Studies of consomic mice bearing the Y chromosome of the BXSB mouse

Previous studies have demonstrated that the Y chromosome of the BXSB mouse can lead to accelerated autoimmunity in inbred BXSB mice and in F1 hybrids. To additionally study the effects of the BXSB-Y, we have studied three sets of Y-consomic mice, NZB.BXSB-Y, NZW.BXSB-Y, and CBA/J.BXSB-Y, each consisting of background genes from the non-BXSB parent and the Y chromosome from the BXSB mouse. The effect of the BXSB-Y on autoantibody production, immunopathology, and survival was assessed. We found that the CBA/J.BXSB-Y mice showed few differences from control CBA/J males. In contrast, NZW.BXSB-Y males had accelerated renal and cardiac disease and early death, resembling that previously reported for (NZW X BXSB)F1 mice. NZB.BXSB-Y males had accelerated anti-erythrocyte autoantibodies but not accelerated anti-DNA. They lived almost as long as NZB mice. The presence of the BXSB-Y in all of the consomic mice was confirmed by crossing the consomic mice with BXSB females and demonstrating accelerated disease in the male offspring. This study demonstrates that the BXSB-Y chromosome autoimmune accelerating factor does not act alone but operates through other genes, and that the effects on different genetic backgrounds are different. The studies have implications for human lupus; they also provide a basis for future molecular biology studies of the BXSB-Y and the genes upon which it acts.     

Alterations of the T-cell population in BXSB mice: early imbalance of 9F3-defined Lyt-2+ subsets occurs in the males with rapid onset lupic syndrome

BXSB mice represent a model for systemic lupus erythematosus (SLE). Due to a Y chromosome-linked genetic defect, males of this strain suffer from SLE much earlier in life than do the females. Comparative study of male and female BXSB mice therefore provides a way to identify abnormalities of the immune system leading to accelerated SLE development. The present work is part of an effort to examine whether T-cell alterations accompany such immune abnormalities. We focused on the evolution of Lyt-2+ T-cell subsets as defined by the 9F3 monoclonal antibody (MAb). By means of two-color flow cytofluorometry analysis, 9F3+ Lyt-2+ and 9F3- Lyt-2+ cell subsets could be clearly distinguished in the lymph nodes (LN) of BXSB mice. At as early as 2 months of age, BXSB males showed an increase of 9F3+ Lyt-2+ cell frequency compared to the females. This sex-related difference became more pronounced upon further aging. In 9- to 11-month-old mice, 9F3+ cells accounted for 80-85% of the LN Lyt-2+ population in the males versus 40-45% in the females. This difference reflected the selective expansion of 9F3+ Lyt-2+ cells in the males. It was also observed at a younger age in autoimmune (NZW X BXSB)F1 hybrids but not in old nonautoimmune C57Bl/6 or (CBA/N X BXSB)F1 mice. Moreover, adult thymectomy of BXSB mice was found to hasten the shift of 9F3-defined Lyt-2+ subset proportions. We postulate that the early imbalance of 9F3-defined Lyt-2+ subsets seen spontaneously in BXSB males may result from some thymus dysfunction and may be related to the development of autoimmunity.     

Genetic control of allogenic inhibition of hematopoietic stem cells]

Adult mice of C57BL/6, CBA (CBA X C57BL/6) F1, (CBA X C57BL/6) F2, F1 X CBA and F1 X C57BL/6 strains were lethally irradiated and reconstituted with a constant dose of 3-10(5) C57BL/6 bone marrow cells. At the 9th day after the bone marrow transplantation the colony count was performed in spleen of irradiated recipients. In the spleen of F1, CBA and C57BL/6 mice were registered low (0--8, intermediate (6--18) and high (22-40) numbers of colonies respectively. The segregation ratios in F2 progeny were close to 2 (low): 1(intermediate): 1(high). The segregation ratios in backcross (F1 X CBA) were close to 1(low): 1(intermediate)numbers of colonies. Backcrosses (F1 X C57BL/6) were distributed to low and high numbers of colonies with the ratio 1:1. The number of spleen colonies of males and females was the same in all segregating progeny. The results of hybrid analysis suggest that a single pair of allelic genes is involved in genetic control of allogenic inhibition, and that the resistance (manifestation of inhibition) to C57BL/6 stem cells is conferred by the dominant allele.     

