythematosus. J Clin Invest. 1998, 102:754-763.

66 Mattioli M, Reichlin M. Physical association of two nuclear antigens and mutual occurrence of their antibodies: the relationship of the SM and RNAprotein (MO) systems in SLE sera. J Immunol. 1973, 110:1318-1324.

67 Font J, Cervera R, Ramos-Casals M, Garcia-Carrasco M, Sents J, Herrero C, del Olmo JA, Darnell A, Ingelmo M. Clusters of clinical and immunologic features in systemic lupus erythematosus: analysis of 600 patients from a single center. Semin Arthritis Rheum. 2004, 33:217-230.

68 von Muhlen CA, Tan EM. Autoantibodies in the diagnosis of systemic rheumatic diseases. Semin Arthritis Rheum. 1995, 24:323-358.

69 Sharp GC, Irvin WS, LaRoque RL, Velez C, Daly V, Kaiser AD, Holman HR. Association of autoantibodies to different nuclear antigens with clinical patterns of rheumatic disease and responsiveness to therapy. J Clin Invest. 1971, 50:350-359.

70 Fisher DE, Reeves WH, Wisniewolski R, Lahita RG, Chiorazzi N. Temporal shifts from Sm to ribonucleoprotein reactivity in systemic lupus erythematosus. Arthritis Rheum. 1985, 28:1348-1355.

71 Arbuckle MR, Reichlin M, Harley JB, James JA. Shared early autoantibody recognition events in the development of anti-Sm B/B' in human lupus. Scand J Immunol. 1999, 50:447-455.

72 James JA, Harley JB. Linear epitope mapping of an Sm B/B' polypeptide. J Immunol. 1992, 148:2074-2079.

73 James JA, Gross T, Scofield RH, Harley JB. Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B'-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity. J Exp Med. 1995, 181:453-461.

74 James JA, Harley JB. A model of pep-tide-induced lupus autoimmune B cell epitope spreading is strain specific and is not H-2 restricted in mice. J Immunol. 1998, 160:502-508.

75 Harley JB, James JA. Epstein-Barr virus infection may be an environmental risk factor for systemic lupus erythematosus in children and teenagers. Arthritis Rheum. 1999, 42:1782-1783.

76 James JA, Kaufman KM, Farris AD, Taylor-Albert E, Lehman TJ, Harley JB. An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. J Clin Invest. 1997, 100:3019-3026.

77 James JA, Neas BR, Moser KL, Hall T, Bruner GR, Sestak AL, Harley JB. Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure. Arthritis Rheum. 2001, 44:1122-1126.

78 Kang I, Quan T, Nolasco H, Park SH, Hong MS, Crouch J, Pamer EG, Howe JG, Craft J. Defective control of latent Epstein-Barr virus infection in systemic lupus erythematosus. J Immunol. 2004, 172:1287-1294.

79 Habets WJ, de Rooij DJ, Hoet MH, van de Putte LB, van Venrooij WJ. Quantitation of anti-RNP and anti-Sm antibodies in MCTD and SLE patients by immuno-blotting. Clin Exp Immunol. 1985, 59:457-466.

80 Jaekel HP, Klopsch T, Benkenstein B, Grobe N, Baldauf A, Schoessler W, Werle E. Reactivities to the Sm autoantigenic complex and the synthetic SmD1-aa83-119 peptide in systemic lupus erythema-tosus and other autoimmune diseases.

J Autoimmun. 2001, 17:347-354.

81 Tsao BP, Grossman JM, Riemekasten G, Strong N, Kalsi J, Wallace DJ, Chen CJ, Lau CS, Ginzler EM, Goldstein R, Kalunian KC, Harley JB, Arnett FC, Hahn BH, Cantor RM. Familiality and co-occurrence of clinical features of systemic lupus erythematosus. Arthritis Rheum. 2002, 46:2678-2685.

82 Riemekasten G, Marell J, Hentschel C, Klein R, Burmester GR, Schoessler W, Hiepe F. Casein is an essential cofactor in autoantibody reactivity directed against the C-terminal SmD1 peptide AA 83-119 in systemic lupus erythema-tosus. Immunobiology. 2002, 206:537545.

