Circulating and pokeweed mitogen-induced immunoglobulin-secreting cells in systemic lupus erythematosus.

Peripheral blood mononuclear cells (PBM) obtained from patients with active untreated systemic lupus erythematosus (SLE) were evaluated both for the number of cells spontaneously secreting immunoglobulin (Ig) as well as for their capacity to generate immunoglobulin-secreting cells (ISC) in vitro in response to pokeweed mitogen (PWM). ISC were enumerated by a reverse haemolytic plaque assay designed to quantify the number of cells secreting IgG, IgM and IgA. PBM obtained from eight patients with active untreated SLE contained markedly increased numbers of ISC compared to age-, sex-, and race-matched normal control PBM. SLE PBM contained a mean of 13,805 +/- 3266 ISC per 10(6) cells, of which 74% secreted IgG, 10% IgM and 22% IgA, while normal PBM contained a mean of 779 +/- 143 ISC per 10(6) cells, with 57% secreting IgG, 25% IgM and 33% IgA. PBM obtained from SLE patients were also examined for their ability to generate ISC in vitro in response to PWM. SLE PBM were markedly deficient in their capacity to respond to PWM with the differentiation of ISC. This diminished responsiveness could not be ascribed to serum factors, the presence of increased numbers of cells with suppressive capacity or the absence of potentially responsive B cells. Rather, a deficiency of helper T cell activity appeared to be responsible. This was indicated by the observation that PWM responsiveness could be restored to SLE PBM by co-culturing them with purified mitomycin C-treated normal T cells.     

Paraneoplastic IgG striational autoantibodies produced by clonal thymic B cells and in serum of patients with myasthenia gravis and thymoma react with titin.

Autoantibodies with heterogeneous specificities for contractile elements of striated muscle are found in 80 to 90% of patients who have myasthenia gravis (MG) with thymoma. The stimulus for production of these paraneoplastic striational autoantibodies (StrAb) is unknown. One approach to understanding their association with MG and thymoma is to define the antigenic specificities of monoclonal StrAb secreted by B cell lines established from patients who have MG and thymoma. Here, we report the isolation from a single patient of two independent thymic B cell clones secreting StrAb of IgG isotype. In immunoblots, both StrAb bound monospecifically to an antigen of human skeletal muscle that comigrated with the high molecular weight protein, titin. The pattern of immunofluorescence staining yielded by both antibodies in cultured human muscle cells was similar to that produced by rabbit polyclonal anti-titin antibodies. Each monoclonal antibody bound to a different region of the sarcomere in stretched myofibrils; these corresponded to sites previously reported to bind murine anti-titin monoclonal antibodies. The pattern of sarcomere immunostaining produced by combining the two human monoclonal antibodies was indistinguishable from that produced by serum IgG from the patient whose thymus yielded the B cell clones. Thus, the monoclonal antibodies appear to identify two epitopes of titin that are recognized by IgG StrAb in serum. The finding that IgG anti-titin autoantibodies are restricted to serum of MG patients who have thymoma suggests that titin is a major specificity of IgG StrAb. Our additional finding that anti-titin IgG binds to striated elements in medullary myoid cells of the human thymus supports the hypothesis that StrAb represent an intrathymic B cell immune response that is initiated by autoantigens that are rendered immunogenic for helper T cells in the course of noeplastic transformation to thymoma.     

Evidence for a malignant proliferation of IgE-class specific helper T cells in a patient with Sézary syndrome exhibiting massive hyperimmunoglobulinemia E

Peripheral blood mononuclear cells (PBM) from a patient with Sézary syndrome exhibiting massive hyperimmunoglobulinemia E were examined in vitro. The patient's PBM and B cells (Bp) but not normal individuals' PBM and B cells (Bn) produced spontaneously large amounts of IgE. The addition of pokeweed mitogen (PWM) did not affect IgE production by both the patient's and normal individuals' PBM. The IgE production by PWM-stimulated Bp was depressed when cocultured with normal T cells but not depressed with the patient's T cells (Tp). When Tp were cocultured with Bn, significantly larger than expected quantities of IgE were produced. Ig assay of the same supernates showed that Tp had significantly less helper activities for IgG, IgA, and IgM production. Almost all Tp possessed the Leu3a and Leu3b antigens which are expressed on the helper/inducer T cell subset. These results indicate that the neoplastic cells in this patient originated from a subset of T cells programmed not for IgG, IgA, and IgM, but for IgE synthesis.     

