Eva Klein Group

Interaction of Epstein Barr Virus (EBV) with B lymphocytes.

EBV is carried by more than 90% of the human population. The viral genome can be found in several tumor types, but only B cell derived tumors express all the virally encoded proteins that are involved in transformation. However, additional mechanisms can contribute to the development of tumors even if they do not express the full set of these proteins. With natural killer (NK) lymphoma lines that carry EBV we have shown that certain cytokines can enhance the expression of the virus coded lmp-1 protein and modulate cell proliferation. This suggests that in these tumors the malignant transformation requires signals from the microenvironment. Half of the individuals with the hereditary X-chromosome linked lymphoproliferative disease Xlp die after primary EBV infection. The survivors have a high risk for lymphoma development. Determined by mutations in the encoding gene, XIP patients lack the function of an adaptor protein SAP that is involved in signal transduction in lymphocytes. We found that SAP expression can be regulated by p53 that has a key role in the control of cell cycle and apoptosis. Absence of SAP function may impair the DNA damage repair function of p53 contributing to lymphoma development. With in vitro infected cord blood cells we could initiate primary lymphocyte mediated immune response to EBV infected b cells. Presently we focus on the participation of NK cells and the contribution of cytokines and leukotrienes in this process. The system is well suited to analyze the effect of leukotrienes on cellular immune response, an issue that has not been explored yet. Among the various mechanisms that operate in the malignant transformation of EBV infected lymphocytes, those that involve the contribution of the microenvironment may be amenable to therapeutical intervention. In these tumors cytokines promote proliferation, inhibit apoptosis or have immunosuppressive roles.

For further details of EBV see the George Klein website:

Georg Klein Research Group

Research Interests:

Variation in the expression of EBV encoded proteins in B lymphocytes

Eva Klein's C.V.

Eva Klein's C.V. (Pdf file, 33 Kb)

Publications

Published more than 500 papers in the fields of experimental cell research and cancer research, general immunology, tumor immunology and tumor biology

cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response.
Madapura H, Salamon D, Wiman K, Lain S, Klein E, Nagy N
Cell Cycle 2016 May;15(9):1267-75

A Contemporary Prostate Cancer Grading System: A Validated Alternative to the Gleason Score.
Epstein J, Zelefsky M, Sjoberg D, Nelson J, Egevad L, Magi-Galluzzi C, et al
Eur. Urol. 2016 Mar;69(3):428-35

Modification of cell differentiation, one of the mechanisms in the surveillance of malignancy.
Klein E, Nagy N, Rasul E
Cancer Immunol Res 2015 Feb;3(2):97-102

The MEC1 and MEC2 lines represent two CLL subclones in different stages of progression towards prolymphocytic leukemia.
Rasul E, Salamon D, Nagy N, Leveau B, Banati F, Szenthe K, et al
PLoS ONE 2014 ;9(8):e106008

Exosomes derived from Burkitt's lymphoma cell lines induce proliferation, differentiation, and class-switch recombination in B cells.
Gutzeit C, Nagy N, Gentile M, Lyberg K, Gumz J, Vallhov H, et al
J. Immunol. 2014 Jun;192(12):5852-62

T cells modulate Epstein-Barr virus latency phenotypes during infection of humanized mice.
Heuts F, Rottenberg M, Salamon D, Rasul E, Adori M, Klein G, et al
J. Virol. 2014 Mar;88(6):3235-45

Cytomegalovirus-seropositive children show inhibition of in vitro EBV infection that is associated with CD8+CD57+ T cell enrichment and IFN-γ.
Sohlberg E, Saghafian-Hedengren S, Rasul E, Marchini G, Nilsson C, Klein E, et al
J. Immunol. 2013 Dec;191(11):5669-76

The role of DNA hypomethylation, histone acetylation and in vivo protein-DNA binding in Epstein-Barr virus-induced CD23 upregulation.
Szenthe K, Koroknai A, Banati F, Bathori Z, Niller H, Wolf H, et al
Biochem. Biophys. Res. Commun. 2013 May;435(1):8-15

p53 contributes to T cell homeostasis through the induction of pro-apoptotic SAP.
Madapura H, Salamon D, Wiman K, Lain S, Klein G, Klein E, et al
Cell Cycle 2012 Dec;11(24):4563-9

Simultaneous detection of the two main proliferation driving EBV encoded proteins, EBNA-2 and LMP-1 in single B cells.
Rasul A, Nagy N, Sohlberg E, Ádori M, Claesson H, Klein G, et al
J. Immunol. Methods 2012 Nov;385(1-2):60-70

