Increased C1q binding immune complexes in Felty's syndrome: comparison with uncomplicated rheumatoid arthritis.

Sera from patients with Felty's syndrome (FS) and rheumatoid arthritis (RA) were examined for the presence of circulating immune complexes (IC) by using the 125I-C1q binding and monoclonal rheumatoid factor (mRF) techniques. Of 15 patients with FS, 9 (60%) had high 125I-C1q binding as compared to 3 of 26 RA patients (12%). The average C1q binding was significantly higher in the FS patients than in the RA patients without FS. C1q binding in both FS and RA patients was significantly higher than a group of 90 normal controls. In addition, serum C4 levels were significantly lower in the FS patients than in the RA patients. In contrast to these findings, IC levels in FS and RA patients were very similar when measured by the mRF technique. These studies indicate that FS patients have higher levels of complement-fixing IC in their sera than RA patients without FS. These findings raise the possibility that the complement-fixing IC found in these patients may play a role in the pathogenesis of neutropenia of FS.     

Anti-HLA-B27 antibodies in sera from patients with gram-negative bacterial infections

Several forms of seronegative polyarthritis are strongly associated with HLA-B27, and a number of microorganisms have been implicated in the etiology of these diseases. To explain the association between HLA-B27 and arthritis initiated by infection with these organisms, it has been proposed that there is immunologic cross-reactivity between the B27 molecule and 1 or more microbial antigens, and that this cross-reactivity leads to tolerance to such infection and/or to the production of anti-HLA-B27 cross-reactive antibodies. Such cross-reactive antibodies were detected in the sera of only 2 of 63 patients recently infected with Shigella flexneri, Campylobacter jejuni, or Yersinia enterocolitica who had highly significant antibody levels against the infecting bacterial species. Most striking was the absence of anti-HLA-B27 antibody in the serum of 16 of 17 patients who developed reactive arthritis following Yersinia infection.     

Comparison of the presence of immune complexes in Felty's syndrome and rheumatoid arthritis.

Evidence has been found to document the presence of circulating immune complexes in all patients with Felty's syndrome. The sera of all 12 patients studied showed intermediate complexes by analytical ultracentrifugation. The sera of 9 of 12 patients (75%) showed precipitin lines upon immunodiffusion against IgM rheumatoid factor. Both findings were statistically increased above those in a matched group of patients with classic rheumatoid arthritis. The presence of circulating immune complexes in the sera of the Felty patients was consistent with the observation that large inclusions containing IgG, IgM, and complement were phagocytized by normal polymorphonuclear cells when incubated with sera of Felty patients. Normal polymorphonuclear cells phagocytosed inclusions from 77% of Felty sera, compared with 27% classic rheumatoid arthritis sera. It is suggested that the uptake of immune complexes by polymorphonuclear cells plays a role in the neutropenia of Felty's syndrome.     

Human gamma interferon increases the binding of T lymphocytes to endothelial cells.

Binding of lymphocytes to human umbilical vein endothelial cells (EC) was quantitated by measuring adhesion of 51Cr labelled lymphocytes to endothelial cell monolayers and rosette formation between lymphocytes and EC in suspension. Mitogen stimulated human peripheral blood mononuclear cell culture supernatants and mixed lymphocyte reaction supernatants enhanced the binding of T lymphocytes to EC monolayers or suspensions preincubated with such supernatants. The active component of these supernatants appeared to be gamma interferon (IFN-gamma) since culture supernatants lost activity after heating at 56 degrees C for 60 min, exposure to pH 2.0 or treatment with anti-IFN-gamma. In addition, purified IFN-gamma increased the binding of T lymphocytes to EC (T-EC). This occurred in a concentration dependent manner when IFN-gamma was preincubated with EC but not with lymphocytes. While the optimum concentration of IFN-gamma was 250 u/ml, a significant enhancement was seen with as little as 10 u/ml. These findings suggest that IFN-gamma may play a part in the emigration of lymphocytes to perivascular chronic inflammatory sites by augmenting the adhesion of lymphocytes to the endothelium of small blood vessels.     