Evidence that Pokeweed-Mitogen-reactive B Cells are Pre-committed in Vivo to the High-rate Secretion of a Single Immunoglobulin Isotype in Vitro

Normal human peripheral blood B cells that respond to pokeweek mitogen (PWM)-activated irradiated T cells with high-rate immunoglobulin secretion in vitro were analysed with respect to the frequency of the cells stimulated to high-rate immunoglobulin secretion in vitro and whether the progeny of each cell had the potential to secrete one or multiple immunoglobulin isotypes. In vitro cultures containing limiting numbers of human B cells were initiated in the presence of PWM and excess irradiated T cells, and the quantity of IgM, IgG and IgA secreted was determined after 9 days. The level of immunoglobulin secretion per cell in limiting-dilution microcultures was shown to be equivalent to that seen in the routinely used macrocultures, indicating that major loss of B-cell function was not occurring in the microcultures. At limiting B-cell numbers, individual microcultures were of ten shown to produce immunoglobulin of a single isotype, either IgM, IgG or IgA. Cultures that did produce multiple immunoglobulin isotypes occurred with a frequency predicted by the random distribution of B cells committed to production of a single isotype. A similar independent distribution of IgM anti-tetanus toxoid and IgG anti-tetanus toxoid antibody-producing precursors was observed when B cells selected on the basis of surface IgM were used in the microcultures. These results suggest that PWM-reactive B cells are at a stage of maturation in vivo such that they have the potential to secrete a single immunoglobulin isotype when activated in vitro.     

Bacterial lipopolysaccharide-induced immunoglobulin synthesis by human blood lymphocytes partially depleted of monocytes.

Bacterial lipopolysaccharide (LPS), a potent polyclonal B cell activator in rodents has not been found to be a consistent activator of human peripheral blood mononuclear cells (PBM). Since LPS activates monocytes to become suppressor cells, we asked whether depletion of monocytes would enhance the ability of LPS to induce in vitro activation and immunoglobulin synthesis and secretion by human B lymphocytes. Addition of 50 micrograms/ml LPS for 7 days to PBM cultures failed to induce a significant increase in IgM and IgG synthesis as measured by radioimmunoassay of culture supernatants. However, after partial depletion of adherent cells, the non-adherent cell population (NAC) produced large amounts of IgM and IgG (IgM: 696 ng/10(6) PBM vs 4236 ng/10(6) NAC, P less than 0.005; IgG: 68 ng/10(6) PBM vs 922 ng/10(6) NAC, P less than 0.02). The LPS-induced response was found to be T cell dependent and could be readily suppressed by the addition of autologous adherent cells. Addition of indomethacin to LPS-stimulated PBM did not result in increased Ig secretion. The poor response of human blood B cells to LPS may be due to the suppressive effect of activated monocytes.     

Natural killer T cells and innate immune B cells from lupus-prone NZB/W mice interact to generate IgM and IgG autoantibodies

Lupus-prone NZB/W F1 mice develop glomerulonephritis after T helper cell-dependent isotype switching of autoantibody secretion from IgM to IgG at about 6 months of age. We compared innate immune natural killer (NK) T cells and conventional T cells for their capacity to help spontaneous in vitro immunoglobulin and autoantibody secretion of innate immune (B-1 and marginal zone) and conventional (follicular) B cell subsets from NZB/W F1 mice. We found that purified NKT cells not only increased spontaneous secretion of IgM and IgM anti-double-stranded (ds)DNA antibodies by B-1 and marginal zone B cells, but also facilitated secretion of IgG anti-dsDNA antibodies predominantly by B-1 B cells. Few IgM or IgG anti-dsDNA antibodies were secreted by follicular B cells, and conventional T cells failed to provide potent helper activity to any B cell subset. All combinations of T and B cell subsets from normal C57BL/6 mice failed to generate vigorous IgM and IgG secretion. NZB/W NKT cell helper activity was blocked by anti-CD1 and anti-CD40L mAb. In conclusion, direct interactions between innate immune T and B cells form a pathway for the development of IgM and IgG lupus autoantibody secretion in NZB/W mice.     

