Studies of immune responses in mice prone to autoimmune disorders: I. Heterogeneity of the affinities of antihapten antibodies produced by NZB,NZW, and related strains of mice

Mice of the NZB and NZW strains and their F₁ hybrid produce antihapten plaque-forming cell (PFC) responses to T-dependent antigens (trinitrophenylated bovine gamma globulin and dansylated keyhole limpet hemocyanin) which are of unusually restricted heterogeneity of affinity, are relatively lacking in low-affinity PFC, and are of relatively high average affinity. Since some low-affinity PFC are present in NZB mice early after immunization, the results suggest a particularly marked down-regulation of low-affinity antibody production by these strains. The non-autoimmune-prone F₁ hybrid (NZB × CBA) produces a typical heterogeneous response containing a high proportion of low-affinity PFC. Thus, the tendency to down-regulate low-affinity PFC is not inherited as a simple Mendelian dominant trait. The response of NZB mice to T-independent antigens does not show the same restricted heterogeneity of affinity. In fact, late after injections of trinitrophenylated Ficoll, NZB mice tend to have more heterogeneous responses than nonautoimmune-prone BALB/c mice in which a marked down-regulation of high-affinity antibody-producing PFC is seen. The possible relationship between these unusual features of the immune response of NZB and some related strains and their tendency to develop autoimmune disease is discussed.     

Effects of calorie restriction on immunologic functions and development of autoimmune disease in NZB mice.

Chronic energy (calorie) intake restriction (CEIR) prolonged life, inhibited autoimmune disease, and influenced immunologic and hematologic parameters in NZB mice. Abnormalities in numbers and proportions of T and B cells populations were corrected. Deficient responses to phytomitogens, mixed lymphocyte reactions, formation of plaque-forming cells to sheep red blood cells in vitro, production of cytotoxic T lymphocytes after in vitro stimulation, and interleukin 2 production were also corrected. CEIR prevented the extreme splenomegaly that normally occurs with age in NZB mice. This influence was associated with reduction of a greatly expanded non-T, non-B lymphoid cell population. Calorie restriction also prevented in NZB mice the rapid decrease in total numbers of colony-forming B cells in bone marrow that is also characteristic of mice of this strain. The influences of CEIR on immune parameters and hematopoiesis were generally less marked in non-autoimmune-prone DBA/2 mice than in autoimmune-prone NZB mice. CEIR has been shown to produce profound influences on several strains of autoimmune-prone mice (NZB x NZW)F1, MRL/lpr, BXSB, and NZB herein). In each of these strains, the pathogenesis and manifestations of autoimmune disease are dissimilar. Therefore, it seems likely that calorie restriction acts on an as yet elusive mechanism that operates to foster development of the diseases associated with aging common to each of these autoimmune strains as well as autoimmune-resistant mice and rats. Further investigation of the molecular and cellular bases of the benefits of CEIR seems urgent.     

Biased expression of variable region gene families of the immunoglobulin heavy chain in autoimmune-prone mice

We have examined usage of variable region gene families of the immunoglobulin heavy chain (VH gene family) in spleens of MRL/MpJ-1pr/lpr (MRL/lpr), (NZB x NZW)F1, and BXSB mice by Northern analysis using various VH probes, including the VHPAR gene which we cloned and identified as a gene encoding the heavy-chain variable region of antipoly(ADP-ribose) antibody. The amount of VHS107 family mRNA was almost constant for the same amount of splenic crude RNA in autoimmune-prone and normal mice, while concentrations of other family mRNAs were elevated in autoimmune-prone mice. For example, per splenic RNA the VHPAR family was expressed in MRL/lpr mice 10 times more than in their normal counterpart, MRL/MpJ-+/+ (MRL/+) mice. These results indicate the bias of VH gene usage in autoimmune-prone mice. Expression of the VHS107 family was depressed from an early life stage of MRL/lpr and male BXSB mice. Furthermore, the expression of IL-4 and IL-5 were quantitatively compared, as B cell differentiation factor was thought to be produced by abnormally proliferative T cells in lymph nodes of MRL/lpr mice. We could not, however, observe overproduction of IL-4 and IL-5 mRNA in the lymph nodes.     

