Lymphoid Malignancies

Human CLL is a malignancy of the CD5+ B cells, characterized by the accumulation of mature appearing, long-lived, slow-growing CD5+ B cells in peripheral blood. Leukemia cells from approximately 95% of CLL patients co-express CD5 and other B-cell markers [24]. Thus, in most cases of CLL, there is a proliferation of B-cell clones characterized by low amounts of surface immunoglobulins and the presence of the CD5 molecule. There is no definite correlation between the expression of CD5 and surface immu-globulin class, type, clinical stage, disease activity or age as diagnosis by other investigators [25]. However, CD5 expression, in conjunction with measurements of surface immunoglobulin intensity and CD22, are regarded as the minimum number of immune markers required for the diagnosis of subtypes of CLL [25]. Expression of CD5 by leukemic cells is only seen in some cases of prolymphocyte leukemia [26], where it is found at low to medium density [27]. Typically, leukocytes of the hairy-cell leukemia type rarely express CD5. Neither is it present in immature B-cell malignancies, such as pre-B acute lymphoblastic leukemia, or in end-stage differentiated B-cell malignancies, including benign mixed cryoglobulinemia, MM or WM [26, 28]. CD5 is expressed by fewer than half of the B-cell derived non-Hodgkin's lymphomas, and this is mainly on those composed predominantly of small lymphocytes, such as well-differentiated lymhocytic or intermediate lymphocytic lymphomas [27].

3.2. Complications With Autoimmunity

Autoimmune traits have been identified in more than 8% of patients with B lymphoproliferative syndromes, compared with 2% of those with myeloproliferative states [29]. For example, autoimmune hemolytic anemia occurs in one-third of CLL patients at some time during the course of the disease, and a positive direct antiglobulin test has been claimed to be as frequent as 35%, depending on the stage of this leukemia [30], Whereas antibodies to polymorphonuclear cells have only been found in a few cases of CLL, both immune thrombocytopenia in about 2% of the patients and a higher incidence of platelet-associed immunoglobulin have been reported [31]. It is interesting that the red cell autoantibodies in these patients are not produced by the malignant B-cell clone. In fact, hemolysis can precede the onset of CLL, indicating that the autoimmune process is not merely the result of autoantibody secretion by the proliferating B cells [32],

Interestingly, it is well documented that the surface immunoglobulin receptors on malignant B cells have specificity for a variety of autoantigens. For example, in a limited series of 13 CLL patients, 31% (4) were found to express surface IgM capable of binding fluorescein-conjugated IgG [33]. Other studies on IgM antibodies released by leukemic B cells [34], after stimulation with phorbol ester or pokeweed mitogen [35], or following fusion of CLL B cells with non-secreting murine myeloma cells [36], In one of these experiments, 12 out of 14 CLL clones appeared to bind to Fc, single- and double-stranded DNA, histones, cardiolipin or cytoskeletal components, of which a number recognized more that one autoantigen. The malignant B cells are thus committed to the production of polyreactive autoantibodies.

A number of specificities have been assigned to MIg, including binding to red blood cells, lipoprotein, fibrin monomers, transferrin, albumin, a2-macroglobulin, cardiolipin and heparin [37]. Interestingly, MIg frequently bind to nuclear components, e.g., DNA, Ro/SSA-La/SSB and Sm/RNP [38], IgM derived from a patient with WM has also been described to react with several cytoskeletal components [39], Such autoantibodies have even been implicated in the pathogenesis of peripheral neuropathy, since they react with myelin-associated glycoprotein. MIg preparations from patients with MM, WM, CLL and BMG have been analyzed, using a panel of autoantigens [40]. In this study, MIg preparations from all, except two patients, showed evidence of reactivity with at least one of the autoantigens, whereas, there was little binding of the control monoclonal IgG. This is in keeping with the concept of the origin of natural autoantibodies and the data put forward by Dighiero et al. [41], The latter investigators made an extensive screening of MIg demonstrating that 10, 5 and 3% of the IgM, IgG and IgA, respectively, displayed autoantibody activity.

Additional evidence supporting an association between B-cell lymphoproliferative disorders and nonorgan-specific autoimmune conditions comes from the demonstration that the incidence of rheumatoid factor, cold lymphocytotoxins, antinuclear and an-tithyroglobulin antibodies is markedly greater in the first-degree relatives of patients with WM [42], CLL [43], MM [44] or benign monoclonal gammopathy

[45] than in the normal controls. Full-blown autoimmune diseases, such as multiple sclerosis, Grave's disease, RA, SLE and pernicious anemia have also been recorded in the family members of these patients, again suggesting that a common genetic factors predispose to B-cell proliferation and antiself reactivity. Conversely, levels of serum IgG, IgM and IgA have been reported to be abnormally high in 25,17 and 50% of RA patients and 10, 23 and 8% of their relatives

[46]. MIgs were detected in the sera of 25% of these patients and 4% of their first-degree relatives.


