Mucosal-associated invariant T (MAIT) cells are activated in the gastrointestinal tissue of patients with combination ipilimumab and nivolumab therapy-related colitis in a pathology distinct from ulcerative colitis.

The aim of this study was to investigate the pathogenesis of combination ipilimumab and nivolumab-associated colitis (IN-COL) by measuring gut-derived and peripheral blood mononuclear cell (GMNC; PBMC) profiles. We studied GMNC and PBMC from patients with IN-COL, IN-treated with no adverse-events (IN-NAE), ulcerative colitis (UC) and healthy volunteers using flow cytometry. In the gastrointestinal-derived cells we found high levels of activated CD8+ T cells and mucosal-associated invariant T (MAIT) cells in IN-COL, changes that were not evident in IN-NAE or UC. UC, but not IN-C, was associated with a high proportion of regulatory T cells (Treg ). We sought to determine if local tissue responses could be measured in peripheral blood. Peripherally, checkpoint inhibition instigated a rise in activated memory CD4+ and CD8+ T cells, regardless of colitis. Low circulating MAIT cells at baseline was associated with IN-COL patients compared with IN-NAE in one of two cohorts. UC, but not IN-COL, was associated with high levels of circulating plasmablasts. In summary, the alterations in T cell subsets measured in IN-COL-affected tissue, characterized by high levels of activated CD8+ T cells and MAIT cells and a low proportion of Treg , reflected a pathology distinct from UC. These tissue changes differed from the periphery, where T cell activation was a widespread on-treatment effect, and circulating MAIT cell count was low but not reliably predictive of colitis.

Characterization of the phenotypic and lymphokine profile associated with strong CD8+ anti-HIV-1 suppressor activity (CASA).

A panel of 22 CD8+ T cell lines, with a broad range of CD8+ anti-HIV-1 suppressor activity (CASA) were generated from a single patient with HIV-1 infection. CD8+ T cell lines with either strong or weak CASA were examined and compared for cell surface and intracellular markers, constitutive chemokine and lymphokine mRNA levels and inducible lymphokine expression. Strong CASA significantly correlated with CD8+ T cell lines that highly coexpressed the molecule CD28+ (r=0.52, P=0.01) and Ki67+ (r=0.88, P=0.02), with strong CASA CD8+ T cell lines demonstrating significantly higher (P < 0.05) expression of CD8+CD28+ and CD8+Ki67+ compared to those with weak activity. No such correlations or findings were observed for the markers CD38, HLA-DR, CD57 or perforin. The Th1 cytokines were expressed at greater levels than the Th2 cytokines, with strong CASA significantly associated with an increased inducible level of IL-2 production (P=0.05). Constitutive RANTES, IP-10 and I-309 mRNA expression were significantly (P < 0.05) elevated in CD8+ T cell lines exhibiting strong CASA compared to those with weak CASA. There was no significant difference in the mRNA expression of the lymphokines IL-2, 4, 5, 8, 9, 10, 14, 15, or chemokines MIP-1alpha, MIP-1beta, MCP-1, and Ltn. Strong CASA was therefore associated with rapidly replicating CD8+ T cells of the phenotype CD8+CD28+Ki67+ that expressed greater levels of IL-2 and the ligands RANTES and I-309.

An examination of signs of disease progression in survivors of the Sydney Blood Bank Cohort (SBBC).

BACKGROUND: The Sydney Blood Bank Cohort (SBBC) was infected between 1981 and 1984 with a nef/LTR defective strain of HIV-1. Different responses to HIV-1 infection have emerged between cohort members in the last 5 years. Three recipients (C135, C64 and C49) remain asymptomatic, have normal CD4 T cell counts, below detection (BD) viral loads (VL), remain therapy naive and are termed long-term non-progressors (LTNP). The donor (D36) and the two recipients (C98 and C54) have significantly declining CD4 T cell counts, detectable VL and are now long-term survivors (LTS). In contrast, in the SA cohort, comparison study group for the SBBC, five of 24 remain therapy naïve after 15 years infection with HIV-1 and all have detectable VL. OBJECTIVES: This paper examines different outcomes to long-term infection with HIV-1 in the SBBC and provides a brief overview of the therapy naïve in a comparison study group, the SA cohort. STUDY DESIGN: Retrospective epidemiological follow-up of the SBBC and the SA cohort has been conducted for >15 years. Analysis of CD4 T cell counts, VL and intermittent monitoring of HIV-specific proliferative responses are reviewed. Viral sequence changes in the SBBC will be considered. RESULTS: Prior to therapy D36 had a CD4 T cell count of 160/mm(3) and plasma VL of 9900 copies/ml while C98 had a CD4 T cell count of 387/mm(3) and plasma VL of 11491 copies/ml. After 1 month of therapy, plasma VL was BD (<400 copies/ml) and both showed significant increase in CD4 T cell counts. Molecular changes have occurred in D36 and C98 viral strains, the most recently evolved quasispecies have larger deletions in the nef/LTR region. CONCLUSIONS: Infection with nef/LTR deleted HIV-1 has resulted in slower disease progression for the SBBC. The three LTNP have maintained normal low levels of activated CD8 T cells and strong HIV-specific proliferative responses to HIV-1 p24, which are associated with control of viral replication.

