• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of iaiPermissionsJournals.ASM.orgJournalIAI ArticleJournal InfoAuthorsReviewers
Infect Immun. Sep 1994; 62(9): 3696–3704.
PMCID: PMC303020

Epitopes of the Onchocerca volvulus RAL1 antigen, a member of the calreticulin family of proteins, recognized by sera from patients with onchocerciasis.

Abstract

RAL1 is an antigen (Ag) encoded by the filarial nematode Onchocerca volvulus, the parasite causing onchocerciasis (river blindness). RAL1 shares 64.4% identity with the autoantigen calreticulin. The striking similarity of the parasite Ag and the human autoantigen has led to the hypothesis that RAL1 may induce a cross-reactive immune response to calreticulin, which in turn may be involved in the pathogenesis of onchocerciasis. To test this hypothesis, we explored the immune response to RAL1 recombinant Ag (RAL1 rAg) and human calreticulin in patients with O. volvulus infection. A total of 86% of the O. volvulus-infected individuals produced antibodies recognizing RAL1 rAg. Antibody reactivity to RAL1 rAg in patient sera was confined primarily to the central and carboxyl-terminal parts of the molecule. No significant correlations were found to associate recognition of RAL1 rAg, or any particular portion thereof, with a particular disease state. Antibodies against RAL1 thus appear to be produced as a general immune reaction to O. volvulus infection and do not necessarily lead to a cross-reacting response with the host protein. In contrast, 33% of the patient sera tested bound recombinant human calreticulin. All of these sera also recognized a polypeptide encompassing the carboxyl-terminal portion of the RAL1 rAg. These results suggest that recognition of an epitope encoded in the carboxyl-terminal portion of RAL1 is at least in part responsible for inducing a cross-reacting immune response to the host protein.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.9M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Baksh S, Michalak M. Expression of calreticulin in Escherichia coli and identification of its Ca2+ binding domains. J Biol Chem. 1991 Nov 15;266(32):21458–21465. [PubMed]
  • Bartlett A, Turk J, Ngu J, Mackenzie CD, Fuglsang H. Variation in delayed hypersensitivity in onchocerciasis. Trans R Soc Trop Med Hyg. 1978;72(4):372–377. [PubMed]
  • Bockarie MJ, Davies JB. The transmission of onchocerciasis at a forest village in Sierra Leone. II. Man-fly contact, human activity and exposure to transmission. Ann Trop Med Parasitol. 1990 Dec;84(6):599–605. [PubMed]
  • Burns K, Helgason CD, Bleackley RC, Michalak M. Calreticulin in T-lymphocytes. Identification of calreticulin in T-lymphocytes and demonstration that activation of T cells correlates with increased levels of calreticulin mRNA and protein. J Biol Chem. 1992 Sep 25;267(27):19039–19042. [PubMed]
  • Chan CC, Nussenblatt RB, Kim MK, Palestine AG, Awadzi K, Ottesen EA. Immunopathology of ocular onchocerciasis. 2. Anti-retinal autoantibodies in serum and ocular fluids. Ophthalmology. 1987 Apr;94(4):439–443. [PubMed]
  • Chou PY, Fasman GD. Prediction of the secondary structure of proteins from their amino acid sequence. Adv Enzymol Relat Areas Mol Biol. 1978;47:45–148. [PubMed]
