Autoimmunity In Bcell Malignancies

Autoimmune phenomena are prevalent in certain B-lymphocyte malignancies [27], Previous work from our group [17] has shown presence of one or more autoimmune manifestations and/or autoantibodies in 42 out of 116 patients with chronic lymphocytic leukemia (CLL). Predominating findings in these patients were Coombs-positive autoimmune haemolytic anemia (AIHA), platelet antibody-positive idiopathic thrombocytopenic purpura (ITP), cold agglutinin syndrome, endocrinopathy involving mainly the thyroid but also the pancreatic islets in the form of autoimmune thyroiditis and diabetes mellitus. A later study which included 57 patients with Waldenstrom's macroglobulinaemia (WM) and 145 patients with non-Hodgkin's lymphomas (NHL) 16 and 13, respectively, had signs of concomitant autoimmune manifestations [18]. An unexpectedly high number (10) of these had Sjogren's syndrome, 8 had autoimmune thyroid disease, 6 peptic ulcers with parietal cell antibodies, 2 rheumatoid arthritis and 1 systemic lupus erythematosus. There was a clear-cut female predominance among the patients. Three WM patients had ITP and one had AIHA. All of the patients with autoimmune manifestations had lymphoid infiltrates at extranodal sites as evidenced through biopsies taken from skin, mucous membranes, stomach, bronchi etc. It should be mentioned that the autoantibodies found in these patients were all of the IgG class, and thus did not correlate to the Ig class of the M-components or the surface Ig. In this regard, they were similar to those found in autoimmune diseases without B-cell malignancies. In addition, the autoantibodies completely agreed with the clinical condition. These autoantibodies are thus unlikely to represent polyreactive natural autoantibodies. In 4 WM patients with axonal polyneuropathy no autoantibodies to nerve tissue components could be demonstrated. Maltomas found in most of the patients with parietal cell antibodies correlated strongly with the presence of a H. pylori infection, and eradication of this infection by antibiotics led to remission of the local lymphoma, indicating that the bacterium was an essential lymphoma-forming stimulus to the local lymphoid system (see below).

It should be mentioned that malignant transformation of B cells is not mandatory for development of autoimmunity. Autoimmune diseases and phenomena are common also in patients with monoclonal gammopathy of undetermined significance [17]. Certain autoimmune diseases are characterized by marked lymphocyte proliferation, and in such conditions B-cell malignancies develop much more often than in the healthy population [28, 29], Autoimmune diseases which have been found associated with B-cell malignancies are primarily autoimmune thyreoiditis, Sjo-

gren's syndrome, systemic lupus erythematosus, poly-and dermatomyositis, the Guillain-Barre syndrome, myasthenia gravis, sensorimotor neuropathies, autoimmune hemolytic anaemia and thrombocytopenia, acquired haemophilia and acquired Von Willebrand's syndrome [17].

4. NATURAL AUTOANTIBODIES, FRIENDS OR FOES?

How should we regard the significance of natural autoantibodies in malignant B-cell proliferative diseases? The fact that we see several multiorgan autoimmune manifestations in malignant B-cell disorders would indicate an untoward effect of the immune system on tissues. Such effects may relate to a number of immunodeficiencies associated with the malignant B-lymphoproliferative disorder as discussed above. On the other hand natural autoantibodies have been ascribed a role as scavenger molecules for getting rid of injured cells and altered self-antigens, and thus they may normally fulfill a role for the good. If the concentration of such autoantibodies, however, are very high they may cause tissue damage (see preceeding chapter).

4.1. Lessons from Gastric Pseudolymphomas and Maltomas

Although parietal cell antibodies have not been mentioned among the many natural autoantibodies recognized to be strongly represented in B-lymphoproliferative diseases [17] we have certainly found an overrepresentation of parietal cell antibodies in several of these disease states [30]. Among 128 consecutive patients with B-cell malignancies, 19 patients had an ongoing infection with //. pylori as evidenced by the presence of specific IgG antibodies to the microorganism by Western blotting technique and ELISA technique (Table 1). Attempts at cultur-ing the H. pylori bacteria from the gastric mucosa were considered inappropriate, since all patients had been treated with antibiotics for different bacterial infections prior to the investigation. The patients all underwent gastroscopy which disclosed severe gastritis and often ulceration of the mucosa. In 8 patients we took biopsies large enough for additional PCR analyses to look for clonality among TCR and IgH. In 4 of the patients, the malignant B-cell clone found in the blood also was present in the inflammatory infiltrate of the gastric mucosa, while in the remaining patients the gastric biopsies only showed weak B-cell clonality, possibly indicating an effect of long-standing helicobacter infection leading to pseudolymphoma or a newly transformed maltoma. None of the patients had pure monoclonal infiltrates corresponding to the B-lymphoproliferative disease. One patient later developed cancer of the stomach. Our findings are compatible with the idea that the lymphoma may start as a polyclonal response to a bacterial infection, may turn into an oligoclonal lymphoid infiltrate which may eventually transform into a maltoma [15, 16].

