The differential impact of natural killer (NK) cell education via KIR2DL3 and KIR3DL1 on CCL4 secretion in the context of in-vitro HIV infection.

Carriage of certain inhibitory natural killer (NK) cell receptor (iNKR)/HLA ligand pairs is associated with protection from infection and slow time to AIDS implicating NK cells in HIV control. NK cells acquire functional potential through education, which requires the engagement of iNKRs by their human leucocyte antigen (HLA) ligands. HIV infection down-regulates cell surface HLA-A/B, but not HLA-C/E. We investigated how NK cell populations expressing combinations of the iNKRs NKG2A, KIR2DL3 (2DL3) and KIR3DL1 (3DL1) responded to autologous HIV infected CD4 (iCD4) cells. Purified NK cells from HIV-uninfected individuals were stimulated with autologous HIV iCD4 or uninfected CD4 T cells. Using flow cytometry we gated on each of the 8 NKG2A+/- 2DL3+/- 3DL1+/- populations and analysed all possible combinations of interferon (IFN)-γ, CCL4 and CD107a functional subsets responding to iCD4 cells. Infected CD4 cells induced differential frequencies of NKG2A+/- 2DL3+/- 3DL1+/- populations with total IFN-γ+ , CCL4+ and CD107a+ functional profiles. 2DL3+ NKG2A+ NK cells had a higher frequency of responses to iCD4 than other populations studied. A higher frequency of 2DL3+ NK cells responded to iCD4 from individuals that were not HLA-C1 homozygotes. These results show that 2DL3+ NK cells are mediators of HIV-specific responses. Furthermore, responses of NK cell populations to iCD4 are influenced not only by NK cell education through specific KIR/HLA pairs, but also by differential HIV-mediated changes in HLA expression.

Phenotypical and functional profiles of natural killer cells exhibiting matrix metalloproteinase-mediated CD16 cleavage after anti-HIV antibody-dependent activation.

Natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) has been linked to protection from HIV infection and slower progression towards AIDS. However, antibody-dependent activation of NK cells results in phenotypical alterations similar to those observed on NK cells from individuals with progressive HIV infection. Activation of NK cells induces matrix metalloproteinase (MMP)-mediated cleavage of cell surface CD16. In the present study we assessed the phenotype and functional profile of NK cells exhibiting post-activation MMP-mediated CD16 cleavage. We found that NK cells achieving the highest levels of activation during stimulation exhibit the most profound decreases in CD16 expression. Further, we observed that educated KIR3DL1(+) NK cells from human leucocyte antigen (HLA)-Bw4-carrying donors exhibit larger decreases in CD16 expression post-activation than the KIR3DL1(-) NK cell subset containing cells educated via other inhibitory receptor/ligand combinations and non-educated NK cells. Lastly, we assessed the ex-vivo expression of CD16 on educated KIR3DL1(+) NK cells and the KIR3DL1(-) NK cell subset from HLA-Bw4-carrying HIV-uninfected and HIV-infected donors. Suggestive of in-vivo activation of KIR3DL1(+) NK cells during HIV infection, CD16 expression was higher on KIR3DL1(+) than KIR3DL1(-) NK cells in uninfected donors but similar on both subsets in HIV-infected donors. These results are discussed in the context of how they may assist with understanding HIV disease progression and the design of immunotherapies that utilize antibody-dependent NK cell responses.

Persistent human immunodeficiency virus-1 antigenaemia affects the expression of interleukin-7Ralpha on central and effector memory CD4+ and CD8+ T cell subsets.