Immunity to Plasmodium berghei yoelii in mice. II. Specific and nonspecific cellular and humoral responses during the course of infection.

The kinetics of various specific and nonspecific immunologic responses were examined in BALB/c mice infected with 17X nonlethal Plasmodium berghei yoelii (a self-limiting infection). The sequence of events after infection was characterized by rapid sensitization of splenic T cells to malaria antigen and polyclonal B cell activation, followed by a period of depressed splenic proliferative responses in vitro to mitogens (PHA and LPS) and malaria (specific) antigen. At the same time, suppressed primary in vitro splenic PFC responses to trinitrophenyl-aminoethylcarbamylmethyl-Ficoll (TNP-F) were seen. This suppression was an active process requiring adherent cells. During this period, levels of antimalarial antibody also increased exponentially. As the infection was cleared, splenic malaria antigen-specific proliferative responses were again observed and splenic PFC and in vitro mitogen responses returned to preinfection levels after variable periods of time. Both splenic proliferative responses to malaria antigen and antimalarial antibody responses remained persistently elevated. In addition, some responses were examined in mice infected with 17X lethal P.b. yoelii (a fatal infection); in comparison to the early responses of mice infected with the nonlethal substrain, there was a decrease and delay in the development of a splenic T cell response to malaria antigen and a blunted antimalarial antibody response.     

Ability of chicken B cells from different compartments to respond to TNP-Ficoll

The responsiveness of chicken B cells from various compartments to T-independent antigens was studied by immune transfers of spleen and bursa cells into immunosuppressed recipients. Bursa cells from 8- to 10-wk-old donors failed to respond to trinitrophenylated Ficoll (TNP-F) even when thymus cells or splenic T cells were added. Spleen cells from the same donors transferred responses, as judged both by anti-TNP plaque-forming cells (PFC) per spleen and serum anti-TNP titers. In contrast, responses to TNP-Brucella abortus (TNP-BA) were transferred at least as well as by bursa as by spleen cells. Rabbit anti-chicken T cell serum plus complement treatment of the spleen cells reduced their ability to transfer responses to sheep erythrocytes, but either did not affect or enhanced serum antibody responses to TNP-BA and TNP-F. In intact animals, responsiveness to i.v. injected TNP-F was found to develop slowly after hatching in the chicken. At the age of 2 and 3 mo, PFC/spleen on day 4 after TNP-F injection were only 20% and 40%, respectively, of the adult response. Thymectomy at hatching further delayed this development, resulting in 12% and 45% of the adult control response at ages of 3 and 4 mo. It is concluded that responsiveness to the TI-2 antigen, TNP-F, develops slower than that to the TI-1 antigen, TNP-BA, and is restricted to the splenic B cell compartment. In addition, this development appears to be faster in the presence rather than in the absence of the thymus. In view of the previously shown effect of thymus on bursa development, these data suggest that the maturation of TI-1 antigen (TNP-F)-respondent chicken B cells requires residence in both the bursa and spleen before the development of responsiveness to such antigens.     

Aberrant maturational characteristics of the immune responses of NZB mice to autologous and heterologous erythrocyte antigens

The maturational characteristics of the humoral immune responses of C3H and NZB mice to autologous and heterologous erythrocyte antigens were investigated. Clonal selection of antibody-secreting B lymphocytes was examined at the plaque-forming cell level of analysis of changes in mean antibody affinity and the heterogeneity of binding affinities. The primary immune response of C3H mice to SRBC exhibited a progressive temporal increase in mean relative antibody affinity and a concomitant restriction in the heterogeneity of binding affinities consistent with clonal selection and restriction of B lymphocytes to high affinity antibody-secreting cells. By contrast, the anti-SRBC immune response of NZB mice displayed aberrant maturational characteristics with a progressive decrease in mean relative antibody affinity but also clonal restriction with selection of clones of cells secreting low affinity antibodies. The spontaneous autoimmune responses of NZB mice to autologous erythrocyte surface autoantigens X and HB were different from the response to heterologous erythrocytes in that there was neither a progressive change in mean relative binding affinity nor evidence of progressive clonal restriction. Although the precise mechanisms responsible for the aberrant selection and derepression of B lymphocyte clones in NZB mice have not been identified, the very nature of the aberration suggests the existence of one or more defects which may be intrinsic to the B lymphocytes of NZB mice.     

