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Lymphoma is a group of lymphatic system malignancies.
A complex inter-relationship exists between lymphoma and autoimmunity.
Peripheral nervous system abnormalities occur in 5% of lymphoma patients.
Autoimmune neuropathy occurs rarely in lymphoma patients.
Accurate neuropathy diagnosis is important for correct treatment plan.
Lymphoma consists of a variety of malignancies of lymphocyte origin. A spectrum of clinical peripheral neuropathy syndromes with different disease mechanisms occurs in about 5% of lymphoma patients. There exists a complex inter-relationship between lymphoproliferative malignancies and autoimmunity. An imbalance in the regulation of the immune system presumably underlies various immune-mediated neuropathies in patients with lymphoma. This article reviews lymphoma and more-or-less well-defined dysimmune neuropathy subgroups that are caused by humoral and/or cell-mediated immune disease mechanisms directed against known or undetermined peripheral nerve antigens.
Lymphoma is a group of lymphatic system malignancies. Many lymphoma classification systems were devised over the years; most hematologists/oncologists adopted the WHO International Classification of Diseases (ICD) system (presently ICD-10 version of 2010) (www.lymphomainfo.net). About 90% of lymphomas are of the non-Hodgkin type (NHL), a diverse group of diseases each distinguished by the specific characteristics of lymphocytes (85% B-cells, less commonly T- or NK-cells). About 10% of lymphomas are of the Hodgkin type (HL), characterized by the presence of germinal center B-lymphocyte-derived Reed–Sternberg cells. This review includes patients with chronic lymphocytic leukemia (CLL), because it is considered the same disease as small lymphocytic lymphoma (SLL), a NHL subtype, though with abnormal cells in the blood (www.lymphomas.org.uk).
A wide variety of peripheral nervous system abnormalities occur in 5% of patients with lymphoma [
]. Lymphoma can involve any part of the peripheral nervous system. The mechanisms of lymphoma-associated neuropathy (i.e., excluding chemotherapy exposure, viral infections [e.g., HIV/Herpes zoster], and established nutritional disturbances) may entail [
]: (a) local or diffuse peripheral nerve lymphomatous (specifically NHL/T-) cell invasion i.e., neurolymphomatosis; (b) deposition in the endoneurium of circulating monoclonal antibodies (mostly IgM paraprotein) secreted by malignant or non-malignant lymphocytes/plasma cells; (c) autoantibodies directed against specific peripheral nerve antigens (e.g., myelin-associated glycoprotein or gangliosides) probably produced by non-lymphomatous clonal B-cell expansion due to immune “escape” mechanisms [
]; (d) lymphoma-induced (particularly HL) immune dysregulation that underlies immune-mediated inflammatory neuropathy; (e) ischemic neuropathy due to: (1) hematogenous metastases (angiotropic B-cell lymphoma) that occlude vessels by local intravascular proliferation, direct pressure, or tumor emboli; (2) cryoglobulin deposition (types I and II) [
]; and (g) “other”/unclear explanation, possibly toxic/metabolic/nutritional.
This article reviews lymphoma-associated peripheral nerve disorders with presumed immune-mediated pathogeneses. Specifically, this review concentrates on lymphoma and more-or-less well-defined immune neuropathy subgroups that are caused by humoral and/or cell-mediated immune attacks against either known or undetermined peripheral nerve antigens. The selective approach to this topic entailed careful screening of the literature and the exclusion of reports with variables that interfered with the interpretation of chosen, defined neuropathy subgroups: (a) cryoglobulinemic neuropathy (mechanism is vasculitic ischemic damage to nerves); (b) plasma cell dyscrasias that are not usually classified with the lymphomas [
]. A systematic search was conducted of relevant publications using databases such as MEDLINE [PubMed], EMBASE and DynaMed, and included case reports and series, retrospective studies, and reviews. Search terms included “neuropathy”, “immune-mediated”, “autoantibody”, “autoimmune”, and “lymphoma”. Publications were retrieved and scrutinized, and article bibliographies were cross-referenced to ensure that this review is accurate and comprehensive.
