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Keywords:

  • autoimmunity;
  • extranodal lymphoid infiltrates;
  • hypogammaglobulinaemia;
  • lymphoproliferative disorders;
  • M-component

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Abstract. Jønsson V, Wiik A, Hou-Jensen K, Christiansen M, Ryder LP, Madsen HO, Geisler C, Hansen MM, Thomsen K, Vorstrup S, Svejgaard A (Rigshospital, University of Copenhagen and State Serum Institute, Copenhagen, Denmark). Autoimmunity and extranodal lymphocytic infiltrates in lymphoproliferative disorders. J Intern Med 1999; 245: 277–86.

Objective. To examine the relationship between autoimmunity and extranodal lymphocytic infiltrates in different lymphoproliferative disorders with immunoglobulin alterations.

Subjects and design. A clinical review combined with a retrospective cohort study of 380 patients, 28 with monoclonal gammopathy of undetermined significance, three with common variable immunodeficiency, 147 with chronic lymphocytic leukaemia, 57 with Waldenström's macroglobulinaemia and 145 with non-Hodgkin's malignant lymphoma.

Setting. A university hospital and The State Serum Institute in Copenhagen.

Intervention. Clinical examination of each patient with special attention to chronic inflammatory and autoimmune manifestations. Biopsies were taken from non-infectious infiltrates, some of which were additionally tested with PCR analysis for gene rearrangements. Serological screening with a test battery for various autoantibodies was used in combination with techniques for the detection of M-components and monoclonal B-cell proliferation.

Main outcome measures. Clinical and/or serological autoimmune manifestations, M-component and other immunoglobulin alterations, and inflammatory tissue changes were studied in patients with chronic inflammatory, polyclonal or oligoclonal pseudolymphomas and in monoclonal, malignant extranodal lymphomas.

Results. In 380 consecutive patients, 49 (12.9%) had extranodal manifestations, of whom 47 also had autoimmune manifestations. Nearly half of the 47 patients had more than one autoimmune manifestation. There was a strong correlation between clinical signs and corresponding autoantibodies such as anti-SSA and -SSB antibodies in Sjögren's syndrome (10 cases), antithyroid peroxidase antibodies in thyroiditis and Graves' disease (10 cases), and parietal cell antibodies in gastric ulcers with maltoma (12 cases). Clinical and serological signs of autoimmunity correlated strongly with female sex (34, 72% women; and 13, 28% men) and with immunoglobulin alterations.

Conclusions. To our knowledge this is the first systematic review of B-lymphoproliferative and autoimmune disorders indicating that pseudolymphoma and malignant lymphomas, including maltomas, may develop in the context of a permanent autoantigenic drive.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Autoimmunity, defined as an abnormal immunological reactivity against own tissue components, is commonly seen in lymphoproliferative disorders, e.g. Coombs' positive autoimmune haemolytic anaemia (AIHA) in chronic lymphocytic leukaemia (CLL) [ 1–3], antimyelin associated glycoprotein (MAG) antibody-related neuropathy in monoclonal gammopathy of undetermined significance (MGUS) [ 4–6], and Sjögren's syndrome in malignant B-cell lymphomas [ 7–9]. More rarely, patients with lymphoproliferative disorders manifest symptoms such as idiopathic autoimmune thrombocytopenia (ITP), thyroiditis, myasthenia gravis, Kawasaki disease, Guillain–Barré syndrome, systemic lupus erythematosus, polyarthritis, polymyositis, acquired von Willebrand's disease and acquired haemophilia [ 10–12].