Interleukin (IL)-7 and its receptor (IL-7Ralpha) play important roles in regulating lymphopoiesis. Previous studies have reported that human immunodeficiency virus-1 (HIV-1) viraemia affects the expression of IL-7Ralpha, but its effects on CD4+ and CD8+ T cell memory subsets have not been studied. Using eight-colour flow cytometry, we compared the immunophenotypic patterns of CD4+ and CD8+ T cell subsets expressing IL-7Ralpha and activation markers, as well as circulating IL-7 levels, in three well-defined groups of HIV-1-infected subjects: successfully treated, viraemic and long-term non-progressor (LTNP). Compared with successfully treated and LTNP subjects, viraemic patients had reduced expression of IL-7Ralpha on both CD4+ and CD8+ T cells, particularly on central and effector memory T cell compartments, and substantially elevated expression of activation markers on CD8+ T cell subsets. Circulating IL-7 levels were correlated negatively with the number of CD4+ and CD8+ T cell subsets expressing IL-7Ralpha; these associations were stronger with CD4+ T cell subsets and mainly with central and effector memory cells. The expression of activation markers on CD4+ and CD8+ cell T subsets was not related to circulating IL-7 levels. A strong negative correlation was observed between central memory CD4+ or CD8+ T cells expressing IL-7Ralpha and those expressing activation markers, independently of IL-7 levels. Collectively, these results provide further insight on the role of unsuppressed viral load in disrupting the IL-7/IL-7Ralpha system and contributing to HIV-1 disease progression.

High incidence of thyroiditis and anti-thyroid autoantibodies in NOD mice.

NOD mice develop spontaneous insulin-dependent diabetes mellitus (IDDM) associated with infiltration of pancreatic islets with mononuclear cells. Islet infiltration results in autoimmune destruction of insulin-secreting beta-cells. Because in humans and BB rats diabetes is often associated with autoimmune thyroid disease (ATD), the NOD mouse model was examined for evidence of thyroiditis and serum antibodies reactive with mouse thyroid membrane antigens (MTMAs). The incidence of thyroiditis was 77% in mice greater than 180 days old, 67% in mice 61-180 days old, 72% in mice 31-60 days old, 74% in mice 21-30 days old, 78% in mice 11-20 days old, and 90% in mice less than or equal to 10 days old. NOD mice less than or equal to 30 days old had less-severe thyroiditis than animals greater than 180 days old. There was no significant different in severity of thyroiditis between any of the other age-groups tested. The incidence of thyroiditis was not increased in diabetic compared with nondiabetic animals, nor was an association found between thyroiditis and sex. The high incidence of thyroiditis in the less than or equal to 30-day-old age-group indicates that infiltration of lymphocytes into the thyroid can precede initiation of insulitis in this model. Although both thyroiditis and insulitis in NOD mice began early (by the 1st and 2nd mo of life, respectively), no significant association between infiltration of these two organs was noted in individual mice.(ABSTRACT TRUNCATED AT 250 WORDS)

HIV-specific cytotoxic T-lymphocyte activity in immunologically normal HIV-infected persons.

BACKGROUND: CD8+ T-cell counts usually increase soon after infection with HIV, whereas CD4+ cell counts decrease. The result of these changes in T-cell subpopulation subsets in most HIV-infected subjects is inversion of the CD4 : CD8 ratio from greater than 1.0 typical of uninfected persons to less than 1.0 after infection. SUBJECTS: Six HIV-infected individuals were identified in whom the CD4 : CD8 ratio remained normal throughout follow-up (4.0-11.25 years). They all maintained levels of CD4+ cells above 500 x 10(6)/l and had never received antiretroviral therapy. Because HIV-specific cytotoxic T lymphocytes (CTL) have been implicated in control of HIV during the asymptomatic phase of disease, we screened these individuals for the presence of HIV-specific CTL activity. METHODS: CTL activity was assessed in freshly isolated peripheral blood mononuclear cells (PBMC) and in phytohaemagglutinin-stimulated interleukin-2 expanded cell lines established from PBMC. Cytotoxicity to HIV-1 env, gag, pol and nef gene products was surveyed in a 4 h 51Cr-release assay using autologous Epstein-Barr virus (EBV) transformed B cells infected with vaccinia constructs expressing each of these HIV genes. The immunodominant CTL epitope and MHC class I antigen restriction specificity of HIV-specific CTL was mapped when present. Plasma viral load was assessed by branched DNA assay. Attempts were made to isolate virus from these individuals by the PBMC coculture assay. RESULTS: None of the six immunologically normal HIV-infected (INHI) subjects exhibited direct HIV-specific CTL activity in their freshly isolated PBMC compared with 16 (47%) out of 34 HIV disease progressors (P = 0.03, chi2 test) and one out of 10 seronegative subjects. Three of the six INHI subjects had detectable memory HIV-specific precursor CTL (pCTL) activity in in vitro-activated T-cell lines compared with 25 (73.5%) out of 34 HIV-1 disease progressors and in none out of 10 seronegative individuals. All three INHI subjects had Gag-specific pCTL, and none had reverse transcriptase-specific pCTL. Plasma HIV viraemia in all six INHI subjects was below the level of detection by branched DNA assay (< 500 copies/ml). Virus could not be isolated from four of these individuals despite multiple attempts to do so by PBMC coculture assays. CONCLUSION: Direct HIV-specific CTL activity mediated by activated circulating PBMC was undetectable in six INHI individuals under conditions where it is frequently observed in HIV disease progressors. Despite the absence of cells activated for killing HIV-infected targets in the circulation of these individuals, they appeared able to control their HIV infection by maintaining normal levels of CD4 and CD8 cells and low viral load.