2. Immune-mediated polyneuropathies
Reviews exist on the presumed immunopathogenesis of the acquired inflammatory demyelinating polyneuropathies [
], and will not be discussed in detail here. To summarize, in inflammatory demyelinating polyneuropathies, cellular and humoral immune responses both participate in the disease mechanism (Fig. 1, Fig. 2). This immune response is directed against the myelin or axon of the peripheral nerve; no specific antigen has been consistently identified. Cellular immunity participation is supported by evidence of T-cell activation, crossing of the blood–nerve barrier by activated T-cells followed by macrophage-mediated demyelination, and by expression of cytokines, tumor necrosis factor, interferons, and interleukins. Humoral immunity is implicated by the demonstration of immunoglobulin and complement deposition on Schwann cells and myelinated nerve fibers, and by passive transfer experiments that induce conduction block and demyelination (by injecting serum or purified IgG from patients into rodent nerves).
Anti-MAG antibodies have been implicated in a chronic demyelinating peripheral neuropathy. There is compelling evidence that anti-MAG antibodies play a causative role in the pathogenesis of neuropathy e.g., intraneural injection of serum from patients with demyelinating neuropathy and anti-MAG antibodies induced nerve demyelination in animal models. Studies of nerve biopsy specimens showed loss of myelinated fibers, thinned myelin sheaths, segmental demyelination, and occasionally tomacula and onion bulbs. Antibodies bind to an oligosaccharide determinant that is shared by MAG and the glycolipid sulfoglucuronyl paragloboside (SGPG).
Anti-GM1 IgM antibodies are presumed to be pathogenic in the development of MMNCB, but it is not absolutely established whether antibodies are disease causative or merely an associated abnormality.
2.2 Autoantibody-mediated polyneuropathies
In this literature search 23 cases were retrieved of polyneuropathy associated with autoantibodies directed against specific peripheral nerve antigens in patients with various types of lymphoma (Table 1a and b ). The temporal association between neuropathy onset and lymphoma diagnosis varied: (1) In most patients, onset of neuropathy preceded by variable periods the diagnosis of lymphoma: (a) lymphoma was diagnosed only at autopsy in a patient with a 3-year history of polyradiculoneuropathy [
]; (b) a patient with a 6-year progressive sensory demyelinating polyneuropathy associated with MGUS (? undetected lymphoma) developed fatal EBV+ intracerebral lymphoma after treatment with various courses of immunotherapy [
]; analyses of intrathecal and peripheral M-protein as well as brain immunocytochemical studies suggested a common clonal origin of both immunoblastic cerebral proliferation and the serum paraprotein-secreting cells. Presumably, immune deficiency due to monoclonal B-cell proliferation and/or immunosuppressive therapy resulted in EBV-reactivation and dysregulation of CNS-restricted T-cell control of B-cell proliferation; autopsy did not include search for systemic lymphoma; (c) chronic (up to 3-year duration), slowly progressive [
] neuropathies preceded diagnoses of either indolent/low grade or diffuse large cell lymphoma, respectively; (d) a patient with a 2-year slowly progressive sensorimotor neuropathy developed B-cell CLL [
]. (2) In some patients lymphoma diagnosis preceded onset of neuropathy: (a) in 1 report, relapsing–remitting cranial polyneuropathy occurred in a patient with established cutaneous lymphoma in remission and subsequent recurrence [
] lymphoma preceded the onset of neuropathy symptoms at intervals of 2 years, 10 and 6 months in 3 patients, respectively. (3) In the remainder of patients, lymphoma was diagnosed during the initial presentation and evaluation of neuropathies of variable duration [
In this non-uniform group of patients, serum autoantibodies were detected against a spectrum of peripheral nerve antigens. Presumably, these antibodies played a pathogenic role in the development of neuropathies. There was no evidence to suggest that autoantibodies were produced in response to peripheral nerve damage of direct lymphoma spread; moreover, any fortuitous association was minimized by adequate search for other causes of polyneuropathy in these patients. In most, but not all [
CSF analyses were reported on 12 patients: protein was elevated in 9 patients; cell count was elevated in 3 patients. By definition, any patient with malignant cells in CSF was not included in this review.
Peripheral nerve specimens were obtained by biopsy or autopsy from 7 patients: all showed a predominant decrease of large myelinated fibers; in some samples there was evidence also of active or chronic (i.e., sparse onion bulb formation) demyelination [
Based on the presumed autoimmune pathogenesis of neuropathy, the majority of patients was offered and responded to some form of immunomodulatory therapy. Any neuropathy clinical response was independent of time of discovery or any treatment of the underlying lymphoma. Less frequently, cytotoxic therapy was aimed at lymphoma, and proved either effective [
]. Any reported deaths among patients during the varying length observation periods were ascribed to the lymphoma or associated systemic complications; no patient death was directly related to polyneuropathy.
