Skip to main content
SpringerLink
Log in

Early Complement Component Deficiency in a Single-Centre Cohort of Pediatric Onset Lupus

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Objectives

To assess complement levels C1q, C2, C3 and C4 in children with pediatric-onset lupus during the quiescent stage of disease.

Methods

Thirty-four consecutive children with pediatric-onset SLE (onset below 12 years), in the quiescent stage were enrolled for the study. Twenty-nine age and sex matched healthy children were also enrolled for the purpose of comparison. Complement C1q and C2 levels were estimated by enzyme-linked immunosorbent assay (ELISA) whereas C3 and C4 were measured by end-point nephelometry. Genetic mutation analysis and functional assessment of classical complement pathway by ELISA were carried out in children with depressed levels of these complements. The study protocol was approved by the Institute Thesis Committee and the Institute Ethics Committee.

Results

Mean complement C1q, C2, C3 and C4 levels were 50.32, 17.28, 1320 and 236 mg/L respectively. Levels of complements were low in 7/34 children with SLE. An early age at onset, low anti-dsDNA titres and predominant skin manifestations were noted in children with decreased levels of complement C1q. Mutation analysis of C1qA gene revealed a homozygous nonsense mutation: C1QA (NM_015991) c.622C>T, p.Q208X in one child. A homozygous acceptor splice site mutation at the −2 position of intron2 of C1QA (c.164-2A>C) was detected in another child. The age at onset of disease was early in both these children, at 2.5 and 1.5 years respectively.

Conclusion

Children with inherited deficiency of C1q and other early complement components present with early onset lupus that has a distinct clinical and immunological profile.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Klein-Gitelman MS, Lane JC. Systemic lupus erythematosus. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn LR, editors. Textbook of pediatric rheumatology. 7th ed. Philadelphia: Saunders Elsevier; 2015. p. 285–317.

    Google Scholar 

  2. Botto M, Walport MJ. C1q, autoimmunity and apoptosis. Immunobiology. 2002;205(4–5):395–406.

    Article  CAS  PubMed  Google Scholar 

  3. Reich D, Thangaraj K, Patterson N, Prince AL, Singh L. Reconstructing Indian population history. Nature. 2009;461(7263):489–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Wouters D, van Schouwenburg P, van der Horst A, de Boer M, Schooneman D, Kuijpers TW, et al. High-throughput analysis of the C4 polymorphism by combination a of MLPA and isotype-specific ELISA’s. Mol Immunol. 2009;46(4):592–600.

    Article  CAS  PubMed  Google Scholar 

  5. Manderson AP, Botto M, Walport MJ. The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol. 2004;22:431–56.

    Article  CAS  PubMed  Google Scholar 

  6. Stegert M, Bock M, Trendelenburg M. Clinical presentation of human C1q deficiency: how much of a lupus? Mol Immunol. 2015;67(1):3–11.

    Article  CAS  PubMed  Google Scholar 

  7. Hayakawa J, Migita M, Ueda T, Itoh Y, Fukunaga Y. Infantile case of early manifestation of SLE-like symptoms in complete C1q deficiency. J Nippon Med Sch. 2011;78(5):322–8.

    Article  CAS  PubMed  Google Scholar 

  8. Inai S, Akagaki Y, Moriyama T, Fukumori Y, Yoshimura K, Ohnoki S, et al. Inherited deficiencies of the late acting complement components other than C9 found among healthy blood donors. Int Arch Allergy Appl Immunol. 1989;90(3):274–9.

    Article  CAS  PubMed  Google Scholar 

  9. Fukumoru Y, Yoshimura K, Ohnoki S, et al. High incidence of C9 deficiency among healthy blood donors in Osaka. Jpn Int Immunol. 1989;1(1):85–9.

    Article  Google Scholar 

  10. Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014;61(2):110–7.

    Article  CAS  PubMed  Google Scholar 

  11. Koide M, Shirahama S, Tokura Y, Takigawa M, Hayakawa M, Furukawa F. Lupus erythematosus associated with C1 inhibitor deficiency. J Dermatol. 2002;29(8):503–7.

    Article  PubMed  Google Scholar 

  12. Pickering MC, Walport MJ. Links between complement abnormalities and systemic lupus erythematosus. Rheumatology. 2000;39(2):133–41.

    Article  CAS  PubMed  Google Scholar 

  13. Aggarwal R, Sestak AL, D’Sousa A, et al. Complete complement deficiency in a large cohort of familial systemic lupus erythematosus. Lupus. 2010;19(1):52–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Deapen D, Escalante A, Weinrib L, et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 1992;35(3):311–8.

    Article  CAS  PubMed  Google Scholar 

  15. Berkel AI, Birben E, Oner C, et al. Molecular, genetic and epidemiologic studies on selective complete C1q deficiency in Turkey. Immunobiology. 2000;201(3–4):347–55.

    Article  CAS  PubMed  Google Scholar 

  16. Vassallo G, Newton RW, Chieng SE, et al. Clinical variability and characteristic autoantibody profile in primary C1q complement deficiency. Rheumatology. 2007;46(10):1612–4.

    Article  CAS  PubMed  Google Scholar 

  17. Kallel-Sellami M, Baili-Klila L, Zerzeri Y, et al. Hereditary complement deficiency and lupus: report of four Tunisian cases. Ann N Y Acad Sci. 2007;1108:197–202.

    Article  CAS  PubMed  Google Scholar 

  18. Wu YL, Hauptmann G, Viguier M, et al. Molecular basis of complete complement C4 deficiency in two North-African families with systemic lupus erythematosus. Genes Immunol. 2009;10(5):433–45.

