Many intracellular pathogens, including Toxoplasma gondii, survive within macrophages by residing in vacuoles that avoid fusion with lysosomes. It is important to determine whether cell-mediated immunity can trigger macrophage antimicrobial activity by rerouting these vacuoles to lysosomes. We report that CD40 stimulation of human and mouse macrophages infected with T. gondii resulted in fusion of parasitophorous vacuoles and late endosomes/lysosomes. Vacuole/lysosome fusion took place even when CD40 was ligated after the formation of parasitophorous vacuoles. Genetic and pharmacological approaches that impaired phosphoinositide-3-class 3 (PIK3C3), Rab7, vacuolar ATPase, and lysosomal enzymes revealed that vacuole/lysosome fusion mediated antimicrobial activity induced by CD40. Ligation of CD40 caused colocalization of parasitophorous vacuoles and LC3, a marker of autophagy, which is a process that controls lysosomal degradation. Vacuole/lysosome fusion and antimicrobial activity were shown to be dependent on autophagy. Thus, cell-mediated immunity through CD40 stimulation can reroute an intracellular pathogen to the lysosomal compartment, resulting in macrophage antimicrobial activity.

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Objective. To examine health disparities as a function of ethnicity using data from LUpus in MInorities, NAture versus nurture (LUMINA), a longitudinal study of patients with systemic lupus erythematosus (SLE); to build an explanatory model of how ethnic disparities occur in this setting; and to suggest appropriate interventions. Methods. LUMINA patients (meeting American College of Rheumatology criteria for SLE) ages >16 years of African American, Hispanic (from Texas), Hispanic (from Puerto Rico), or Caucasian ethnicity were studied. In addition to examining the basic features of the cohort, we examined, by univariable and multivariable analyses, the factors associated with disease activity, damage accrual, lupus nephritis, and mortality. An empiric model based on the data presented (and the literature reviewed) was derived to explain the disparities observed. Results. There were substantial differences in the socioeconomic/demographic, clinical, and genetic features among patients from the different ethnic groups, with Texan Hispanic and African American patients exhibiting overall a lower socioeconomic status, different genetic associations, more serious disease at a younger age, and worse intermediate and final outcomes than the Caucasian and Puerto Rican Hispanic patients. A model of disease outcome as a function of the disparities observed was created.Conclusion. Ethnic disparities occur in SLE. Environmental, socioeconomic/demographic, psychosocial, genetic, and clinical factors play an important role as determinants of the ethnic differences observed. Measures aimed at eliminating these disparities are suggested while further research is conducted to elucidate the basis of these disparities and their changes at the societal level and to eliminate the gap between the rich and the poor.

Objective. To determine the impact of the patient's sex on the manifestations and outcome of systemic lupus erythematosus (SLE).Methods. We studied SLE patients who were ages 16 years or older and had a disease duration of <5 years at the time of enrollment in the LUpus in MInorities, NAture versus nurture cohort, a multiethnic cohort consisting of Hispanic, African American, and Caucasian patients. Socioeconomic/demographic, clinical, and serologic features, as well as disease activity (by the Systemic Lupus Activity Measure, Revised) and damage accrual (by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) were compared between male and female patient groups. Multivariable analyses using male sex and damage accrual as dependent variables were then performed.Results. Sixty-three male SLE patients (10.2%) from all ethnic groups were included. The mean ages of the male and female patients were comparable. Factors that were either more frequent or tended to be more frequent among male SLE patients were Caucasian ethnicity, smoking, alcohol use, lupus anticoagulant (LAC) positivity, and renal involvement, whereas musculoskeletal involvement was less common. American College of Rheumatology criteria accrual time and disease duration were shorter in the male patients; damage was more common and of higher magnitude in this group. LAC positivity, shorter disease duration, and higher early damage scores were independently associated with male SLE. Male sex was a strong predictor of baseline damage, measured as a categorical variable (t-test ‫؍‬ 2.357, ␤-standardized coefficient 0.113; P ‫؍‬ 0.019) or a continuous variable (hazard ratio 3.179 [95% confidence interval 1.999-5.056]; P < 0.001). Male sex was also positively associated with the development of damage over most of the course of the disease.Conclusion. Poorer long-term prognosis among men with SLE appears to be decisively determined by their accelerated development of damage, particularly early in the course of the disease.Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs more frequently among women, predominantly during their childbearing years. Its wide range of clinical manifestations and its overall prognosis have been repeatedly differentiated by sex as well. Male SLE patients have been reported to develop more severe skin lesions (1-3), serositis (i.e., pericarditis and/or pleuritis) (2-5), renal involvement (5), thrombotic events (6), and seizures (7) as compared with

Autophagy is a homeostatic mechanism of lysosomal degradation. Defective autophagy has been linked to various disorders such as impaired control of pathogens and neurodegeneration. Autophagy is regulated by a complex array of signaling pathways that act upstream of autophagy proteins. Little is known about the role of altered regulatory signaling in disorders associated with defective autophagy. In particular, it is not known if pathogens inhibit autophagy by modulation of upstream regulatory pathways. Cells infected with HIV-1 blocked rapamycin-induced autophagy and CD40-induced autophagic killing of Toxoplasma gondii in bystander (non-HIV-1 infected) macrophage/monocytic cells. Blockade of autophagy was dependent on Src-Akt and STAT3 triggered by HIV-1 Tat and IL-10. Neutralization of the upstream receptors VEGFR, β-integrin or CXCR4, as well as of HIV-1 Tat or IL-10 restored autophagy in macrophage/monocytic cells exposed to HIV-1-infected cells. Defective autophagic killing of T. gondii was detected in monocyte-derived macrophages from a subset of HIV-1+ patients. This defect was also reverted by neutralization of Tat or IL-10. These studies revealed that a pathogen can impair autophagy in non-infected cells by activating counter-regulatory pathways. The fact that pharmacologic manipulation of cell signaling restored autophagy in cells exposed to HIV-1-infected cells raises the possibility of therapeutic manipulation of cell signaling to restore autophagy in HIV-1 infection.