An apparent pathogenic role of circulating antibody with affinity for peripheral nerve antigen(s) was demonstrated by immunofluorescent study on some reported lymphoma patients [
], or was otherwise presumed. Some evidence suggested that circulating anti-nerve monoclonal autoantibodies, usually immunoglobulin-M paraprotein, were actually produced by lymphoma B-cells. A single report provided evidence of production of monoclonal IgMλ anti-GM1/GD1b autoantibody by tumor cells in a patient with diffuse large B-cell NHL [
]: (a) on immunofluorescent flow cytometry simultaneous expression of CD79b (part of a heterodimer transmembrane protein) and IgMλ on the surface of CD19-positive lymphoma cells indicated that most IgMλ antibodies were not adherent to the lymphoma cells; rather, they were present on the surface in a secretory form; and (b) levels of monoclonal antibody (with affinity for Galβ1-3GalNAc terminal disaccharide antigenic determinant) were significantly higher in the supernatant from a 2-d culture of lymphoma cells compared to normal lymphocytes.
In another report, the clonal origin of monocytoid B-cell lymphoma suggested that lymphoma cells synthesized IgMκ paraproteins, and were determined to be autoantibodies to MAG and SGPG [
]. The clinical improvement of neuropathy in response to chemotherapy also favored the production of these autoantibodies by neoplastic lymphoid proliferation.
In conclusion, in patients with established lymphoma an accurate neuropathy diagnosis should guide the appropriateness of serum autoantibody determination, with consequent treatment implications. Based on reviewed literature it is difficult to advise on the value of such antibody determination in patients with “atypical” neuropathy syndromes, or of the yield of a comprehensive lymphoma screen in patients with antibody-mediated polyneuropathies.
]. A retrospective study assessed the neurological complications in 229 patients with the “reticuloses” (a group of disorders characterized by the usually malignant proliferation of any of the cells of the reticuloendothelial system) [
]: 4 patients were diagnosed with peripheral neuropathy (2 severe; 2 mild) without evidence of a primary demyelinating process on post-mortem examination (reported on 3 patients). Another retrospective study of the non-metastatic neurological syndromes “of obscure origin” in 774 patients with the “reticuloses”, established 5 cases of peripheral neuropathy in patients with HL, lymphosarcoma and CLL: resolved GBS was reasonably diagnosed in 1 patient with HL in remission [
]. A combined prospective (in-patients) and retrospective (out-patients) study evaluated for peripheral nervous system and spinal cord involvement in 989 patients with lymphoma (563 NHL; 426 HL): GBS was diagnosed in only 1 patient with HL [
]. A smaller, prospective clinical and electrophysiological study of 30 patients with lymphoma established 1 patient each with acute/remitting and subacute/unremitting severe demyelinating polyneuropathies; the main histological abnormality was segmental demyelination/remyelination, but with negative immunofluorescence studies [
]. A series of 16 patients with peripheral neuropathy and lymphoma without monoclonal gammopathy included 3 patients with GBS (insufficient information to tabulate cases); other cases of neuropathy were not immune-mediated [
Conversely, lymphoma is also rarely detected in patients with GBS. In a retrospective study of 1100 patients with GBS reported in the literature since 1949, an associated/underlying malignancy was found in 33 patients; HL accounted for only 3 of these cases [
Case histories and series report on lymphoma-associated GBS (Table 2). Sufficient information existed on 35 patients (16 females; 19 males) for inclusion in this review; this included 3 children (<18 years) and 11 elderly (>65 years) patients. From these case reports it could not be established that there exists particular age or gender susceptibility to lymphoma-associated GBS, despite the observation that lymphoma occurs more common in older patients and in men (for NHL) (www.cancer.org). The type of lymphoma varied, and included 11 patients with HL, 7 patients with CLL, with various subtypes of NHL comprising the remainder. Thus, this collected case report information could not support published statements that HL (more than other types of lymphoma) is more commonly associated with immune-mediated polyneuropathies [
The time correlate between the diagnosis of GBS and discovery of lymphoma followed no consistent pattern: (1) In 11 patients, lymphoma was diagnosed during the initial hospitalization/evaluation for GBS (with delay up to 274 days) [
]. In cases reported herein, cranial nerve involvement was documented in 20 patients. Respiratory muscle involvement was reported in 11 patients; 8 of these 11 patients required ventilation assistance. CSF analysis was performed on 31 patients; findings were compatible with GBS, and by definition showed no evidence of lymphomatous spread or infectious disease. Electrodiagnostic studies were performed on 25 patients and were consistent with acquired, mostly acquired IDP; predominant axonal injury was recorded in 3 of these patients [