In lymphoproliferative disorders, the difference between lymphoma and autoimmunity as above is particularly difficult to interpret when the autoimmune reaction develops as tissue infiltrates without evident humoral autoimmune abnormalities. The interacting inflammatory cells, which may be recruited by reactive autoantibody (autoAb) and uncovered autoantigen (autoAg) [ 13, 14] mostly comprise both normal polyclonal T- and B-lymphocyte subsets, granulocytes, monocytes-macrophages and often a malignant lymphocytic clone as well [ 5]. If a tissue antigenic drive proceeds, e.g. by means of long-standing infections with Epstein–Barr virus (EBV), human T-lymphocytotrophic virus (HTLV) or Helicobacter pylori, an excess production of growth factors and cytokines results in increased proto-oncogene expression. When important proto-oncogenes such as c-myc, p53, or the Bcl-2, Bax-, Bad superfamily exert their action [ 15–18], oligoclonal lymphocytes present in the autoimmune tissue infiltrate may acquire apoptotic, cell cycle-related abnormalities in such a way that the inflammatory infiltrate in time turns into a low-grade malignant lymphoma [ 19–21]. The initially polyclonal cell infiltrates, resembling what were earlier called pseudolymphomas, can be difficult to distinguish from a monoclonal, low-grade malignant lymphoma, especially in case of maltomas and paltomas [ 22–25]. Therefore, molecular markers become useful tools in distinguishing between monoclonal and polyclonal proliferating lymphocytes.

The aim of the present paper is to report on inflammatory tissue reactions and autoimmunity in a range of lymphoproliferative disorders and to discuss the pathophysiological relationship between polyclonal, inflammatory pseudolymphomas and the development of monoclonal malignant lymphoma in the light of an ongoing infection or an autoimmune drive.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Study population

Consecutive series of patients with monoclonal gammopathy of undetermined significance (MGUS), common variable immunodeficiency (CVI), chronic lymphocytic leukaemia (CLL), Waldenström's macroglobulinaemia (WM) and low- or intermediate-grade non-Hodgkin's malignant lymphoma (NHL) seen in the Department of Haematology, Rigshospital, during the period April–September 1995 were carefully identified from the patient data base register. These patients were surveyed for study until April 1997.

Some of the patients with CLL, WM and NHL were treated with prednisolone, chlorambucil or fludarabine for shorter or longer periods, but never during the sampling period or the preceding month. No patients with high-grade malignant lymphomas receiving intensive chemotherapy were included. No values were obtained during acute infection. Blood specimens for analysis of autoantibodies and immunoglobulins were taken simultaneously.

MGUS. Twenty-eight patients (20 women and eight men) (IgM kappa = 6, IgM lambda = 3, IgG kappa = 15, IgG lambda = 3, and IgA lambda = 1), of mean age 61 years and with a duration of disease from 3 to 8 years, were selected. These MGUS patients constitute a highly selected cohort, admitted in order to exclude a malignant haematological disorder or owing to complicating autoimmune manifestations. The diagnosis of MGUS was based on traditional diagnostic criteria [ 26].

CVI. Three women, referred originally for suspected malignant lymphoma, satisfied the diagnostic criteria for common variable immunodeficiency (CVI) syndrome [ 27, 28]. Mean age was 57 years, with a duration of disease from 0 to 4 years. They were all characterized by marked polyclonal pseudolymphoid proliferation, pronounced quantitative alterations in the immunoglobulins with hypogammaglobulinaemia and repeated severe respiratory bacterial infections, malabsorption and concomitant autoimmune manifestations.

CLL. One hundred and forty-seven patients (52 women and 95 men) with CD5 and SmIg-positive CLL according to the traditional diagnostic criteria [ 1, 29, 30] were selected. Mean age was 68 years, with a duration of disease from 1 to 17 years.

WM. Fifty-seven patients (26 women and 31 men) with monoclonal expansion of CD5, CD20, CD22 or CD38, SmIg-positive plasmocytoid cells satisfied the diagnostic criteria for Waldenström's macroglobulinaemia [ 26]. Mean age was 74 years, with a duration of disease from 1 to 19 years.

NHL. One hundred and forty-five patients (74 women and 71 men) were selected, comprising 135 low-grade malignant lymphomas (follicular small cleaved cell, 51; follicular mixed small cleaved cell and large cell, 47; follicular large cell, 12; monocytoid B-cell, 4; other follicular cell types, 18; Lennert's lympho-epitheloid T-cell lymphoma, 1; Sézary's syndrome, 1; angioimmunoblastic lymphadenopathy, 1) and 10 intermediate-grade malignant lymphomas (diffuse small cell, 6; diffuse mixed small and large cell, 4). Mean age was 69 years, with a duration of disease from less than 1 year to 12 years. The diagnosis was based on the Working Formulation of malignant lymphomas until 1994 when the REAL classification appeared [ 30]. It was ensured that the diagnoses of all included patients were uniform with regard to the main groups of B- and T-cell lymphomas, low- and intermediate-grade, nodal and extranodal. The diagnoses were based on traditional histological and immunophenotypic criteria with a test panel as described previously [ 30, 31].

