Summary

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. The mechanism the mechanism of the disease development still remains unrevealed. In recent years new unique molecular and clinical features of CLL have emerged leading to a unified hypothesis of CLL origin. Major progress in understanding CLL biology was made after identification of mutational status of immunoglobulin variable heavy chain (IGHV) genes, which also improved prediction of patients’ clinical outcome. Preferential usage of IGHV genes has led to recognition of CLL-specific B cell receptors (BCRs), called stereotyped BCRs. Taken together, these data point to antigen stimulation of CLL progenitor cells. Studies on CLL antibody reactivity have shown affinity to molecular motifs on apoptotic cells and bacterial cell structures, supporting the cur­rent hypothesis of the CLL pathomechanism. In this paper we have summarized information available to date regarding current theory of cellular origin and pathology of CLL.

Key words:CLL • chronic lymphocytic leukemia • pathogenesis • antigen • autoimmunity

Introduction

Chronic lymphocytic leukemia (CLL) is the most com­mon leukemia in the western world and it represents about 25-30% of all leukemias. It affects mainly older people; the average age at the time of diagnosis is 65 years old [1,21,30,32,54]. In the course of CLL accumu­lation of B CD5⁺ lymphocytes in peripheral blood, bone marrow, lymph nodes and spleen is observed [30,32,54]. It is known that CLL is a very heterogeneous disease. Some patients demonstrate signs of rapid progression and need immediate therapy, while many cases experi­ence a more favorable course and never require treat­ment [1]. Clinical heterogeneity of CLL is a reflection of genetic and epigenetic abnormalities as well as the microenvironmental influence involved in its patho­genesis, but the mechanism of the disease still remains unrevealed [32,69].

After the milestone discovery which was the mutational status of immunoglobulin variable heavy chain (IGHV) genes, immunoglobulin (Ig) genes became important prognostic markers allowing prediction of patient out­come. Comprehensive analysis of IGHV genes and defi­nition of stereotyped B cell receptors (BCRs) have led to the most important theory of CLL pathogenesis known to date, namely the potential role of antigen (Ag) selec­tion (fig. 1). Studies on CLL antibody (Ab) reactivity have provided hints about the nature of recognized by malig­nant cells Ags and what the cell of origin is [55,65].

Figure 1. Schematic illustration of chronic lymphocytic leukemia development; MZ B cell – mantle zone B cell; Ags – antigens; SHM – somatic hypermutation; CLL – chronic lymphocytic leukemia. Mantle zone B cells independently of T cells can be exposed on autoAgs stimulation. Some of these B cells might undergo SHM and/or isotype class switching, others not, which leads to the development of either mutated or unmutated CLL clones expressing B cell receptors characteristic of particular autoAg.

Cellular origin of CLL

Taking into account that CLL clones use mutated as well as unmutated IGHV genes, which divides patients into clinically distinct subgroups, a two-cell origin model can be considered. However, gene expression profiling (GEP) analysis shows a relatively small number of gene usage differences between unmutated CLL (U-CLL) and mutated CLL (M-CLL) in contrast to thousands of differ­ences between healthy B lymphocytes [14]. The most distinctive phenotypic characteristic of CLL cells is expression of the CD5 molecule coupled with low levels of monoclonal surface immunoglobulins (sIg), usually class IgM or IgD; also the CD23 marker is present on leu­kemic cells. Although the precise origin of leukemic cells is still not clear, GEP and immunogenetic data suggest that CLL clones derive from competent B lymphocytes selected for clonal expansion and eventual transforma­tion by multiple encounters and responses to antigens (fig. 1). Therefore the unified parsimonious hypothesis that CLL is a malignancy of the mantle zone (MZ) sub­population has been adopted [7,26,27,55].

The features of MZ cells could explain the origin of CLL cells. MZ B cells are defined as IgM^highIgD^low, they can respond to bacterial polysaccharides in a T cell-indepen­dent manner, express either mutated or unmutated IGV genes, and the majority of human MZ B cells experience somatic hypermutations (SHM) [14,27,55]. The most sig­nificant feature of normal CD5⁺ B lymphocytes (B1) is an ability to produce polyreactive Ig that recognize variety of auto-antigens (autoAg) and cross-react with bacterial Ags. These natural auto-antibodies (autoAb) are encoded by the same group of IGV genes that are expressed in many cases of CLL. CLL cells and B1 cells also have in common other features, such as low expression of CD20 or myelomonocytic Ags – most frequently My4/CD14 [7,14,55].