Correlation of presentation of insulin with surface I-Ad and A alpha and A beta mRNA expression by cloned B lymphoma hybridoma variants.

We investigated the relationship between Ia expression and antigen presentation in cloned B cells, using variants of TA3 antigen presenting cells. Two TA3 subclones were selected as high presenters and 5 as low presenters of insulin to pork insulin/I-Ad restricted T cells. All TA3 subclones express the surface I-Ak, I-Ek, I-Ad and I-Ed Ia antigens characteristic of the parental cell line. However, surface I-Ad levels correlated best with the ability to present insulin, since high presenters express 2- to 4-fold more I-Ad than low presenters. High presenters possess 2- to 4-times more A alpha and A beta Ia mRNA than low presenters and also transcribe these mRNAs 2- to 5-fold faster than most low presenters. Thus, the correlation noted between I-Ad surface density and capacity to present insulin by our panel of TA3 variants is regulated at the level of transcription and not translation of I-Ad specific mRNAs.

Improvement of HIV-specific immunity in HIV-infected twins treated with highly active antiretroviral therapy, interleukin 2, and syngeneic adoptively transferred cells.

Five HIV-seropositive twins were treated with HAART and given cycles of treatment consisting of adoptive cellular therapy from their HIV-seronegative identical twins followed by a 5-day course of intravenous IL-2. Changes in absolute and percent CD4(+) and CD8(+) cell count were monitored and compared with changes in these parameters occurring in seven age-, sex-, and disease stage-matched HIV-infected patients treated with HAART alone. Increase in the magnitude and breadth of HIV-specific immune responses was monitored in three twin subjects who received multiple treatment cycles. Absolute and percent CD4(+) cell counts rose dramatically and to significantly higher levels in the recipient twins than in control subjects treated with HAART only. The subjects who received multiple cycles of treatment developed new and increased levels of HIV-specific activated and memory cytotoxic T lymphocyte responses, and interferon gamma-secreting effector cells. Treatment consisting of HAART, adoptive cellular therapy, and IL-2 was superior to treatment with HAART alone for improving absolute and percent CD4(+) cell counts and inducing new, or increasing the magnitude of, HIV-specific immune responses in HIV infected patients.

Active immunization of patients with HIV infection: a study of the effect of VaxSyn, a recombinant HIV envelope subunit vaccine, on progression of immunodeficiency.

Infection with the human immunodeficiency virus (HIV) leads to a progressive immunodeficiency characterized by decreasing levels of CD4+ T lymphocytes. VaxSyn, a vaccine based on the recombinant envelope glycoprotein subunit (rgp160) of HIV-1IIIB, was used to immunize HIV-infected patients to determine whether its administration was beneficial with respect to slowing disease progression. A 3-year multicenter, randomized, placebo-controlled, double-blinded, efficacy and safety trial of repeated immunization with VaxSyn was used to evaluate the long-term impact on the progression of immunodeficiency. VaxSyn in alum, or alum alone, was given to 278 HIV-infected asymptomatic individuals with initial CD4 counts of > or =500 cells/mm3. Clinical findings, the CD4 count, and both virological and immunological parameters were followed. No significant differences were observed between the treatment and placebo control groups in rate of CD4 T cell decline, time to initiation of antiretroviral therapy, incidence of opportunistic infections, HIV RNA plasma viremia, HIV viral infectivity as measured by quantitative HIV coculture assay, and death. This study revealed no effect on either clinical or laboratory virological parameters from the administration of VaxSyn.

Studies of autoantibodies reactive with thyroid membrane antigens and insulin in non obese diabetic mice.