Latency type-dependent modulation of Epstein-Barr virus-encoded latent membrane protein 1 expression by type I interferons in B cells.
Salamon D, Adori M, Ujvari D, Wu L, Kis L, Madapura H, et al
J. Virol. 2012 Apr;86(8):4701-7

Soluble factors produced by activated CD4+ T cells modulate EBV latency.
Nagy N, Adori M, Rasul A, Heuts F, Salamon D, Ujvári D, et al
Proc. Natl. Acad. Sci. U.S.A. 2012 Jan;109(5):1512-7

Type I interferons directly down-regulate BCL-6 in primary and transformed germinal center B cells: differential regulation in B cell lines derived from endemic or sporadic Burkitt's lymphoma.
Salamon D, Adori M, He M, Bönelt P, Severinson E, Kis L, et al
Cytokine 2012 Mar;57(3):360-71

Exosomes containing glycoprotein 350 released by EBV-transformed B cells selectively target B cells through CD21 and block EBV infection in vitro.
Vallhov H, Gutzeit C, Johansson S, Nagy N, Paul M, Li Q, et al
J. Immunol. 2011 Jan;186(1):73-82

Chronic lymphoid leukemia cells are highly sensitive to the combination of prednisolone and daunorubicin, but much less to doxorubicin or epirubicin.
Skribek H, Otvos R, Flaberg E, Nagy N, Markasz L, Eksborg S, et al
Exp. Hematol. 2010 Dec;38(12):1219-30

STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus-encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma.
Kis L, Gerasimcik N, Salamon D, Persson E, Nagy N, Klein G, et al
Blood 2011 Jan;117(1):165-74

Interaction of Epstein-Barr virus (EBV) with human B-lymphocytes.
Klein G, Klein E, Kashuba E
Biochem. Biophys. Res. Commun. 2010 May;396(1):67-73

IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter.
Kis L, Salamon D, Persson E, Nagy N, Scheeren F, Spits H, et al
Proc. Natl. Acad. Sci. U.S.A. 2010 Jan;107(2):872-7

Deficiency of the proapoptotic SAP function in X-linked lymphoproliferative disease aggravates Epstein-Barr virus (EBV) induced mononucleosis and promotes lymphoma development.
Nagy N, Klein E
Immunol. Lett. 2010 May;130(1-2):13-8

Burkitt lymphoma.
Klein E, Klein G
Semin. Cancer Biol. 2009 Dec;19(6):345-6

To the genesis of Burkitt lymphoma: regulation of apoptosis by EBNA-1 and SAP may determine the fate of Ig-myc translocation carrying B lymphocytes.
Nagy N, Klein G, Klein E
Semin. Cancer Biol. 2009 Dec;19(6):407-10

Effect of frequently used chemotherapeutic drugs on the cytotoxic activity of human natural killer cells.
Markasz L, Stuber G, Vanherberghen B, Flaberg E, Olah E, Carbone E, et al
Mol. Cancer Ther. 2007 Feb;6(2):644-54

Epstein-Barr virus infection in humans: from harmless to life endangering virus-lymphocyte interactions.
Klein E, Kis L, Klein G
Oncogene 2007 Feb;26(9):1297-305

Pathogenesis of Epstein-Barr virus (EBV)-carrying lymphomas.
Klein E, Kis L, Takahara M
Acta Microbiol Immunol Hung 2006 Dec;53(4):441-57

Epstein-Barr virus infection in humans: from harmless to life endangering virus-lymphocyte interactions.
Klein E, Kis L, Klein G
Oncogene 2007 Feb;26(9):1297-305

Pathogenesis of Epstein-Barr virus (EBV)-carrying lymphomas.
Klein E, Kis L, Takahara M
Acta Microbiol Immunol Hung 2006 Dec;53(4):441-57

Concomitant increase of LMP1 and CD25 (IL-2-receptor alpha) expression induced by IL-10 in the EBV-positive NK lines SNK6 and KAI3.
Takahara M, Kis L, Nagy N, Liu A, Harabuchi Y, Klein G, et al
Int. J. Cancer 2006 Dec;119(12):2775-83

Natural killer cells in cancer.
Höglund P, Klein E
Semin. Cancer Biol. 2006 Oct;16(5):331-2