Increased turnover of CCR5+ and redistribution of CCR5- CD4 T lymphocytes during primary human immunodeficiency virus type 1 infection.

CCR5 is the major coreceptor for human immunodeficiency virus (HIV) type 1 during primary infection. CCR5+ CD4 T lymphocytes were studied in subjects with primary HIV-1 infection (PHI) or acute Epstein-Barr virus (EBV) infection and in HIV-uninfected controls. The early decline of CD4 T lymphocytes during PHI resulted from depletion of CCR5- CD4 T lymphocytes. After antiretroviral therapy, Ki-67- CCR5- CD4 T cell counts rapidly increased in the circulation, which suggests that the initial decrease was due to an alteration in trafficking and/or sequestration. In the CCR5+ subset of CD4 T cells, there was an elevation in the proliferative (Ki-67+) fraction during PHI, yet their total number remained in the normal range. In contrast, in acute EBV infection, proliferating CCR5+ CD4 T cells accumulated to very high levels, suggesting they have an important role in the early antiviral response, which may be impaired in HIV-1 infection.

HIV induces lymphocyte apoptosis by a p53-initiated, mitochondrial-mediated mechanism.

HIV-1 induces apoptosis and leads to CD4+ T-lymphocyte depletion in humans. It is still unclear whether HIV-1 kills infected cells directly or indirectly. To elucidate the mechanisms of HIV-1-induced apoptosis, we infected human CD4+ T cells with HIV-1. Enzymatic analysis with fluorometric substrates showed that caspase 2, 3, and 9 were activated in CD4+ T cells with peak levels 48 h after infection. Immunoblotting analysis confirmed the cleavage of pro-caspase 3 and 9, and of specific caspase substrates. Release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria was observed in HIV-infected cells. The cytochrome c and AIF release preceded the reduction of the mitochondrial transmembrane potential and nuclear chromatin condensation. H IV infection led to phosphorylation of p53 at the Ser15 residue, detectable as early as 24 h after infection. The p53 phosphorylation was followed by increased mRNA and protein expression of p21, Bax, HDM2, and p53. Up-regulation of surface FasL expression, accompanied by a down-regulation of Fas-associated proteins (FADD, DAXX, and RIP), was observed 72 h after infection. Our results suggest that HIV activates the p53 pathway, leading to cytochrome c and AIF release with ensuing caspase activation.

Rapid restoration of CD4 T cell subsets in subjects receiving antiretroviral therapy during primary HIV-1 infection.

OBJECTIVE: To compare the effect of highly active antiretroviral therapy on immune reconstitution in subjects with acute and chronic HIV-1 infection. DESIGN: Prospective study including 58 treatment-naive subjects who commenced indinavir or nelfinavir and two nucleosides during primary (PHI; n = 28) or chronic HIV-1 infection (CHI; n = 30). METHODS: Naive (CD45RA+ 62L+), memory (CD45RA-) and activated (CD38+ HLA-DR+) T cell subsets were quantified at 1-2 monthly time intervals using 4-colour flow cytometry. RESULTS: At 1 year, HIV-1 RNA declined in both cohorts to undetectable levels (< 50 copies/ml), while median CD4 lymphocyte count increased from 470 to 758 x 10(6) cells/l in PHI and from 204 to 310 x 10(6) cells/l in CHI, reaching > 500 x 10(6) cells/l in 93% of PHI, but only in 37% of CHI subjects (P < 0.001). Naive CD4 lymphocytes increased from 106 to 176 x 10(6) cells/l in PHI and from 41 to 44 x 10(6) cells/l in CHI (PHI versus CHI at 12 months: P = 0.003), while memory cells rose from 368 to 573 x 10(6) cells/l in PHI and from 148 to 223 x 10(6) cells/l in CHI (P < 0.001). Early increases (< 3 months) of CD4 lymphocytes were larger in subjects with PHI, consisting of naive CD45RA+ CD62L+ as well as memory CD45RA- CD62L+ cells (P = 0.001). CD4 activation declined from 5 to 2% in PHI and from 13 to 6% in CHI (P = 0.001), while CD8 cell activation was reduced from 33 to 15% in PHI and from 42 to 19% in CHI (P = 0.02). CONCLUSION: Immune reconstitution was more complete, occurred earlier and comprised both naive and memory CD4 T lymphocytes in subjects who commenced antiretroviral therapy during primary HIV-1 infection.