Induction of T15-specific suppressor T cells in mice with the CBA/N defect by neonatal injection with anti-T15 idiotype antibody

Mice with the CBA/N defect (xid) are unresponsive to phosphorylcholine (PC), To determine whether idiotype-specific suppressor T cells can also be generated in these defective mice, defective (CBA/N X BALB/c)F1 male and nondefective (CBA/N X BALB/c)F1 female or (BALB/c X CBA/N)F1 male mice were neonatally injected with antibodies specific for the major idiotype of anti-PC antibody, i.e., anti-TEPC-15 idiotype (T15id) antibody. Suppressor cell activity was examined by co-culturing spleen cells from neonatally treated F1 mice with spleen cells of normal nondefective F1 mice in the presence of antigen. Spleen cells from defective (CBA/NM X BALB/c)F1 mice treated with anti-T15id antibody demonstrated a level of suppressor activity (greater than 83% suppression) comparable to that of similarly treated nondefective F1 mice. This suppression was specific for the T15id of anti-PC response, and a Lyt-1-2+-bearing T cell population appeared to be responsible for the active suppression. These suppressor T cells recognized T15 but not PC, based on a functional absorption test. These results indicate that the CBA/N defects, including the deficiency in the anti-PC response by B lymphocytes and a possible T cell defect, do not influence the generation of T15id-specific suppressor T cells by neonatal injection with anti-T15id antibody.     

In vitro studies of the genetically determined unresponsiveness to thymus-independent antigens in CBA/N mice.

The X-chromosome-linked B lymphocyte defect of CBA/N mice has been studied in vitro by comparing the ability of (CBA/N X DBA/2)F1 (X-/X- X X+/Y) male (X-/Y) and female (X-/X+) spleen cells to respond to the thymus-independent antigen DNP (or TNP)-AECM-Ficoll. (CBA/N X DBA/2)F1 male spleen cells failed to generate significant in vitro anti-TNP antibody responses to DNP- or TNP-AECM-Ficoll, in contrast to spleen cells from F1 female (X-/X+) mice which responded normally to these T-independent antigens. Spleen cells from male F1 mice responded almost as well as F1 female cells to the thymus-dependent antigen, TNP-sheep red blood cells (TNP-SRBC) in vitro. Adding F1 male cells to F1 female cells failed to reduce the response of the latter to DNP-AECM-Ficoll, suggesting that the inability of F1 male cells to respond was not due to active suppression. The response of F1 male spleen cells to TNP-SRBC was not impaired by adding high concentrations of TNP-AECM-Ficoll indicating that the mechanism of unresponsiveness was not tolerance induction in all TNP-specific precursors. Lymphocytes from F1 male mice were capable of forming anti-TNP antibody after stimulation with lipopolysaccharide (LPS) in high concentrations; DNP-AECM-Ficoll had no effect on this polyclonal response. B lymphocytes from mice bearing only the X-chromosome of the CBA/N strain thus display a profound defect in B cell activation. This functional defect may represent either an inability of the defective B cells to be activated by thymus-independent antigens or the absence of a sub-class of B cells which respond to thymus-independent antigens.     

The Lyb-3+5+ subset of B cells is not required for lupus-like autoantibody formation caused by graft-vs-host reaction

We asked the question whether or not the Lyb-3+5+ B cell subset, which is lacking in CBA/N immune defective mice, is required for the lupus-like autoantibody formation caused by graft-vs-host reaction (GVHR). (CBA/N X DBA/2)F1 male defective mice injected with DBA/2 T cells produced IgG autoantibodies to the same extent as did nondefective F1 mice suffering from GVHR. Although a very small number of DBA/2 B cells might have contaminated the T cell inocula, it was shown that these were B cells of the defective F1 mice that produced autoantibodies during the GVHR. This was demonstrated by detecting autoantibodies carrying an immunoglobulin allotype of the F1 recipient. Furthermore, the defective F1 male mice injected with CBA/N lymphoid cells, which were lacking Lyb-3+5+ B cells, also produced autoantibodies. Isotype analysis of antinuclear antibodies revealed that some of them belonged to IgG3 isotype. It was concluded that the ontogenically late-appearing B cell subset is not required for GVH autoimmunity.     