Almost 100% of circulating neoplastic cells are in the G₀ phase of the cell cycle, but there is a characteristic asyn­chronism observed between the resting position of CLL cells and their activated phenotype. Resting malignant cells express molecules associated with B cell activa­tion, such as CD23 and CD27. What is more, in leukemic cells there was found mRNA for IL-1α, IL-1β, IL-6, IL-7, IL-8, IL-10, IL-13, IFN-γ, TNF, GM-CSF and TGF-β1, but the role of cytokines in development of the disease is not clear. CLL cells do not respond to any of the cytokines; they remain in a resting position [7].

However, a MZ origin of CLL cells faces difficulties. There are some differences in the surface phenotype between normal B and CLL cells. MZ B cells express surface IgM and IgD, but with phenotype of CD5^–CD23^–CD22⁺, that differs from leukemic cells. This discrepancy could reflect up-regulation of CD5 and CD23 upon activation as CLL cells are constantly activated according to GEP and immunogenetic analysis. Also, expression of CD21, a receptor for the Epstein-Barr virus (EBV), cannot be explained by MZ origin of CLL. EBV immortalizes nor­mal B cells regardless of CD5 expression. But it is almost impossible to immortalize CLL cells with EBV, even though EBV-receptor binding activity and EBV uptake of malignant cells are complete [7,14,27].

In contrast to current theory of cellular origin in CLL, recently published data have suggested that the disease initiating event may occur in hematopoietic stem cells. Apparently hematopoietic stem cells obtained from CLL patients and transplanted to xenograft models have a predisposition to generate clonal B cells with a CLL-like phenotype and certain IGHV genes usage [26,41].

Immunoglobulin genes in CLL

The discovery that somatic mutations of the Ig varia­ble region genes occur in a subset of CLL patients and that the absence or presence of these mutations signifi­cantly correlates with clinical outcome was a milestone in understanding the biology of CLL [37,62]. In general, patients with mutated IGHV genes follow a more indo­lent course compared to those with unmutated IGHV genes, who have more progressive leukemia, adverse cytogenetic profiles, clonal evolution and resistance to therapy [44]. Based on these observations, it was spe­culated that the U-CLL cells derive from pregerminal center or naive B cells, while M-CLL cells originate from postgerminal center or memory B cells. However, this theory, as mentioned above, is not supported by GEP analysis, which shows that CLL cells, independently of mutational status, and memory B cells have similar IGHV gene expression profiles. It is also known that malignant cells carry antigen experienced (CD27) and activated (CD23, CD25, CD69, CD71) phenotype of sIg [33].

Since 1999, when Chiorazzi’s, Hamblin’s and Stevenson’s independent groups confirmed that the IG gene reperto­ire in CLL cells is not random and that SHM among these genes do not occur uniformly, several studies have esta­blished that IGHV mutational status has prognostic value independent of the clinical stage. However, it is obse­rved that relative frequencies of individual genes signi­ficantly vary among subsets. Performed analysis of IGHV rearrangement genes has revealed a striking association between particular gene usage and clinical/phenotypic features or outcome for selected subsets of CLL patients. And this points to antigen binding as a critical issue in determining clinical presentation [4,57].

A number of studies have confirmed biased usage of the IGHV1-69 gene in CLL. Although over-usage of IGHV1-69 is observed also in other B cell proliferative disorders, it is important that IGHV1-69 is the most frequent gene over­-represented in U-CLL patients [11,65]. Several alleles of this gene has been found. They can be grouped into two types based on different sequences that encode the second complementarity-determining region (CDR2), but only 1 type of allele appears to be generally used in CLL – 51p1 [40,65]. Moreover, IGHV1-69 rearrangements are preferentially biased towards the usage of IGHD3-3, IGHD2-2 as well as IGHJ6 genes [37,44,65]. Another unu­sual molecular characteristic of IGHV1-69 rearrange­ments is a longer than average CDR3 sequence, which in that case have 19 codons [40,65]. These features of IGHV1-69 over-usage are clearly different from those seen in B cells of the normal elderly population [65]. It has been reported that apart from IGHV1-69 also other genes from the IGHV1 family are over-used among U-CLL patients, namely: IGHV1-2, IGHV1-18, IGHV1-3, IGHV1-46, IGHV7-4-1. The prognosis for patients with over-expres­sion of the mentioned genes is poor [37].