Enzyme-linked immunosorbent assay (ELISA) was used to study the temporal relationship between the appearance of murine autoantibodies reactive to insulin and thyroid membrane antigens (TMA) and the development of diabetes and thyroiditis in the non obese diabetic (NOD) mouse. Overall, 28% of NOD mice had antibodies specific for mouse thyroid membrane antigens (MTMA), 30% had antibodies to human thyroid membrane antigens (HTMA) and 23% of NOD mice had insulin autoantibodies (IAA), in at least one of their serial monthly blood samples. Non autoimmune BALB/c mice did not develop antibodies to these antigens. Presence of IAA was associated with the development of diabetes and in 87% of cases such antibodies were detected before the diabetes was diagnosed. IAA were usually demonstrated before insulitis. No association between thyroiditis and IAA was noted. Anti-MTMA and anti-HTMA antibodies were detected more frequently in NOD mice with thyroiditis than in those without thyroid inflammation. No significant association was noted between detection of serum anti-TMA antibodies and the development of diabetes. In young mice, anti-TMA antibodies were not detected in the absence of thyroiditis. Western blot analysis of NOD sera positive for MTMA by ELISA revealed a heterogeneous pattern of reactivity. The significance of these findings with respect to the pathogenesis of diabetes and thyroiditis and their association, is discussed.

Expression of major histocompatibility complex class II antigen in NOD mouse thyroid.

Non obese diabetic (NOD) mice spontaneously develop thyroiditis in addition to diabetes. Mononuclear cells begin to infiltrate the thyroid of these animals in the first month of life. The expression of major histocompatibility complex (MHC) class II (Ia) antigens by cells in the thyroid from NOD mice of various ages with and without thyroiditis was examined. We found that only 1 of the 9 infiltrated thyroids from 18 8-33 day old NOD mice surveyed expressed MHC class II antigens. Therefore Ia antigen expression appears to be secondary to infiltration and does not initiate the autoimmune process. Fourteen of 17 (82.2%) infiltrated and 7 of 11 (63.6%) uninfiltrated thyroids from NOD mice aged 51-73 days contained cells expressing Ia antigens. Sixteen of 18 (88.9%) infiltrated and all 7 of the uninfiltrated thyroids from mice aged > 89 days contained Ia positive cells. These MHC class II expressing cells included thyroid epithelial cells (TEC), as well as interstitial cells such as macrophages. Ia positive cells in the thyroid have the potential of presenting thyroid specific antigen to infiltrating T cells and thereby maintaining or potentiating thyroid autoimmune destruction. Macrophages were observed in thyroid tissue from 9 of 11 (81.8%) infiltrated and 12 of 15 (80%) uninfiltrated 8-33 day old NOD mice, thyroids from 11 of 16 (68.7%) infiltrated and 6 of 9 (66.7%) uninfiltrated 51-73 day old NOD mice, as well as 28 of 29 (96.5%) uninfiltrated and all 9 of the uninfiltrated thyroid from NOD mice aged > 89 days. Thyroids from control age matched non autoimmune BALB/c mice were consistently Ia antigen negative while macrophages were seen in some of the animals aged > 60 days.

Isotype and immunoglobulin subclass distribution of eye muscle membrane reactive antibodies in the serum of patients with thyroid-associated ophthalmopathy as detected in Western blotting.

We have determined the immunoglobulin (Ig) class (isotype) and IgG subclass of autoantibodies in the serum of patients with thyroid-associated ophthalmopathy (TAO) or autoimmune thyroid disorders without evident ophthalmopathy reactive in Western blotting with antigens of 55, 64, 75 and 95 kDa in pig eye muscle membrane (PEMM). The 22 sera studied were shown, previously, to contain IgG antibodies reactive with one or more of the four antigens. The majority of sera antibodies reactive with PEMM antigens were of two or more IgG subclasses. Of the IgG subclass specificities IgG3 and IgG4 subclass antibodies were, overall, the most common. We were unable to demonstrate IgG subclass restriction for antibodies reactive with the 95 or 55 kDa antigens in PEMM, antibody activity being equally distributed in all four subclasses tested. While most of the sera which recognized a 64 kDa antigen did so with an IgG4 antibody, all other subclasses were also represented. On the other hand all 13 sera reactive with a 75 kDa antigen did so using Ig of the IgG3 subclass and 12 of these used the IgG4 subclass as well, IgG1 and IgG2 subclasses being represented in only 3 and 4 sera, respectively. There were no differences, in respect to Ig class or IgG subclass distribution of eye muscle reactive antibodies between patients with Graves' hyperthyroidism with ophthalmopathy and those with Hashimoto's thyroiditis, and eye disease. Control sera from five normal subjects and three patients with nonautoimmune thyroid disorders did not contain antibodies reactive with these PEMM antigens of any Ig class or IgG subclass.(ABSTRACT TRUNCATED AT 250 WORDS)