Age-dependent changes in B lymphocyte lineage cell populations of autoimmune-prone BXSB mice

BXSB mice, a recently developed autoimmune strain, develop a human lupus-like disease with B cell hyperplasia in peripheral lymphoid organs. Unlike other experimental models of autoimmunity and human lupus, BXSB male mice manifest accelerated autoimmune phenomena through the influence of a Y chromosome-linked enhancing factor. The present studies were performed to investigate the features of B lymphopoiesis in BXSB mice and to determine whether differences exist between BXSB males and females in this respect. B lineage cell populations in the marrow of BXSB mice were identified phenotypically by studying the cytoplasmic mu-heavy chains of IgM (c mu), and functionally by their ability to acquire clonability and sIg in short-term liquid cultures. Male BXSB mice became deficient in both the precursors of functional B cells and c mu + pre-B cells by the age of 8 to 12 wk. This followed a transient increase in this population, which peaked when the mice were 2 to 4 wk old. In females, substantial numbers of functional B cell precursors and c mu + cells were maintained until more than 4 mo of age. Cells lacking Ig but bearing a B lineage cell antigen (14.8) were elevated in numbers in both BXSB males and females until 16 wk of age when compared to normal strains of mice. At the time pre-B cells and functional B precursors were elevated in numbers, some sIg- cells were shown to form colonies in mitogen-stimulated semisolid agar cultures without a period of preculture. Most of these sIg- cells seemed to bear the B lineage cell antigen (14.8). They were independent of both G-10 adherent regulatory cells and Thy-1+ cells for their colony formation. These results indicate that B lymphocyte formation may be maintained in a hyperactive state in BXSB females, whereas males become deficient in B cell precursors very early in life. This early decline might be related to the accelerated development of autoimmune disease in BXSB mice. Bone marrow transplantation studies showed that these unusual characteristics of B lymphopoiesis were reciprocally transferable with unseparated bone marrow cells between BXSB males and females. This finding indicates that sex hormones are not a critical variable in abnormal B lymphocyte formation in this strain, and that the premature deficiency of immediate B precursors in males may be regulated by a genetic factor(s) located on the Y chromosome.     

Increased spontaneous polyclonal activation of B lymphocytes in mice with spontaneous autoimmune disease.

Early in life, mice of four kinds [NZB, (NZB X NZW)F1, MRL/1, and male BXSB] with autoimmune disease spontaneously produced far more (greater than 3 S.D.) anti-hapten antibody-forming cells in spleens and greater concentrations of anti-hapten antibodies in sera than immunologically normal strains of mice (AKR, BALB/c, C57BL/6, DBA/1-J, DBA/2J, LG/J, 129, NZW, and female BXSB). This increased nonspecific antibody production by the abnormal animals' B cells correlated well with the spontaneous development of anti-single-stranded DNA antibodies, but not with serum levels of the viral envelope glycoprotein, gp70. These results suggest that the spontaneous formation of autoantibodies in mice whose immunologic disorder is manifested by a lupus-like disease may result from polyclonal activation of B cells by endogenous or exogenous B cell activators.     

Administration of monoclonal anti-T cell antibodies retards murine lupus in BXSB mice

Murine lupus in BXSB mice is associated with B cell hyperactivity, monocyte proliferation, and impaired T cell function. However, the significance of these abnormalities, and the relationship among them, has not been clearly established. To examine the role of T cells in the pathogenesis of autoimmune disease in BXSB mice, we depleted specific T cell subsets from BXSB males by using rat IgG2b monoclonal antibodies (MAb) to either Thy-1.2 (on all T cells) or L3T4 (on "helper/inducer" T cells). A single injection of anti-Thy-1.2 (6 mg i.v.) at age 3 mo produced a sustained 40 to 50% reduction in circulating T cells for 6 mo. Treatment prevented monocytosis, reduced anti-DNA antibody concentration, and retarded renal disease, but it did not prolong life. Repeated injections of rat MAb to Thy-1.2 were precluded by the development of a host immune response to rat immunoglobulin (Ig) that can cause anaphylaxis in BXSB mice. In contrast, rat MAb to L3T4 stimulated little or no immune response to rat Ig. We therefore were able to treat BXSB mice weekly with anti-L3T4 (2 mg i.p.) from age 3 to 12 mo. Treatment reduced circulating L3T4+ cells beneath the level of detection by fluorescence analysis. It also significantly reduced monocytosis, anti-DNA antibody production, renal disease, and mortality. These findings establish that monocytosis and autoimmunity in BXSB mice are promoted by T cells. They extend our previous observation that MAb to L3T4 retard autoimmunity in NZB/NZW F1 mice. Our finding that treatment with MAb to L3T4 is effective in two strains of lupus-prone mice suggests that treatment with MAb to Leu-3/T4, the human homologue for L3T4, may be effective in people with systemic lupus erythematosus.     