There may be two different antigenic drives leading to this result, one coming from the H. pylori bacteria themselves and one from parietal cell autoantigens released from injured gastric tissue (Fig. 2). Parietal cell autoantibodies reacting with exposed parietal cell autoantigens in the environment of the inflammatory infiltrate are likely to promote the inflammation. An excess production of growth-factors and cytokines by cells in the inflammatory infiltrate consisting of T and B cells, neutrophils, macrophages, and possibly dendritic cells may influence subclones of the lymphocytes differently. Subclones can acquire different growth rates, and overexpanded clones will gradually dominate the infiltrate, thus transforming it from a polyclonal to an oligoclonal stage. Cell cycle abnormalities induced by the inflammation can then lead to monoclonal transformation and a low grade malignant lymphoma [16]. The fact that autoantibody may be a stimulating mechanism for tissue injury on the other hand could lead to eradication of malignant lymphocytes by a process of apoptosis or necrosis, and in that situation the antibody would have a beneficial role. The fact that eradication of H. pylori in patients with maltomas often leads to regression of the tumor clearly indicates that infective agents should be eliminated if possible. When natural autoantibodies or autoantibodies produced through autoantigen presentation by de novo activated B or dentritic cells occur at low concentrations they are normally framed by anti-Id antibodies [6, 7], However, when B-cell malignancy occurs both anti-infectious responses, T-cell responses and adequate B-cell responses may be deficient. Hence, a whole host of B-cell repertoires can be malfunctioning and among these anti-Id to autoantibodies. Autoreactive T cells and autoantibodies can

Lymph Node

Blood Vessel w w

Lymph Node

Gastric Mucosa

Figure 2. Gastritis caused by H. pylori = A. As part of the inflammatory infiltrate are shown neutrophils = N, monocytes = M and T-helper against H. pylori = T. Recirculating T cells reach lymphoid tissue in lamina propria and in the regional nodes, where B cells produce antibody against H. pylori = X. In case of long-standing antigenic stimulation, A will not be totally eliminated by X and T cells, and B-cell proliferation will be upregulated. The B cell may then undergo transformation, changing the polyclonal inflammatory infiltrate into an oligoclonal one, shown by means of two clones: B and B-transformed = O. Furthermore, we have shown that the malignant B cell (®) in patients with CLL, NHL and Waldenstrom's macroglobulinaemia can also infiltrate the inflammatory site. We interpret our findings in such a way that exposed parietal cell autoantigens = A together with H. pylori = A exert the antigenic drive. Parietal cell autoantibodies are shown as X and mutations as v*. Now, the diversity of the pseudolymphoma/maltoma consists of the following clones: (1) B cells against H. pylori = B; (2) transformed B cells = O; (3) B-memory against parietal cell autoantigens = Bp; and (4) the malignant clone itself = Presumably, the four different clones have different growth rates. In the course of time and if the antigenic drives persists, the clone with the highest growth rate will be dominating.

thus be left free and reactive and autoimmune mechanisms lead to tissue damage and/or clonal expansion and transformation. A given autoantibody may thus have the potential to function both as a friend and as a foe.

A clear evidence for beneficial clinical effects of mixtures of autoantibodies comes from the use of polyclonal IgG for intravenous high-dose treatment of autoimmune diseases [5, 7], Among the many mechanisms considered to be important for the efficacy of intravenous immunoglobulin preparations is presence of anti-Id antibodies, anti-TCR antibodies, anticytokine antibodies, Fcy-receptor blocade, anti-MHC class I antibodies, antiadhesion molecule antibodies and a number of other antibodies directed to surface components on immunocompetent cells. Anti-Id activity in such preparations are mainly directed to idiotypes found on autoantibodies [7], The recent discovery of anti-Fas activity in immunoglobulin preparations [20] may explain the long- lasting effect of highdose IgG treatment in many autoimmune conditions, since this activity can induce apoptosis in activated immunocytes and monocytes and thus the selection of the B-cell repertoire. Since clearance of apoptotic cell elements is mandatory to avoid proinflammatory stimulation of the immune system [2] polyreactive, nonphlogistic autoantibodies may have a role in clearing autoantigen particles, and thus prevent production of high affinity autoantibodies.

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