Another very frequent IGHV gene in CLL is IGHV4-34, usually over-expressed in M-CLL, although IGHV4-34 is also used at high frequency among healthy individu­als [29,33,44,65]. There are 2 different types of IGHV4-34 rearrangements reported: with short CDR3 associated with IGHJ4 gene usage and with a long CDR3 sequence coexisting with IGHJ6 over-expression [65]. Several scientific groups have established that more than 1% of CLL patients over-using IGHV4-34 with long CDR3 also over-express the IGKV2-30 gene [29,33,44]. In this sub­set CDR3 is positively charged and enriched in aromatic amino acids. What is more, VH and VK domains among this group display very characteristic patterns of SHM with frequent introduction of acidic residues, typically glutamic and aspartic residues [29]. Of note, all anti­bodies with IGHV4-34 sequences within the IGHV4-34/ IGKV2-30 subset recognize N-acetyllactosamine (NAL) and are autoreactive in the germline state to the deter­minant of the I/I blood group antigen. Carrying intact NAL-binding motifs could possibly mean that these CLL cells were bound and stimulated for clonal expansion by NAL-containing epitopes of autoAgs and exoAgs [29,50]. Furthermore, patients belonging to this subset, in com­parison with other cases, are significantly younger at the time of diagnosis and follow an indolent course of malignancy, rarely needing any treatment [29,33,44]. Among the IGHV4-34/IGKV2-30 subset distinct GEP with generalized low expression of genes involved in proli­feration and regulation of the cell cycle was observed, which might explain the indolent course of CLL [33]. It has been reported that about 6% of CLL Abs express IgG as a result of deletional isotype switch. Interestingly, this feature concerns CLL IgG with IGHV4-34 and IGHV4- 39 gene over-usage [37,62].

IGHV3 family genes are also very frequently over-expres­sed in CLL cells, together with IGHV1-69 and IGHV4-34. Especially IGHV3-21, IGHV3-23 and IGHV3-7 are highly used and, what is more, have the highest mutational load in CLL [19]. The IGHV3-21 subgroup is very interesting as it has been proven that these genes are an exception from the prognostic classification of IGHV mutational status and were proposed as an independent adverse progno­stic factor [19,55,65]. IGHV3-21 genes are usually expres­sed in M-CLL, although they can also be found in U-CLL. The whole subset of IGHV3-21, expressed by 11% of CLL patients, is associated with poor survival. Surprisingly, among M-CLL cases median survival is even shorter com­pared to U-CLL [11,19,29,33,37,40,44,55,65]. About 50% of patients with IGHV3-21 rearrangements have a very homologous, short CDR3 region, in most cases compo­sed of 9 amino acids with a conserved motif DANGMDV. Additional analysis of this subset has shown restricted usage of IGLV3-21/IGLJ3 light chain genes with highly homologous CDR3 [19,50,55,65]. In contrast to the IGHV3- 21/IGLV3-21 subset there is a second subgroup of IGHV3- 21 genes with heterogeneous CDR3 rearrangements and light chain gene usage, characterized by variable CD38 expression and alternating clinical outcome [29]. M-CLL patients belonging to IGHV3-21/IGLV3-21 clearly demon­strate more aggressive leukemia, shorter time to treat­ment and shorter time to progression compared to other M-CLL IGHV3-21 [19,29,55,65]. Several studies have reve­aled the biological basis for the disease’s aggressiveness. All current well-known negative prognostic markers, such as Rai stages III and IV, abnormalities in chromoso­mes 11 and 17, and expression of CD38 and ZAP-70, were more frequently found in patients with IGHV3-21/IGLV3- 21 rearrangements [37,44,55,70]. Furthermore, GEP ana­lysis of CLL with IGHV3-21 versus non- IGHV3-21 showed up-regulation of genes involved in transcription, cell cycle and protein kinase activity (PPP5C, E2F4, SMARCD1, ARHGEF1, TYMS, HMGA1, EIF4G1, VIPR1, RND1, PPP1R15B) in the IGHV3-21 subset. Also in this subset down-regula­tion of genes involved in repression of transcription and negative control of the cell cycle (SPEN, SAP18, TBL1X, MXI-1, CDKN1B, CDKN2D, SMAD2, RUNX1, TGFB2, RERG, ABI1, PMP22) was demonstrated [19,24,65]. In summary, all these data indicate that the IGHV3-21 subset repre­sents an independent biological and possibly prognostic entity of CLL [24,65].