Nature and significance of orbital autoantigens and their corresponding autoantibodies in thyroid-associated ophthalmopathy.

There is now considerable evidence that the pathogenesis of thyroid-associated ophthalmopathy is closely linked to the presence of a shared autoantigen(s) in the thyroid and the eye muscle, against which cytotoxic mechanisms are directed. Although the orbital connective tissue is certainly involved in the orbital inflammatory process, a 64 kDa membrane protein expressed by both the eye muscle and the thyroid and recognized consistently by antibodies in the sera of TAO patients, seems to be the most likely target candidate. While its presence in non ocular skeletal muscle is not as well established, more recent data tend to suggest the existence of a 64 kDa molecule in the three tissues. The availability of a cDNA encoding a 572 amino acid protein corresponding to a MW of 63-64 kDa, which may be the same molecule, will allow us to determine more clearly the structural characteristics of the different molecules proposed as targets. The role of the corresponding autoantibodies in the pathogenesis of the eye disease is far less well defined. Whether they play a role in the induction of the ophthalmopathy or only represent helpful markers remains to be clarified.

Effect of splenectomy on slowing human immunodeficiency virus disease progression.

BACKGROUND: Lymphoreticular tissue is the most important site for human immunodeficiency virus (HIV) replication in HIV-infected individuals. OBJECTIVE: To compare the long-term effect of splenectomy on survival and time to development of acquired immunodeficiency syndrome in subjects who had undergone splenectomy with subjects who had not undergone splenectomy. DESIGN: A cohort study with a follow-up of up to 13.4 years. SETTING: Subjects were recruited from a hospital outpatient clinic population and a multicenter study of patients with hemophilia. PARTICIPANTS: Forty-five HIV-infected individuals were observed prospectively for up to 13.4 years (17 had undergone splenectomy and 28 had not undergone splenectomy). Five subjects underwent splenectomy before acquiring HIV infection and 12 underwent splenectomy during the asymptomatic phase of HIV infection. The group who did not undergo splenectomy consisted of HIV-infected individuals who were asymptomatic at study enrollment. MAIN OUTCOME MEASURES: A Cox proportional hazards model was used to test the effects of splenectomy on survival and time to development of acquired immunodeficiency syndrome when adjusting for potential confounders (age, initial CD4+ cell count, and treatment with antiretroviral drugs). Splenectomy was treated as a time-dependent covariate to account for the variation in its timing. RESULTS: During the average follow-up of 8.6 years, 9 (53%) of the 17 subjects who underwent splenectomy and 23 (82%) of the 28 subjects who did not undergo splenectomy died; acquired immunodeficiency syndrome developed in 6 (35%) of the subjects who underwent splenectomy and 23 (82%) of the subjects who did not undergo splenectomy. Splenectomy was associated with a significant reduction of risk of developing acquired immunodeficiency syndrome (adjusted relative risk [RR] <0.4, P<.05), whereas the effect on risk of mortality approached, although it did not reach, significance (adjusted RR approximately 0.5, P approximately .10). CONCLUSION: The absence of a spleen during the asymptomatic phase of HIV infection seems to have a beneficial effect on HIV disease progression.

Markers predicting progression of human immunodeficiency virus-related disease.