83 Rokeach LA, Haselby JA, Hoch SO. Molecular cloning of a cDNA encoding the human Sm-D autoantigen. Proc Natl Acad Sci USA. 1988, 85:4832-4836.

84 Rokeach LA, Jannatipour M, Haselby JA, Hoch SO. Mapping of the immunoreac-tive domains of a small nuclear ribonu-cleoprotein-associated Sm-D autoantigen.

Clin Immunol Immunopathol. 1992, 65:315-324.

85 Riemekasten G, Kawald A, Weiss C, Meine A, Marell J, Klein R, Hocher B, Meisel C, Hausdorf G, Manz R, Kamradt T, Burmester GR, Hiepe F. Strong acceleration of murine lupus by injection of the SmD1 (83-119) peptide. Arthritis Rheum. 2001, 44:2435-2445.

86 Riemekasten G, Langnickel D, Ebling FM, Karpouzas G, Kalsi J, Herberth G, Tsao BP, Henklein P, Langer S, Burmester GR, Radbruch A, Hiepe F, Hahn BH. Identification and characterization of SmD 183-119-reactive T cells that provide T cell help for pathogenic anti-double-stranded DNA antibodies. Arthritis Rheum 2003, 48:475-485.

87 Staikou EV, Routsias JG, Makri AA, Terzoglou A, Sakarellos-Daitsiotis M, Sakarellos C, Panayotou G, Moutsopou-los HM, Tzioufas AG. Calreticulin binds preferentially with B cell linear epitopes of Ro60 kD autoantigen, enhancing recognition by anti-Ro60 kD autoantibod-ies. Clin Exp Immunol. 2003, 134:143150.

88 Riemekasten G, Langnickel D, Enghard P, Undeutsch R, Humrich J, Ebling FM, Hocher B, Humaljoki T, Neumayer H, Burmester GR, Hahn BH, Radbruch A, Hiepe F. Intravenous injection of a D1 protein of the Smith proteins postpones murine lupus and induces type 1 regula-toryT cells. J Immunol. 2004, 173:58355842.

89 Brahms H, Raymackers J, Union A, De Keyser F, Meheus L, Luhrmann R. The C-terminal RG dipeptide repeats of the spliceosomal Sm proteins D1 and D3 contain symmetrical dimethylarginines, which form a major B-cell epitope for anti-Sm autoantibodies. J Biol Chem. 2000, 275:17122-17129.

90 Mahler M, Stinton LM, Fritzler MJ. Improved serological differentiation between systemic lupus erythematosus and mixed connective tissue disease by use of an SmD3 peptide-based immunoas-say. Clin Diagn Lab Immunol. 2005, 12:107-113.

91 Mahler M, Fritzler MJ, Bluthner M. Identification of a SmD3 epitope with a single symmetrical dimethylation of an arginine residue as a specific target of a subpopulation of anti-Sm antibodies. Arthritis Res Ther. 2005, 7:R19-R29.

92 Anderson JR, Gray KG, Beck JS, Kinnear WF. Precipitating autoantibodies in Sjogren's disease. Lancet. 1961, 2:456-460.

93 Clark G, Reichlin M, Tomasi TB, Jr. Characterization of a soluble cytoplasmic antigen reactive with sera from patients with systemic lupus erythma-tosus. J Immunol. 1969, 102:117-122.

94 Alspaugh MA, Tan EM. Antibodies to cellular antigens in Sjogren's syndrome. J Clin Invest. 1975, 55:10671073.

95 Franceschini F, Cavazzana I. Anti-Ro/ SSA and La/SSB antibodies. Autoimmunity. 2005, 38:55-63.

96 O'Brien CA, Harley JB. A subset of hY RNAs is associated with erythrocyte Ro ribonucleoproteins. EMBO J. 1990, 9:3683-3689.

97 Itoh Y, Reichlin M. Ro/SS-A antigen in human platelets. Different distributions of the isoforms of Ro/SS-A protein and the Ro/SS-A-binding RNA. Arthritis Rheum. 1991, 34:888-893.

98 Ben Chetrit E, Chan EK, Sullivan KF, Tan EM. A 52-kD protein is a novel component of the SS-A/Ro antigenic particle.

J Exp Med. 1988, 167:1560-1571.