BCR stereotypy

The BCR is a multimeric complex formed by sIg non­-covalently associated with heterodimer Igα/Igβ respon­sible for signal transduction (CD79a/CD79b) [7,21,61]. The BCR is the key molecule that allows mature B lym­phocytes to bind to specific Ag. A number of functio­nal IG genes together with the mechanisms causing Ig diversification are responsible for huge variations of BCR structure and uniqueness of the Ig expressed by B lymphocytes [21,61].

A skewed repertoire of IGHV genes has been described in different types of B cell lymphoproliferative disorders, but CLL is a model leukemia for understanding oncogenesis by IG gene analysis. SHM patterns of IGHV are a characteristic process for BCRs undergoing Ag selection. Therefore it is suggested that antigen is involved in the development of leukemia by stimulating proliferation of B cells expressing BCR with Ig encoded by specific genes [4,44,57].

In the past decade several studies analyzing sequences of IG genes in CLL cells have confirmed that unrelated and geographically distinct patients might display simi­lar IGHV/IGHD/IGHJ rearrangements with highly homo­logous, if not identical, CDR3. To describe the striking phenomenon that distinct Ig could be repeated in dif­ferent subsets of CLL patients, in 2004 Chiorazzi’s group applied the term 'stereotyped BCRs’ [4,31,33,44,57]. The first criteria proposed by Chiorazzi’s group were as fol­lows: (i) usage of the same IGHV/IGHD/IGHJ germline genes, (ii) usage of the same IGHD gene reading frame and (iii) VH CDR3 amino acid identity >=60% in line with established bioinformatics concepts for evaluation of sequence conservation in protein sequences, such as amino acid substitution matrices [4,44]. Most studies on stereotyped BCRs are focused on IGHV genes, parti­cularly HCDR3, based on the fact that the more similar primary HCDR3 sequences of independent Igs are, the more similar are their folding and specificities. Further research was performed using different techniques in order to establish new subsets of patients with stereo­typed BCRs [4,57].

In 2007 Stamatopoulos et al. [59] published an analy­sis of 916 CLL cases of Mediterranean origin with total analysis of 927 IG genes. They found that 20% of CLL patients carrying stereotyped BCRs can be grouped in one of 48 stereotyped subsets. The clustering algorithm that was used in the study has been modified, essen­tial criteria being >=60% HCDR3 similarity and length, regardless of IGHV gene usage. It was observed that IGHV genes might be phylogenetically linked and carry related germline sequences, and therefore they can produce overall homologous VH domains when recom­bined with identical IGHD and IGHJ genes. For example, subset #1 is characterized by usage of the IGHD6-19 and IGHJ4 genes in association with different IGHV genes (IGHV1-2, IGHV1-3, IGHV1-18, IGHV1-8, IGHV5-a, IGHV7-4- 1) [4,29,44,55,59]. Based on the clustering approach, this study revealed that BCR stereotypy exists among unmu­tated as well as mutated cases with the frequency exce­eding 25%. What is more, many different subsets with distinct BCR stereotypy were identified and the rela­tive size of each subset might differ significantly. In the quoted paper the authors also described the phenome­non whereby subsets with stereotyped VH CDR3 share unique molecular and clinical features that can be cha­racterized by restricted IG light chain genes usage and CDR3 properties. This once again raises the possibility that a particular antigen-binding site can be crucial in determining clinical features and prognosis for sub­sets of CLL patients [4,29,44,59]. Thus identification of shared amino acid patterns leading to BCR stereotypy could be useful in investigating the nature of selecting antigens and furthermore might impact allocation of patients into different groups with diverse biological and clinical characteristics. Due to progressively rising Ig sequence data, Stamatopoulos’s group have develo­ped a bioinformatic method based on sequence pattern discovery that allows for the identification of VH CDR3 similarities in disregard of IGHV/IGHD/IGHJ gene usage. This approach enabled recognition of more distant rela­tionships between sequences forming the basis of subset discovery, on higher levels characterized by more widely shared sequence patterns and therefore greater size. Interestingly, high level clusters were found to be cha­racterized by striking IGHV repertoire restrictions with only six IGHV genes, namely IGHV1-69, IGHV1-3, IGHV1-2, IGHV3-21, IGHV4-34 and IGHV4-39, accounting for >80% of CLL patients [4,44].