Clinical examination

At each patient examination, special attention was paid to clinical symptoms and laboratory findings that could be ascribed to chronic inflammation and/or autoimmune manifestations.

Biopsies were performed when an inflammatory tissue infiltrate was noted or suspected. These were mainly from the skin and the gastrointestinal mucous membranes, but a considerable number of bronchoalveolar lavage fluid investigations were also performed, as well as bronchoscopic biopsies in order to ensure a microbiological diagnosis and possibly support a histological categorization. All patients with signs of suspected peripheral polyneuropathy underwent neurological and neurophysiological examination and, if possible, a sural nerve biopsy as well.

Analysis of gene rearrangements was performed in those cases where a histological distinction between polyclonal inflammation and a mono- clonal malignancy was difficult. PCR was performed on genomic DNA using consensus primers for TCRγV1–8-J1/J2 [ 32] and IgH-FR3-J [ 33] gene rearrangements. The direct sequence analysis was performed on the PCR products by solid-phase sequencing [ 34] and the dideoxynucleotide termination method [ 35], using sequencing primers specific for Vγ3/5, Vγ8 and IgH-J.

However, none of the patients with goitre, thyroiditis or myxoedema underwent a thyroid biopsy. The diagnoses of thyroiditis, myxoedema, and Graves' disease were based on traditional clinical criteria, including a thyroid scintigram, measurements of thyroid-stimulating hormone (TSH), T-3 and T-4, and thyroid peroxidase autoAb. Biopsy of the salivary glands was not attempted in those cases of Sjögren's syndrome where malignancy of the glands was not suspected or where the CT scan showed no solitary infiltrate. One patient ( Table 1, no. 3) underwent diagnostic splenectomy. Skin infiltrates of CLL patients after mosquito bites were not included.

Table 1.   Extranodal inflammation and autoimmunity Thumbnail image of

Autoimmunity

All patients with extranodal lymphoid proliferation underwent a thorough serological screening with a test battery comprising Coombs' direct and indirect tests, platelet autoAb, IgM and IgA rheumatoid factors (RF), antinuclear autoAb (ANA) and antineutrophil cytoplasmic antibodies (ANCA). Specific autoAb against thyroperoxidase, SSA (Ro) and SSB (La), cardiolipin, mitochondria, parietal cells and smooth muscle cells were also tested for. The neurological autoAbs comprised ganglioside monosialic acid (GM1), asialo-GM1 and myelin-associated glycoprotein (MAG) antibodies, sulphoglucuronyl paragloboside (SGPT) and intermediate filament GD1a,b antibodies, sulphatide antibodies and neuronal nuclear Hu antibodies [ 36].

Immunoglobulins

Sera from all patients were screened for M-components and quantitative abnormalities by appropriate agarose electrophoresis, capillary blotting, immunofixation, radial immunodiffusion and ultracentrifugation using standard procedures as described previously [ 37–39]. Normal ranges were as follows: IgM = 0.3–3.7, IgG = 36.0–89.0 and IgA = 3.8–21.0 μmol L−1.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Extranodal lymphoid infiltrates

Table 1 shows that 49 (12.9%) out of the 380 patients with lymphoproliferative disorders had one or more extranodal lymphoid infiltrates of the following types:

In the MGUS group of 28 patients, eight (28.6%; five men and three women, mean age 67 years) ( Table 1) presented with such inflammatory manifestations.

In the three CVI patients (all women, mean age 57 years), two had pronounced pseudolymphomas of the duodenum, one also with affection of the gastric mucosa, enlarged lymph nodes and spleen, the diagnoses being proved by histological examination of repeated biopsies and a removed spleen. Another patient ( Table 1) had polyclonal inflammatory infiltration of the liver in accordance with primary biliary cirrhosis.

In the CLL group of 117 patients, nine (6.1%; eight women and one man, mean age 71 years) ( Table 1) had extranodal inflammatory manifestations. There were two cases of gastric maltomas where the patients went into clinical remission during treatment with amoxcillin, metronidazole and omeprazole.

