Defective T cell-mediated, isotype-specific immunoglobulin regulation in B cell chronic lymphocytic leukemia.
The consistent occurrence of T cell abnormalities in patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that the non-neoplastic host T cells may be involved in the pathogenesis of this B cell neoplasm. Because potential defects of immunoglobulin regulation are evident in B-CLL patients, we investigated one aspect of this by studying the T cell-mediated immunoglobulin isotype-specific immunoregulatory circuit in B-CLL. The existence of class-specific immunoglobulin regulatory mechanisms mediated by Fc receptor-bearing T cells (FcR + T) through soluble immunoglobulin binding factors (IgBFs) has been well established in many experimental systems. IgBFs can both suppress and enhance B cell activity in an isotype-specific manner. We investigated the apparently abnormal IgA regulation in a B-CLL patient (CLL249) whose B cells secrete primarily IgA in vitro. Enumeration of FcR + T cells showed a disproportionate increase in IgA FcR + T cells in the peripheral blood of this patient. Our studies showed that the neoplastic B cells were not intrinsically unresponsive to the suppressing component of IgABF produced from normal T cells, but rather the IgABF produced by the CLL249 host T cells was defective. CLL249 IgABF was unable to suppress IgA secretion by host or normal B cells and enhanced the in vitro proliferation of the host B cells. Size fractionation of both normal and CLL249 IgABF by gel-filtration high-performance liquid chromatography (HPLC) demonstrated differences in the ultraviolet-absorbing components of IgABF obtained from normal T cells v that from our patient with defective IgA regulation. Such T cell dysfunction may not be restricted to IgA regulation, since we have found similar expansion of isotype-specific FcR + T cells associated with expansion of the corresponding B cell clone in other patients with B-CLL. These data suggest that this T cell-mediated regulatory circuit could be significantly involved in the pathogenesis of B-CLL.
D000328:Adult; D000368:Aged; D015703:Antigens, CD; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D007071:Immunoglobulin A, Secretory / Q000096:biosynthesis; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis* / Q000502:physiology; D007153:Immunologic Deficiency Syndromes / Q000097:blood / Q000276:immunology*; D007945:Leukemia, Lymphoid / Q000097:blood / Q000276:immunology*; D007958:Leukocyte Count; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000096:biosynthesis / Q000302:isolation & purification / Q000502:physiology; D008297:Male; D008875:Middle Aged; D029584:Prostatic Secretory Proteins; D011961:Receptors, Fc / Q000032:analysis; D013491:Suppressor Factors, Immunologic / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000145:classification / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; C036832:Fc(alpha) receptor; D007070:Immunoglobulin A; D007071:Immunoglobulin A, Secretory; D007132:Immunoglobulin Isotypes; D008222:Lymphokines; D029584:Prostatic Secretory Proteins; D011961:Receptors, Fc; D013491:Suppressor Factors, Immunologic; C043076:beta-microseminoprotein; C013059:immunoglobulin-binding factors