Skip to main content
Log in

Molecular case report: IgVH analysis in acute humoral and cellular liver allograft rejection suggests a selected accumulation of effector B cells and plasma cells

  • Case Report
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Acute cellular (CLR) and humoral liver allograft rejection (HLR) are the most important immunological obstacles to successful liver transplantation. In HLR, serum antibodies play the central pathogenetic role. In CLR, CD3+ T lymphocytes drive the destructive immune response. Although CLR and HLR show different clinical symptoms and can be kept apart in most cases, they share histomorphological similarities. In CLR, hepatic B lymphocytes and plasma cells as well as B-cell-activating cytokines have recently been described, indicating that, in addition to T cells, antibody-mediated mechanisms might be involved. To analyze the impact of hepatic B cells in CLR and HLR, the immunoglobulin (Ig) variable (V)-region gene repertoire was determined from tissue of one case of CLR and one case of HLR. Complement deposits and lymphocytic infiltrate were determined using immunohistochemistry. T cells, B lymphocytes and plasma cells could be detected in both cases, whereas C3c and C4d deposits could only be demonstrated in the HLR case. The molecular analysis of 63 V-region genes showed that B cells in both allografts expressed selected V-gene repertoires. All sequences differed from the putative germline sequences by multiple somatic mutations. This suggests a clonal expansion of selected effector B cells in the portal tracts of liver allografts. Locally accumulated B cells and their antibodies might be involved in IgG-mediated complement activation in CLR and HLR.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  1. Demetris AJ, Jaffe R, Tzakis A, Ramsey G, Todo S, Belle S, Esquivel C, Shapiro R, Markus B, Mroczek E (1988) Antibody-mediated rejection of human orthotopic liver allografts. A study of liver transplantation across ABO blood group barriers. Am J Pathol 132:489–502

    Google Scholar 

  2. Demetris A, Adams D, Bellamy C, Blakolmer K, Clouston A, Dhillon AP, Fung J, Gouw A, Gustafsson B, Haga H, Harrison D, Hart J, Hubscher S, Jaffe R, Khettry U, Lassman C, Lewin K, Martinez O, Nakazawa Y, Neil D, Pappo O, Parizhskaya M, Randhawa P, Rasoul-Rockenschaub S, Reinholt F, Reynes M, Robert M, Tsamandas A, Wanless I, Wiesner R, Wernerson A, Wrba F, Wyatt J, Yamabe H (2000) Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection. An International Panel. Hepatology 31:792–799

    CAS  PubMed  Google Scholar 

  3. Dollinger MM, Howie SE, Plevris JN, Graham AM, Hayes PC, Harrison DJ (1998) Intrahepatic proliferation of “naive” and “memory” T cells during liver allograft rejection: primary immune response within the allograft. FASEB J 12:939–947

    Google Scholar 

  4. Dubel L, Farges O, Johanet C, Sebagh M, Bismuth H (1998) High incidence of antitissue antibodies in patients experiencing chronic liver allograft rejection. Transplantation 65:1072–1075

    Google Scholar 

  5. Haga H, Egawa H, Shirase T, Miyagawa A, Sakurai T, Minamiguchi S, Yamabe H, Manabe T, Tanaka K (2004) Periportal edema and necrosis as diagnostic histological features of early humoral rejection in ABO-incompatible liver transplantation. Liver Transpl 10:16–27

    Google Scholar 

  6. Kim HJ, Krenn V, Steinhauser G, Berek C (1999) Plasma cell development in synovial germinal centers in patients with rheumatoid and reactive arthritis. J Immunol 162:3053–3062

    Google Scholar 

  7. Krukemeyer MG, Moeller J, Morawietz L, Rudolph B, Neumann U, Theruvath T, Neuhaus P, Krenn V (2004) Description of B-lymphocytes and plasma cells, complement and chemokines/receptors in acute liver allograft rejection. Transplantation 78:65–70

    Google Scholar 

  8. Magalhaes R, Stiehl P, Morawietz L, Berek C, Krenn V (2002) Morphological and molecular pathology of the B-cell response in synovitis of rheumatoid arthritis. Virchows Arch 441:415–427

    Google Scholar 

  9. Michaels PJ, Fishbein MC, Colvin RB (2003) Humoral rejection of human organ transplants. Springer Semin Immunopathol 25:119–140

    Google Scholar 

  10. Mitchison NA (2004) T-cell-B-cell cooperation. Nat Rev Immunol 4:308–312

    Google Scholar 

  11. Neumann UP, Guckelberger O, Langrehr JM, Lang M, Schmitz V, Theruvath T, Schonemann C, Menzel S, Klupp J, Neuhaus P (2003) Impact of human leukocyte antigen matching in liver transplantation. Transplantation 75:132–137

    Google Scholar 

  12. Stott DI, Hiepe F, Hummel M, Steinhauser G, Berek C (1998) Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease. The salivary glands of patients with Sjogren’s syndrome. J Clin Invest 102:938–946

    Google Scholar 

  13. Takakura K, Kiuchi T, Kasahara M, Inomata Y, Tanaka K (1999) Humoral immunity in acute cellular rejection after living-donor liver transplantation. Transplant Proc 31:526–527

    Google Scholar 

  14. Tannapfel A, Geissler F, Witzigmann H, Hauss J, Wittekind C (2001) Analysis of liver allograft rejection related genes using cDNA-microarrays in liver allograft specimen. Transplant Proc 33:3283–3284

    Google Scholar 

  15. Vella JP, Magee C, Vos L, Womer K, Rennke H, Carpenter CB, Hancock W, Sayegh MH (1999) Cellular and humoral mechanisms of vascularized allograft rejection induced by indirect recognition of donor MHC allopeptides. Transplantation 1999 67:1523–1532

    Google Scholar 

  16. Weigert M (1986) The influence of somatic mutation on the immune response. Prog Immunol VI: 138–142

    Google Scholar 

  17. Wu GD, Gochi E, Jin YS, Swensson J, Starnes VA, Cramer DV (2001) Maturation of xenoantibody gene expression during the humoral immune response of rats to hamster xenografts. Xenotransplantation 8:291–302

    Google Scholar 

Download references

Acknowledgements

The excellent technical assistance of Ms. Gabriele Fernahl and Ms. Janine Karle is gratefully acknowledged. This work was supported by the SFB 421. The Deutsches Rheumaforschungszentrum is supported by the Berlin Senate of Research and Education.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Claudia Berek.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moeller, J., Krukemeyer, M.G., Morawietz, L. et al. Molecular case report: IgVH analysis in acute humoral and cellular liver allograft rejection suggests a selected accumulation of effector B cells and plasma cells. Virchows Arch 446, 325–332 (2005). https://doi.org/10.1007/s00428-004-1182-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-004-1182-2

Keywords

Navigation