Thyroid autoantibody synthesis by lymphocytes from different lymphoid organs: fractionation of B cells on density gradients

Lymphocytes from thymus, blood, lymph nodes and thyroid tissue of patients with autoimmune thyroid disease have been assessed for their ability to synthesize thyroid autoantibodies spontaneously or following stimulation by Pokeweed mitogen (PWM). Blood and thymic lymphocytes synthesized IgG and microsomal or thyroglobulin antibodies of IgG class in response to PWM (and were therefore probably B-memory cells), while thyroid lymphocytes frequently secreted autoantibodies spontaneously. Lymph node lymphocytes resembled blood lymphocytes in terms of increased production of IgG in response to PWM; however, spontaneous secretion of thyroid autoantibodies was observed in some lymph node suspensions, and the magnitude of the increment in thyroid autoantibodies synthesized in response to PWM was lower than that observed for blood lymphocytes. Fractionation of B-cell enriched populations on density gradients and subsequent incubation of the fractions with T cells and PWM demonstrated that, whereas blood B cells capable of synthesizing autoantibody were found in both medium and low density fractions, lymph node precursors of thyroid autoantibody-secreting cells were associated almost exclusively with the light fractions. The presence in lymph nodes of small numbers of low density B cells, compared with a much higher proportion of the heterogeneous population capable of secreting IgG, could account for the discrepancy between the IgG and autoantibody response to PWM. Further, it seems likely that the density difference in the autoantibody precursor population of lymph nodes and blood is related to the difference in the state of activation of B cells in these lymphoid organs.     

Enrichment and depletion of thyroglobulin autoantibody synthesizing lymphocytes.

Lymphocyte populations enriched for (or depleted of) a receptor for thyroglobulin (Tg) have been prepared from Hashimoto peripheral blood mononuclear cells (PBM) by rosetting with Tg coated erythrocytes. Removal of Tg binding cells from PBM or B cell preparations resulted in greater than 85% reduction in their ability to synthesize Tg antibody when stimulated with pokeweed mitogen (PWM) or EB virus (EBV); the depletion was specific since the ability of Tg receptor negative cells to secrete microsomal antibody and total IgG was unimpaired. Hashimoto lymphocytes (PBM or B cells) enriched for Tg binding cells produced only small amounts of Tg antibody when cultured with PWM even in the presence of irradiated T cells and monocytes; exposure to autoantigen followed by mitogen appeared to be inhibitory. However, the Tg receptor positive fraction was readily activated by EBV to synthesize Tg antibody with a specific activity 4-10 times higher than that secreted by unfractionated lymphocytes. The ability to isolate Tg specific B cells from peripheral blood will facilitate the development of EBV transformed cell lines secreting monoclonal Tg antibody and such antibodies will provide invaluable probes in the investigation of autoimmune thyroid disease.     

Are cord blood B cells functionally mature?

Very low immunoglobulin secretion occurs in pokeweed mitogen (PWM) stimulated cord blood mononuclear cells (MNC) and has been attributed to an 'immaturity' of both T and B cells of the newborn. The cord blood T cells are phenotypically 'naive' cells, in which suppressor activity for B cell function appears to dominate over helper activity. The cord blood B cells, in spite of their expression of different membrane immunoglobulin isotypes, secrete almost no IgG and IgA in the various B cell assays so far compared. We found that cord blood B cells are as competent as B cells from adults to generate clonal IgM, IgG and IgA responses in a culture system in which a cell contact with mutant EL-4 thymoma cells in conjunction with T cell supernatant leads to strong B cell activity. As regarding the possible causes of the low cord blood PWM response, we studied the role of transforming growth factor-beta 1 (TGF-beta 1), a potent inhibitor of lymphocyte functions. TGF-beta 1 sensitivity of B cells and TGF-beta 1 mRNA levels in MNC were found to be similar for adult and cord blood cells. A neutralizing anti-TGF-beta 1 antibody enhance the adult PWM response, but the immunoglobulin secretion in cord MNC remained very low. We conclude that suppression by endogenous TGF-beta 1 occurs in the PWM system but is not responsible for the low immunoglobulin response of cord blood MNC and that the newborn's B cell 'immaturity' can be overcome with potent T cell signals in vitro. This is consistent with the newborn's capacity to generate a T-dependent B cell response in vivo.     

Is the activated T helper stimulus able to induce Ig isotype switching in cultured human B cells?

