Francisco P. Quismorio

CD4+ and CD8+ Regulatory T Cells Generated Ex Vivo with IL-2 and TGF-β Suppress a Stimulatory Graft-versus-Host Disease with a Lupus-Like Syndrome

Regulatory T cells generated ex vivo from conventional mouse T cells have been used to prevent and alter the course of a stimulatory graft-vs-host disease with a lupus-like syndrome. DBA/2 mouse T cells induce this syndrome when injected into (DBA/2 × C57BL/6) F1 mice. Stimulating DBA/2 T cells with irradiated C57BL/6 in the presence of IL-2 and TGF-β induced both CD4+ and CD8+ cells to develop potent suppressive activity and enhanced their survival. The IL-2 and TGF-β-treated T cells lost their ability to induce graft-vs-host disease and, instead, prevented other parental T cells from inducing lymphoid hyperplasia, B cell activation, and an immune complex glomerulonephritis. Moreover, a single transfer of TGF-β-conditioned T cells to animals that had already developed anti-dsDNA Abs decreased the titer, suppressed proteinuria, and doubled survival. This study raises the possibility that autologous regulatory T cells generated ex vivo have the potential to be used as an adoptive immunotherapy to induce allograft tolerance and to control autoimmunity.

The Choroid Plexus in Systemic Lupus Erythematosus

Abstract Gamma globulin deposits were found in the choroid plexus of two patients with systemic lupus erythematosus and mental disturbances but not in the choroid plexus of controls. The cerebrum, ...

Synergistic effect between IL-10 and bcl-2 genotypes in determining susceptibility to systemic lupus erythematosus

OBJECTIVE To determine whether genes participating in programmed cell death, including bcl-2, IL-10, Fas-L, and CTLA-4, may contribute to the genetic predisposition to systemic lupus erythematosus (SLE). METHODS First, intragenic markers for the bcl-2, IL-10, Fas-L, and CTLA-4 genes were characterized and their extent of polymorphism in normal populations was determined. The allelic distribution of these gene markers in a large Mexican American SLE cohort of 158 patients and 223 ethnically matched controls was determined using fluorescent-labeled primers and semiautomated genotyping. RESULTS The bcl-2, Fas-L, and IL-10 loci showed significantly different allelic distribution in SLE patients compared with controls, indicating an association between these genes and SLE. No association was found between SLE and the CTLA-4 gene. Further analysis revealed a synergistic effect between susceptibility alleles of the bcl-2 and IL-10 genes in determining disease susceptibility. Alone, the presence of each of these alleles was associated with a moderate increase in SLE risk, while the occurrence of these alleles together increased the odds of developing SLE by more than 40-fold. CONCLUSION The results suggest that individuals carrying specific genotypes of both bcl-2 and IL-10 are at significant risk of developing SLE.

Impairments of the Protein C System and Fibrinolysis in Infection-Associated Stroke

BACKGROUND AND PURPOSE Infection/inflammation appears to be an important predisposing risk factor for brain infarction, but little is known regarding underlying molecular mechanisms. We examined the hypothesis that patients with brain infarction preceded by infection/inflammation within 1 week could be identified by a distinctive procoagulant laboratory profile characterized by abnormalities in the protein C system and endogenous fibrinolysis. METHODS We performed a case-control study examining the relationship between preceding systemic infectious/inflammatory syndromes and selected immunohematologic variables in 36 patients with acute brain infarction and 81 control subjects (community control subjects [n = 47] and hospitalized nonstroke neurological patient controls [n = 34]). RESULTS The stroke group had a lower mean level of the circulating antithrombotic enzyme activated protein C (APC) (4.33 +/- 0.34% [log-transformed percentage of control value, mean +/- SD]) than community control subjects (4.51 +/- 0.27%, P < .02) or hospitalized neurological patient controls (4.57 +/- 0.31%, P < .005). The lowest circulating APC levels were found in the stroke group with antecedent infection/inflammation within 1 week preceding index brain infarction (4.23 +/- 0.4%, n = 12). Within the stroke group, circulating APC levels were inversely related to IgG isotype anticardiolipin antibody titers (r = -.55, P < .001). Only the stroke group with infection/inflammation within 1 week had elevated plasma C4b binding protein compared with control subjects (141 +/- 61% versus 112 +/- 44%, P < .05). Stroke patients with antecedent infection/inflammation had a distinctively lower ratio of active tissue plasminogen activator to plasminogen activator inhibitor (0.11 +/- 0.04, n = 9) than other stroke patients (0.19 +/- 0.06, n = 9, P < .01) and control subjects (0.22 +/- 0.16, n = 17, P < .02). CONCLUSIONS Impairments in the protein C pathway and endogenous fibrinolysis may contribute to the increased risk for brain infarction after recent (< or = 1 week) infection/inflammation. A decrease in the circulating anticoagulant APC may be related to elevated antiphospholipid antibody titers.