99 Chan EK, Hamel JC, Buyon JP, Tan EM. Molecular definition and sequence motifs of the 52-kD component of human SS-A/Ro autoantigen. J Clin Invest. 1991, 87:68-76.

100 Itoh K, Itoh Y, Frank MB. Protein heterogeneity in the human Ro/SSA ribonucleoproteins. The 52- and 60-kD Ro/SSA autoantigens are encoded by separate genes. J Clin Invest. 1991, 87: 177-186.

101 Kurien BT, Chambers TL, Thomas PY, Frank MB, Scofield RH. Autoantibody to the leucine zipper region of 52 kDa Ro/SSA binds native 60 kDa Ro/SSA: identification of a tertiary epitope with components from 60 kDa Ro/SSA and 52 kDa Ro/SSA. Scand J Immunol. 2001, 53:268-276.

102 Stefano JE. Purified lupus antigen La recognizes an oligouridylate stretch common to the 3' termini of RNA polymerase III transcripts. Cell. 1984, 36:145-154.

103 Chen X, Quinn AM, Wolin SL. Ro ribonucleoproteins contribute to the resistance of Deinococcus radiodurans to ultraviolet irradiation. Genes Dev. 2000, 14:777-782.

104 Chen X, Smith JD, Shi H, Yang DD, Flavell RA, Wolin SL. The Ro autoantigen binds misfolded U2 small nuclear RNAs and assists mammalian cell survival after UV irradiation. Curr Biol. 2003, 13:2206-2211.

105 Xue D, Shi H, Smith JD, Chen X, Noe DA, Cedervall T, Yang DD, Eynon E, Brash DE, Kashgarian M, Flavell RA, Wolin SL. A lupus-like syndrome develops in mice lacking the Ro 60-kDa protein, a major lupus autoantigen. Proc Natl Acad Sci USA. 2003, 100:75037508.

106 Ramakrishnan S, Sharma HW, Farris AD, Kaufman KM, Harley JB, Collins K, Pruijn GJ, van Venrooij WJ, Martin ML, Narayanan R. Characterization of human telomerase complex. Proc Natl Acad Sci USA. 1997, 94:10075-10079.

107 Sontheimer RD, Maddison PJ, Reichlin M, Jordon RE, Stastny P, Gilliam JN. Serologic and HLA associations in sub-acute cutaneous lupus erythematosus, a clinical subset of lupus erythemato-sus. Ann Intern Med. 1982, 97:664671.

108 Dörner T, Feist E, Pruss A, Chaoui R, Göldner B, Hiepe F. Significance of autoantibodies in neonatal lupus erythematosus. Int Arch Allergy Immunol. 2000, 123:58-66.

109 Brucato A, Frassi M, Franceschini F, Cimaz R, Faden D, Pisoni MP, Mus-cara M, Vignati G, Stramba-Badiale M, Catelli L, Lojacono A, Cavazzana I, Ghirardello A, Vescovi F, Gambari PF, Doria A, Meroni PL, Tincani A. Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmu-noelectrophoresis: a prospective study of 100 women. Arthritis Rheum. 2001, 44:1832-1835.

110 Costedoat-Chalumeau N, Amoura Z, Lupoglazoff JM, Thi Huong dL, Denjoy

I, Vauthier D, Sebbouh D, Fain O, 116

Georgin-Lavialle S, Ghillani P, Musset L, Wechsler B, Duhaut P, Piette JC. Outcome of pregnancies in patients with anti-SSA/Ro antibodies: a study of 165 pregnancies, with special focus on 117 electrocardiographic variations in the children and comparison with a control group. Arthritis Rheum. 2004, 50: 3187-3194.

111 Brucato A, Doria A, Frassi M, Castelli- 118 no G, Franceschini F, Faden D, Pisoni

MP, Solerte L, Muscara M, Lojacono A, Motta M, Cavazzana I, Ghirardello A, Vescovi F, Tombini V, Cimaz R, Gam- 119 bari PF, Meroni PL, Canesi B, Tincani A. Pregnancy outcome in 100 women with autoimmune diseases and anti-Ro/SSA antibodies: a prospective controlled study. Lupus. 2002, 11:716-721.