The results of the joint Mediterranean-Scandinavian analysis of 1939 CLL patients were published in 2008. The authors employed the same criteria to assign patient sequences to subsets and reported an even higher proportion of patients belonging to different subsets. Almost 30% of sequences among the analyzed cohort were ascribed to one of 110 stereotyped subsets. The described study was focused on SHM patterns and based on the findings it has been concluded that among mutated subsets several of them showed distinctive mutations, which probably occurred due to the antigen response. These 'CLL-biased’ and 'subset-biased’ muta­tion patterns confirm the theory of antigen stimula­tion in the development of the IG gene repertoire in CLL and moreover show that beside CDR3 also other regions of V genes are involved in the antigen reaction (fig. 1).

Interestingly, a large proportion of stereotyped patients carried a recurrent somatically introduced deletion of a serine codon from VH CDR2. Comparison amongst a cohort of heterogeneous CLL IGHV3-21 rearrangements with IGHV3-21 sequences from non-malignant cells sho­wed that the VH CDR2 serine codon deletion is subset­-biased [4,50,55].

Subsequent studies on stereotypy were based on an algorithm developed by Stamatopoulos et al. [59] in 2007. In 2010 Darzentas et al. [20] analyzed HCDR3 sequ­ences of 2800 patients with a slightly modified algori­thm: amino acid identity between sequences was 50%, but with at least 70% similarity in terms of hydropathy, volume properties and chemical characteristics [20,55]. Also in a recently published paper Stamatopoulos et al. [2] updated their clustering algorithm to test the Ig repertoire of 7424 CLL cases. Changes were addressed mainly to HCDR3 length and the exact location of shared patterns within the HCDR3 sequence. In this algorithm variant roles of CDR1 and CDR2 sequences in recognition and binding of Ags were taken into account [2,44].

Nevertheless, all aforementioned studies have confir­med that CLL patients can be divided into two separate categories, either with stereotyped or with heteroge­neous IG genes in a ratio of 1:2. Furthermore, all of the performed analyses provided strong evidence for the existence of subsets with stereotyped BCRs encoded by different, although phylogenetically related, IGHV genes. It is worth mentioning that BCR stereotypy in CLL is fundamentally different from that established in other B cell malignancies. Defined sequence patterns among each subset are encoded by the germline sequ­ences of the D-region and J-region of IGHD-IGHJ genes or by N-diversity regions of IGHV-IGHD and/or IGHD-IGHJ genes [4,9,13,44,57,61].

Antigen stimulation

The above-described BCR stereotypy might suggest the role of superantigen in development of the disease (fig. 1). In addition to asymmetric usage of IGHV genes, con­served sequences in HCDR3 point to selection of conven­tional antigen [62]. Monoclonal antibodies found in the circulation of malignant patients were defined as similar to natural IgM Abs with low affinity to microbes, lacking in SHM and with autoreactivity/polyreactivity. Enzyme immunoassay techniques provided further information. Auto- and polyreactivity are conversely associated with the mutational load of IG genes in BCRs [15,37,44,51,55]. Interestingly, it was observed that monoreactivity of several M-CLL mAbs can be converted to polyreacti­vity by reversal of the Ab amino acidic structure to that of the germline gene, suggesting that most CLL B cells derive from normal B lymphocytes with poly- or autoreactive BCRs [35,37]. Chiorazzi’s and Rosenquist’s group have demonstrated that CLL mAbs could react with molecular motifs on apoptotic cells and bacteria [10,12,15,51,55].