Human immunodeficiency virus (HIV) interacts with the immune system throughout the course of infection. For most of the disease process, HIV activates the immune system, and the degree of activation can be assessed by measuring serum levels of molecules such as beta 2-microglobulin and neopterin, as well as other serum and cell surface phenotype markers. The levels of some of these markers correlate with clinical progression of HIV disease, and these markers may be useful as surrogate markers for development of clinical AIDS. Because the likelihood and timing of development of clinical AIDS following seroconversion, for any particular individual, are not readily predictable, the use of nonclinical disease markers has become critically important to patient management. Surrogate markers of HIV infection are, by definition, measurable traits that correlate with disease progression. An ideal marker should identify patients at highest risk of disease progression, provide information on how long an individual has been infected, help in staging HIV disease, predict development of opportunistic infections associated with AIDS, monitor the therapeutic efficacy of immunomodulating or antiviral treatments, and the easily quantifiable, reliable, clinically available, and affordable. This review examines the current state of knowledge and the role of surrogate markers in the natural history and treatment of HIV infection. The clinical usefulness of each marker is assessed with respect to the criteria outlined for the ideal surrogate marker for HIV disease progression.

H-2-linked Ir gene control of T cell recognition of the Sm nuclear autoantigen and the aberrant response of autoimmune MRL/Mp-+/+ mice.

We have examined T cell recognition of the nuclear autoantigen Sm. Rabbit Sm-primed cells from autoimmune MRL/Mp-+/+ (+/+) mice and from all normal strains tested were able to proliferate to rabbit Sm in vitro. In contrast, the reactivity of normal strains to Sm of murine origin was genetically restricted; only H-2f strains B10.M and A.CA, and H-2s strains B10.S and A.SW could recognize mouse Sm, suggesting that responsiveness to mouse Sm was under the control of H-2-linked Ir genes. Although five Iak-bearing normal strains (B10.A, B10.A(2R), B10.BR, A/Sn, and CBA) did not recognize mouse Sm, autoimmune +/+ (Iak) mice were responders. The responsiveness of the +/+ mice to Sm was probably not due to differences in their Iak region, compared with other strains, because the Iak region of normal strains and the autoimmune +/+ strain were indistinguishable by interstrain MLC, immune response gene product function, and recognition by anti-Iak mAb. Inhibition of Sm-induced proliferation by mAb demonstrated that T cells from autoimmune +/+ mice, responder normal strains, and nonresponder normal strains recognized rabbit and mouse Sm in the context of I region-encoded products. The T cell response to Sm antigen in normal mice is therefore Ia region restricted and, for the murine antigen, under Ir gene control. Autoimmune mice that spontaneously make anti-Sm antibodies (+/+) also perceive Sm in an Ia-restricted manner, but their responder status abrogates H-2-linked Ir gene control.

Identification of antigenic epitopes of 1D antigen recognized by antibodies in the serum of patients with thyroid-associated ophthalmopathy.

Random fragments of full-length 1D cDNA encoding the 64-kDa antigen were cloned and expressed in Escherichia coli as fusion proteins. Antigenic peptides were detected by colony blotting with sera from patients with thyroid-associated ophthalmopathy (TAO) and corresponding cDNA inserts were sequenced. Four antigenic peptides were characterized and positioned with respect to the 1D amino acid sequence. One antigenic peptide (G-8) was found to be close to the C-terminal end of 1D, and three others (G-2, G-4, and G-5) were clustered at sites between amino acids 76 and 205. The immunoreactivities of a panel of sera were tested against full-length 1D and the four peptides. A panel consisting of sera from (1) 15 patients with TAO, (2) 9 patients with Graves' hyperthyroidism without ophthalmopathy, (3) 6 patients with Hashimoto's thyroiditis without ophthalmopathy, and (4) 12 normal subjects were tested against the four peptides and full-length 1D protein by Western blotting. Sera from patients with TAO also reacted more often with G-4 and/or G-5 peptides than did those from normal subjects [7 of 15 (47%) sera from TAO patients versus 1 of 12 (8%) sera from normal subjects; P < 0.05]. Based on positioning of peptides onto the full-length 1D sequence and the reaction pattern of the serum panel, six immunogenic epitopes were identified on the 1D molecule.

Tissue distribution and quantitation of a gene expressing a 64-kDa antigen associated with thyroid-associated ophthalmopathy.