The treatment protocols for GBS varied. In earlier reports, patients were offered only supportive care or treatment with oral corticosteroids; treatment of more recent cases reflects modern “standard” care of GBS with intravenous corticosteroids, IVIG and/or plasmapheresis. Additional immune therapy was offered to patients who developed GBS after completing or while undergoing chemotherapy for lymphoma. Immunomodulatory treatment for GBS was not offered when: (a) onset of GBS coincided with relapsed [
]. In a case with recurrent Burkitt's lymphoma, no specific treatment for GBS was offered (no explanation given) so that the patient died of rapidly progressive bulbar weakness and respiratory failure [
The prognosis of GBS was mostly favorable, so that most patients improved or recovered. A total of 8 patients died in the acute phase of illness: (a) 5 patients died of cardio-/respiratory failure within 3 to 12 days after onset of GBS; (b) 1 patient died after approximately 17 days of sepsis/organ failure [
Four cases of lymphoma-associated somewhat “atypical” MFS were retrieved from the literature (Table 3). The temporal association between a diagnosis of MFS and lymphoma varied: (a) onset of MFS coincided with the 2nd relapse of lymphoma [
]; neurological response to systemic chemotherapy was interpreted as evidence of a “paraneoplastic” pathogenesis (herein defined as the production of a specific antibody against an antigen of malignant cells that cross-reacts with an antigen of normal neurological tissue).
Lymphoma-associated CIDP has a potential for misdiagnosis. A study assessed the clinical, electrophysiological and histopathological features of 32 patients with treatment-unrelated neuropathy associated with NHL [
]. Eleven patients fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic criteria of “definite” CIDP. However, neuropathology established 5 patients with neurolymphomatosis, 1 patient with sensory ganglionopathy, and 3 patients with primary axonal degeneration and secondary demyelination (clinically manifesting as multiple mononeuropathy). Moreover, some patients (including cases of neurolymphomatosis) at least initially responded to immune modulation therapy. Therefore, peripheral nerve pathological study is recommended to guide appropriate treatment, because neurolymphomatosis may mimic CIDP in patients with lymphoma.
Case histories and short series report on lymphoma-associated SIDP (evolution 4–8 weeks) in 8 patients and CIDP (evolution >8 weeks) in 15 patients (Table 4). Most patients were diagnosed with various types of NHL at various stages of disease, and also did not support (see GBS) literature statements that immune disorders of the nervous system more commonly affect patients with HL compared to NHL [
The temporal correlation between onset of CIDP/SIDP and the diagnosis/treatment of lymphoma varied: (a) onset of CIDP followed a diagnosis of recurrent/untreated lymphoma by periods as long as 132 months [
]. In earlier case reports, such studies had not yet become a routine part of patient evaluation.
Peripheral nerve specimens were obtained by biopsy or at autopsy from 11 patients: findings were consistent with an inflammatory demyelinating process with variable loss of myelinated fibers; however, in 2 patients the pathology was interpreted as a predominantly axonal variant of acquired IDP [
Treatment protocols for CIDP varied. Immunomodulatory treatment was offered when: (a) a new diagnosis or recurrence of CIDP/SIDP preceded the diagnosis of lymphoma; (b) treatment of CIDP preceded treatment of relapsed lymphoma; (c) treatment of CIDP followed completed treatment of lymphoma (i.e., in remission), or (d) onset of CIDP coincided with unrecognized lymphoma recurrence. Eight patients were not offered immunotherapy for neuropathy: a decision was made to aim chemotherapy at the malignancy when a diagnosis of new lymphoma [
Treatment programs of lymphoma varied, so that appropriate or preferred protocols were chosen according to the biology and staging of the malignancy. Lymphoma was not treated when the patient refused treatment [
Prognosis of CIDP/SIDP was favorable during the reported observation periods; benefit was observed both in patients treated with immunotherapy for neuropathy and in patients treated with chemotherapy directed at lymphoma. Patients died of ventilatory failure [
The immunopathogenesis of acquired IDP in patients with lymphoma has not been much studied. A report showed variable depression of indices of cell-mediated immunity, transient abnormality in B:T cell ratios, and abnormal serum immunoglobulin levels [
]. It was postulated that selective/unique depression of cell-mediated immunity in NHL allowed the development of a humoral and/or cellular immune reaction to peripheral nerve antigens; the rare association between GBS and lymphoma was attributed to the role of host genetic control on the development of antigen-reactive cells in the pathogenesis of disease. Support for this autoimmune hypothesis came from an electron microscopic study that showed activated (i.e., immune competent) lymphocytes penetrating Schwann cells [
]. In a report, the distinction between neoplastic and autoimmune/paraneoplastic processes was somewhat blurred in a patient with IDP associated with T-cell type CLL because tumor cells appeared the likely effectors of active demyelination [
] by infiltrating CLL B-cells may contribute to the mechanism of a demyelinating component of the inflammatory response.