Production of auto-anti-idiotype antibody during the normal immune response. X. Response to TNP-Ficoll in the chicken

The spontaneous production of auto-anti-idiotype (Id) was demonstrated after injection of chickens with trinitrophenylated Ficoll (TNP-F) by: (a) the presence of hapten-augmentable plaque-forming cells (PFC), (b) the ability of serum and of hapten eluates from immune spleen cells to cause hapten-reversible inhibition of anti-TNP plaque formation, and (c) an enzyme-linked immunosorbent assay (ELISA). Tests for anti-Id using the ELISA and hapten-reversible inhibition of PFC correlated very well. As in the mouse, the incidence of hapten-augmentable PFC was reduced by thymectomy and increased by the transfer of TNP-F-immune spleen cells. Hapten-augmentable PFC were also observed during the immune response of chickens to p-azobenzene arsonate-conjugated Brucella abortus.     

Immunological studies of aging. Normal B-cell repertoire in aged mice: studies at a clonal level

As previously reported, old mice produce lower avidity plaque-forming cells (PFC) after immunization with 2,4,6-trinitrophenyl-Ficoll (TNP-F) than do young mice. However, if spleen cells from TNP-F-immunized old mice are incubated with hapten to elute auto-anti-idiotype antibody then high avidity PFC, comparable to those in young mice, are detected. To further evaluate the effect of age on the B-cell repertoire anti-2,4,6-trinitrophenyl-bovine gamma globulin (TNP-BGG) hybridomas were prepared from young (6 to 8 weeks old) and old (18 to 24 months old) mice which had been primed and boosted with TNP-BGG. The monoclonal antibodies (MoAb's) were TNP-specific. Spleens from old and young mice were comparable with respect to the incidence of immunoglobulin-secreting hybridomas obtained, the incidence of TNP-BGG-specific hybridomas obtained, and the isotype distribution of the anti-TNP-BGG hybridomas. The avidities for TNP-BGG of the IgG1 anti-TNP-BGG MoAb's obtained from old and young donors were also comparable. The overall results thus suggest that old and young mice have similar B-cell repertoires and that differences in the antibodies produced are due to regulatory influences.     

Selective improvement of thymus and some T cell dysfunctions in NZB mice by in utero thymulin treatment

NZB mice were treated during gestation with thymulin, a thymus-secreted, zinc-associated nonapeptide. Control pregnant NZB mice received either zinc alone or saline alone. Offspring from all three groups of NZB mothers, and age-matched DBA/2 mice, were tested for the following immunologic parameters: thymulin serum levels at 2 and 5 wk of age; splenic anti-sheep red blood cell (anti-SRBC) plaque-forming cell (PFC) numbers after immunization at birth or at 2 wk of age; anti-human gamma-globulin (anti-HGG) antibody titers after immunization at 2 wk of age, with or without prior tolerance induction at birth with deaggregated HGG; spontaneous IgM serum levels at 2 and 5 wk of age; spontaneous splenic anti-trinitrophenyl (anti-TNP) PFC numbers at 2 wk of age. As compared with DBA/2 mice, young NZB mice exhibited low circulating thymulin titers, high antibody responses to SRBC and to HGG, resistance to tolerance induction by deaggregated HGG, increased spontaneous IgM serum levels, and increased spontaneous anti-TNP PFC numbers. However, marked reductions in anti-SRBC and anti-HGG antibody production, both thymus-dependent responses, were observed in the young NZB offspring of thymulin-treated mothers as compared with NZB controls born from zinc- or saline-treated mothers. A delay in the postnatal decrease of serum thymulin levels was also noted in the offspring of thymulin-treated mothers. Interestingly, these effects of in utero thymulin treatment tended to become more pronounced with advancing age during the postnatal period. Conversely, IgM serum levels, spontaneous anti-TNP PFC and sensitivity to tolerance induction were not affected by thymulin treatment during fetal life. Taken together, the data suggest that in utero exposure to pharmacologic concentrations of thymulin induces a persistent and selective improvement of some thymus and T cell dysfunctions but has no effect on intrinsic B cell abnormalities of NZB mice.     