In the WM group of 57 patients, 16 (28.1%; eight women and eight men, mean age 75 years) ( Table 1) had one or more (up to three) different extranodal lymphocytic infiltrates. Six cases of peptic ulcer in gastric maltoma remitted when treated with antibiotics as described above. There were no cases of plain monoclonal extranodal infiltrates.

In the NHL group of 145 patients, 13 (8.4%; 12 women and one man, mean age 66 years) ( Table 1) had extranodal, extramedullary manifestations.

The malignant extranodal infiltrates of the NHL group consisted of lachrymal, salivary and urinary bladder maltomas plus two cases of skin lymphomas. Thus, within the NHL cohort having extranodal lymphocytic infiltrates, B-proliferative disorders were predominant and only two T-lymphoproliferative disorders could be found: one case of Lennert's lympho-epitheloid lymphoma and one case of angioimmunoblastic lymphadenopathy.

Correlation of extranodal lymphoid proliferation with autoimmunity

From Table 1 it can be seen that 47 (96%) of the 49 patients with extranodal lymphoid proliferation had autoimmune manifestations: in CLL in nine (6.1%) out of 147 patients; in WM in 16 (28.1%) out of 57 patients; and amongst low- and intermediate-grade NHL in 11 (7.6%) out of 145 patients. In the MGUS cohort, which was a highly selected one, eight (28.6%) out of 28 patients exhibited such combined manifestations. All three CVI patients had autoimmune manifestations in accordance with the diagnostic criteria. Only two patients, both with skin pseudolymphomas, had no concomitant autoimmunity.

As also seen from Table 1, nearly half of the patients with autoimmunity exhibited more than one such manifestation. Women dominated the material since 34/47 (72%) were female patients compared with 175/380 (46%), the most conspicuous female predominance being seen in CLL (8/9) and in NHL (10/11). The following autoimmune entities were defined from the material:

Correlation of extranodal lymphoid proliferation with infections

As expected, numerous bacterial infections, mainly in the respiratory system and in the bowel, were noted during the time of study amongst the patients with CVI, CLL, WM and NHL (data not shown). Also, many cases of viral infections, mainly herpes simplex and herpes zoster were noted, neither having demonstrable correlation to any particular form of autoimmunity, nor to extranodal lymphoid infiltration (data not shown). However, two CLL patients, one patient with a monocytoid B-cell lymphoma and all six WM patients with gastric ulcers had ongoing Helicobacter pylori infection proved by serological, culturing and staining techniques. They obtained partial clinical remission of the gastric maltoma during treatment with amoxycillin, metronidazole, and omeprazole. Another CLL patient had had chronic hepatitis C for years with positive C22 and C33, but negative C100 serology (Riba Ortho Comp.). None of the patients had HIV or HTVL-8 infection.

Correlation of extranodal lymphoid proliferation with immunoglobulin abnormalities

Nine (18.4%) of the 49 patients had quantitatively normal IgM, D, G and A levels with a normal electrophoretic pattern. Amongst the remaining 40 (81.6%) patients, a variety of hyper- and hypogammaglobulinaemic states were found, including 32 cases with M-components (20 IgM, eight IgG, two IgA), and two cases with two M-components (IgG together with IgA, and IgM together with IgM) showing a kappa light-chain dominance and associated polyclonal hypogammaglobulinaemia. Thus, IgM M-components were dominating whilst no relationship between the size of the M-component and the pattern of autoimmunity could be demonstrated. Two NHL patients had a polyclonal IgG1 increase whilst three had generalized hypogammaglobulinaemia associated with CVI. Within the material, only one case of AL amyloidosis was seen in a patient with MGUS and axonal polyneuropathy. Only two patients presented with extranodal tissue infiltrates without demonstrable autoantibodies and with normal immunoglobulins (two patients with follicular B-cell skin lymphoma). No alterations in IgD were noted.