In conclusion, the uncommon occurrence of acquired IDP in patients with lymphoma requires complete evaluation (including CSF analysis and nerve biopsy) to rule out lymphomatous polyneuropathy; results have management implications. The rare association between acquired IDP and lymphoma suggests that the yield is bound to be low of a “routine” search for neoplasm, and should be guided by other more specific clinical suspicions.
2.4 Multifocal motor neuropathy with conduction block (MMNCB)
There exist 2 case reports of lymphoma-associated, anti-ganglioside antibody-negative MMNCB; a case with anti-GM1-associated MMNCB was included in the discussion on autoantibody-associated polyneuropathies earlier [
]. A 67-year-old man was diagnosed with MMNCB and prurigo nodularis. MMNCB responded slightly to pulse IVIG and moderately to intravenous methylprednisolone. Diffuse large B-cell NHL was detected 19 months later. Treatment with CHOP and consolidation radiotherapy resulted in a “dramatic” improvement also of MMNCB, so that no further immune treatment was required. Based on sequence of events, the authors proposed that the undetected/preclinical lymphoma caused “paraneoplastic” skin and nerve disease via an undefined common autoimmune pathogenic mechanism [
A 47-year-old woman with recurrent DLBCL isolated to the CNS developed MMNCB. Neuraxis MRI showed parenchymal mass lesions and leptomeningeal enhancement. CSF analysis confirmed recurrent lymphoma. Despite imaging and CSF response to combined systemic and intra-thecal chemotherapy, the patient developed progressive limb weakness. Electrodiagnostic study fulfilled the criteria for MMNCB. Pulse and maintenance IVIG achieved neurological improvement over a 22-month follow-up period; cycles of chemotherapy resulted in lymphoma remission [
]. In this patient, more than a single cause of weakness existed, so that a precise electrophysiological study diagnosis was important to determine the appropriate management decisions.
In conclusion, based on the strong association between well-defined MMNCB and positive serum anti-GM1 antibodies at least some suspicion should arise of a possible lymphoproliferative disease in antibody-negative patients.
2.5 Diverse retrospective studies
In a report of 62 patients with various types of lymphoma, sural nerve biopsy was performed on 5 of 22 patients with clinical and/or electrophysiological evidence of generalized peripheral neuropathy [
]. Teased fiber preparation showed segmental demyelination/remyelination (2 patients), mixed segmental demyelination/axonal degeneration (2 patients), or predominant axonal degeneration (1 patient), without evidence of cellular infiltration. The authors speculated about an unidentified lymphoma-associated toxic/metabolic disorder affecting Schwann cells and/or nerve cells; to the reviewer an immune-mediated mechanism seems more likely.
In a series of 13 patients with NHL and neuropathy, an immune-mediated pathogenesis included 1 case of GBS (see Table 2) [
]; Waldenström's macroglobulinemia (usually not included under NHL) was associated with CIDP (1 patient) and “dysglobulinemic” polyneuropathy i.e., serum ± endoneurial deposits of monoclonal IgMκ with antimyelin activity (3 patients).
In a subset of 26 patients with lymphoma and neuropathy (unrelated to drugs or IgM-antimyelin antibodies), 13 patients were diagnosed with demyelinating polyneuropathy [
]. Onset of neuropathy was acute (<4 weeks) or subacute (4–8 weeks) in 10 patients, and progressive (>8 weeks) in 3 patients. Neuropathy preceded lymphoma diagnosis in 9 patients (mean = 13 months); lymphoma diagnosis preceded onset of neuropathy in 4 patients (mean = 48 months). HL was exclusively associated with demyelinating polyneuropathy, but not vice versa. Immunotherapy (IVIG/PPH) combined with chemotherapy offered the best neurological prognosis. Neurological and hematological improvement was observed in 69% and 46% of patients, respectively. With the application of appropriate investigations, the identification of the etiopathogenesis of neuropathy in patients with lymphoma was deemed important to limit diagnostic delay and error, define therapeutic options, and improve the neurological prognosis.