Long-term immunological response in HIV-1-infected subjects receiving potent antiretroviral therapy.

OBJECTIVE: To determine the long-term T-lymphocyte response to highly active antiretroviral therapy (HAART) and to define predictors of the immunological response. DESIGN: Cohort study, including 135 HIV-1-infected subjects at a city general practice who commenced HAART between 1996 and 1998. METHODS: Collection of plasma HIV-1 RNA, CD4+ and CD8+ T-lymphocyte data at 3-6 monthly time intervals over 2 years. RESULTS: Seventy-three subjects (54%) achieved suppression of plasma HIV-1 RNA to levels below 400 copies/ml during the observation period, 31 individuals (23%) had detectable plasma HIV-1 RNA below 10,000 copies/ml and 31 subjects (23%) had virological failures with viral loads above 10,000 copies/mL. Median CD4+ T lymphocytes increased from 246 to 463 x 10(6) cells/l, showing a median rise of 20 x 10(6) cells/l per month in the first 3 months and 7 x 10(6) cells/l per month thereafter. The proportion of individuals who reached CD4+ cell counts above 500 x 10(6) cells/l increased from 8% at baseline to 54% at 2 years. Treatment-naïve individuals, subjects with a large reduction of HIV-1 RNA or a large early CD8+ increase had better early CD4+ responses. Long-term CD4+ T-cell increases were inversely correlated with mean plasma HIV-1 RNA levels. Baseline CD4+ T-cell count was the most important determinant of reaching CD4+ cell counts above 500 x 10(6) cells/l. Nineteen per cent of subjects had no further CD4+ T-cell increases in the second year of therapy despite undetectable viral load. CONCLUSIONS: Immune reconstitution is a slow process, showing a large individual variability. The virological response to HAART was the most important determinant of the immunological short- and long-term response.

Effect of long-term infection with nef-defective attenuated HIV type 1 on CD4+ and CD8+ T lymphocytes: increased CD45RO+CD4+ T lymphocytes and limited activation of CD8+ T lymphocytes.

Members of the Sydney Blood Bank Cohort (SBBC) have been infected with an attenuated strain of HIV-1 with a natural nef/LTR mutation and have maintained relatively stable CD4+ T lymphocyte counts for 14-18 years. Flow cytometric analysis was used to examine the phenotype of CD4+ and CD8+ T lymphocytes in these subjects, including the immunologically important naive (CD45RA+CD62L+), primed (CD45RO+), and activated (CD38+HLA-DR+ and CD28-) subsets. The median values were compared between the SBBC and control groups, comprising age-, sex-, and transfusion-matched HIV-1-uninfected subjects; transfusion-acquired HIV-1-positive LTNPs; and sexually acquired HIV-1-positive LTNPs. Members of the SBBC not only had normal levels of naive CD4+ and CD8+ T lymphocytes, but had primed CD45RO+ CD4+ T lymphocytes at or above normal levels. Furthermore, these primed cells expressed markers suggesting recent exposure to specific antigen. SBBC members exhibited variable activation of CD8+ T lymphocytes. In particular, SBBC members with undetectable plasma HIV-1 RNA had normal levels of activated CD8+ T lymphocytes. Therefore, the result of long-term infection with natural nef/LTR mutant HIV-1 in these subjects suggests a decreased cytopathic effect of attenuated HIV-1 on susceptible activated CD4+ T lymphocyte subsets in vivo, and minimal activation of CD8+ T lymphocytes.

Phenotypic analysis of CD8+ T lymphocytes in a cohort of HIV type 1-infected patients treated with saquinavir, ritonavir, and two nucleoside analogs for 1 year, and association with plasma HIV type 1 RNA.