It Is confirmed that large amounts of IgM, IgG, and IgA areproduced when human B cells are cultured with T cells activatedby immobilized CD3 antibody (CD3 system). IL-2 was essential;lowerlevels of Ig production with different isotype ratios were obtainedif IL-4 or IL-6 replaced IL-2. Depletion of sIgG⁺ or sIgA⁺ cellsfrom the B population to be cultured markedly reduced productionof IgG or IgA. Culturesof B cells selected with the pan-B markersCD19, CD72, or CD21 contained similar levels of Ig of all threeisotypes, whereas B cells selected for sIgM or sIgD expressionproduced IgM but very little IgG or IgA indicating that littleisotype switching was occurring. Production of IgG or IgA fromcells expressing these isotypes was more efficient than productionof IgM from IgM⁺ IgD⁺ cells. These results are considered inthe light of the demonstration by others of the production ofmultiple isotypes from single sIgM⁺-selected B cells. Clonedhuman T cells from a single donor induced production of allthree isotypes, but the proportions varied indicating that thepotent T-B cell interactions inducing B cell activation mayoverride and conceal the operation of isotype specific cellinteractions. Some T clones used at an optimal dose were aseffective untreated as X-irradiated, whereas with other clonesmaximumIg production was not achieved without irradiation.     

Human post-thymic precursor cells in health and disease. I. Characterization of the autologous rosette-forming T cells as post-thymic precursors.

Human autologous-rosette-forming T cells (Tar cells) have many of the characteristics of post-thymic precursor cells. Thus, they bind to sheep erythrocytes but have neither receptors for the Fc portion of IgG nor for that of IgM. They include a subpopulation that binds peanut agglutinin which suggests that they are immature and, as opposed to T cells with either receptors for the FC portion of IgM (T mu) or of IgG (T gamma), Tar cells adhere to nylon wool, another possible indicator of immaturity, as is their extreme sensitivity to hydrocortisone both in vitro and in vivo. There are more Tar cells in cord blood than in the peripheral blood of young adults and there are more Tar cells in the peripheral blood of young adults than in the peripheral blood of elderly subjects. By co-culturing T mu and B cells, or T mu, or Tar and B cells in the presence of pokeweek mitogen (PWM) we were able to determine that these cells cause feedback inhibition, a function considered characteristic of post-thymic precursors. In co-cultures in which we placed mononuclear cells (MNC) or MNC plus Tar cells, or MNC depleted of Tar cells or MNC depleted of Tar cells plus Tar cells stimulated with PWM, we determined that Tar cells play a role in the generation of suppression thereby confirming that human Tar cells are precursor cells. We also found that Tar cells proliferated and generated T gamma and T mu cells both spontaneously and in greater numbers, under the effect of serum thymic factor.     

T cell dependent differentiation of human B cells: direct switch from IgM to IgE, and sequential switch from IgM via IgG to IgA production.

Ig production by splenic human B cells that express different surface Ig isotypes were analysed in limiting dilution cultures. Therefore, FACS sorted IgM+, IgG+ and IgA1+ B cells were stimulated with PMA-activated EL4 thymoma cells as helper cells in the presence of IL-2 and IL-4. We found that at least every second B cell responded in vitro and secreted the antibody corresponding to its surface Ig isotype. IgE secreting cells developed from surface IgM+ D+ cells (1/31 to 1/167), but not from IgG+ or IgA1+ cells (much less than 1/5000). Negative signalling of the IgM+ B cells by addition of anti-IgM antibodies into the cultures reduced the number of single IgM producing cells by greater than 85%, and completely inhibited IgE switch. In contrast, anti-IgG and anti-IgA antibodies did not reduce the IgE response. The results indicate a direct switch from IgM to IgE secretion in vitro. In contrast to IgE, IgA secreting cells developed from IgM+D+ (1/30 to 1/51) and from IgG+ B cells (1/14 to 1/25). Negative signalling of the IgG+ B cell subset within total B cells by anti-IgG antibodies suppressed the development of IgG as well as IgA producing cells, but did not inhibit IgM and IgE responses. This indicates a sequential switch from IgM via IgG to IgA. Taken together, this study indicates that IgE secreting cells are derived directly from IgM+D+ B cells by non-sequential switching, whereas IgA producing cells preferentially develop by sequential switching via IgG+ B cells.     