Studies on CLL mAbs have revealed reactivity against oxidation-specific epitopes (table 1). These neoepito­pes are formed during oxidation of lipids, proteins and DNA, which occurs in response to microbial infection or chronic inflammation for example. Oxidized low density lipoprotein (oxLDL) arises from conjugation of metabo­lites of lipid peroxidation and can be found on apopto­tic cells and microbial surfaces. To date oxLDL has been reported to play a role in rheumatoid arthritis, Alzhe­imer’s disease, atherosclerosis and hemochromatosis [16,47,55]. Recently this MDA-modified (malondialde­hyde-modified) oxLDL epitope was found to be recogni­zed by stereotyped CLL mAbs from subset #1 and subset #32 as well as non-stereotyped CLL mAbs IGHV3-21UM, IGHV1-2UM and IGHV3-30M [51,55]. Moreover Catera’s group reported that stereotyped subset #1, #6, #8 and #9 CLL mAbs bind to oxidation epitope MDA, and these reactivities correspond with apoptotic cell binding [10,55]. These facts emphasize that most CLL mAbs have the capacity of binding different epitopes, all of which are generated in the process of oxidation [10,16,51,55].

Table 1. Antigen reactivities reported in CLL

Also microbial epitopes were found to be targeted by CLL sIgs [9,44,55]. In 2003 Binder et al. [5] revealed molecu­lar mimicry between Streptococcus pneumoniae capsular polysaccharides and oxLDL (table 1). This phenomenon appears to be a crucial link between auto- and alloreac­tivity of mAbs [5,33,44,55]. What is more, CLL sIgs reac­tivity against certain Gram-positive and Gram-negative bacteria was shown, namely: Streptococcus pyogenes, Ente­rococcus faecium, Enterococcus faecalis, Enterobacter cloacae (table 1). Particularly high binding properties were noti­ced in IGHV1-69UM mAbs [5,44,55]. Lately, viral infections were suggested to drive subgroups of CLL patients. It was observed that persistent infections with EBV and CMV (cytomegalovirus) are associated with subset #4 IGHV4-34 (table 1). Also IGHV1-69 and IGHV3-21 displayed capacity of binding to CMV pUL32 protein (table 1). Likewise HCV (hepatitis C virus) has been implicitly correlated with CLL (table 1) [33,44,45,55,60]. In a recent paper Hoogeboom et al. [38] identified a subset of patients expressing mutated IGHV3-7 and semi-identical IGKV2-24 genes, defined as sub­set V3-7Sh, recognizing β-(1,6)-glucan (table 1). β-(1,6)- glucan is a polysaccharide found in the cell wall of certain yeast, fungi, mushrooms and bacteria. It is known that β-(1,6)-glucan can be recognized by healthy Abs and acti­vate the immune system. According to these data, 0.3% of all CLL cases belong to the mutated V3-7Sh subset and respond to the natural antigenic determinant shared by an extensive group of pathogens, e.g. commensal yeast species of Candida, Trichosporon, Malassezia and Saccharo­myces, filamentous fungus Aspergillus, and also spores and conidia of Aspergillus fumigatus, Penicillium chrysogenum, Fonsecaea pedrosoi, and Rhizopus oryzae [38].

A novel fact from the research on antigen affinity in CLL is that malignant mAbs with particular features can react with cytoskeletal proteins. With the excep­tion of IGHV4-54M, which exhibits a nuclear binding pattern as observed on Jurkat cells, IgG1 mAbs react with autoAgs of cytoplasmic and perinuclear origin [25,28,39,43,44,48,49,58]. Interestingly, all of these pro­teins have a functional connection with microbial infec­tions and/or apoptotic cell eradication [55]. Nonmuscle myosin heavy chain IIA (MYHIIA) is an important pro­tein in eukaryotic cells that plays a role in several cel­lular processes, including cell motion. Chu et al. [17,18] published two separate papers in Blood on the subject of MYHIIA. They established that MYHIIA is targeted by stereotyped mAbs from subset #6 with IGHV1-69/IGHD3- 16/IGHJ3 rearrangements (table 1). This 225 kDa protein is cleaved by caspases and rearranges in the cytoplasm, transferring to the surface of the cell during apoptosis, then recognition of MYHIIA by CLL mAbs becomes possi­ble. Such MYHIIA-exposed apoptotic cells were defined as MEACs. Interestingly, MEAC binding was observed among U-CLL patients and high reactivity correlated with poor survival. Data obtained by Chu et al. [17,18] indicate that MEAC reactivity might determine CLL clone behavior [39,44,55,58].

