For 30 years now, evidence has been accumulating which suggest that the mechanisms governing nonorgan-specific autoimmune diseases are similar to those leading to lymphoproliferative disorders [1], In other words the mechanisms governing polyclonal B-cell activation are thought to be similar to those leading to the monoclonal B-cell expansion.

Autoimmune phenomena can occur in association with several B-cell malignancies. Monoclonal immunoglobulins (MIg) appear in the serum of patients with multiple myeloma (MM), Waldenstrom's macroglobulinemia (WM) and related disorders, such as chronic lymphocytic leukemia (CLL). Moreover, there is a growing awareness that chronic inflammatory conditions, which are thought to have an autoimmune basis, may be predispose to cancer. It appears, therefore, that all these derangements are manifestations of a single underlying cause.

The T-lymphocyte CD5 antigen is shared by leukemic cells from patients with CLL, but also expressed by a limited fraction of normal B lymphocytes [2], One connection between connective tissue diseases and lymphoid malignancies might be established by this B-cell's subpopulation [3]. In addition to acting as a first line of defense, this minor B-cell subset makes natural autoantibodies [4], and malignant cells of most of the CLL of the B-cell lineage express the CD5 molecules [5]. This B-cell subset might be responsible for autoantibody production in one kind of disease and susceptible to malignant transformation in the other. Since autoimmune features are common in lymphoproliferative disorders, and the latter may be a complication in nonorgan-specific autoimmune diseases, CD5-positive B cells may be a key link between these pathological conditions [6],

2. AUTOIMMUNE DISEASES 2.1. Role Of The CD5+ B Cells

The CD5 molecule is present on a minority of B cells and the vast majority of B cells referred to as conventional B cells do not carry this marker. Given the usage of different Vh4 germline genes, CD5-positive and conventional B cells possibly belong to separate lineages [7], Several groups have established that this CD5+ B-cell subset may be expanded in patients with rheumatoid arthritis (RA) (reviewed in [8]). It was found to comprise of an average of 20% of the circulating B cells of 16 RA patients, compared to a maximum of 3% in 8 normal controls [9], Although CD5 molecules are present at low density on B lymphocytes, this is increased following treatment of B-cell-enriched suspensions with phorbol myristic acetate. Thus, it becomes possible to detect a co-expression of CD5 on a larger population of B cells from patients and controls than from earlier studies, but the mean proportions of B cells that express CD5 was still higher in RA patients than in normal subjects [10], The elevation of this B-cell subset is insufficient to give rise to RA since some reports showed no significant differences in the percentage of circulating CD5-positive B cells in patients, compared with controls [11], However, the number of circulating CD5+ B cells appears to correlate with the titer of rheumatoid factor. Increases in the total serum immunoglobulin and autoantibody levels were frequently encountered in the patients as well as their family members, in whom there was a correlation between the titers of rheumatoid factor of the IgM class and the percentage of CD5+ B cells [12], In-triguingly, patients with systemic lupus erythematosus (SLE) do not have elevated numbers of CD5-positive B cells [9]. Augmented numbers have been described, however, in some lupus patients [12, 13], suggesting that polyclonal activation may also affect this B-cell subset in a proportion of patients with SLE. Nonorgan-specific autoimmune diseases other that RA and SLE, may be associated with high numbers of circulating CD5-positive B cells, particularly primary Sjogren's syndrome (pSS) [14]. Furthermore, B cells expressing CDS have been identified in minor labial salivary glands of such patients [15],

Other nonorgan-specific as well as organ-specific autoimmune diseases have been associated with high numbers of circulating CD5+ B cells. These include systemic sclerosis, seronegative juvenile arthritis, Graves' disease, infectious mononcleosis, myasthenia gravis, chronic hepatitis and liver cirrhosis, notably in hepatitis B surface antigen-positive patients. Interestingly, augmented numbers of CD5+ B cells have been observed in psychiatric patients [3]. In general, levels of CD5+ B cells are independent of disease activity in the autoimmune conditions.

2.2. Complications With Lymphoid Malignancy

While monoclonal spikes have been detected in the sera of some patients with RA [16] and SLE [17], pSS appears to be the archetype of a condition midway between nonorgan-specific autoimmunity and B-cell malignancy [18], Between 5-10% of patients have been claimed to progress to lymphoma [19]. MIg has been identified in the serum and urine of these patients, of whom one-third produce monoclonal rather than polyclonal cryoglobulins [20]. The exocrine glands are indeed sites of intense immunologic activity—a feature associated with the production of rheumatoid factor [21], Moreover, clonally expanded lymphocytes have been identified in the early labial salivary gland infiltrates of patients who do not experience further progression to pseudolymphoma or lymphoma [22], Collectively, these results suggest that B cells are activated in RA, SLE and pSS [23].

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