  • Dadzie KY, Remme J, Baker RH, Rolland A, Thylefors B. Ocular onchocerciasis and intensity of infection in the community. III. West African rainforest foci of the vector Simulium sanctipauli. Trop Med Parasitol. 1990 Dec;41(4):376–382. [PubMed]
  • Devereux J, Haeberli P, Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. [PMC free article] [PubMed]
  • Donelson JE, Duke BO, Moser D, Zeng WL, Erondu NE, Lucius R, Renz A, Karam M, Flores GZ. Construction of Onchocerca volvulus cDNA libraries and partial characterization of the cDNA for a major antigen. Mol Biochem Parasitol. 1988 Dec;31(3):241–250. [PubMed]
  • Donelson JE, Zeng W. A comparison of trans-RNA splicing in trypanosomes and nematodes. Parasitol Today. 1990 Oct;6(10):327–334. [PubMed]
  • Donnelly JJ, Rockey JH, Bianco AE, Soulsby EJ. Ocular immunopathologic findings of experimental onchocerciasis. Arch Ophthalmol. 1984 Apr;102(4):628–634. [PubMed]
  • Donnelly JJ, Taylor HR, Young E, Khatami M, Lok JB, Rockey JH. Experimental ocular onchocerciasis in cynomolgus monkeys. Invest Ophthalmol Vis Sci. 1986 Apr;27(4):492–499. [PubMed]
  • Dorfman DM, Zon LI, Orkin SH. Rapid amplification of lambda gt11 bacteriophage library inserts from plaques using the polymerase chain reaction (PCR). Biotechniques. 1989 Jun;7(6):568–570. [PubMed]
  • Garner A, Duke BO. Fundus lesions in the rabbit eye following inoculation of onchocerca volvulus microfilariae into the posterior segment. II. Pathology. Tropenmed Parasitol. 1976 Mar;27(1):19–29. [PubMed]
  • Dupuis M, Schaerer E, Krause KH, Tschopp J. The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes. J Exp Med. 1993 Jan 1;177(1):1–7. [PMC free article] [PubMed]
  • Freedman DO, Lujan-Trangay A, Steel C, Gonzalez-Peralta C, Nutman TB. Immunoregulation in onchocerciasis. Functional and phenotypic abnormalities of lymphocyte subsets and changes with therapy. J Clin Invest. 1991 Jul;88(1):231–238. [PMC free article] [PubMed]
  • Gallin M, Edmonds K, Ellner JJ, Erttmann KD, White AT, Newland HS, Taylor HR, Greene BM. Cell-mediated immune responses in human infection with Onchocerca volvulus. J Immunol. 1988 Mar 15;140(6):1999–2007. [PubMed]
  • Gallin MY, Murray D, Lass JH, Grossniklaus HE, Greene BM. Experimental interstitial keratitis induced by Onchocerca volvulus antigens. Arch Ophthalmol. 1988 Oct;106(10):1447–1452. [PubMed]
  • Gallin MY, Tan M, Kron MA, Rechnitzer D, Greene BM, Newland HS, White AT, Taylor HR, Unnasch TR. Onchocerca volvulus recombinant antigen: physical characterization and clinical correlates with serum reactivity. J Infect Dis. 1989 Sep;160(3):521–529. [PubMed]
  • Greene BM, Gbakima AA, Albiez EJ, Taylor HR. Humoral and cellular immune responses to Onchocerca volvulus infection in humans. Rev Infect Dis. 1985 Nov-Dec;7(6):789–795. [PubMed]
  • Guldner HH. Mapping of epitopes recognized by anti-(U1)RNP autoantibodies. Mol Biol Rep. 1992 Jun;16(3):155–164. [PubMed]
  • Habets WJ, Hoet MH, De Jong BA, Van der Kemp A, Van Venrooij WJ. Mapping of B cell epitopes on small nuclear ribonucleoproteins that react with human autoantibodies as well as with experimentally-induced mouse monoclonal antibodies. J Immunol. 1989 Oct 15;143(8):2560–2566. [PubMed]
  • Handford PA, Mayhew M, Baron M, Winship PR, Campbell ID, Brownlee GG. Key residues involved in calcium-binding motifs in EGF-like domains. Nature. 1991 May 9;351(6322):164–167. [PubMed]