    Article  CAS  Google Scholar 

  19. Sun-Tan C, Ozgur TT, Kilinc G, et al. Hereditary C1q deficiency: a new family with C1qA deficiency. Turk J Pediatr. 2010;52(2):184–6.

    PubMed  Google Scholar 

  20. Sozeri B, Mir S, Berdeli A. Complement-4 deficiency in a child with systemic lupus erythematosus presenting with standard treatment-resistant severe skin lesion. ISRN Rheumatol. 2011;2011:917673.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Agnello V. Association of systemic lupus erythematosus and SLE-like syndromes with hereditary and acquired complement deficiency states. Arthritis Rheum. 1978;21(5):S146–52.

    CAS  PubMed  Google Scholar 

  22. Ram S, Lewis LA, Rice PA. Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin Microbiol Rev. 2010;23(4):740–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Slingsby JH, Norsworthy P, Pearce G, et al. Homozygous hereditary C1q deficiency and systemic lupus erythematosus. A new family and the molecular basis of C1q deficiency in three families. Arthritis Rheum. 1996;39(4):663–70.

    Article  CAS  PubMed  Google Scholar 

  24. Bowness P, Davies KA, Norsworthy PJ, et al. Hereditary C1q deficiency and systemic lupus erythematosus. Q J Med. 1994;87(8):455–64.

    CAS  Google Scholar 

  25. McAdam RA, Goundis D, Reid KB. A homozygous point mutation results in a stop codon in the C1q B-chain of a C1q-deficient individual. Immunogenetics. 1988;27:259–64.

    Article  CAS  PubMed  Google Scholar 

  26. Petry F. Molecular basis of hereditary C1q deficiency. Immunobiology. 1998;199:286–94.

    Article  CAS  PubMed  Google Scholar 

  27. Schejbel L, Skattum L, Hagelberg S, et al. Molecular basis of hereditary C1q deficiency--revisited: identification of several novel disease-causing mutations. Genes Immunol. 2011;12(8):626–34.

    Article  CAS  Google Scholar 

  28. Jlajla H, Sellami MK, Sfar I, et al. New C1q mutation in a Tunisian family. Immunobiology. 2014;219(3):241–6.

    Article  CAS  PubMed  Google Scholar 

  29. Hoppenreijs EP, van Dijken PJ, Kabel PJ, Th Draaisma JM. Hereditary C1q deficiency and secondary Sjogren’s syndrome. Ann Rheum Dis. 2004;63:1524–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Petry F, Le DT, Kirschfink M, Loos M. Non-sense and missense mutations in the structural genes of complement component C1q A and C chains are linked with two different types of complete selective C1q deficiencies. J Immunol. 1995;155:4734–8.

    CAS  PubMed  Google Scholar 

  31. Petry F, Berkel AI, Loos M. Multiple identification of a particular type of hereditary C1q deficiency in the Turkish population: review of the cases and additional genetic and functional analysis. Hum Genet. 1997;100:51–6.

    Article  CAS  PubMed  Google Scholar 

  32. Topaloglu R, Bakkaloglu A, Slingsby JH, Mihatsch MJ, Pascual M, Norsworthy P, et al. Molecular basis of hereditary C1q deficiency associated with SLE and IgA nephropathy in a Turkish family. Kidney Int. 1996;50:635–42.

    Article  CAS  PubMed  Google Scholar 

  33. Holme ER, Veitch J, Johnston A, et al. Familial properdin deficiency associated with chronic discoid lupus erythematosus. Clin Exp Immunol. 1989;76(1):76–81.

    PubMed Central  CAS  PubMed  Google Scholar 

  34. Topaloglu R, Taskiran EZ, Tan C, et al. C1q deficiency: identification of a novel missense mutation and treatment with fresh frozen plasma. Clin Rheumatol. 2012;31(7):1123–6.

    Article  PubMed  Google Scholar 

  35. Arkwright PD, Riley P, Hughes SM, et al. Successful cure of C1q deficiency in human subjects treated with hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2014;133(1):265–7.

    Article  CAS  PubMed  Google Scholar 

  36. Tripodo C, Porcasi R, Guarnotta C, Ingrao S, Campisi V, Florena AM, et al. C1q production by bone marrow stromal cells. Scand J Immunol. 2007;65(3):308–9.

    Article  CAS  PubMed  Google Scholar 

  37. Lipsker D, Hauptmann G. Cutaneous manifestations of complement deficiencies. Lupus. 2010;19(9):1096–106.

    Article  CAS  PubMed  Google Scholar 

  38. Coors EA, von den Driesch P. Pyoderma gangrenosum in a patient with autoimmune haemolytic anaemia and complement deficiency. Br J Dermatol. 2000;143(1):154–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pediatric Allergy and Immunology Unit, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

    Sagar Bhattad, Amit Rawat, Anju Gupta, Deepti Suri, Ravinder Garg & Surjit Singh

  2. Blood Cell Research, Sanquin Blood Supply Foundation, Amsterdam, The Netherlands

    Martin de Boer & Taco W. Kuijpers

Authors
  1. Sagar Bhattad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amit Rawat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anju Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Deepti Suri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ravinder Garg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martin de Boer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Taco W. Kuijpers
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Surjit Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amit Rawat.

Ethics declarations

Ethical standards

The study was approved by the Ethics and Thesis committees of our Institute.

Funding

No financial support or any other benefits from any commercial sources have been obtained in this study. There are no financial interests that any of the authors may have, which could create a potential conflict of interest or the appearance of a conflict of interest concerning the work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bhattad, S., Rawat, A., Gupta, A. et al. Early Complement Component Deficiency in a Single-Centre Cohort of Pediatric Onset Lupus. J Clin Immunol 35, 777–785 (2015). https://doi.org/10.1007/s10875-015-0212-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-015-0212-y

Keywords

Search

Navigation