Acute hepatotoxin exposure effects lymphoid and accessory cell types in inbred mice

The effect of acute hepatotoxin exposure on in vivo and in vitro immune responses were investigated in inbred mice. Splenic anti-SRBC PFC responses were slightly enhanced by carbon tetrachloride or galactosamine administration 5 hr prior to immunization. Whereas splenic anti-SRBC PFC responses were slightly enhanced in euthymic mice exposed to carbon tetrachloride 5 hr prior to immunization, immune responses to the TI antigens, Fl-LPS, Fl-Ficoll, and TNP-LPS, were significantly suppressed. Athymic mice receiving similar hepatotoxin exposure elicited enhanced immune responses to the TI immunogens, thereby suggesting that the activities of B cells and macrophages are enhanced in treated animals and in euthymic mice, T suppressor cells are also activated. By admixture of purified B- and T-cell and macrophage populations from either carbon tetrachloride-treated or control animals, it was demonstrated that hepatotoxin exposure also induces suppressor T cells regulating immune responses to the T-dependent antigen, SRBC, and that macrophages from treated animals are more functional. Further, B-cell responsiveness is enhanced. In addition to these observations, an active factor could be demonstrated in sera from hepatotoxin-treated animals which augments immune responses to SRBC in normal mice and promotes immune responses to this antigen in athymic mice. These findings indicate that the effects of acute hepatotoxin exposure are multifocal, influencing the activity of lymphoid and accessory cells.     

Production of auto-anti-idiotypic antibody during the normal immune response. VIII. Effect of auto-anti-idiotypic antibody on contact sensitivity

An eluate prepared by brief incubation of spleen cells from 2,4,6-trinitrophenyl (TNP) lysyl-Ficoll immunized mice with TNP-epsilon-amino-n-caproic acid causes a specific inhibition of the induction of contact sensitivity by 2,4,6-trinitrochlorobenzene skin painting. The active factor in the eluate binds to an anti-mouse immunoglobulin (Ig) immunoadsorbent column but not to a TNP immunoadsorbent column and is therefore Ig but not anti-TNP antibody. The active factor does bind to an immunoadsorbent prepared from anti-TNP antibody, suggesting that the factor has anti-idiotype specificity. Evidence based upon hapten-reversible inhibition of plaque formation and an enzyme-linked immunosorbent assay (ELISA) indicates that the eluates contain auto-anti-idiotype antibody specific for anti-TNP antibody. It is suggested that auto-anti-idiotype antibody spontaneously produced during the immune response to a T-independent antigen can specifically downregulate contact sensitization to the same epitope.     

Antigen induced alterations in splenic prostaglandin and cyclic nucleotide levels in NZB mice.

Studies were undertaken in order to determine if NZB mice injected with sheep erythrocyte antigens would respond by showing elevated splenic prostaglandin and cyclic nucleotide levels similar to that observed in normal mice. The results show that young NZB mice can respond to sheep erythrocytes by yielding increased levels of splenic PGF2alpha and cAMP. However, because of increased basal levels of PGF2alpha and cAMP, the net increase observed is lower than that observed with normal mice. In old NZB mice exhibiting signs of disease (splenomegaly) and in which defects in immune competence are known to occur, the injection of SRBC results in in no increase in splenic PGF2alpha levels and a decrease in cAMP levels. These animals also have greatly elevated basal levels of PGF2alpha, cAMP, and cGMP. It is concluded that the cellular immune defect in NZB mice is reflected by their faulty metabolic responses to sRBC. Also, the altered basal levels of PG and cyclic nucleotides may be related to the altered cellular immune competence. The latter conclusion is supported by the reduced capacity of spleen cells from young NZB mice to respond to PGE by increasing cAMP levels and by the lack of an effect of inhibitors of PG synthesis on the immune response to sRBC in both young and old NZB mouse spleen cell cultures.     