Bacterial peptidoglycan induces in vitro rheumatoid factor production by lymphocytes of healthy subjects.

The present studies were carried out to further characterize the polyclonal B cell activating properties of bacterial peptidoglycan (PG) and to determine if this ubiquitous agent induces in vitro IgM rheumatoid factor (RF) production by lymphocytes from healthy volunteers. Peripheral blood mononuclear cells (PBMC) were cultured in the presence of peptidoglycan, pokeweed mitogen (PWM), a standard polyclonal B cell activator, or additional culture medium. Supernatants were harvested on days 7-8 for determination of total IgM, total IgG, and IgM RF by an enzyme-linked immunosorbent assay (ELISA). PG and PWM induced comparable amounts of total IgM production but PG was a less potent stimulant of total IgG production. PG induced in vitro IgM-RF production in 9/33 experiments, a frequency of response of less than that observed in corresponding PWM stimulated cultures (22/33 experiments). PG-induced IgM-RF production depended upon active protein synthesis and did not correlate with the magnitude of PG-induced total IgM production. The latter finding suggests that PG-induced IgM-RF may not merely reflect polyclonal B cell activation. These results add to a growing list of PG's functional properties and provide further impetus for considering this ubiquitous agent as a potential stimulant for in vivo RF production.     

Persistence of anti-donor allohelper T cells after neonatal induction of allotolerance in mice

BALB/c mice rendered tolerant to A/J alloantigens by neonatal injection of 10(8) (A/J X BALB/c)F1 spleen cells develop an autoimmune disease associated with a polyclonal activation of donor B cells. To study the mechanisms leading to donor B cell activation in tolerant mice, we prepared mixed lymphocyte cultures (MLC) between splenic T cells from neonatally injected mice and donor-type (A/J X BALB/c)F1 or third-party (C57BL/6 X BALB/c)F1 B cells. T cells from tolerized mice were unable to generate cytotoxic T lymphocytes, to proliferate or to secrete interleukin (IL)2 after stimulation with donor alloantigens in MLC. These T cell responses were present after MLC with third-party antigens, but were of lower intensity than those generated by control BALB/c T cells. In contrast, T cells from tolerized mice stimulated immunoglobulin production by donor-type (A/J X BALB/c)F1 B cells much more powerfully than T cells from control BALB/c mice. The stimulation of donor-type (A/J X BALB/c)F1 B cells was polyclonal, as attested by the levels of anti-hapten and anti-DNA antibodies in the MLC supernatants. IgM was the dominant isotype secreted in vitro, but IgG1 and IgG3 were also produced in significant amounts. Lysis experiments indicated that the T cells responsible for F1 B cell stimulation in MLC were CD4+ host T cells. These T helper cells were alloreactive since they did not stimulate syngeneic BALB/c B cells, and their effect on donor B cells was specifically blocked by anti-donor Ia monoclonal antibodies. Addition of anti-IL 4 monoclonal antibody to MLC between T cells from tolerant mice and (A/J X BALB/c)F1 B cells almost completely abolished the production of IgG1, but not that of IgM or IgG3. Taken together, these findings indicate that neonatal injection of alloantigens in BALB/c mice induces a state of dissociated tolerance, with unresponsiveness of anti-donor T cells secreting IL 2 on the one hand, and persistence of T cells responsible for B cell help and IL 4 secretion on the other hand.     

Antibody to bacteriophage phi X 174 synthesized by cultured human peripheral blood lymphocytes

Following immunization of human subjects with the antigen bacteriophage phi X 174, concomitant with the rise in serum antibody, cells appear in the circulation which in vitro, without antigen stimulation, synthesize antibody of the same class as serum antibody in most subjects studied. This function is inhibited by puromycin or irradiation, is independent of T cells and occurs within the first 36-72 h of culture. Such cells are found only in recently immunized subjects. Peripheral blood mononuclear cells (PBM) from all immunized subjects synthesize more antibody to phi X 174 in vitro if antigen is present during cell culture; none was synthesized by antigen containing PBM cultures from unimmunized subjects. This antigen-induced antibody response is T cell and antigen dose-dependent and inhibited by puromycin or irradiation. Following primary immunization the antibody synthesized in vivo and in vitro is IgM. Following secondary immunization IgG antibody is immediately detected in vivo but in vitro antigen-induced antibody continues to be IgM for at least 3 months. IgG antibody then appears: once this class switch occurs, in vitro antigen-induced IgG antibody can be demonstrated in cultured PBM of subjects for many years, without further booster immunization.     