Vimentin, a type III cytoskeletal protein, was found to function on the external side of the plasma membrane and to be secreted after bacterial infection. This protein not only maintains the architecture of cells, but also par­ticipates in transcellular migration, cell adhesion, cel­lular signaling and wound healing. Vimentin in a stress response can be exhibited on apoptotic primary T cells, neutrophils, platelets and oxLDL-binding macrophages [28,49,51,55]. Myhrinder et al. [51] found that subset #32 mAbs with IGHV3-30.3UM as well as mAbs with muta­ted IGHV3-30 gene rearrangements react with vimentin (table 1) [51].

Filamin was the first discovered non-muscle actin bin­ding protein. There are three isoforms of this protein: filamin A, B and C [25]. Isoforms A and B are cross lin­king proteins participating in over forty molecular inte­ractions, both being exposed on the surface of apoptotic cells. Unmutated HG3/IGHV1-2 mAbs were established to bind filamin B as well as oxLDL Ags and apoptotic Jurkat cells (table 1) [25,51,55].

Cofilin-1 is another cytoskeletal protein that possibly plays a role in CLL pathogenesis. Cofilin-1 is a member of the actin binding and depolarizing family and it has been identified in a wide range of eukaryotic organisms. In an unphosphorylated form this protein has the abi­lity to bind both globular and filamentous actin, promo­ting their dynamics for motility, development, polarity as well as cytokinesis [66,68]. In final stages of apoptosis cofilin-1 is exposed in apoptotic blebs. When oxidation of the protein is inhibited, oxidant-induced apoptosis is stopped [43,48,51]. Cofilin-1 was discovered to be targe­ted by three leukemic mAbs: unmutated Igs belonging to subset #5 CII/IGHV1-69, mutated 232B4/IGHV3-48 and subset #2 mAbs rIGHV3-21M (table 1) [51,55].

Despite strong evidence supporting the role of Ags sti­mulation in CLL ontogeny, it is still not clear when the Ags reaction occurred in malignancy development and whether it was an incident taking place only once at a certain point of neoplastic transformation or it is an ongoing process. Sutton et al. [64] conducted an ana­lysis of intraclonal diversification (ID) within IG genes through ongoing mutational activity. Results from ID study in other B-cell disorders point to ongoing SHM, proving that Ags constantly interact with neopla­stic cells. The CLL ID data showed a little evidence for ongoing Ags stimulation in IgG and IgM B cells with the exception of subset #4, where all cells showed high levels of ID. These findings were confirmed by ID ana­lysis of light chain genes in subset #4 cells. Therefore it seems likely that at least in particular subsets ongoing stimulation by Ags takes place after malignant trans­formation [46,52,55,64].

Autoimmune events in CLL

Patients with CLL might develop autoimmune disorders, primary directed against hematopoietic cells. Autoim­mune complications probably appearing as a result of an impaired immune system frequently are severe and life­-threatening for CLL patients and require medical inte­rvention even when CLL is still quiescent and does not need specific therapy [8,31,34,42,53,67].

Autoimmune hemolytic anemia (AIHA) is strongly asso­ciated with CLL, as are immune thrombocytopenia (ITP) and rarely pure red cell aplasia (PRCA). The occurrence of immune cytopenias has been reported in many recent studies to range up to 25%. The most common disease is AIHA, while ITP and PRCA are more rare [22,36].