Magnetic resonance imaging of the brain in neuropsychiatric systemic lupus erythematosus

To determine the utility of magnetic resonance imaging (MRI) of the brain in diagnosing active neuropsychiatric disease in systemic lupus erythematosus (NP-SLE), a prospective study of 51 hospitalized systemic lupus erythematosus (SLE) patients during 64 separate episodes of suspected NP-SLE was initiated. In addition to standard hematology, chemistry, and serological tests, the workup included MRI in all patients. A computed tomographic scan of the brain was obtained in patients enrolled in the first year of the study. Of the 64 neuropsychiatric episodes, 42 were attributable to NP-SLE and 22 were attributed to causes other than SLE. Neuropsychiatric complaints unrelated to lupus included depression (n = 6), seizures (n = 5), headache (n = 3), altered mental status (n = 2), aseptic meningitis (n = 2), cardiovascular accident (n = 2), transient ischemic attack (n = 1), and vertigo (n = 1). The MRI was abnormal in 34 of 64 (53%) episodes. MRI abnormalities were more common in patients with focal neurological deficits (19/26) than in those without focal findings (15/38; P = .008) and in patients with nephritis (19/24) than in those without renal disease (15/40; P = .002). MRI abnormalities were as frequent in NP-SLE (25/42) as in cases with non-NP-SLE-related causes (9/22). Periventricular increased signal (PIS) was a frequent MRI finding (10/64). Enlargement of the prepontine cistern, an MRI finding not previously described in NP-SLE, was seen (14/64). Both findings were associated with the presence of hypertension and lupus nephritis. PIS similar to that seen in our patients has been described in otherwise healthy elderly individuals with risk factors for stroke, suggesting that vascular abnormalities may be important in the etiology of these lesions. In conclusion, abnormalities in brain MRI occur frequently in NP-SLE, especially in patients with focal neurological deficits. However, the presence of similar MRI abnormalities in SLE patients with neuropsychiatric symptoms and findings with non-SLE-related causes limits the specificity of the MRI for diagnosing NP-SLE.

A long-term study of interstitial lung disease in systemic lupus erythematosus

The clinical course of chronic diffuse interstitial lung disease (ILD) was studied in 14 patients with SLE. The mean duration of follow-up was 7.3 years. All patients had dyspnea on exertion, pleuritic chest pain, chronic cough, and basilar rales. Chest roentgenogram showed diffuse or basilar infiltrates, pleural disease, and elevation of both diaphragms. Systemic corticosteroids were given early in the course of the illness for lung involvement and multisystem disease. Diffusing capacity for carbon monoxide (DLCO) and inspiratory vital capacity (IVC) improved or remained unchanged in the majority of patients. Respiratory complaints improved in all patients; however, two patients died of pulmonary fibrosis and another died of bacterial pneumonia. Alveolar septal deposits of immunoglobulins and complement were found. This study showed that while variability existed among individual subjects, the clinical progression of ILD was slow and tended to improve or stabilize with time.

Interstitial lung disease in systemic lupus erythematosus

Systemic lupus erythematosis (SLE) is a heterogenous disease of unknown etiology. It is not uncommon to see pleuropulmonary involvement in isolation or along with the involvement of other organ systems in SLE. Pulmonary manifestations of SLE can involve the pleura, lung parenchyma, airways, pulmonary vasculature, and the respiratory muscles. In this review we discuss two important pulmonary manifestations of SLE: acute lupus pneumonitis and diffuse interstitial lung disease. These two conditions have a major impact on the mortality and morbidity of patients with SLE and it is essential to recognize and treat them appropriately. High-resolution computed tomographic scans of the chest and pulmonary function tests help to establish a diagnosis and aid long-term follow-up of these patients. High-dose corticosteroids are the mainstay of treatment for the two conditions, although other agents such as cyclophosphamide, azathioprine, intravenous gamma globulin, and plasmapheresis have been used with varying degrees of success.

Immunohematologic characteristics of infection-associated cerebral infarction.

