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OBJECTIVE: Despite the substantial clinical efficacy of tumor necrosis factor alpha (TNFalpha) antagonist therapy in patients with rheumatoid arthritis (RA), some patients respond poorly to such agents. Since an interferon (IFN) signature is variably expressed among RA patients, we investigated whether plasma type I IFN activity might predict the response to TNF antagonist therapy. METHODS: RA patients (n = 35), the majority of whom were Hispanic, from a single center were evaluated before and after initiation of TNF antagonist therapy. As controls, 12 RA patients from the same center who were not treated with a TNF antagonist were studied. Plasma type I IFN activity was measured using a reporter cell assay, and disease status was assessed using the Disease Activity Score in 28 joints (DAS28). Levels of interleukin-1 receptor antagonist (IL-1Ra) were determined in baseline plasma samples using a commercial enzyme-linked immunosorbent assay. The clinical response was classified according to the European League Against Rheumatism criteria for improvement in RA. RESULTS: Plasma type I IFN activity at baseline was significantly associated with clinical response (odds ratio 1.36 [95% confidence interval 1.05-1.76], P = 0.020), with high baseline IFN activity associated with a good response. Changes in DAS28 scores were greater among patients with a baseline plasma IFNbeta/alpha ratio >0.8 (indicating elevated plasma IFNbeta levels). Consistent with the capacity of IFNbeta to induce IL-1Ra, elevated baseline IL-1Ra levels were associated with better therapeutic outcomes (odds ratio 1.82 [95% confidence interval 1.1-3.29], P = 0.027). CONCLUSION: The plasma type I IFN activity, the IFNbeta/alpha ratio, and the IL-1Ra level were predictive of the therapeutic response in TNF antagonist-treated RA patients, indicating that these parameters might define clinically meaningful subgroups of RA patients with distinct responses to therapeutic agents. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the expression of B lymphocyte stimulator (BLyS) in patients with pediatric systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA). METHODS: Blood samples collected from patients with pediatric SLE (n = 56) and patients with JIA (n = 54) at the beginning and end of a 6-month interval were analyzed for plasma BLyS protein levels by enzyme-linked immunosorbent assay and for blood leukocyte full-length BLyS and DeltaBLyS messenger RNA (mRNA) levels by quantitative real-time polymerase chain reaction (normalized to 18S expression). Healthy siblings (n = 34) of these patients served as controls. RESULTS: In pediatric SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels were each significantly elevated, and plasma BLyS protein levels, but not blood leukocyte BLyS mRNA levels, were correlated with disease activity. In contrast, plasma BLyS protein levels were normal in JIA despite blood leukocyte BLyS mRNA levels being elevated to degrees similar to those in pediatric SLE. Among JIA patients, neither BLyS parameter was correlated with disease activity. In both pediatric SLE and JIA, the BLyS expression profiles remained stable at 6 months. CONCLUSION: Our findings indicate that, as previously noted in adult SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels are elevated in pediatric SLE. The correlation of plasma BLyS protein levels with disease activity points to BLyS as a candidate therapeutic target in pediatric SLE. Contrary to previous observations in adults with rheumatoid arthritis, plasma BLyS protein levels are normal in JIA despite elevated blood leukocyte BLyS mRNA levels. The absence of correlation between either of the BLyS parameters and disease activity in JIA calls for circumspection prior to assigning BLyS as a candidate therapeutic target in this disorder. [ABSTRACT FROM AUTHOR]

