Abnormalities in clonable B lymphocytes and myeloid progenitors in autoimmune NZB mice.

Abstract

Cloning procedures were used to study B lymphocytes and progenitors of granulocytes and macrophages in NZB mice. Numbers of B cells that were detected in sheep erythrocyte-containing semisolid cultures were only slightly elevated in NZB tissues, and these were normally sensitive to inhibition by anti-,u or anti-b antibodies or prostaglandin E.However, NZB mice rapidly developed large numbers of B cells that could be cloned in the presence of lipopolysaccharide, and these included unusual anti-,u resistant cells. Numbers of myeloid precursors in NZB bone marrow that were responsive to colony-stimulating activity in L-cell conditioned medium or endotoxin serum were at least normal, but at all ages granulocyte-macrophage precursors were poor responders in cultures stimulated by WEHI-3 cell conditioned medium. Almost no colonies were elicited in NZB cultures with a colony-stimulating activity moiety from WEHI-3 cells. Prostaglandin sensitivity of myeloid precursors from NZB and CBA mice was also different. Codominant genetic control of these abnormalities was suggested by their partial expression in F1 hybrid NZB X CBA and NZB X NZW mice. NZB mice expressed an unexpected IgD allotype allele.Abnormalities have been found in or attributed to T cells, thymic epithelium, B cells, macrophages, and stem cells in autoimmune NZB mice, and they produce high levels of xenotropic virus (1-6). The relevance of each of these abnormalities to the development of the hemolytic anemia in these mice is not clear, but genetic studies tend to minimize the role of viruses and certain hemopoietic abnormalities in the etiology of disease (5, 6). A possible temporal sequence is suggested by findings that B cells of NZB mice are polyclonally activated by 1 week of age, and autoantibodies with preference for suppressor T cells are detectable early in adult life (7-10). A primary B-cell abnormality or defects that are expressed at the B-cell level could thus predispose to subsequent aberrant T-cell function. On the other hand, production of antierythrocyte autoantibody may occur in the absence of significant numbers of T cells, and potential for autoimmunity is transferrable with fetal liver or bone marrow cells from NZB mice (3, 11). Some gene products influencing manifestation of autoimmunity might therefore be expressed in pre-B cells, B cells, or nonlymphoid cells capable of activating B cells. Limiting dilution cloning techniques are available for enumerating and characterizing several hemopoietic precursors as well as lymphocytes, and we propose that these can be of value for identifying intrinsic defects in various cell types and for following changes in these with progression of disease. Thus far, we have found that particular culture conditions reveal an exceptional category of B lymphocytes in NZB lymphoid tissues, which, unlike B cells from many other strains, proliferate in the presence of anti-ji antibody. In addition, a severe abnormality was detected in the ability of precursor cells of NZB mice to form myeloid colonie...

Detection of neuropeptide Y and its mRNA in megakaryocytes: enhanced levels in certain autoimmune mice.

“…However, the fact that MRL/lpr mice have circulating immune complexes (23) but no detectable splenic NPY mRNA suggests that there may be an alternative explanation for the enhanced splenic levels of NPY mRNA in the other autoimmune strains used in this study. For instance, Kincade et al (35) reported abnormalities in responsiveness ofhematopoietic stem cells to colony-stimulating factors in the NZB mouse, which may affect megakaryocyte production.…”

Rationale for bone marrow transplantation in the treatment of autoimmune diseases.

“…MRL/MP-lpr/lpr (MRL/l) and BXSB mice as well as NZB mice and NZB x NZW F1 hybrids spontaneously develop autoimmune diseases characterized by anti-double-stranded (ds) DNA antibodies, immune-complex glomerulonephritis, and death from renal failure (1). Abnormalities have been found in or attributed to T cells, thymic epithelium, B cells, and/or macrophages in these mice (2)(3)(4)(5)(6)(7)(8). Recently, several groups have shown that the proneness to develop autoimmune diseases actually resides in defects at the lymphoid stem-cell level and that defects of function are not directly attributable to environmental factors such as hormones or viruses (9)(10)(11).…”

Phenotypic and Functional Analysis of Activated B Cells of Autoimmune NZB × NZW F1 Mice

“…Polyclonal activation of B cells might be the critical background abnormality in the pathogenesis of autoimmunity in NZB-derived mice [5][6][7]. The severity of polyclonal B-cell activation might determine the production of autoantibodies and the fate of the autoimmune mice.…”