For many years autoimmune diseases have been considered to be a consequence of faulty self/nonself-discrimination due to incomplete deletion of certain clones of autoreactive immune cells, or some kind of breakage of self-tolerance due to abnormal activation of such clones, e.g., through stimulation by extrinsic factors. Today, there is strong evidence that healthy individuals have both T and B cells and circulating antibodies that can recognize and react with self-components. Some hypotheses for the induction of autoimmune diseases maintain that excessive presentation of self-compounds during tissue damage or altered self-antigens produced due to aberrant apopto-sis pathway regulation may explain the breakdown of self-tolerance seen in autoimmune disease [1]. However, it is equally likely that insufficient removal of self-antigen components, or deficient regulation of autoimmune networks, may lead to a similar result [2].

The so-called natural autoantibodies (see proceeding chapter), which are probably not produced as a consequence of autoantigen stimulation, have multiple properties that are important for maintaining a normal immune homeostasis [3-5], These natural autoantibodies can belong to all three major Ig classes and are encoded by germline genes and show little or no signs of mutations. They are commonly multireac-tive, having the capacity to recognize both microbial agents and many self-constituents. They constitute an important natural host defense against infections and may have functions relating to scavenger mechanisms of self-components derived from senescent cells or altered self-antigens. Due to their ability to react through their V-regions with idiotypes on pathogeni-cally important autoantibodies, B and T cells and with other cell surface molecules, they can induce a selection of immune repertoires and limit autoaggressive mechanisms [6, 7], Any disturbance in this shelter against autoreactivity may be an important contributor to autoimmunity and the emergence of autoimmune disease. There are several reasons to believe that autoimmunity arising in patients with premalignant and malignant B-cell proliferative conditions can be regarded either as an effect of excessive IgM monoclonal autoantibody production (see preceeding chapter), or a hole in the antiself-protective immune system. Since certain infections may drive the immune system towards self-reactivity through epitope mimicry it is also possible that infectious agents may thrive in a host organism that is immunodeficient because of the malignancy and/or the treatment given to control it (see below). Natural autoantibody production in healthy individuals seems to be tightly regulated, and it is not known whether the genes encoding them may be the template for high affinity autoantibody production in patients with autoimmune diseases [4, 6].

1.1. The B-cell Pathway

The malignant B-lymphoproliferative disorders comprise of the acute lymphoblastic and the chronic lymphocytic leukemias, multiple myelomas, Waldenstrom's macroglobulinemia and the malignant lymphomas. These malignancies represent monoclonal expansions of B lymphocytes at a certain stage in the B-cell maturation/differentiation pathway and, thus, carry the characteristic phenotypes corresponding to each particular B-cell pathway stage (Fig. 1) [8, 9]. The inclusion of Hodgkin's disease in this classification has been hotly debated until documentation for its B-cell origin was provided a few years ago [10, 11],

Early Pre-B Cell

Pre-B Cell

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