Case history I. This case involved a 56-year-old woman with CVI ( Table 1, CVI, no. 3) who had a 20-year period of recurrent infection, especially pneumonia, and with severe IgD, IgG and IgA hypogammaglobulinaemia and increased polyclonal IgM (IgM = 38 μmol L−1). She had been treated for infections with polyclonal high-dose IgG for many years. Since 1993 she suffered from progressive lymphoid hyperplasia with growth of peripheral lymph nodes and enlargement of the spleen. A diagnostic splenectomy (900 g) showed a polyclonal T- and B-lymphoid proliferation. Biopsies from jejunum and ileum also showed polyclonal T- and B-lymphocytic hypertrophy in the lamina propria with non-villous small intestine and bile malabsorption. Serologically, she had IgM cardiolipin autoAb, IgG thyroperoxidase, parietal cell autoAb and ANCA. Gene rearrangement studies showed bi- and oligoclonal rearrangement of TCRγ both in blood lymphocytes ( Fig. 1, B2) and in lymphocytes from lymph nodes ( Fig. 1, C1 and C2).

image

Figure 1.  T-cell receptor (TCRγ) and immunoglobulin heavy chain (IgH) gene rearrangement analysis by direct DNA sequence analysis. (A) Normal blood lymphocytes. (B) Case history I, blood lymphocytes. (C) Case history I, lymphocytes from lymph node. (D) Case history II, lymphocytes from gastric mucosa. Box 1: TCRγV3/V5 rearrangements. Box 2: TCRγV8 rearrangements. Box 3: IgH-VDJ rearrangements. Each box (comprising four sequencing lanes of T, C, G and A bases) shows an independent sequence analysis. The dotted horizontal lines indicate the sites of TCRγ gene rearrangements, whilst the IgH gene rearrangements only include sequences following the rearrangement site. Normal, polyclonal state– bands of equal intensities in the same horizontal position in all four lanes following the rearrangement site as seen in A. Mono- or biclonality–‘ladder of intense bands’, i.e. a unique sequence of bands following the site of gene rearrangements as seen, for example, in B2. Oligoclonality– a mixture of unique sequences as seen for example in C1, C2 and D1.

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Case history II. This case involved a 79-year-old woman ( Table 1, included in NHL) with rheumatoid arthritis since 1960. The antithyroperoxidase Ab was positive, as were the IgM and IgA rheumatoid factors. In 1987 she developed thyroiditis with goitre. In the autumn of 1995, however, progression to thyrotoxicosis was noted. A thyroid scintigram showed marked goitre with little iodine absorption. Since October 1995, a monocytoid B-cell lymphoma ( Fig. 2) was treated with chlorambucil and prednisolone. At this time an increased polyclonal IgG kappa (99 μmol L−1) was found.

image

Figure 2.  Case history II: lymph node biopsy from the neck showing a marginal zone monocytoid B-cell lymphoma. The lymphoma cells are CD20-positive without Bcl-2 rearrangement centrocyte-like B-lymphocytes with abundant clear cytoplasma. Also, there is a massive infiltration of antibody-producing plasma cells (H&E, ×300).

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She had had a gastric ulcer since October 1995 with parietal cell autoAbs, and gastroscopy showed lymphoid hypertrophy of the gastric mucosa. Analysis performed on a gastric mucosa biopsy ( Fig. 1, D1) showed TCRγ oligoclonality and not a normal, polyclonal inflammatory pattern. Unfortunately, the gastric biopsy from October 1995 was too small for an IgH analysis. Her ulcer disappeared on treatment with amoxycillin, metronidazole, and omeprazole.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Several models have been suggested to explain the increased rate of autoimmunity in lymphoproliferative disorders. Self-reactive CD5 positive B-lymphocytes [ 5] and activated B-lymphocytes carrying surface immunoglobulins in the form of polyreactive autoantibodies may play a role in the presentation of antigens to T-lymphocytes in inflammatory sites, so that they amplify the local autoimmune reaction to neo-epitopes and even to neo-antigens which participate in higher-order autologous structures [ 40–42]. Furthermore, in accordance with a modern network theory, the natural autoantibodies, which are present in all healthy persons, are normally bound or masked by anti-idiotypic antibodies in such a way that they are serologically undetectable in whole serum. However, in the case of disturbances in the immunoglobulins, such an idiotypic masking may not take place owing to an insufficient anti-idiotypic repertoire [ 10, 11]. Under these circumstances, autoantibodies can be found in free forms, possessing the ability to react with autoantigens, e.g. in the case of IgA deficiency with its propensity to develop autoimmune manifestations [ 11]. Another possibility is that the M-component may contain an autoantibody itself, and being present in high concentrations these antibodies can give rise to clinical or paraclinical autoimmune symptoms [ 11, 13, 36].