The phenotype of circulating CD8+ T lymphocytes and its association with plasma HIV-1 RNA were analyzed in 34 HIV-1-infected subjects, who were treated with saquinavir, ritonavir, and two nucleoside analogs (HAART) for 1 year. Four-color flow cytometry was applied to measure the expression of cell surface antigens CD38, HLA-DR, CD45RA, CD28, and CD62L on CD8+ T lymphocytes. The results were compared with data on 35 HIV-1-seronegative subjects, 18 untreated asymptomatic HIV-1-seropositive individuals, and 24 HIV-1-infected subjects receiving reverse transcriptase inhibitors (RTIs). Subjects receiving HAART showed a significantly elevated number and percentage of CD38- and HLA-DR-positive and CD28-negative CD8+ T lymphocytes as well as a lower percentage of naive (CD45RA+62L+) CD8+ T lymphocytes compared with HIV-1-uninfected controls. Even subjects with undetectable plasma HIV-1 RNA showed a persistent elevation of activated CD8+ T lymphocytes. However, fewer activated CD8+ T lymphocytes were observed in subjects receiving HAART than in untreated individuals and subjects administered RTIs. In individuals receiving RTIs, CD8+ cell activation was not significantly reduced compared with untreated subjects. Of all evaluated activation markers, the percentage of CD8+ T lymphocytes expressing CD38 and the combination of CD38 and HLA-DR showed the best correlation with plasma HIV-1 RNA. The persistence of CD8+ T lymphocyte activation in subjects receiving HAART strongly suggests ongoing viral activity, even in subjects with undetectable plasma HIV-1 RNA. A complete normalization of immunologic changes of CD8+ T lymphocytes would therefore require a more potent drug regimen or a longer duration of therapy.

Potent antiretroviral therapy of primary human immunodeficiency virus type 1 (HIV-1) infection: partial normalization of T lymphocyte subsets and limited reduction of HIV-1 DNA despite clearance of plasma viremia.

Antiretroviral therapy commenced during primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) may limit the extent of viral replication and prevent early loss of HIV-specific CD4 lymphocyte function. We studied the effect of current standard therapy (2 nucleoside analogues and a protease inhibitor) in 16 patients with symptomatic PHI. In the 13 patients who completed 1 year of treatment, plasma HIV RNA was <50 copies/mL and median CD4 cell counts were comparable to HIV-uninfected controls, with naive (CD45RA+CD62L+), primed (CD45RO+), and T cell receptor Vbeta subsets all within normal ranges. However, HIV-1 DNA levels in treated and untreated PHI patients were similar. Furthermore, CD8 cell counts remained elevated, including activated (CD38+HLA-DR+), replicating (Ki-67+), and cytotoxic (perforin+CD28-) lymphocytes. In conclusion, early antiretroviral therapy resulted in clearance of viremia and prevented loss of crucial CD4 subsets. The persistence of HIV-1 DNA together with increased CD8 T lymphocyte turnover and activation indicate continued expression of viral antigens.

CD8+ anti-human immunodeficiency virus suppressor activity (CASA) in response to antiretroviral therapy: loss of CASA is associated with loss of viremia.

CD8+ anti-human immunodeficiency virus (HIV) suppressor activity (CASA) defines the noncytolytic suppression of HIV mediated by secreted soluble factors. Changes in CASA in patients receiving combination antiretroviral therapy have not been described. Thirty-two HIV-infected patients receiving mono- or dual therapy for 52 weeks followed by highly active antiretroviral therapy (HAART) for a further 52 weeks were analyzed. T cell number and functional subsets, cutaneous delayed-type hypersensitivity, and plasma HIV RNA were assessed in 17 patients for CASA. Prior to therapy, CASA correlated inversely with HIV RNA (P<.001). Dual therapy yielded greater and more sustained changes in CASA than monotherapy, but HAART decreased CASA to levels observed in HIV-uninfected individuals. The magnitude of HIV RNA suppression correlated significantly with a decrease in activated CD8+ T lymphocytes (CD38+HLA-DR+), increases in naive CD4+ T lymphocytes (CD45RA+62L+), and increases in the delayed-type hypersensitivity score. However, changes in CASA did not correlate with changes in any T lymphocyte subset. CASA increases with improving immune function but appears more dependent on ongoing HIV replication.

Radiation pneumonitis: a possible lymphocyte-mediated hypersensitivity reaction.