  • Hawn TR, Tom TD, Strand M. Molecular cloning and expression of SmIrV1, a Schistosoma mansoni antigen with similarity to calnexin, calreticulin, and OvRal1. J Biol Chem. 1993 Apr 15;268(11):7692–7698. [PubMed]
  • Horsfall AC. Molecular mimicry and autoantigens in connective tissue diseases. Mol Biol Rep. 1992 Jun;16(3):139–147. [PubMed]
  • Khalife J, Trottein F, Schacht AM, Godin C, Pierce RJ, Capron A. Cloning of the gene encoding a Schistosoma mansoni antigen homologous to human Ro/SS-A autoantigen. Mol Biochem Parasitol. 1993 Feb;57(2):193–202. [PubMed]
  • Koerner TJ, Hill JE, Myers AM, Tzagoloff A. High-expression vectors with multiple cloning sites for construction of trpE fusion genes: pATH vectors. Methods Enzymol. 1991;194:477–490. [PubMed]
  • Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. [PubMed]
  • Lieu TS, Newkirk MM, Capra JD, Sontheimer RD. Molecular characterization of human Ro/SS-A antigen. Amino terminal sequence of the protein moiety of human Ro/SS-A antigen and immunological activity of a corresponding synthetic peptide. J Clin Invest. 1988 Jul;82(1):96–101. [PMC free article] [PubMed]
  • Lux FA, McCauliffe DP, Büttner DW, Lucius R, Capra JD, Sontheimer RD, Lieu TS. Serological cross-reactivity between a human Ro/SS-A autoantigen (calreticulin) and the lambda Ral-1 antigen of Onchocerca volvulus. J Clin Invest. 1992 Jun;89(6):1945–1951. [PMC free article] [PubMed]
  • Mackenzie CD, Williams JF, Sisley BM, Steward MW, O'Day J. Variations in host responses and the pathogenesis of human onchocerciasis. Rev Infect Dis. 1985 Nov-Dec;7(6):802–808. [PubMed]
  • McCauliffe DP, Zappi E, Lieu TS, Michalak M, Sontheimer RD, Capra JD. A human Ro/SS-A autoantigen is the homologue of calreticulin and is highly homologous with onchocercal RAL-1 antigen and an aplysia "memory molecule". J Clin Invest. 1990 Jul;86(1):332–335. [PMC free article] [PubMed]
  • Meilof JF, Van der Lelij A, Rokeach LA, Hoch SO, Smeenk RJ. Autoimmunity and filariasis. Autoantibodies against cytoplasmic cellular proteins in sera of patients with onchocerciasis. J Immunol. 1993 Nov 15;151(10):5800–5809. [PubMed]
  • Michalak M, Milner RE, Burns K, Opas M. Calreticulin. Biochem J. 1992 Aug 1;285(Pt 3):681–692. [PMC free article] [PubMed]
  • Munro S, Pelham HR. A C-terminal signal prevents secretion of luminal ER proteins. Cell. 1987 Mar 13;48(5):899–907. [PubMed]
  • Netter HJ, Guldner HH, Szostecki C, Will H. Major autoantigenic sites of the (U1) small nuclear ribonucleoprotein-specific 68-kDa protein. Scand J Immunol. 1990 Aug;32(2):163–176. [PubMed]
  • Newland HS, White AT, Greene BM, D'Anna SA, Keyvan-Larijani E, Aziz MA, Williams PN, Taylor HR. Effect of single-dose ivermectin therapy on human Onchocerca volvulus infection with onchocercal ocular involvement. Br J Ophthalmol. 1988 Aug;72(8):561–569. [PMC free article] [PubMed]
  • Ngu JL. Immunological studies on onchocerciasis. Varying skin hypersensitivity and leucocyte migration inhibition in a clinical spectrum of the disease. Acta Trop. 1978 Sep;35(3):269–279. [PubMed]
  • Oldstone MB. Molecular mimicry and autoimmune disease. Cell. 1987 Sep 11;50(6):819–820. [PubMed]