Carbazole is a naturally occurring inhibitor of angiogenesis and inflammation isolated from antipsoriatic coal tar.
Arbiser J, Govindarajan B, Battle T, Lynch R, Frank D, Ushio-Fukai M, et al
J. Invest. Dermatol. 2006 Jun;126(6):1396-402

Cytokine mediated induction of the major Epstein-Barr virus (EBV)-encoded transforming protein, LMP-1.
Kis L, Takahara M, Nagy N, Klein G, Klein E
Immunol. Lett. 2006 Apr;104(1-2):83-8

IL-10 can induce the expression of EBV-encoded latent membrane protein-1 (LMP-1) in the absence of EBNA-2 in B lymphocytes and in Burkitt lymphoma- and NK lymphoma-derived cell lines.
Kis L, Takahara M, Nagy N, Klein G, Klein E
Blood 2006 Apr;107(7):2928-35

Publications 2003-2006

Eva Klein Publications 2003-2006 (pdf file)

Publications 1954-2002

Eva Klein Publications 1954-2002 (Pdf file, 330 Kb)

Group Members

Professor emerita

Eva Klein

Phone: 86774
Organizational unit: George Klein group
E-mail: Eva.Klein@ki.se

Associated

Noemi Nagy

Phone: +46-(0)8-524 867 61
E-mail: Noemi.Nagy@ki.se

Senior research specialist

Daniel Salamon

E-mail: Daniel.Salamon@ki.se

 

Self Portrait

As a teenager science was one of the many things to which I wished to devote my life. Obviously I knew very little about it; in the romantic view generated by the biography of Marie Curie, the life style, the shared work of the married couple appealed mainly to me. However, it was only one of the possible roads I considered.

My decision for the future would have been difficult, but circumstances helped. Sport contests became closed for me in Fascist Hungary and so it seemed for the prospect of entrance to the Theater Academy and to the University. It took not much time to drop art, when I compared myself to my talented friends in the private school I attended in the afternoons.

The year after I finished secondary school , Hitler occupied Hungary and from the problem of selecting a vocation, survival became the concern. We emerged from the chaos after the war - we felt reborn - I did not wish for anything else but a well ordered life. After a short period as actress in an enthusiastic young theater I decided that life in the theater is not for me.

Then I entered medical school I enjoyed student life, passed my examinations in time without thought about where I will end up in the medical profession.

In the third year I met George who did not hesitate to decide our marriage. Before I knew I was on the train to Stockholm, significantly among the last persons that left Hungary.

My scientific life started in 1948. I got an appointment as assistent in Torbjörn Caspersson´s Department of Cell Research and Genetics at Karolinska. I realized much, much later that Torbjörn paid special attention to my future. He cared about my career, tried to separate my work from George's,(husband) in order to establish my own profile. I started medical school when George finished. Therafter I wrote my thesis. It was Torbjörn who insisted that I should defend the thesis when I was in the 8th month of pregnancy with Margareta, our second child. Obviously, I strongly resented his insistence at that time but was immensely grateful later.

I am lucky because I can still function in the area of my earlier topic. I still get support both for work and for participation in meetings. Earlier I was not involved in the direction of our department, thus my situation after retirement did not change much. As earlier, I can fully concentrate on my students and on the work that is still in area of central interest: tumor immunology and virology.

An accidentally late 'discovery' is my ability to translate Hungarian poetry into Swedish. In spite of the fact that I do not master the language, it worked, provided that I was engaged in the poem. I plan to make a small volume of my translations. I am not sure, however, whether I wish to be able to take the time to realize it.

Poetry

These are a few of my translations of Hungarian poetry into Swedish.

Poetry translations (Pdf file, 84 Kb)

 

 

Awards

 

 

Eva Klein receives her honorary degree from Ohio State University 1993

  • Karolinska Institutet 200 Year Anniversary Silver Medal for Medical Research 2011
  • MTC Scientist of the Year Award from the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 2006
  • Mendel Honorary Medal for Merit in the Biological Sciences, 2003
  • Fellow of the European Union Contra Cancer, 2002
  • Orden Nacional al Mérito de la República de Colombia, 1998
  • Thomas P. Infusino Prize and Lectureship in Cancer Causation and Epidemiology, 1996
  • Nordic Prize of the Erik Fernström Foundation of Lund University, 1983
  • Björken Prize, Uppsala University, 1978
  • Recipient of the Award of the Cancer Research Institute, New York, in Tumor Immunology, 1975
  • Bertha Goldblatt Teplitz Award; Ann Langer Cancer Research Foundation, Chicago, 1960
Tumour Biology