Development of the autoimmune B cell repertoire in MRL-lpr/lpr mice

The processes responsible for the production of autoantibodies have been shown to include both Ag-specific and generalized (polyclonal) forms of B cell activation. The relative contribution and temporal association of these processes to the genesis of systemic autoimmunity are incompletely understood. To study this relationship, the B cell repertoires of MRL-lpr/lpr mice were analyzed by ELISA spot assay over an 8-mo period. Between 6 and 12 wk of age, the number of splenic lymphocytes producing antibodies reactive with both autoantigens and conventional Ag increased proportionately. The repertoires of MRL-lpr/lpr mice under 12 wk were dominated by IgM-secreting B cells that showed no bias toward the production of specific autoantibodies. From 12 to 38 wk of age, an increasing proportion of animals developed repertoires dominated by IgG-secreting B cells that were skewed toward reactivity against one or very few (auto)antigens. Although there was no single Ag against which all mice developed skewed reactivity, 55% of MRL-lpr/lpr adults had increased numbers of B cells producing antibodies to the Sm Ag and 13 to 16% developed increased reactivity toward DNA, myosin, histone, thyroglobulin, or T cells. These data indicate that generalized (polyclonal) B cell activation dominates early repertoire development whereas (auto)-antigen-specific responses become increasingly important during the latter stages of disease in these autoimmune-prone mice.     

Aberrant regulation of IL-1 expression in macrophages from young autoimmune-prone mice

IL-1 is a multifunctional, immunoregulatory polypeptide produced by many cell types. Because activated macrophages are a major source of IL-1 and have also been implicated in the pathogenesis of autoimmune disease, we investigated the regulation of IL-1 expression in several autoimmune-prone strains of mice. Peritoneal macrophages derived from the autoimmune-prone strains MRL/lpr, MRL/+, NZB, and NZB/W F1, as well as NZW, displayed transient expression of IL-1 in contrast to the stable expression characteristic of control normal strains including A. Thy, A/J, B10, B10.A, B10.D2, C57BL/6, BALB/c, and C3H/HeN. The down-regulation of IL-1 by macrophages from the autoimmune-prone mice was not attributable to inherently defective signal transduction because macrophages from both the normal and autoimmune-prone strains displayed substantial initial levels of cell-associated and secreted IL-1. However, during the first 2 to 3 days in culture, macrophages from autoimmune-prone mice became progressively refractory to both induction and maintenance of IL-1, a pattern that correlated with changes in the levels of IL-1 alpha and beta mRNA. The progressive reduction in IL-1 expression by macrophages from these autoimmune-prone strains was not due to a reduction in general metabolism or viability, because expression of cell surface antigens, including MHC class I and II Ag and LFA-1, was comparable to that of control macrophages. Because IL-1 plays a critical role in the homeostasis of a variety of cell lineages, defective expression, and maintenance of IL-1 (and perhaps other cytokines) by macrophages from the autoimmune-prone strains may contribute to the immune dysregulation that develops in these mice. Alternatively, cytokine dysregulation might not contribute directly to disease, but rather reflect a more basic defect related to specific signal transducing or gene regulatory pathways.     

Studies on the influence of the internal environment on autoantibody production by B cells

Purified splenic B cells from autoimmune NZB and nonautoimmune DBA/2 mice were transferred to unmanipulated H-2 compatible xid recipients. The number of autoantibody-secreting clones present in recipient mice was quantitated at varying times after transfer using a splenic fragment assay. We found that NZB and DBA/2 B cells expanded equally well in equivalent xid environments. Cells from either donor expanded significantly better in autoimmune-prone NZB.xid as compared with DBA/2.xid recipients. Moreover, clones producing antibodies reactive with T cell surface antigens, bromelain-treated mouse red cells, or DNA expanded more rapidly than did cells producing antibodies to the nonautoantigen TNP-KLH. Serum autoantibody levels rose in concert with the increased numbers of autoantibody-producing lymphocytes. We conclude that factors present in the internal milieu of autoimmune-prone NZB.xid mice, rather than an intrinsic B cell defect, facilitate the expansion of (auto)antibody-secreting B cells.     