Treatment with high doses of anti-IgM prevents, but with lower doses accelerates autoimmune disease in (NZW x BXSB)F1 hybrid mice

We have treated autoimmune-prone (NZW x BXSB)F1 hybrid mice with polyclonal rabbit anti-mouse IgM antibodies starting from birth to define conditions leading to quantitative and functional elimination of the B cell compartment and to determine the effect of anti-IgM treatment on the development of autoimmune disease. A maintenance dose of anti-IgM antibodies (600 micrograms/wk), which efficiently induced B cell depletion in various non-autoimmune strains of mice, was not sufficient to deplete B cells from autoimmune-prone (NZW x BXSB)F1 mice. (NZW x BXSB)F1 mice required approximately twice as many anti-IgM antibodies (1200 micrograms/wk) to maintain the suppression of B cell development. Continuous treatment with the sub-suppressive dose of anti-IgM antibodies led to a marked acceleration of autoimmune disease in (NZW x BXSB)F1 mice. In contrast, elimination of B cells in (NZW x BXSB)F1 mice with a higher dose of anti-IgM antibodies (1200 micrograms/wk) completely prevented autoantibody production, immune complex formation, and development of glomerulonephritis and vascular lesions associated with mononuclear cell infiltrations. Our results are a direct demonstration of the primary role of autoantibodies for the development of various tissue lesions seen in systemic lupus erythematosus (SLE) and indicates that autoreactive effector T cells, if they exist, play no major direct role in the pathogenesis of SLE, at least in (NZW x BXSB)F1 hybrid mice.     

Expression of Lyb-5 and Mls determinants by Peyer's patch B lymphocytes of X-linked immunodeficient mice

Treatment of the Peyer's patch (PP) B cells from X-linked immunodeficient (xid) (CBA/N X DBA/2)F1 male mice with anti-Lyb-5 plus complement kills approximately 75% of these cells, although xid spleen B cells are unaffected. Cytotoxic depletion of Lyb-5+ cells renders the xid PP B cell population unable to generate an in vitro direct plaque-forming cell response to the TI-2 antigen TNP-Ficoll. In addition, the B cell-enriched population from the PP of xid (CBA/N X CBA/J)F1 male mice were strong stimulators of proliferation in an M1s-defined MLR, thereby demonstrating that they also express the M1s antigen(s). Two cell surface antigens associated with mature B cells are therefore expressed by xid PP B cells, suggesting that the TNP-Ficoll responsive cells in this population are mature B cell.     

Phenomenon of parental resistance and its genetic regulation]

Lymphocytes of mice F1 (CBA X M523) and F1 (A X M523) transplanted to 1000 R irradiated CBA or A mice responded to the test antigens--SRBC or S. typhi Vi-antigen--by formation of 100--1000 times less antibody forming cells than in syngeneic recipients. An intermediate result is achieved when the lymphoid cells are transplanted to the irradiated M523 mice. Lymphocytes of mice F1 (A X CBA), F1 (CBA X C57Bl/6), or F1 (A X A.CA) developed a similar immune response in the irradiated syngeneic mice and in both parental lines. The ability of parental line M523 to respond to SRBC was the same as in the other lines studied when examined in situ or in adoptive transfer experiments. The stem hemopoietic cells of mice F1 (CBA X M523) develop in the spleen of CBA mice 2--2.5 times less hemopoietic colonies than in the spleen of syngeneic animals. A conclusion was drawn that mutation M523 in CBA mice inhibited the proliferation and differentiation of hemopoietic and lymphoid cells in the irradiated nonsyngeneic recipients.     