Lymphocyte subpopulations in non-neoplastic thymus from myasthenia gravis patients.

Lymphocyte populations in non-neoplastic thymuses from fifteen patients with myasthenia gravis (MG) were examined. As in normal subjects, the great majority of thymic lymphocytes of MG patients are T cells. When MG thymuses were compared to normal glands, lower percentages of lymphocytes able to form E rosettes resistant to incubation at 37 degrees C (stable E rosettes) were found in MG thymuses. A negligible B cell content was detected in eight normal and in eight MG thymuses with absent or rare lymph follicles; but there was a substantial B cell presence in the thymuses of seven MG cases with thymic hyperplasia containing many germinal centres. Normal and MG thymuses contain the same percentage of lymphocytes bearing receptors for the Fc portion of IgM (TM). Moreover, the IgM Fc receptor was found mostly on cells which did not form stable E rosettes and did not bear surface immunoglobulin. The possible significance of these findings is discussed.     

Epstein-Barr-virus-transformed lymphoblastoid cell lines derived from patients with X-linked agammaglobulinaemia and Wiskott-Aldrich syndrome: responses to B cell growth and differentiation factors.

Epstein-Barr-virus-transformed B lymphoblastoid cell lines (EBV-transformed LCL) from three patients with X-linked agammaglobulinaemia (XLA), six patients with Wiskott-Aldrich Syndrome (WAS), and seven normal donors, were tested for growth and differentiation in response to human recombinant IL-4, a commercially available, low molecular weight B cell growth factor (BCGFlow), and B cell differentiation factor (BCDF) secreted by the T24 cell line, now known to be IL-6. Proliferation (3H-TdR uptake) by EBV-transformed LCL from both XLA and WAS patients in response to BCGFlow was similar to that obtained with the normal cell lines. In addition, three normal and three WAS, but none of the XLA EBV-transformed LCL, proliferated a little in response to IL-4. All the normal B cell lines secreted IgM, and six out of the seven secreted IgG in response to BCGFlow and BCDF. A similar pattern of response was obtained with the WAS EBV-transformed LCL (6/6 secreted IgM and 4/6 secreted IgG). Several of the normal and WAS EBV-transformed LCL also secreted IgM and IgG in response to IL-4. In contrast, the lines from the XLA patients were abnormal. One secreted large amounts of IgM and two secreted small amounts, but none of the XLA lines secreted IgG constitutively or in response to any of the factors (IL-4, BCDF). The lack of detectable IgG secretion by the XLA lines was probably due to an absence of precommitted IgG B cell precursors transformed by EBV rather than an intrinsic inability to respond to BCGF and BCDF. All of the lines, including those derived from XLA patients, were shown to secrete B cell growth and differentiation factors detected on indicator B cell lines. These results suggest that the abnormal X-linked genes responsible for XLA and WAS do not interfere with B cell responses to B cell growth and differentiation factors.     

Aberrant immunoregulatory control of B lymphocyte function in lepromatous leprosy.

The capacity of peripheral blood mononuclear (PBM) cells from patients with leprosy to generate immunoglobulin-secreting cells in response to pokeweed mitogen (PWM) was evaluated by a reverse haemolytic plaque forming cell (PFC) assay. The PFC responses of PBM cells from patients with lepromatous (Lpr) leprosy were significantly higher (P less than 0.01) than those of PBM cells from normal controls and patients with tuberculoid leprosy. Co-culture of T lymphocytes from normal donors with PBM cells from Lpr patients reduced the PFC response of these cells to the normal range. T4+-helper lymphocytes from Lpr donors did not induce supranormal responses to PWM by normal PBM cells enriched for B lymphocytes. T8+-suppressor lymphocytes from normal donors greatly reduced the response of cultures containing normal allogeneic B cells plus T4+ cells. Conversely, when T8+ cells from Lpr donors were cocultured with normal B cells plus T4+ cells, they failed to suppress the response to PWM. In summary, these studies have demonstrated abnormally high PWM-stimulated PFC responses by B lymphocytes from patients with Lpr leprosy. This aberration, in turn, is associated with a loss of regulatory function by T8+-suppressor cells in Lpr patients.