Hormonal modulation of responses to thymus-independent and thymus-dependent antigens in autoimmune NZB/W mice

Previous work suggested that gonadal steroids influence immunity through the thymus, but the mechanisms were unclear. To investigate the effects of these hormones on immune responses to T1 and TD antigens in autoimmune mice, we studied hybrid NZB/W mice and the nonautoimmune DBA/2 strain. Mice castrated at 14 days of age were implanted with Silastic capsules releasing, in adults, physiologic levels of E2 in males or Te in females. Sham-operated controls received empty capsules. Splenic PFC were quantified 4 to 5 days after challenge with the TI2 antigen TNP-Ficoll, the TI1 antigen TNP-LPS, or the TD antigen SRBC. Young castrated NZB/W males implanted with E2 had striking enhancement of IgM responses to TNP-Ficoll when compared to castrated Te-treated females and comparable sham-operated controls of both sexes. E2 also stimulated responses to TNP-LPS. In response to challenge with SRBC, young E2-treated NZB/W males had a consistent trend to increased IgM PFC, and the stimulatory effect of E2 on IgG plaques was variable. Physiologic doses of Te had no consistent effect on responses in young mice. In old female NZB/W mice, Te caused PFC response after immunization with TNP-Ficoll to resemble age-matched NZB/W males. As sham-operated NZB/W females grew older, PFC responses to SRBC fell. This age-related phenomenon was delayed, however, in female castrates implanted with Te. In contrast, Te clearly suppressed responses to TNP-LPS. Implantation of E2 did not alter responses to TNP-Ficoll, TNP-LPS, or SRBC in nonautoimmune DBA/2 males. This finding suggested that exogenous E2 given in physiologic doses did not influence immunologic responsiveness in a normal strain to the degree seen in hormone-sensitive NZB/W mice. It was concluded that E2 enhanced responses to a variety of exogenous antigens in autoimmune NZB/W mice. The most consistent E2-induced increase in PFC response was observed with TI antigens, suggesting that E2 exerted its effects on B cells or Ts.     

LPS regulation of the immune response: suppression of immune responses to orally administered T-independent antigen

The regulation of immune responses to gastrically administered TI antigens has been investigated, and the characterization of a regulatory cell population has been performed. Intragastric administration of TNP-haptenated homologous erythrocytes (TNP-MRBC) induced splenic IgM anti-TNP PFC responses in LPS nonresponsive C3H/HeJ mice that were higher than those in LPS-responsive C3H/HeN mice and similar to those noted in athymic (nu/nu) C3H/HeN animals. The simultaneous intragastric administration of LPS with TNP-MRBC augmented immune responses in a manner similar to that previously reported for parenterally administered LPS and antigen. Further, LPS-induced augmentation of TNP-MRBC responses was greater in athymic mice. These findings were substantiated using in vitro spleen cultures. Intragastric challenge with a 2nd TI antigen, TNP-LPS, induced approximately 8-fold higher splenic anti-TNP PFC responses in athymic C3H/HeN mice compared with those in euthymic littermates. By admixture of B and T cell populations, it was demonstrated that the host responsiveness to TNP-LPS was negatively regulated by suppressor cells. Suppressive activity resided in a Thy 1.2-bearing, irradiation-resistant, nylon wool-nonadherent cell population. These cells could be demonstrated in spleen and Peyer's patches from young or old LPS-responsive C3H/HeN mice, but not in tissues from LPS nonresponsive C3H/HeJ mice. The specificity of the regulator cells was not limited to TNP-LPS responses, since immune responsiveness to another TI antigen, TNP-dextran, was also under the control of this cell population. These studies confirm the TI nature of TNP-MRBC and indicate that immune responses to gastrically administered antigens such as TNP-LPS, TNP-dextran, and possibly TNP-MRBC are negatively regulated by a suppressor T cell population. A role for endogenous LPS in the generation of regulator cells and the effect of these cells on host responses to gut-derived antigens is discussed.     