112 Buyon JP, Hiebert R, Copel J, Craft J, 120 Friedman D, Katholi M, Lee LA, Provost TT, Reichlin M, Rider L, Rupel A, Saleeb S, Weston WL, Skovron ML. Autoimmune-associated congenital 121 heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol. 1998, 122 31:1658-1666.

113 Eronen M, Siren MK, Ekblad H, Tika-noja T, Julkunen H, Paavilainen T. Short- and long-term outcome of children with congenital complete heart 123 block diagnosed in utero or as a newborn. Pediatrics. 2000, 106:86-91.

114 Julkunen H, Kaaja R, Siren MK, Mack

C, McCready S, Holthofer H, Kurki P, 124 Maddison P. Immune-mediated congenital heart block (CHB): identifying and counseling patients at risk for having children with CHB. Semin Arthritis Rheum. 1998, 28:97-106.

115 Buyon JP, Winchester RJ, Slade SG, 125 Arnett F, Copel J, Friedman D, Lock-

shin MD. Identification of mothers at risk for congenital heart block and other neonatal lupus syndromes in their children. Comparison of enzyme-

linked immunosorbent assay and im-munoblot for measurement of anti-SS-A/Ro and anti-SS-B/La antibodies. Arthritis Rheum. 1993, 36:1263-1273. Salomonsson S, Dorner T, Theander E, Bremme K, Larsson P, Wahren-Herle-nius M. A serologic marker for fetal risk of congenital heart block. Arthritis Rheum. 2002, 46:1233-1241. Dörner T, Feist E, Chaoui R, Hiepe F. Enhanced frequency of autoimmune congenital heart block in female offspring. Rheumatology (Oxford). 1999, 38:380-382.

Bravo R, Frank R, Blundell PA, Mac-donald-Bravo H. Cyclin/PCNA is the auxiliary protein of DNA polymerase-delta. Nature. 1987, 326:515-517. Prelich G, Tan CK, Kostura M, Mathews MB, So AG, Downey KM, Stillman B. Functional identity of proliferating cell nuclear antigen and a DNA poly-merase-delta auxiliary protein. Nature. 1987, 326:517-520. Chou CH, Satoh M, Wang J, Reeves WH. B-cell epitopes of autoantigenic DNA-binding proteins. Mol Biol Rep. 1992, 16:191-198. Miyachi K, Fritzler MJ, Tan EM. Auto-antibody to a nuclear antigen in proliferating cells. J Immunol. 1978, 121:2228-2234.

Takasaki Y, Fishwild D, Tan EM. Characterization of proliferating cell nuclear antigen recognized by autoantibodies in lupus sera. J Exp Med. 1984, 159:981-992.

Tan EM. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol. 1989, 44:93-151. Asero R, Origgi L, Crespi S, Bertetti E, D'Agostino P, Riboldi P. Autoantibody to proliferating cell nuclear antigen (PCNA) in SLE: a clinical and serological study. Clin Exp Rheumatol. 1987, 5:241-246.

Grimaudo SA, Guilleron CMJA. Im-munoblotting for detectionof anti-self reactivities in collagen diseases: autoan-tibody profiles and clinical significance in patients with SLE. Lupus. 2005, 4:160.

126 Grimaudo SA, Guilleron CMJA. Im-munoblotting for detection of anti-self reactivities in collagen diseases: autoantibody profiles and clinical significance in patients with SLE. Lupus. 1995, 4:160.

127 Bonfa E, Golombek SJ, Kaufman LD, Skelly S, Weissbach H, Brot N, Elkon KB. Association between lupus psychosis and anti-ribosomal P protein antibodies. N Engl J Med. 1987, 317:265271.

128 Elkon KB, Parnassa AP, Foster CL. Lupus autoantibodies target ribosomal P proteins. J Exp Med. 1985, 162:459471.

129 Elkon K, Bonfa E, Llovet R, Danho W, Weissbach H, Brot N. Properties of the ribosomal P2 protein autoantigen are similar to those of foreign protein antigens. Proc Natl Acad Sci USA. 1988, 85:5186-189.

130 Hasler P, Brot N, Weissbach H, Parnassa AP, Elkon KB. Ribosomal proteins P0, P1, and P2 are phosphory-lated by casein kinase II at their conserved carboxyl termini. J Biol Chem. 1991, 266:13815-13820.