There are a few clinical and biological characteristics of CLL that have been associated with an increased risk of autoimmune cytopenia. It is known that advanced stage of CLL and age of patients correlate with more frequent occurrence of AIHA [3,36]. AIHA and ITP have also been associated with poor prognostic factors, such as unmu­tated IGHV gene, high ZAP-70 expression and increased serum β2-microglobulin level [36].

In the case of AIHA and ITP autoimmunity can be trig­gered by bystander non-malignant B cells or CLL cells. The etiology of anti-RBC Abs in CLL is not fully described yet, but several mechanisms have been proposed. Non­-neoplastic B cells via T-cell mediated manner produce polyclonal high-affinity IgG that targets RhD, RhCcEe and B3 epitopes in AIHA and GpIIIb/IIIa in case of ITP. Then opsonized cells are destroyed via antibody-depen­dent cellular cytotoxicity. It is unknown which normal cells are involved in this process, but significant incre­ases of CD4⁺ T cells and NK cells in peripheral blood have been observed [22,63]. It has also been suggested that autoreactive T helper cells occurrence might be induced by autoAgs directly presented by CLL cells. In that case tumor necrosis factors, such as B-cell activator factor (BAFF) and proliferation-inducing ligand (APRIL), pro­bably play an important role [22,36,63].

In the case of PRCA in CLL the mechanism is not well defined, but it appears to be humorally mediated [22].

Non-hematological autoimmune events in CLL are rare. To date in numerous reports cases of rheumatoid arth­ritis, systemic lupus erythematosus, ulcerative colitis, pernicious anemia, Sjogren’s syndrome, Grave’s disease, nephritic syndrome, pemphigus, glomerulosclerosis and paraneoplastic neurological syndrome have been descri­bed [34,53].

The process underlying development of autoimmune disorders in CLL is complex. It requires interactions between neoplastic cells, pathologically functioning T cells, the microenvironment and the immune system. Occurrence of autoimmune disorders in CLL is not fully understood yet, but autoreactivity against formed ele­ments of blood appears to be related to the ability of malignant cells to process and present Ags derived from blood cells [3,36].

Alternative approach to CLL pathomechanism

Recently Duhren-von Minden et al. [23] presented a novel theory for CLL development. According to their data, CLL is driven by antigen-independent, cell-autono­mous signaling. Apparently HCDR3 interacts with intrin­sic motifs, such as a sequence in the second framework region (FR2), within the same or nearby BCRs, consequ­ently inducing cell-autonomous signaling independent of extrinsic epitopes. Moreover, HCDR3 sequences deri­ved from leukemic BCRs are able to transfer autonomous signaling capacity to other BCRs. Irrespectively of IGHV mutational status and BCR stereotypy, in all CLL sIgs autonomous signaling was observed [13,23]. In Cell Rese­arch Chiorazzi and Efremov commented on this newly discovered signaling as Ag-dependent. According to the authors, the described interaction of HCDR3 with epito­pes can be considered as an example of autoreactivity, where selection of B cells with HCDR3 sequences reco­gnizing FR2 autoepitopes takes place [13]. Therefore the newly discovered interaction of HCDR3 sequences with the FR2 region may be a confirmation of the current antigen-driven CLL development hypothesis.

Conclusions

Aforementioned evidence indicates the importance of Ag stimulation in the leukemogenesis of CLL. Analysis of BCRs has provided considerable information about malignant cells and the possible mechanism under­lying the biology of the disease. Available data show that most likely CLL cells after BCR-mediated stimula­tion, irrespectively of IGHV mutational status, express activated membrane markers and secrete various cyto­kines similarly to MZ Ag-experienced B cells, there­fore promoting expansion of respective CLL clones. The BCR stereotypy and studies on Ag reactivity sug­gest that CLL cells originate from B cells involved in rather innate functions, such as MZ B cells, as expres­sed Abs bind to autoAgs exposed on apoptotic cells or conserved microbial epitopes. The thesis on Ag stimu­lation via BCR is also supported by skewed usage of IGHV genes found in neoplastic BCRs. Prognostic value of IGHV mutational status and existence of subsets of patients expressing stereotyped BCRs enforce this the­ory [7,31,44,55].

Although new facts in regard of CLL biology and cell ori­gin are continuously emerging, the primary cause of leukemia still needs to be investigated for better under­standing of CLL etiology.

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