Stimulation of PIP2 hydrolysis by aluminum fluoride in resting T cell subsets of normal and autoimmune-prone lpr mice

T cells of autoimmune-prone mice homozygous for the lpr mutation respond poorly to mitogens in terms of proliferation and of IL-2 production. In a previous study, we have correlated this deficient activation with the inability of mitogens to stimulate hydrolysis of phosphatidylinositol 4,5-bisphosphate in lpr T cells, although these cells bind mitogen and express the TCR/CD3 complex. In order to determine whether activation-deficient lpr T cells contain functional GTP-binding (G) protein(s) and phospholipase C, we examined the effects of the G protein activating agent sodium fluoride plus Al+3 (AlF-4). AlF-4 stimulated phosphatidylinositol turnover, a response characteristic of TCR/CD3 occupancy, in mature L3T4+ and Ly2+ T cells. Second, and more important, AlF-4 stimulated the same biochemical events in L3T4-, Ly2- (double-negative) T cells from the normal thymus or from the enlarged lymph nodes of autoimmune-prone mice homozygous for the lpr mutation. However, these double-negative T cells were unresponsive to receptor-active ligands such as T cell mitogens or anti-CD3-epsilon mAb, despite their ability to bind these ligands. These findings suggest that activation-deficient double negative T cells express the receptors, G protein(s) and effector enzymes necessary for second messenger formation and further suggest that the failure of these cells to generate the relevant second messengers in response to mitogens or anti-CD3-epsilon antibody may be due to inefficient coupling of the TCR/CD3 complex to G proteins.     

Studies of congenitally immunologic mutant New Zealand mice. II. Absence of T cell progenitor populations and B cell defects of congenitally athymic (nude) New Zealand Black (NZB) mice.

Congenitally athymic (nude) mice on an NZB, NZW, and BALB/c background were produced by repetitive selective backcrossing. F'12 generation nude mice of these three strains were compared to their littermate nu/+ controls with respect to survival, histology, blood counts, splenic surface markers, response to mitogens, spontaneous plaque-forming cells, and appearance of naturally occurring thymocytotoxic antibodies (NTA). Under specific pathogen-free conditions, NZB nude mice survive less than 3 weeks, dying of a runting-like disease with infection by local normally noninvasive organisms. A contributing factor to his premature death is the relative absence of T cell progenitor populations in the NZB nude vs NZW nude or BALB/c nude groups. Furthermore, NZB nude mice have a significantly earlier appearance of NTA than nu/+ littermates and likewise appear to have heightened spontaneous polyclonal B cell responses against the haptens dansyl, nitroiodophenyl, trinitrophenyl,2,4 dinitrophenyl, and sulfonate. It is suggested that NZB mice have several critical immunologic defects, including abnormalities of thymic epithelial cells, T cell differentiation pathways, and chronically polyclonal activated B cell populations. These defects interact to produce the clinical expression of autoimmunity.     

The differential ability of splenic adherent cells from B6.lpr mice to induce suppressor T cells

Hapten-coupled splenic adherent cells or resident peritoneal cells from autoimmune B6.lpr mice that are over 5 mo of age fail to induce first-order inducer suppressor T cells (Ts1). However, the same population of hapten-coupled cells can induce both delayed-type hypersensitivity responses and third-order effector suppressor T cells (Ts3). Thus, splenic and peritoneal antigen-presenting cells from B6.lpr mice display a defined defect in the ability to induce certain suppressor T cell responses. The cellular defect in Ts1 induction is controlled by the lpr gene, since age-matched congenic B6 mice do not display this defect. The splenic adherent cell defect is temporarily correlated with the autoimmunity that develops in B6.lpr animals. The antigen-presenting defect in the B6.lpr splenic adherent population for Ts1 induction is reversible by culturing the cells in interferon-gamma. The results are discussed as an illustration of the relationship between experimental models of autoimmunity and defects in a suppressor T cell cascade.