Acute SLE in F1 hybrids between SB/Le and NZW mice; prominently enhanced formation of gp70 immune complexes by a Y chromosome-associated factor from SB/Le mice

Both sexes of the F1 hybrids between SB/Le and NZW mice developed a spontaneous lupus-like disease. Their disease is essentially identical in time course and nature with autoimmune responses that are seen in the F1 hybrids between BXSB and NZW mice. The presence of abnormal Y chromosomes in the SB/Le strain was proved by the finding that the accelerated disease occurred in the F1 hybrid males only when the male parent was SB/Le but not NZW. The acceleration of disease in male F1 hybrids with abnormal Y chromosome was significantly associated with the enhanced formation of gp70 IC but not anti-DNA antibodies. These results indicate that all or almost all of the genetic abnormalities expressed in the BXSB strain are contributed by the SB/Le strain, and the Y chromosome-associated factor enhances the autoimmune response to serum gp70 antigen more markedly than to DNA antigens.     

Effect of cortisone-resistant thymocytes on endogenous colony formation in inbred mice]

Endogenous colonies in the spleen of sublethally irradiated (CBA X C57BL/6) E1 hybrid mice were recorded after the injection of thymocytes and the lymph node cells from the hydrocortisone-treated and intact CBA mice. Cortisone-resistant thymocytes failed to suppress the endogenous colony formation, whereas the lymph node cells produced a distinct suppressive effect on the endogenous colonies. After the injection of cortisone-resistant thymocytes the number of colonies in the spleen of individual recipients was double that in control irradiated hybrids.     

Influence of the maternal effect on allogenic inhibition of hematopoietic stem cells]

Bone marrow cells (0,5-10(6)) of female mice of CBA or C57BL strains were injected intravenously to lethally irradiated CBA, C57BL/6, (femaleCBA X maleC57BL/6)F1 and (femaleC57BL/6 X maleCBA)F1 mice. Spleen of recipients as assayed for colony count on the 9th day after bone marrow transplantation by the method of Till and McCullouch. Stem cells of CBA mice demonstrated failure of allogenic inhibition in (CBA X C57BL/6)F1 hybrid mice and formed the same number of colonies as in the spleen of syngenic recipients. The level of allogenic inhibition of CBA stem cells transplanted to (C57BL/6 X X CBA)F1 hybrid mice was 50%. Bone marrow cells of C57BL/6 mice formed colonies in spleen of (CBA X C57BL/6)F1 mice at least in 20 times less than in syngenic combination. In the transplantation of bone marrow from C57BL/6 mice to (C57BL/6 X CBA)F1 hybrid mice the allogenic inhibition was less pronounced (77-85%) as compared with the transfer of cells to (CBA X C57BL/6)F1 hybrid mice (95%). The sex of a recipient did not influence the number of formed colonies. The different level of allogenic inhibition of parental stem cells can not be explained by the effect of linkage with sex as the female of reciprocal hybrid mice have identical structure of sex chromosomes (X(CBA)XC57BL/6). The data obtained indicate that the maternal effect affects allogenic inhibition of stem cells in parent--F1 system. It is possible that the maternal influence may be determined by cytoplasmic factors of inheritance which affect the expressivity of recessive genes Hh, controlling the inheritance of specific haematopoietic cell antigens.     

Autoimmunity and immune complex disease after neonatal induction of transplantation tolerance in mice

Mice made neonatally tolerant to alloantigens were found to develop an immunologic disease resembling systemic lupus erythematosus. In BALB/c mice neonatally injected with C57BL/6 X BALB/c F1 hybrid spleen cells, features of autoimmunity were observed first. After 5-24 wk, antinuclear, anti-SS DNA, thymocytotoxic, and rheumatoid factor-like antibodies were detected in association with hypergammaglobulinemia and with the occurrence of circulating immune complexes and cryoglobulins. Some of the antinuclear antibodies were found to be produced by F1 donor B cells persisting in the host. Second, immunopathologic changes were detected in tolerant mice. In the kidneys, an immune complex glomerulonephritis of the membranous type was observed. Immunoglobulin deposits were also found in the choroid plexus and at the dermoepidermal junction. In addition, thrombocytopenia was a common finding, and a positive direct Coomb's test occasionally was detected. Features of autoimmune disease were closely associated with the effective induction of transplantation tolerance, as revealed by the inability of spleen cells to generate in vitro cytolytic responses against C57BL/6 alloantigens. It is suggested that, although transplantation tolerance is associated with a lack of cytolytic reaction of the host against F1 hybrid donor alloantigens, other types of allogeneic interactions could lead in this model to the development of autoimmunity and immunopathology.     