CD5-positive B lymphocytes represent such a unique physiological subset that they act as the source of natural autoantibodies, are involved in setting up the idiotypic network as well as the repertoire of the immune system, and in addition play some role in antigen presentation and tolerance induction [47]. These cells are located at the crossroads of systemic diseases and B-cell lymphoproliferative disorders. Thus, higher numbers of circulating CD5-positive B cells are present in pSS patients with serum monoclonal immunoglobulins than in those without it [23], In fact, the mechanism of expansion of CD5-positive B cells in the nonlymphoproliferative conditions is unclear and may reflect a proliferation of these cells and/or their release into the circulation from peripheral lymphoid tissues. Moreover, while it has been largely documented that both normal and malignant CD5+ B cells produce polyreactive autoantibodies in the absence of extensive somatic hypermutation [3,4], it has also now been clearly demonstrated that CD5+ B CLL cells harbor somatically mutated V-region genes [48], In addition, mutated V genes were also found in CD5+ B cells from patients suffering autoimmune diseases and producing high-affinity rheumatoid factor [49]. Therefore, CD5+ B cells secreting mutated V genes-derived immunoglobulins might be involved in im mune dysfunctions, i.e., autoimmunity and lymphoid malignancy [50].

4.2. Molecular Features

Furthermore, studies are now achieve to understand the role of oncogenes and apoptotic genes in the development of cancer as well as autoimmunity. Regarding the CD5+ B cells few data are to date available but shed light on differences between CD5+ B cells in CLL and their normal counterpart. Normal CD5+ B cells regularly express the c-myc oncogene, at least in mice [51], while it is not expressed in CLL cells [52] suggesting that these latter cells are in a resting state of the cell-cycle. Conversely, with regard to autoimmune states, peripheral blood lymphocytes from patients with SLE, RA [53], pSS [54] and systemic sclerosis [55] over-express c-myc, suggesting that these cells, and likely the CD5+ B cells, are activated.

One of the well known genes involved in the regulation of apoptosis is Bcl-2 [56], which was identified at 18q21 of the chromosomal breakpoint of t(14;18) translocation in follicular lymphoma [57], Bcl-2 is commonly highly expressed in CLL cells while normal CD5+ B cells express low amounts of Bcl-2 [58] which may explain the inability of CLL cells to progress in the cell-cycle. Intringingly, the rate of apoptosis of SLE-[59] or pSS-derived lymphocytes (Garchon, personal communication) in vitro is strick-ingly accelerated, albeit the expression of Bcl-2 is also enhanced in circulating mononuclear cells of patients with SLE [60] or pSS [61]. Enforced expression of this antiapoptotic gene in B cells prolongs antibody responses and elicits autoimmune disorders in transgenic mice [62]. Furthermore, it is still uncertain whether the enhanced apoptosis reflects intrinsic abnormalities or ongoing activation, due to a putative superantigen. The latter hypothesis is substantiated by the V/6 gene biased usage in systemic autoimmune conditions [63],

The Fas receptor (APO-1, CD95), when ligated with a monoclonal antibody leads to the apoptosis of the target cells [64], Recently, it was shown that CD5+ B cells in mice do not constitutively express Fas but only after activation [65]. After stimulation with CD40 ligation, these cells express Fas at only low level and have a reduced susceptibility to Fasmediated apoptosis compared to conventional B cells [66]. CD5+ B CLL cells also express low level of

Fas receptor [67], but in some cases, APO-1 antigen expression of CLL cells increased, correlated with a down-regulaton of Bcl-2 expression, following in vitro stimulation with Staphylococcus aureus Cowan I and interleukin-2. This upregulation prepared the cells for monoclonal antibody anti-APO-1 mediated apoptosis [67]. The expression of the Fas receptor appears to be also upregulated in SLE [68]. Two mutations that accelerate autoimmunity and lympho-proliferation, lpr and gld, are known to correspond to mutations within genes encoding Fas receptor and Fas ligand, respectively [69]. Cell-free Fas ligand has been shown to prevent apoptosis in SLE patients [70], which does not fit to the accelerated apoptosis. The susceptibility of CD5+ B cells to Fas-mediated apoptosis in autoimmune diseases remain however to be determined.

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