131 Hasler P, Brot N, Weissbach H, Danho W, Blount Y, Zhou JL, Elkon KB. The effect of phosphorylation and site-specific mutations in the immunodomi-nant epitope of the human ribosomal P proteins. Clin Immunol Immuno-pathol. 1994, 72:273-279.

132 Mahler M, Kessenbrock K, Raats J, Williams R, Fritzler MJ, Bluthner M. Characterization of the human autoimmune response to the major C-ter-minal epitope of the ribosomal P proteins. J Mol Med. 2003, 81:194-204.

133 Caponi L, Bombardieri S, Migliorini P. Anti-ribosomal antibodies bind the Sm proteins D and B/B'. Clin Exp Immunol. 1998, 112:139-143.

134 Caponi L, Chimenti D, Pratesi F, Migliorini P. Anti-ribosomal antibodies from lupus patients bind DNA. Clin Exp Immunol. 2002, 130:541-547.

135 Reichlin M. Cellular dysfunction induced by penetration of autoantibodies into living cells: cellular damage and dysfunction mediated by antibodies to dsDNA and ribosomal P proteins. J Autoimmun. 1998, 11:557-561.

136 Mahler M, Kessenbrock K, Reeves W, Takasaki Y, Garcia-De La Torre I, Shoenfeld Y, Hiepe F, Shun-le C, von Mühlen C, Wiik A, Höpfl P, Szmyrka M, Fritzler MJ. Multi-centre evaluation of a new assay to detect autoantibodies to ribosomal P proteins. Arthritis Res Ther (in press).

137 Nojima Y, Minota S, Yamada A, Takaku F, Aotsuka S, Yokohari R. Correlation of antibodies to ribosomal P protein with psychosis in patients with systemic lupus erythematosus. Ann Rheum Dis. 1992, 51:1053-1055.

138 Schneebaum AB, Singleton JD, West SG, Blodgett JK, Allen LG, Cheronis JC, Kotzin BL. Association of psychiatric manifestations with antibodies to ribosomal P proteins in systemic lupus erythematosus. Am J Med. 1991, 90:54-62.

139 Gerli R, Caponi L, Tincani A, Scorza R, Sabbadini MG, Danieli MG, De AV, Cesarotti M, Piccirilli M, Quartesan R, Moretti P, Cantoni C, Franceschini F, Cavazzana I, Origgi L, Vanoli M, Boz-zolo E, Ferrario L, Padovani A, Gambini O, Vanzulli L, Croce D, Bombardieri S. Clinical and serological associations of ribosomal P autoantibodies in systemic lupus erythematosus: prospective evaluation in a large cohort of Italian patients. Rheumatology (Oxford). 2002, 41:1357-1366.

140 Sato T, Uchiumi T, Ozawa T, Kikuchi M, Nakano M, Kominami R, Arakawa M. Autoantibodies against ribosomal proteins found with high frequency in patients with systemic lupus erythema-tosus with active disease. J Rheumatol. 1991, 18:1681-1684.

141 Chindalore V, Neas B, Reichlin M. The association between anti-ribosomal P antibodies and active nephritis in systemic lupus erythematosus. Clin Immunol Immunopathol. 1998, 87: 292-296.

142 Reichlin M, Wolfson-Reichlin M. Evidence for the participation of anti-ribo-somal P antibodies in lupus nephritis. Arthritis Rheum. 1999, 42:2728-2729.

143 Reichlin M, Wolfson-Reichlin M. Correlations of anti-dsDNA and anti-ribo-somal P autoantibodies with lupus nephritis. Clin Immunol. 2003, 108: 69-72.

144 Hulsey M, Goldstein R, Scully L, Surbeck W, Reichlin M. Anti-ribosomal P antibodies in systemic lupus erythema-tosus: a case-control study correlating hepatic and renal disease. Clin Immunol Immunopathol. 1995, 74:252-256.

145 Ohira H, Takiguchi J, Rai T, Abe K, Yokokawa J, Sato Y, Takeda I, Kanno T. High frequency of anti-ribosomal P antibody in patients with systemic lupus erythematosus-associated hepatitis. Hepatol Res. 2004, 28:137-139.