Cell cycle analysis of lymphocyte activation in normal and autoimmune strains of mice

The spontaneous spleen cell proliferation and the proliferation induced by in vivo or in vitro stimulation with such polyclonal B cell activators (PBA) as LPS, poly rI.rC, and anti-mu were studied in normal and autoimmune mice. The various murine models of autoimmunity differ in the level of naturally occurring splenic cellular hyperactivity as well as in the ability of their spleen cells to be further stimulated in vitro by polyclonal stimulators. Both the NZB strain and the MRL/Ipr strain had markedly increased numbers and percentages of spontaneously proliferating spleen cells, whereas the BXSB strain did not. Nonautoimmune strains were found to have very small numbers of activated cells in the spleen. However, such normal strains could be induced in vivo to mimic the natural splenic hyperactivity observed in older NZB and MRL/Ipr autoimmune strains by the injection of polyclonal B lymphocyte stimulators. In contrast, old hyperactive NZB mice were not further induced to undergo proliferation by in vivo administration of such stimulators. Density-separated, T depleted, spleen cells of normal and autoimmune mice were stimulated in vitro with PBA in 48-hr cultures. Cells from old MRL/Ipr and NZB mice were abnormal in both the anti-mu response and the LPS response; BXSB mice had normal anti-mu responses. These studies suggest that there is no prerequisite for spontaneous splenic hyperactivity in the development of autoimmunity. In addition, different PBA stimulate separate subsets of B cells that differ in their state of activation in the various autoimmune strains. Finally, different B cell subsets appear to be abnormal in different types of autoimmune mice.     

Thymosin activation of T-killer precursors for hematopoietic stem cells]

Lymph node cells of normal CBA mice, syngeneic radiation chimerae CBA leads to CBA and B-mice after incubation with thymosin (fraction 5) were transplanted to sublethally irradiated recipients (CBA X C57BL) F1; the number of endogenic colonies in the recipient's spleen was then recorded. Thymosin was shown to increase the killer activity of the lymph node cells of normal mice CBA, syngeneic chimerae CBA leads to CBA, but not of B-mice. As suggested, TU-cells' subpopulation served as target cells for thymosin.     

Antibody formation to autologous erythrocytes following the immunization with rat erythrocytes of normal animals and mice tolerant to the immunizing antigen

(CBA X C57B1/6)F1 mice immunized three times with rat erythrocytes produced antibodies both to this antigen and to autologous erythrocytes. Most of the antibodies to rat erythrocytes belonged to IgM isotype while antibodies to autologous red cells were of IgG isotype. Combined injection of thymectomized (CBA X C57B1/6)F1 mice with a massive dose of rat spleen cells and cyclophosphamide induced in animals stable tolerance to rat cells. Inducibility of antibodies to autologous red cells in tolerant mice injected 3-5 times with rat erythrocytes was drastically reduced. Nonspecific suppression (thymectomy and cyclophosphamide) did not prevent production of autoantibodies.     

The effect of thymectomy on lupus-prone mice

The effect of neonatal thymectomy on the induction and/or modification of murine SLE disease was examined in several representative groups of mice with early-life SLE (MRL/Mp-lpr/lpr females, BXSB males, (NZB X W)F1 females, (NZW X BXSB)F1 males and females), late-life SLE (MRL/Mp-+/+ and BXSB females), and normal strains (BALB/c and C57BL/6 females). Our results indicated that thymectomy prevented disease only in the MRL/Mp-lpr/lpr SLE mice, and that this effect diminished as thymectomy was delayed beyond 3 wk post-natally. In the other SLE mice studied, neonatal thymectomy did not modify disease symptoms to any significant degree. Moreover, depletion of mature T cells from donor BXSB male bone marrow did not affect the expression of early-life SLE in thymectomized BXSB female recipients. Neonatal thymectomy did not induce SLE in normal mice. Of note, neonatal thymectomy did not completely deplete the Thy-1.2+ cell population, i.e., 10 to 15% remained in the spleens of the thymectomized mice. This incomplete T cell depletion, together with the previously demonstrated dependence on and hyperresponsiveness of BXSB and (NZB X W)F1 B cells to T helper cell-derived accessory signals, cast doubts on earlier conclusions that B cells from some SLE mice can autonomously proliferate and differentiate to autoantibody-secreting cells. It seems more appropriate to conclude that B cells from the various SLE mice vary in their degree of response to, and production of, T cell-derived helper signals, and thus in their expression of B cell hyperactivity and disease.