OBJECTIVE: To determine if unilateral thoracic irradiation results in a lymphoid alveolitis in both irradiated and unirradiated lung fields. DESIGN: A prospective, nonrandomized study. PATIENTS: Women receiving postoperative radiotherapy for carcinoma of the breast were evaluated both before and 4 to 6 weeks after radiotherapy. Findings after radiotherapy in 15 asymptomatic patients were compared with findings in a group of patients with clinical radiation pneumonitis. MEASUREMENTS: History, physical examination, chest radiograph, quantitative gallium lung scanning, respiratory function tests, bronchoalveolar lavage, and lavage lymphocyte subset analysis. RESULTS: After irradiation, lavage lymphocytes increased significantly (34.5% versus 46.8%; P = 0.01) in the 17 patients studied prospectively. There was an associated reduction in vital capacity (102.5% versus 95.5%; P = 0.04). Comparison of results in patients before treatment, after treatment without clinical pneumonitis, and after treatment with clinical pneumonitis showed a dramatic increase in total lymphocytes after irradiation (6.3 versus 9.4 versus 35.2 million, respectively; P = 0.005), particularly in those with clinical pneumonitis. Only in those with clinical pneumonitis was this accompanied by an increase in the gallium index (3.7 versus 3.4 versus 9.0, respectively; P < 0.001). Vital capacity was also progressively reduced (102.5% versus 96.9% versus 76.7%, respectively; P = 0.04), as was diffusing capacity (98.6% versus 91.4% versus 72.6%, respectively; P = 0.003). No statistical differences existed between irradiated and unirradiated sides of the chest in either lavage or gallium lung scan studies. CONCLUSION: In most patients, a lymphocytic alveolitis develops in both lung fields after strictly unilateral thoracic irradiation; this is more pronounced in patients developing clinical pneumonitis. These findings suggest that radiotherapy may cause a generalized lymphocyte-mediated hypersensitivity reaction.

Changes in epithelial lining fluid albumin associated with smoking and interstitial lung disease.

Albumin is an important plasma protein which is useful in the assessment of in vivo membrane permeability in the lung. In subjects with interstitial lung disease (ILD) the relationship between albumin recovered from bronchoalveolar lavage (BAL) and other markers of inflammatory activity may provide useful information of the pathogenesis of the disease process. Unfortunately, its measurement is hampered by the variable dilution in BAL fluid. In this study, urea was used as a marker of epithelial lining fluid (ELF) dilution allowing the calculation of an apparent epithelial lining fluid volume and adjusted albumin content. We examined the relationship between ELF albumin content and BAL cell counts, immunoglobulin content, respiratory function tests and gallium lung scans in both smokers and nonsmokers with and without interstitial lung disease. Forty seven subjects with connective tissue disease and interstitial lung disease and 51 subjects with either connective tissue disease but no pulmonary involvement or non pulmonary malignancy (18 current smokers) underwent BAL, gallium lung scans and respiratory function tests. The subjects with ILD were further subdivided into those with active ILD or bronchiolitis using cluster analysis. In smokers without ILD an increased ELF volume and a decrease in ELF albumin were found. Increased ELF albumin was related to increased age. In subjects with ILD, increased albumin was strongly correlated with increased BAL lymphocyte absolute and differential counts, which overwhelmed any age or smoking effect. These findings suggest a possible causal relationship between lung vascular permeability and lymphocyte numbers in subjects with interstitial lung disease and reinforce the need to consider smoking and age as confounding factors in BAL analysis.

Smoking-induced changes in epithelial lining fluid volume, cell density and protein.

Bronchoalveolar lavage has proved a useful research technique for recovering cellular and molecular contents of the lower respiratory tract. Because the recovered fluid is variably diluted, an accurate estimation of molecular and cellular concentrations can only be made if the epithelial lining fluid volume recovered is also known. It has been suggested that smoking may alter epithelial lining fluid volume by reducing clearance or by stimulating production and, thus, affect the interpretation of bronchoalveolar lavage studies. In this study, urea was used as an endogenous marker of epithelial lining fluid volume in a comparison of 26 smokers and 31 nonsmokers. The mean epithelial lining fluid volume recovered from smokers was significantly greater than that of nonsmokers (2.4 +/- 1.40 ml vs 1.2 +/- 0.75 ml, p less than 0.005). The total cellular concentration in the bronchoalveolar lavage fluid in smokers was also greater (94.2 +/- 46 x 10(6) vs 33.9 +/- 21.5 x 10(6) cells per 300 ml lavage), even when corrected for bronchoalveolar lavage volume recovered (63.1 +/- 32.5 x 10(6) vs 24.9 +/- 13.3 x 10(6) cells per 100 ml recovered lavage fluid). This was true for macrophage, lymphocyte and neutrophil cell numbers. However, when corrected for the apparent epithelial lining fluid volume, only the macrophage count remained significantly higher in the smokers compared with nonsmokers (30.66 +/- 20.7 x 10(6) vs 18.21 +/- 8.6 x 10(6) macrophages.ml-1 ELF). In addition, concentrations of albumin and immunoglobulin M (IgM) were significantly lower in smokers after correction for epithelial lining fluid volume. These results highlight smoking as a confounding factor in the interpretation of bronchoalveolar lavage data.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of IgE synthesis in vitro by allogeneic T cells from atopic and non-atopic subjects.