146 Galli M. Antiphospholipid syndrome: association between laboratory tests and clinical practice. Pathophysiol Haemost Thromb. 2003, 33:249-255.

147 Gromnica-Ihle E, Schossler W. Antiphospholipid syndrome. Int Arch Allergy Immunol. 2000, 123:67-76.

148 Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, Brey R, Derksen R, Harris EN, Hughes GR, Triplett DA, Khamashta MA. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999, 42:1309-1311.

149 Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost. 1995, 74:1185-1190.

150 Petri M. Diagnosis of antiphospholipid antibodies. Rheum Dis Clin North Am. 1994, 20:443-469.

151 Buttgereit F, Grunewald T, Schuler-Maue W, Burmester GR, Hiepe F. Value of anticardiolipin antibodies for monitoring disease activity in systemic lupus erythematosus and other rheumatic diseases. Clin Rheumatol. 1997, 16:562-569.

152 Karassa FB, Ioannidis JP, Touloumi G, Boki KA, Moutsopoulos HM. Risk fac tors for central nervous system involvement in systemic lupus erythematosus. QJM. 2000, 93:169-174.

153 West SG, Emlen W, Wener MH, Kotzin BL. Neuropsychiatric lupus erythematosus: a 10-year prospective study on the value of diagnostic tests. Am J Med. 1995, 99:153-163.

154 Sanna G, Bertolaccini ML, Cuadrado MJ, Laing H, Khamashta MA, Mathieu A, Hughes GR. Neuropsychiatric manifestations in systemic lupus erythema-tosus: prevalence and association with antiphospholipid antibodies. J Rheumatol. 2003, 30:985-992.

155 Asherson RA, Cervera R, Piette JC, Font J, Lie JT, Burcoglu A, Lim K, Munoz-Rodriguez FJ, Levy RA, Boue F, Rossert J, Ingelmo M. Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients. Medicine (Baltimore). 1998, 77:195207.

156 Hiepe F, Pfüller B, Wolbart K, Bruns A, Leinenbach H-P, Hepper M, Schöss-ler W, Otto V. C1q - a multifunctional ligand for a new immunoadsorption treatment. Ther Apher. 1999, 3:246251.

157 Nydegger UE, Lambert PH, Gerber H, Miescher PA. Circulating immune complexes in the serum in systemic lupus erythematosus and in carriers of hepatitis B antigen. Quantitation by binding to radiolabeled C1q. J Clin Invest. 1974, 54:297-309.

158 Hay FC, Nineham LJ, Roitt IM. Routine assay for the detection of immune complexes of known immunoglobulin class using solid phase C1q. Clin Exp Immunol. 1976, 24:396-400.

159 Schössler W, Hiepe F, Montag T, Schmidt HE. The use of glass as solid phase in enzyme immunoassay as exemplified by the detection of circulating immune complexes. Biomed Bio-chim Acta. 1985, 44:1247-1253.

160 Uwatoko S, Aotsuka S, Okawa M, Egu-sa Y, Yokohari R, Aizawa C, Suzuki K. C1q solid-phase radioimmunoassay: evidence for detection of antibody directed against the collagen-like region of C1q in sera from patients with sys temic lupus erythematosus. Clin Exp Immunol. 1987, 69:98-106.

161 Uwatoko S, Mannik M. Low-molecular weight Clq-binding immunoglobulin G in patients with systemic lupus erythematosus consists of autoantibodies to the collagen-like region of Clq.

J Clin Invest. 1988, 82:816-824.

162 Wisnieski JJ, Naff GB. Serum IgG antibodies to C1q in hypocomplementemic urticarial vasculitis syndrome. Arthritis Rheum. 1989, 32:1119-1127.

163 Wener MH, Uwatoko S, Mannik M. Antibodies to the collagen-like region of C1q in sera of patients with autoimmune rheumatic diseases. Arthritis Rheum. 1989, 32:544-551.

164 Siegert CE, Daha MR, van der Voort EA, Breedveld FC. IgG and IgA antibodies to the collagen-like region of C1q in rheumatoid vasculitis. Arthritis Rheum. 1990, 33:1646-1654.

165 Seelen MA, Trouw LA, van der Hoorn JW, Fallaux-van den Houten FC, Huizinga TW, Daha MR, Roos A. Auto-antibodies against mannose-binding lectin in systemic lupus erythematosus. Clin Exp Immunol. 2003, 134:335343.