OBJECTIVE. To assess the effects of B lymphocyte depletion on serum B lymphocyte stimulator (BLyS; trademark of Human Genome Sciences, Rockville, MD) levels in patients with rheumatoid arthritis (RA), and to assess the relationship of serum BLyS levels with peripheral blood B cell depletion, levels of autoantibodies and antimicrobial antibodies, the return of peripheral blood B cells, and clinical relapse. METHODS: Fifteen patients with active RA underwent rituximab-based B cell depletion therapy (BCDT). Disease activity was assessed clinically, peripheral blood CD19+ B cell counts were determined by flow cytometry, and serum levels of BLyS, IgM, IgA, and IgG rheumatoid factors (RFs), anti-cyclic citrullinated peptide, and antimicrobial antibodies were assessed using enzyme-linked immunosorbent assays. RESULTS: Peripheral blood B cell depletion was achieved in all 15 patients, and an American College of Rheumatology 20% response was achieved in 13 patients. Following clinical relapse, 7 patients underwent at least 1 additional cycle of BCDT. In every case, serum BLyS levels markedly rose post-BCDT and remained elevated for at least 1-2 months. Serum levels of RF, but not those of anti-tetanus toxoid or anti-pneumococcal polysaccharide antibodies, fell significantly. A decline in serum BLyS levels was associated with the reemergence of B cells in peripheral blood, which, in turn, antedated clinical relapse by variable periods of time. The patterns of B cell depletion, serum BLyS and antibody levels, and clinical relapse for each BCDT cycle were remarkably similar in re-treated patients. CONCLUSION: Rituximab-based BCDT leads to marked increases in serum BLyS levels. This may contribute significantly to the survival and/or regeneration of B cell populations capable of triggering clinical relapse. [ABSTRACT FROM AUTHOR]

To determine whether non-T cells contribute to impaired generation of nonrestricted cytotoxic T lymphocyte (CTL) activity in human SLE, peripheral blood mononuclear cells (PBMC) and sort-purified T cells from normal subjects and SLE patients were stimulated with anti-CD3 mAb, maintained in IL2, and assayed for cytolytic activity against [sup 51]Cr-labeled Daudi target cells. In addition, T cell and non-T cell fractions were isolated from nine pairs of monozygotic (MZ) twins discordant for SLE, reconstituted in a criss-cross pattern, and stimulated and assayed for cytolytic activity. Cytolytic responses were significantly lower in SLE PBMC cultures than in normal PBMC cultures. Addition of SLE serum to normal PBMC cultures did not inhibit generation of normal cytolytic responses, and neither `resting’ SLE PBMC prior to stimulation nor addition of neutralizing anti-IL10 mAb or costimulating anti-CD28 mAb restored generation of SLE cytolytic responses to normal. Nevertheless, despite the significantly greater cytolytic responses in normal PBMC cultures than in SLE PBMC cultures, cytolytic responses in normal purified T cell cultures were only modestly and insignificantly greater than those in SLE purified T cell cultures. Moreover, substitution of `healthy’ non-T cells for SLE non-T cells in four of the nine MZ twin-pairs appreciably enhanced cytolytic responses, and substitution of SLE non-T cells for `healthy’ non-T cells in five of the seven twin-pairs tested appreciably diminished cytolytic responses. Taken together, these results indicate that, in addition to any inherent SLE T cell abnormalities, impaired function of SLE non-T cells contributes to impaired generation of nonrestricted CTL activity. [ABSTRACT FROM AUTHOR]

A commercially available polyspecific, monomeric IgG preparation suitable for intravenous administration (IgSRK; Sandoglobulin) can inhibit pokeweed mitogen (PWM)-induced proliferation of peripheral blood mononuclear cells (PBMC) by a small, but statistically significant, amount compared to control cultures. Such inhibition could not be demonstrated when PBMC were stimulated with the T cell mitogen phytohaemagglutinin. Surface phenotype analysis of the PWM-stimulated cells indicated that in IgSRK-containing cultures, the proportion of B cells was decreased and the proportion of T cells was increased compared to control cultures. This alteration in T:B ratio was not due to antigenic modulation of B or T cell markers from their surfaces. In addition, IgSRK inhibited the proliferation of T cell-depleted PBMC cultures stimulated by B cell proliferation factors (BCPF) but not by fixed protein A-bearing Staphyococcus aureus strain Cowan I. The capacity to inhibit B cell proliferation was independent of and distinct from its capacity to inhibit B cell differentiation, since IgSRK inhibited the differentiation of a B cell differentiation factor (BCDF)-sensitive line by BCDF (which contains no BCPF activity). IgSRK inhibited PWM-induced generation of cytoplasmic Ig+cells but had no effect on Ig secretion from mature Ig-secreting cells. Taken together, these findings suggest that IgSRK (which contains the IgG fraction from pooled plasma from 2,000 healthy donors) can inhibit T cell-dependent or T cell factor-dependent B cell proliferation and B cell differentiation. [ABSTRACT FROM AUTHOR]