The role of T cells in the regulation of IgE synthesis by human PBMC was studied. PBMC or separated and recombined populations of T and B cells from both normal and atopic donors were cultured for 10 days with and without cycloheximide. IgE and IgG synthesis were determined by specific RIA. IgE synthesis was detected in 0/30 non-atopic, 6/34 mildly atopic and 25/31 severely atopic subjects. Autologous T cells from 10/26 atopic donors, whose B cells synthesised IgE, significantly suppressed this IgE synthesis. The addition of allogeneic T cells from atopic or non-atopic subjects to atopic B cells resulted in greater suppression of IgE synthesis than the addition of autologous T cells. These data support the notion that atopic subjects have naturally occurring IgE isotype-specific suppressor T cells as well as suppressor T cells which can be activated during incubation with alloantigen.

A monoclonal antibody-based radioimmunoassay for the in vitro production of IgE by lymphocyte cultures.

Very sensitive radioimmunoassay systems have been described for the measurement of IgE produced in cultures of human peripheral blood mononuclear cells. However, differing results have been reported when cultures from non-atopic donors are stimulated with pokeweed mitogen, which may be due to cross-reactivity of anti-IgE antibodies with IgG. A monoclonal antibody specific for the Fc region of human IgE, and two polyclonal affinity-purified antibodies to IgE were tested for binding to 125I-labelled IgE myeloma proteins and polyclonal IgG in a sensitive double antibody precipitation assay. The monoclonal antibody and one of the polyclonal antibodies bound only IgE, whereas the other polyclonal antibody bound a significant proportion of labelled IgG. A solid phase radioimmunoassay was developed which combined the specificity of the monoclonal antibody with the sensitivity of the first polyclonal antibody as radioactive tracer. A second assay system was also tested using the cross-reacting antibody as tracer. Supernatants of pokeweed mitogen-stimulated peripheral blood mononuclear cell cultures from non-atopic donors were examined for IgE synthesis using both assays. The assay based on the monoclonal antibody did not detect IgE synthesis, whilst the second assay, based on the cross-reacting antibody indicated that spurious IgE had been produced in the same cultures. This study shows that protein-binding assays provide a simple means for checking the specificity of antibodies in solid phase radioimmunoassays, and confirms that pokeweed mitogen does not stimulate IgE production by cells from non-atopic donors when measured by a specific radioimmunoassay.

Immunoregulation in juvenile chronic arthritis.

The presence of hyperimmunoglobulinaemia and antinuclear antibodies in patients with juvenile chronic arthritis (JCA) suggests a possible role for immunoregulatory abnormalities in the pathogenesis of the disease. This is further supported by the demonstration in the sera of such patients of an autoantibody active against a suppressor inducer T cell subset. To identify immunoregulatory defects in JCA, a method of measuring concanavalin A (Con A)-inducible lymphocyte suppression of IgG production in vitro has been established. Peripheral blood mononuclear cells were cultured in the presence of either medium alone, pokeweed mitogen (PWM), Con A, or PWM together with Con A. IgG present in culture supernates at 8 days was measured by a double-antibody radioimmunoassay. Spontaneous IgG synthesis by lymphocytes by both patients and child controls was found to be more than double that of lymphocytes from adult control subjects. However, lymphocytes of children (patients or controls) did not show stimulation of IgG production in the presence of PWM. Con A-induced suppression of spontaneous IgG synthesis was reduced compared to adult controls in both patients (p less than 0.02) and child controls (p less than 0.05). Con A-induced suppression of IgG synthesis in the presence of PWM was also reduced compared to adult controls in both patients (p less than 0.01) and child controls (p less than 0.01) but was also reduced in the patient group compared to the child controls (p less than 0.01). Thus, spontaneous IgG synthesis in children is increased compared to adults, and IgG-producing cells appear less subject to regulation.(ABSTRACT TRUNCATED AT 250 WORDS)