The present study demonstrates a very close association between autoimmunity and M-component or other forms of dysgammaglobulinaemia ( Table 1). An interaction between autoantibody and autoantigen can sometimes give rise to an inflammatory reaction, which in B-lymphoproliferative disorders might recruit the expanding B-lymphocytic clone, intermixed with other types of polyclonal inflammatory cells under the formation of a pseudolymphoma.

Most likely, such different mechanisms are acting in concert during the development of autoimmunity and subsequent formation of pseudolymphoma in patients with lymphoproliferative disorders (for review, see Isaacson [ 31]). The present material shows that a broad spectrum of different autoimmune manifestations are seen, often with more than one manifestation in each patient. Autoimmunity accompanied both the low-grade, potentially premalignant conditions like MGUS and CVI and the manifest malignant conditions such as CLL, WM and NHL. Clearly, the rates of combined autoimmune manifestations are higher than in age-matched normal, elderly persons, although no precise data are available for a calculation of this difference. Most likely, the present material underestimates the rates of autoimmunity since some weak forms have probably been overlooked during the survey or suppressed by the use of steroids, which would explain the seronegative cases of thyroiditis.

It has recently been described how a persistent antigenic drive in connection with disturbances of the lymphoid growth factors can transform an inflammatory infiltrate into a low-grade and subsequently a high-grade malignant lymphoma [ 43–46]. Seemingly, the antigenic drive can be of both an infectious or an autoimmune origin. The relationship between Helicobacter pylori infection and the development of gastric maltoma is well known, as is the relationship between Epstein–Barr virus or HIV virus infection and the development of malignant lymphomas. There is also a well–known association between thyroid lymphoma and Hashimoto's thyroiditis [ 47, 48], between lymphoma and primary Sjögren's syndrome [ 8, 9, 49], and between ulcerative colitis and diffuse colonic mantle cell lymphoma [ 50]. Recently, an association between Helicobacter pylori infection and the induction of autoantibodies to gastric mucosa antigens has been shown [ 51] in accordance with the high frequency of parietal cell autoantibodies in patients with gastric ulcers seen in the present material ( Table 1).

In the assumed pathophysiological models, the borders between inflammation and low-grade malignancy are elusive, depending upon the stage of transformation of activated lymphocytes from an antigenic drive ( Fig. 1). In the beginning, the activated B-lymphocytes show a polyclonal diversity, but later on, the infiltrates become dominated by oligoclonal and sometimes finally monoclonal expansion of that precise clone with the highest mutation rate and the lowest rate of apoptosis, thus evading a number of normally tightly controlled counter-regulatory mechanisms [ 11, 15–19]. Thus, in patients with established B-lymphoproliferative disorders, both normal lymphocytes and the malignant B-cell clone can be recruited for inflammation and antigenic drive. In the beginning of the development of a gastrointestinal pseudolymphoma/maltoma, a polyclonal diversity of lymphocytes is available for antigenic drive, as can be seen in low-grade potentially malignant conditions (case history I) and in patients with manifest malignant lymphoproliferative disease (case history II). In both cases the maltoma must be interpreted as a paramalignant, oligoclonal ‘inflammatory’ phenomenon which (i) under the influence of a further antigenic drive in time can transform into a ‘new, monoclonal malignancy’; or (ii) can be eliminated if the antigenic drive is deleted, e.g. if the infection is cured. In contrast, monoclonal infiltrates of only malignant B-cells must be designated a primary gastric lymphoma, which, in the case of CLL, MW and low-grade NHL, can transform from low to intermediate and high malignant states if the antigenic drive persists. The well-known female predominance in autoimmune disorders such as Sjögren's disease, thyroiditis, Graves' disease a.o. is clearly seen in the present material ( Table 1), pointing towards a hormonal influence upon the combined autoimmune disease picture.

From a clinical point of view, this underlines the need to detect and suppress the antigenic drive both from autoantigens and from infectious agents so as to prevent malignant transformation of a lymphoid infiltrate which initially might be interpreted as harmless chronic inflammation [ 52].

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  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References
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Received 19 December 1997; accepted 29 July 1998.