The effect of a commercially available intravenous gammaglobulin preparation (IgSRK; Sandoglobulin) on the antigen-non-specific activation of the immune system was examined using pokeweed mitogen (PWM)-induced B cell differentiation. In cultures of peripheral blood mononuclear cells from 16 normal donors. IgSR K (300 μg/ml) inhibited PWM-induced generation of plaque-forming cells by 76% (P &lt 0.001), whereas human serum albumin (300 μg/ml) induced no significant inhibition (5%; P not significant). The IgSRK-mediated suppression was demonstrable in both serum-containing (76%) and serum-free (63%) media, and monomeric IgSRK suppressed as effectively as did heataggregated IgSRK. F(ab')2 fragments exhibited no inhibitory capacity (mean inhibition -- 11%: P not significant) suggesting that the Fc portion of IgSRK may be required for suppression. In addition, IgSRK had lo be added to the cultures at their initiation to effect full inhibition. These studies suggest a potential beneficial pharmacological role for IgSRK in the treatment of disorders characterized by pathogenic autoantibodies, but also warn of a potential deleterious effect of inhibiting the host's humoral response to an infectious challenge. [ABSTRACT FROM AUTHOR]

The T-cell differentiation antigen T4/Leu3 has been described as a non-polymorphic molecule important in T-cell recognition of class II major histocompatibility complex antigens. We report the polymorphism of this molecule in black individuals as manifest by a heterogeneity of staining with OKT4 monoclonal antibody. No such heterogeneity was observed when staining with other monoclonal antibodies that bind to different epitopes of the same molecule. No heterogeneity of staining with any of the monoclonal antibodies was observed in whites. Three patterns of OKT4 staining emerged: intact, deficient, and intermediate. This heterogeneity is likely to be due to an intrinsic heterogeneity in T4 epitope expression and not secondary to an interfering plasma factor as shown by the preservation of the T4 epitope pattern after a 3-day culture; in the presence or absence of mitogen. Family studies strongly suggest that this heterogeneity in T4 epitope expression is inherited in an autosomal codominant fashion. [ABSTRACT FROM AUTHOR]

BAFF, a vital B cell survival and differentiation factor, has three receptors: B-cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) and BR3. Although B cells are greatly reduced in B6.Baff -/- (which harbour no BAFF) and B6.Br3 -/- mice (which harbour supra-normal levels of BAFF), the distributions of B cell subsets and relationships between Foxp3 + and CD4 + cells in these mice differ. Using a large panel of B6 congenic knockout and/or transgenic mice, we demonstrate that (1) supra-normal levels of BAFF per se do not explain the phenotypic differences between B6.Baff -/- and B6.Br3 -/- mice; (2) B cells are expanded in B6.Taci -/- mice, with preferential expansion of follicular (FO) B cells at the expense of CD19 + CD21 -/lo CD23 -/lo B cells but without the preferential expansion of Foxp3 + cells observed in B6 mice bearing a Baff transgene; (3) despite no expansion in total B cells, percentages of FO B cells and marginal zone B cells are higher and percentages of CD19 + CD21 -/lo CD23 -/lo B cells are lower in young B6.Bcma -/- mice, consistent with the inability of B6.Br3 -/- .Taci -/- mice to recapitulate the B cell profile of B6.Baff -/- mice; and (4) percentages of Foxp3 + cells in B6.Br3 -/- .Taci -/- mice are intermediate between those in B6.Br3 -/- and B6.Taci -/- mice despite the B cell profile of B6.Br3 -/- .Taci -/- mice strongly resembling that of B6.Br3 -/- mice. Collectively, our findings point to a non-redundant role for each of the BAFF receptors in determining the ultimate lymphocyte profile of the host. This may have clinically relevant ramifications in that the degree that a candidate therapeutic agent blocks engagement of any given individual BAFF receptor may affect its clinical utility., (© 2024 The Author(s). Immunology published by John Wiley & Sons Ltd.)