Clinical relevance of soluble HLA-I and β2-microglobulin levels in non-Hodgkin's lymphoma and Hodgkin's disease
Introduction
Human leukocyte antigen-class I (HLA-I) molecules are cell–surface-associated proteins expressed on most nucleated cells. HLA-I molecules consist of a 44-kDa α (heavy) chain, encoded by a gene in the major histocompatibility complex on chromosome 6, and a 12-kDa β chain (beta-2 microglobulin (β2M)) encoded by a gene on chromosome 15. Although the heavy chain and β2M genes are located on different chromosomes, their expression is coordinated and cells generally express equal numbers of each subunit. The rate of transcription of both genes increases upon exposure to interferon [1], [2], [3], [4]. Free circulating HLA-I (sHLA-1) as well as β2M can be detected as soluble proteins in serum and plasma. Both β2M and the HLA-I protein may shed from the surface of various cell types [3], [4]. However, it is also possible that the spontaneous turnover of tumor cells results in free circulating β2M and the HLA-I proteins [2]. Both molecules have been investigated as potential disease markers. β2M levels are associated with prognosis in various solid tumors and hematologic malignancies, including multiple myeloma [5], Hodgkin's disease (HD) [6] and chronic lymphocytic leukemia (CLL) [7]. The correlation between β2M levels and disease aggressiveness suggests that soluble β2M may reflect an important biological process that represents tumor mass, immune response to the tumor, or both. The relationship of sHLA with lymphoproliferative disorders is less well established.
sHLA appears to function as an immunomodulator [8]. sHLA levels increase in response to T- and B-cell activation, but not interferon-gamma [9], and are also elevated in patients with evidence of cellular destruction (e.g., autoimmune diseases [10], [11], graft verses host disease [GVHD] [12], acute rejection after solid-organ transplantation [13], viral infection [14], [15], tumor proliferation [16]). In vitro data indicate that increased HLA-I expression on the surface of the tumor cells enhances their susceptibility to cytolytic activity of T-cells. Down-modulation of HLA-I expression reduces the cytolytic effects of the T-cells and may be a mechanism of immune system evasion in some leukemias and solid tumors [17], [18], [19]. This down-regulation seems to be limited to the heavy chain and does not involve β2M [17], [18]. On the other hand, the presence of sHLA-I in circulation induces apoptosis of natural killer cells and plays a role in reducing the cytolytic effects of T-cells by binding to these cells and preventing them from reaching tumor cells [20], [21].
Although increased sHLA-I levels have been reported in patients with NHL [20], [21], the clinical relevance of sHLA measurement in HD and NHL remains unknown. In this study, we measured plasma levels of sHLA-I and β2M in NHL and HD patients to: (1) assess the correlation between these markers; (2) compare their utility in predicting clinical behavior; (3) determine whether these markers provide redundant or complementary prognostic information in NHL and HD.
Section snippets
Patients and samples
Serum samples from patients with NHL or HD treated at the University of Nebraska Medical Center were analyzed at the MD Anderson Cancer Center for levels of β2M and HLA-I in a blinded manner. Samples were collected before initiating therapy in all patients. Post-therapy samples were evaluated if available.
All samples were collected using institutional review board-approved protocols and all patients gave informed consent. Clinical data were collected from the patients’ charts and were part of
High levels of sHLA-I in NHL and HD
The records of 102 consecutive patients were included in the analysis. Table 1, Table 2 list the clinical and prognostic characteristics of the NHL (n = 65) and HD (n = 37) patients, respectively.
Pre-therapy sHLA-I levels were significantly higher in HD and NHL patients than in control subjects, but did not differ significantly between the two disease groups (Fig. 1). In NHL patients, Spearman rank correlation coefficients showed significant correlation between sHLA-I and β2M levels in pre-therapy (
Discussion
The results of this study demonstrate that serum sHLA-I levels are elevated in HD as well as NHL. This increase in HLA-I levels does not appear to be related to infection or inflammatory process, since we did not find any correlation between B-symptoms and HLA-I levels. This is particularly important because upregulation of the expression of the HLA-I has been reported in infection or in response to TNF-γ. In NHL, β2M and sHLA-I correlate with each other and with disease aggressiveness. The
Acknowledgements
Contributions. Maher Albitar and Francis J. Giles contributed in designing the research. Maher Albitar, Marcella M. Johnson, Kim-Ann Do, Hagop Kantarjian, Michael Keating, Susan M. O’Brien and Francis J. Giles analyzed the data. Maher Albitar, Julie M. Vose, Srdan Verstovsek and James O. Armitage contributed vital new reagents. Maher Albitar and Francis J. Giles wrote the paper. Amanda Day and Iman Jilani performed the research.
References (26)
- et al.
Regulation of human beta 2-microglobulin transactivation in hematopoietic cells
Blood
(2003) - et al.
Soluble HLA class I, HLA class II, and Fas ligand in blood components: a possible key to explain the immunomodulatory effects of allogeneic blood transfusions
Blood
(1999) - et al.
Soluble HLA-I in rheumatic diseases
Hum Immunol
(1998) Soluble HLA class I molecules: biological significance and clinical implications
Mol Med Today
(1998)- et al.
Increased soluble serum HLA class I antigens in patients with lymphoma
Hum Immunol
(1997) - et al.
Interferon-dependent induction of mRNA for the major histocompatibility antigens in human fibroblasts and lymphoblastoid cells
Proc Natl Acad Sci USA
(1982) - et al.
Transactivation of classical and nonclassical HLA class I genes through the IFN-stimulated response element
J Immunol
(1999) - et al.
Gamma interferon and 5-azacytidine cause transcriptional elevation of class I major histocompatibility complex gene expression in K562 leukemia cells in the absence of differentiation
Mol Cell Biol
(1986) - et al.
Serum beta2 microglobulin and survival duration in multiple myeloma: a simple reliable marker for staging
Br J Haematol
(1983) - et al.
An elevated serum beta-2-microglobulin level is an adverse prognostic factor for overall survival in patients with early-stage Hodgkin disease
Cancer
(2002)
Beta 2-microglobulin in chronic lymphocytic leukaemia
Scand J Haematol
Soluble HLA class I antigen secretion by normal lymphocytes: relationship with cell activation and effect of interferon-gamma
Clin Exp Immunol
Soluble class I HLA antigens in patients with rheumatoid arthritis and their families
J Rheumatol
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