166 Siegert C, Daha M, Westedt ML, van dV, Breedveld F. IgG autoantibodies against C1q are correlated with nephritis, hypocomplementemia, and dsDNA antibodies in systemic lupus erythe-matosus. J Rheumatol. 1991, 18: 230-234.

167 Moroni G, Trendelenburg M, Del Papa N, Quaglini S, Raschi E, Panzeri P, Testoni C, Tincani A, Banfi G, Bales-trieri G, Schifferli JA, Meroni PL, Pon-ticelli C. Anti-C1q antibodies may help in diagnosing a renal flare in lupus nephritis. Am J Kidney Dis. 2001, 37:490-498.

168 Marto N, Bertolaccini ML, Calabuig E, Hughes GR, Khamashta MA. Anti-C1q antibodies in nephritis: correlation between titres and renal disease activity and positive predictive value in systemic lupus erythematosus. Ann Rheum Dis. 2005, 64:444-448.

169 Siegert CE, Daha MR, Tseng CM, Core-mans IE, van EL, Breedveld FC. Predic tive value of IgG autoantibodies against C1q for nephritis in systemic lupus erythematosus. Ann Rheum Dis. 1993, 52:851-856.

170 Mannik M, Wener MH. Deposition of antibodies to the collagen-like region of C1q in renal glomeruli of patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 1997, 40: 1504-1511.

171 Mannik M, Merrill CE, Stamps LD, Wener MH. Multiple autoantibodies form the glomerular immune deposits in patients with systemic lupus erythe-matosus. J Rheumatol. 2003, 30:14951504.

172 Fremeaux-Bacchi V, Noel LH, Schifferli JA. No lupus nephritis in the absence of antiC1q autoantibodies? Nephrol Dial Transplant. 2002, 17:2041-2043.

173 Trendelenburg M, Marfurt J, Gerber I, Tyndall A, Schifferli JA. Lack of occurrence of severe lupus nephritis among anti-C1q autoantibody-negative patients. Arthritis Rheum. 1999, 42:187-188.

174 Hogarth MB, Norsworthy PJ, Allen PJ, Trinder PK, Loos M, Morley BJ, Walport MJ, Davies KA. Autoantibodies to the collagenous region of C1q occur in three strains of lupus-prone mice. Clin Exp Immunol. 1996, 104:241-246.

175 Trinder PK, Maeurer MJ, Schorlemmer HU, Loos M. Autoreactivity to mouse C1q in a murine model of SLE. Rheumatol Int. 1995, 15:117-120.

176 Trouw LA, Groeneveld TW, Seelen MA, Duijs JM, Bajema IM, Prins FA, Kishore U, Salant DJ, Verbeek JS, Van Kooten C, Daha MR. Anti-C1q autoan-tibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes. J Clin Invest. 2004, 114:679-688.

177 Illei GG, Tackey E, Lapteva L, Lipsky PE. Biomarkers in systemic lupus erythematosus: II. Markers of disease activity. Arthritis Rheum. 2004, 50: 2048-2065.

178 Illei GG, Tackey E, Lapteva L, Lipsky PE. Biomarkers in systemic lupus erythematosus. I. General overview of biomarkers and their applicability. Arthritis Rheum. 2004, 50:1709-1720.

179 Schiffenbauer J, Hahn B, Weisman MH, Simon LS. Biomarkers, surrogate markers, and design of clinical trials of new therapies for systemic lupus erythematosus. Arthritis Rheum. 2004, 50:2415-2422.

180 Hiepe F, Dorner T, Burmester G. Antinuclear antibody- and extractable nuclear antigen-related diseases. Int Arch Allergy Immunol. 2000, 123:5-9.

181 von Mühlen CA, Tan EM. Autoantibodies in the diagnosis of systemic rheumatic diseases. Semin Arthritis Rheum. 1995, 24:323-358.

Was this article helpful?

0 0
Arthritis Joint Pain

Arthritis Joint Pain

Arthritis is a general term which is commonly associated with a number of painful conditions affecting the joints and bones. The term arthritis literally translates to joint inflammation.

Get My Free Ebook


Post a comment