Tobacco smoking: a comparison between alcohol and drug abuse inpatients

This study compared the tobacco smoking of alcohol and drug abuse patients. The subjects were male inpatients (67 alcohol, 60 drug, and 13 mixed alcohol and drug abusers) of a Veterans Administration substance abuse program who had completed the Tolerance Questionnaire (Fagerstrom, 1978) and the Michigan Alcohol Screening Test (Skinner, 1979) as part of routine intake assessment procedures. As expected, an extremely high percentage (89.6%) of the alcohol abusers reported smoking cigarettes. Interestingly, an equally high prevalence of smoking was noted among the drug (90.0%) and mixed substance abuse (100%) groups. Comparisons conducted between abuse groups indicated that the alcohol abusers smoked significantly more cigarettes per day and had significantly higher Tolerance Questionnaire scores than the drug abusers, but did not differ from the mixed abuse group on any smoking variable. Additional comparisons of the total substance abuse population with a national sample of similarly aged males indicated that only the alcohol group smoked more cigarettes per day, but that all substance abuse groups smoked higher nicotine delivery cigarettes than the national sample.     

Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic acid type 1 receptor-selective antagonist

Lysophosphatidic acid (LPA) is a bioactive phospholipid that signals through a family of at least six G protein-coupled receptors designated LPA???. LPA type 1 receptor (LPA?) exhibits widespread tissue distribution and regulates a variety of physiological and pathological cellular functions. Here, we evaluated the in vitro pharmacology, pharmacokinetic, and pharmacodynamic properties of the LPA?-selective antagonist AM095 (sodium, {4'-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetate) and assessed the effects of AM095 in rodent models of lung and kidney fibrosis and dermal wound healing. In vitro, AM095 was a potent LPA? receptor antagonist because it inhibited GTPγS binding to Chinese hamster ovary (CHO) cell membranes overexpressing recombinant human or mouse LPA? with IC?? values of 0.98 and 0.73 μM, respectively, and exhibited no LPA? agonism. In functional assays, AM095 inhibited LPA-driven chemotaxis of CHO cells overexpressing mouse LPA? (IC??= 778 nM) and human A2058 melanoma cells (IC?? = 233 nM). In vivo, we demonstrated that AM095: 1) had high oral bioavailability and a moderate half-life and was well tolerated at the doses tested in rats and dogs after oral and intravenous dosing, 2) dose-dependently reduced LPA-stimulated histamine release, 3) attenuated bleomycin-induced increases in collagen, protein, and inflammatory cell infiltration in bronchalveolar lavage fluid, and 4) decreased kidney fibrosis in a mouse unilateral ureteral obstruction model. Despite its antifibrotic activity, AM095 had no effect on normal wound healing after incisional and excisional wounding in rats. These data demonstrate that AM095 is an LPA? receptor antagonist with good oral exposure and antifibrotic activity in rodent models.     

CTLA-4 is required for the induction of high dose oral tolerance

Mucosal and systemic administrations of high dose antigens induce long- lasting peripheral T cell tolerance. We and others have shown that high dose peripheral T cell tolerance is mediated by anergy or deletion and is preceded by T cell activation. Co-stimulatory molecules B7-1 (CD80)/B7-2 (CD86) and their counter-receptors CD28/CTLA-4 play pivotal roles in T cell activation and immune regulation. In the present study, we examined the roles of the B7 co-stimulation pathway in the generation of high dose peripheral T cell tolerance. We found that blocking B7:CD28/CTLA-4 interaction at the time of tolerance induction partially prevented T cell tolerance, whereas selective blockade of B7:CTLA-4 interaction completely abrogated peripheral T cell tolerance induced by either oral or i.p. antigens. These results suggest that CTLA-4-mediated feedback regulation plays a crucial role in the induction of high dose peripheral T cell tolerance.