We have developed a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) assay for the quantitation of 1D mRNA, which encodes a 64-kDa protein associated with thyroid-associated ophthalmopathy, in preparations of total RNA from a variety of human tissues. This competitive RT-PCR assay is based on coamplification of competing 1D cDNA internal control template (pGEM-1D') and target cDNA template. 1D-specific mRNA was quantified in 10 human tissues. The level of 1D transcript expression in these tissues decreased in the following order: thyroid (5 pg/mg total RNA) > eye muscle (3.2 pg/mg) > skeletal muscle (2.4 pg/mg) > ovary (2 pg/mg) > cerebellum (0.4 pg/mg), kidney (0.33 pg/mg), pancreas (0.27 pg/mg), spleen (0.22 pg/mg), and thymus (0.19 pg/microgram) > retina (0.016 pg/mg). Graves' disease may be a multisystem autoimmune disorder of the connective tissue and skeletal muscle (and thyroid) that is mainly localized in the orbit and skin. One mechanism for this localization may be increased expression of target autoantigens, of which the 64-kDa protein 1D is a candidate, in the involved tissues. The higher expression of the 1D molecule in thyroid and eye supports this hypothesis.

Response of MRL/Mp-+/+ mice to mouse Sm: non-H-2-linked genes determine T cell recognition.

In normal mouse strains, the T cell proliferative response to the nuclear autoantigen Sm is under MHC-linked Ir gene control. Autoimmune MRL/Mp-+/+ (+/+) mice, which spontaneously make anti-Sm antibodies, have the nonresponder H-2k MHC genotype, yet their T cells respond to mouse Sm. In the present study, we have used Sm-reactive continuous T cell lines to show that the Sm responsiveness of +/+ T cells is not due to aberrancy of the Iak molecules expressed on +/+ antigen-presenting cells. Additionally, the failure of normal Iak mouse strains to respond to mouse Sm could not be attributed to the influence of suppressor cells. Therefore, the response of +/+ mice to mouse Sm is probably due to the development of an abnormal repertoire of T cells capable of recognizing self-antigens in the context of Ia. Analyses of F1 hybrid and backcross mice indicated that their responsiveness was inherited in a dominant manner, probably as a single gene not linked to H-2. Further investigation of this gene and its mode of action may lead to increased understanding of the mechanisms of spontaneous autoimmunity in SLE mice.

Cross-reactions of HLA antibodies: VII. Rate of sensitization and serological specificity.

Varying the sensitization time of the complement-dependent antibody mediated cytotoxicity test, while carefully controlling other test conditions, has enabled us to characterize the subtle reactivities of several broadly reactive sera. In particular, we can discriminate between classes of cells, e.g., HLA-B7 from B27; subclasses cells, e.g., Bw51 from Bw52; and cells carrying new antigens, e.g., Ao79. This manipulation of the cytotoxicity test is discussed in view of its usefulness in separating primary from cross-reactive specificities and in detecting new specificities.

Effect of splenectomy on T-cell subsets and plasma HIV viral titers in HIV-infected patients.

OBJECTIVE: In previous studies we have shown that removal of the spleen in HIV-infected people during the asymptomatic phase of disease results in slower time to AIDS and may also result in improved survival. In this paper, we examine whether splenectomy affects lymphocyte counts, T-cell subsets, and HIV plasma viremia in a manner that could explain the clinical benefits associated with this intervention. METHODS: 10 HIV-infected patients who underwent splenectomy and 23 HIV-infected controls with idiopathic thrombocytopenia purpura who did not undergo splenectomy were studied. These groups were compared for changes in cell subpopulations and HIV plasma viremia. RESULTS: Splenectomy resulted in increases in absolute lymphocyte numbers with rises in both CD4 and CD8 counts, whereas CD4 and CD8 percentage levels remained unchanged. In controls, absolute and percentage CD4+ T-cell counts declined with time from date of HIV infection. Plasma viremia decreased more than threefold, the limit of biologic variation, after splenectomy in 4 of 9 subjects and in only 1 of 18 controls. The proportion of subjects exhibiting reduced viremia following splenectomy was greater than that in HIV-infected patients that did not undergo splenectomy (chi 2 test, P = .015). CONCLUSIONS: Improved survival and time to AIDS in splenectomized HIV-infected patients is associated with temporary reduction of plasma viremia and increase in absolute CD4 and CD8 counts. These effects could not be attributed to antiretroviral therapy because subjects were either untreated or treated with antiretroviral monotherapy during the observation period. These observations may have importance in the understanding of T-cell dynamics and the potential for splenectomy as an HIV reservoir-debulking procedure.