We evaluated 50 consecutive patients with acute ischemic stroke to assess the prevalence of systemic infection preceding the neurological event. We analyzed the immunohematologic characteristics of patients with and without signs and/or symptoms of a preceding infectious process. Patients were examined less than or equal to 7 days after cerebral infarction and evaluated for fibrinogen, anticardiolipin antibodies, fibrin D-dimer (a fragment of cross-linked fibrin), plasminogen activator inhibitor-1, and protein S. Of the 50 patients, 17 had symptoms of infection beginning less than or equal to 1 month before the stroke (11 had upper respiratory tract infections, three urinary tract infections, two subacute bacterial endocarditis, and one pneumonia). Compared with patients without infection, patients with infection had significant increases in fibrin D-dimer concentration (5.3 +/- 1.1 versus 4.7 +/- 0.9 log-transformed ng/ml, p less than 0.05) and cardiolipin immunoreactivity, IgG isotype (1.8 +/- 1.3 versus 1.1 +/- 0.9 log-transformed phospholipid units, p less than 0.04), and, when studied less than or equal to 2 days after the stroke, increased fibrinogen levels (459 +/- 126 versus 360 +/- 94 mg/dl, p less than 0.05). In conclusion, infection-associated cerebral infarction is common and is associated with substantial immunohematologic abnormalities.

Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions

Significance Natural regulatory T cells (nTregs) play important roles in preventing autoimmune diseases, but they may be unstable in the presence of inflammation. Here we report that all-trans RA (atRA) but not rapamycin prevents human nTregs from converting to Th1/Th17 cells and sustains their suppressive function in inflammatory environments. Adoptive transfer of nTregs pretreated with atRA enhances their suppressive effects on xenograft-vs.-host diseases. Moreover, we show that atRA suppresses IL-1 receptor upregulation, accelerates IL-6 receptor downregulation, and affects the epigenetic modifications in Foxp3 locus in nTregs following inflammatory stimulation. We suggest that nTregs primed with atRA may represent a novel treatment strategy to control established chronic immune-mediated diseases. Recent studies have demonstrated that thymus-derived naturally occurring CD4+Foxp3+ regulatory T cells (Tregs) in human and mouse may be unstable and dysfunctional in the presence of proinflammatory cytokines. All-trans RA (atRA), the active derivative of vitamin A, has been shown to regulate Treg and T effector cell differentiation. We hypothesize atRA stabilizes human natural Tregs (nTregs) under inflammatory conditions. atRA prevents human nTregs from converting to Th1 and/or Th17 cells and sustains their Foxp3 expression and suppressive function in vitro or in vivo following encounters with IL-1 and IL-6. Interestingly, adoptive transfer of human nTregs pretreated with atRA significantly enhanced their suppressive effects on xenograft-vs.-host diseases (xGVHDs), and atRA- but not rapamycin-pretreated nTregs sustained the functional activity against xGVHD after stimulation with IL-1/IL-6. atRA suppresses IL-1 receptor (IL-1R) up-regulation, accelerates IL-6R down-regulation, and diminishes their signaling events as well as prevents the up-regulation of STIP1 homology and U-Box containing protein 1 on Foxp3+ cells following IL-1/IL-6 stimulation. atRA also increases histone acetylation on Foxp3 gene promoter and CpG demethylation in the region of Foxp3 locus (i.e., Treg-specific demethylated region). These results strongly implicate that nTregs primed with atRA may represent a novel treatment strategy to control established chronic immune-mediated autoimmune and inflammatory diseases.

Esophageal dysfunction in patients with mixed connective tissue diseases and systemic lupus erythematosus.

We sought to correlate esophageal symptoins with esophaged motility abnormality in 17 patients with mixed connective tissue disease (MCTD) and in 14 patients with systemic lupus erythematosus (SLE). Heartburn and regurgitation were common symptoms (11/17) in patients with MCTD, and most of them (10/11) exhibited significant manometric abnormalities. Additionally, impairment of esophageal peristalsis was found in four of the remaining asymptomatic patiens. Severe esophageal aperistalsis was noted in nine MCTD patients. Patients with SLE also frequently reported esophageal symptoms (8/14), but significant motility abnormalities were seen in only three cases. In both patient groups good correlation between Raynauds phenomenon and esophageal aperistalsis was found. Our results reveal that, although esophageal symptoms are commonly present in patients with both MCTD and SLE, severe esophageal motility abnormalities are more often found in patients with MCTD than in those with SLE.