  • Pearson CA. A major cause of third world rheumatism largely overlooked--onchocerciasis. Br J Rheumatol. 1988 Oct;27(5):414–416. [PubMed]
  • Rokeach LA, Haselby JA, Hoch SO. High-level bacterial expression, purification and characterization of human calreticulin. Protein Eng. 1991 Dec;4(8):981–987. [PubMed]
  • Rokeach LA, Haselby JA, Meilof JF, Smeenk RJ, Unnasch TR, Greene BM, Hoch SO. Characterization of the autoantigen calreticulin. J Immunol. 1991 Nov 1;147(9):3031–3039. [PubMed]
  • Rokeach LA, Hoch SO. B-cell epitopes of Sm autoantigens. Mol Biol Rep. 1992 Jun;16(3):165–174. [PubMed]
  • Rokeach LA, Jannatipour M, Haselby JA, Hoch SO. Mapping of the immunoreactive domains of a small nuclear ribonucleoprotein-associated Sm-D autoantigen. Clin Immunol Immunopathol. 1992 Dec;65(3):315–324. [PubMed]
  • Rokeach LA, Jannatipour M, Hoch SO. Heterologous expression and epitope mapping of a human small nuclear ribonucleoprotein-associated Sm-B'/B autoantigen. J Immunol. 1990 Feb 1;144(3):1015–1022. [PubMed]
  • Rougemont A, Boisson-Pontal ME, Pontal PG, Gridel F, Sangare S. Tuberculin skin tests and B.C.G. vaccination in hyperendemic area of onchocerciasis. Lancet. 1977 Feb 5;1(8006):309–309. [PubMed]
  • Routsias JG, Tzioufas AG, Sakarellos-Daitsiotis M, Sakarellos C, Moutsopoulos HM. Calreticulin synthetic peptide analogues: anti-peptide antibodies in autoimmune rheumatic diseases. Clin Exp Immunol. 1993 Mar;91(3):437–441. [PMC free article] [PubMed]
  • Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PMC free article] [PubMed]
  • Schulz-Key H. A simple technique to assess the total number of Onchocerca volvulus microfilariae in skin snips. Tropenmed Parasitol. 1978 Mar;29(1):51–54. [PubMed]
  • Sekharudu YC, Sundaralingam M. A structure-function relationship for the calcium affinities of regulatory proteins containing 'EF-hand' pairs. Protein Eng. 1988 Jul;2(2):139–146. [PubMed]
  • Smith MJ. A C. elegans gene encodes a protein homologous to mammalian calreticulin. DNA Seq. 1992;2(4):235–240. [PubMed]
  • Tan EM. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol. 1989;44:93–151. [PubMed]
  • Unnasch TR, Gallin MY, Soboslay PT, Erttmann KD, Greene BM. Isolation and characterization of expression cDNA clones encoding antigens of Onchocerca volvulus infective larvae. J Clin Invest. 1988 Jul;82(1):262–269. [PMC free article] [PubMed]
  • Wada I, Rindress D, Cameron PH, Ou WJ, Doherty JJ, 2nd, Louvard D, Bell AW, Dignard D, Thomas DY, Bergeron JJ. SSR alpha and associated calnexin are major calcium binding proteins of the endoplasmic reticulum membrane. J Biol Chem. 1991 Oct 15;266(29):19599–19610. [PubMed]
  • Ward DJ, Nutman TB, Zea-Flores G, Portocarrero C, Lujan A, Ottesen EA. Onchocerciasis and immunity in humans: enhanced T cell responsiveness to parasite antigen in putatively immune individuals. J Infect Dis. 1988 Mar;157(3):536–543. [PubMed]
  • Watson ME. Compilation of published signal sequences. Nucleic Acids Res. 1984 Jul 11;12(13):5145–5164. [PMC free article] [PubMed]
  • Zeng WL, Alarcon CM, Donelson JE. Many transcribed regions of the Onchocerca volvulus genome contain the spliced leader sequence of Caenorhabditis elegans. Mol Cell Biol. 1990 Jun;10(6):2765–2773. [PMC free article] [PubMed]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...