3. Autoimmunity and non-Hodgkin lymphoma
There exists a complex bi-directional inter-relationship between lymphoproliferative malignancies and autoimmunity. The development of lymphatic malignancy during the course of autoimmune and chronic inflammatory conditions is well established; conversely, biological and/or clinical evidence of autoimmunity can be detected at any stage of the lymphoma disease course [
]. Autoimmunity is observed in all lymphoma subtypes; however, it appears that biological and/or clinical autoimmunity is more common in patients with indolent B-cell NHL subtypes (e.g., marginal zone or follicular lymphoma, and CLL) compared to more aggressive types of lymphoma [
Hypotheses exist regarding the biological mechanisms of autoimmunity in lymphoma. More-or-less consistent immune system dysfunction has been established in patients with the relatively well-defined lymphoma subtypes, i.e., HL (Table 5) and CLL (Table 6), but not in patients with NHL (an umbrella term for a large number of distinct lymphoma subtypes divided according to a spectrum of growth pattern aggressiveness and involved lymphocyte types). The development of autoimmunity in NHL patients has been proposed to entail any of the following mechanisms.
], share characteristics of natural autoantibodies (NAA). NAA represent a proportion of circulating normal immunoglobulins, and production does not require antigenic stimulation of secretory CD5+ B-cells. NAA are directed against well-conserved public isotopes i.e., low affinity to bind a wide range of self and non-self antigens [
]. Molecular analysis of V-genes in lymphoma favors a malignant transformation of autoreactive B-cells provoked by continuous challenge by self-antigens (e.g., CDR3 sequence and adjacent regions of immunoglobulin genes from B-cell lymphoma display homology with autoantibody-associated lymphocyte clones) [
]. Also, the asymmetric pattern of usage of the VH4-21 gene (encodes for heavy chain variable region of immunoglobulins with autoantibody activity) by different B-cell tumor types seems to correlate with the frequency of associated autoimmune manifestations [
Secondly, non-lymphoma cells may be the source of autoantibody production in patients with lymphoma. The detection of serum autoantibodies directed against various, yet distinct, antigens implies that a single tumoral clone cannot secrete these immunoglobulins. Thus, autoantibody production results from a lymphoma-induced generalized, more-or-less disordered immune regulation. Such a mechanism appears likely in angioimmunoblastic T-cell lymphoma and Hodgkin disease (Reed–Sternberg cells are incapable of antibody production) [
]. The role of Treg cells in lymphoma-associated autoimmunity has not been established. Treg cells suppress autoreactive T-cells as well as the immune response to malignancy. Treg cells are over-represented in biopsy samples of B-cell NHL, and B-cells may help to recruit Treg cells into lymphoma tissue [
]. Thus, a Treg population that regulates the immune response to lymphoma cells is conceivably involved in the development of autoimmunity. Thirdly, an alteration of the Fas/Fas-ligand pathway can lead to autoimmunity. Fas receptor (CD95) is a cell-surface receptor involved in programmed cell-death (i.e., apoptosis) signaling. Acquired somatic mutations of Fas receptor can occur during normal germinal center proliferation, and are prevalent in NHL (e.g., MALT) with autoimmune manifestations [
]. Moreover, clues to lymphomagenesis were obtained from evidence that Fas-mediated apoptosis can be inhibited by exposure to surface-binding IgM antibody that engages anti-Fas antigen for which the malignant clone has affinity e.g., in Burkitt's lymphoma [
] with frequent and varied autoimmune manifestations. The expression of a limited repertoire of immunoglobulin VH- and VL-genes by HCV-associated lymphoma B-cells due to viral E2 antigenic stimulation can lead to the development of autoimmunity [
]. Moreover, viral antigen can promote production of certain cytokines that are involved in B-cell terminal differentiation via autocrine or paracrine mechanisms e.g., IL-6 can facilitate differentiation of lymphoma cells into antibody-producing cells and, thereby, autoimmunity [
CLL is characterized by the progressive accumulation of monoclonal lymphocytes with a distinctive immunophenotype (CD5+, CD19+, CD20dim, CD23+, SmIgdim) in peripheral blood, bone marrow, and lymphoid tissues [