Publications

Autoimmune-prone nonobese diabetic mice deficient for B7-2 spontaneously develop an autoimmune peripheral neuropathy mediated by inflammatory CD4(+) T cells that is reminiscent of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. To determine the etiology of this disease, CD4(+) T cell hybridomas were generated from inflamed tissue-derived CD4(+) T cells. A majority of T cell hybridomas were specific for myelin protein 0 (P0), which was the principal target of autoantibody responses targeting nerve proteins. To determine whether P0-specific T cell responses were sufficient to mediate disease, we generated a novel myelin P0-specific T cell receptor transgenic (POT) mouse. POT T cells were not tolerized or deleted during thymic development and proliferated in response to P0 in vitro. Importantly, when bred onto a recombination activating gene knockout background, POT mice developed a fulminant form of peripheral neuropathy that affected all mice by weaning age and led to their premature death by 3-5 wk of age. This abrupt disease was associated with the production of interferon gamma by P0-specific T cells and a lack of CD4(+) Foxp3(+) regulatory T cells. Collectively, our data suggest that myelin P0 is a major autoantigen in autoimmune peripheral neuropathy.

BACKGROUND

The benefits of breast-feeding for the prevention of infection in infants and young children have been widely recognized, but epidemiologic studies regarding the role of breast-feeding in protecting against Helicobacter pylori infection have produced conflicting results.

METHODS

We performed a systematic review of relevant epidemiologic studies conducted during the period 1984-2007 after abstracting data from articles that met our inclusion criteria. Study quality was assessed using the Newcastle-Ottawa scale. With use of the random effects model, we calculated the summary odds ratios (ORs) and 95% confidence intervals (CIs) for H. pylori infection according to history of breast-feeding.

RESULTS

For the 14 studies that met inclusion criteria, the summary OR for H. pylori infection was 0.78 (95% CI, 0.61-0.99; 1-sided P = .002). Nine of the 14 studies reported ORs of <1.0, and 6 of these studies reported statistically significant protective effects. Only 1 study reported a statistically significant OR of >1.0. In studies in which the subjects resided in middle- or low-income nations, the summary OR was 0.55 (95% CI, 0.33-0.93; P = .01), compared with 0.93 (95% CI, 0.73-1.19; P = .28) in studies in which subjects resided in high-income nations. The summary OR for studies that use the (13)C-urea breath test was 0.67 (95% CI, 0.32-1.39), compared with 0.91 (95% CI, 0.74-1.11) for studies that used the H. pylori IgG serologic test. We found no statistically significant dose-dependent protective effect against H. pylori associated with increasing duration of breast-feeding.

CONCLUSIONS

Breast-feeding is protective against H. pylori infection, especially in middle- and low-income nations.

OBJECTIVE

To prospectively track work loss among those employed and work entry among those not employed in a cohort of persons with systemic lupus erythematosus (SLE), assess risk factors for these outcomes, and compare rates of the outcomes with a matched national sample.

METHODS

The present study analyzed 4 years of data from the Lupus Outcomes Study (LOS), augmented by information on the local labor market from the Census Bureau and the Bureau of Labor Statistics. We used the Kaplan-Meier method to assess time from study initiation until work loss or work entry, and Cox proportional hazards regression to estimate factors affecting these outcomes. Finally, we compared rates of work loss and work entry in the LOS with rates in the Survey of Income and Program Participation (SIPP).

RESULTS

At study initiation, 394 LOS participants (51%) were employed, of whom 92 (23.4%) experienced work loss. In multivariate analysis, older age, lower cognitive and physical functioning, and higher reports of depressive symptoms predicted work loss. In comparison with the SIPP sample, rates of work loss did not differ. Of the 376 LOS participants not employed, 76 (20.2%) experienced work entry. In multivariate analysis, less disease activity, fewer lung manifestations, better physical functioning, and shorter time since last employment predicted work entry. In comparison with the SIPP, rates of work entry were only lower between ages 35 and 55 years.

CONCLUSION

Until age 55 years, low rates of employment among persons with SLE may be due to lower rates of work entry rather than higher rates of work loss. Beyond age 55 years, both high rates of work loss and low rates of work entry contribute to low rates of employment.

OBJECTIVE

Forgetting to take medications is an important cause of nonadherence. This study evaluated factors associated with forgetting to take medications in a large cohort of persons with systemic lupus erythematosus (SLE) participating in the University of California, San Francisco Lupus Outcomes Study (LOS). Relationships among adherence problems and service utilization (outpatient visits, emergency department visits, and hospitalizations) were also evaluated.

METHODS

The cohort consisted of 834 LOS participants who provided self-reported frequency of forgetting to take medications as directed. Predictors of adherence and service utilization patterns included self-reported sociodemographics, disease-related characteristics (e.g., disease activity, recent SLE flare), and mental health characteristics (Center for Epidemiologic Studies Depression Scale and cognitive function screen). Health care utilization patterns included the presence and quantity of visits to rheumatologists, primary care physicians, other care providers, emergency departments, and hospitalizations.

RESULTS

Forty-six percent of the LOS cohort reported forgetting to take medications at least some of the time. Depressive symptom severity was a strong predictor of adherence difficulties (odds ratio [OR] 1.04, 95% confidence interval [95% CI] 1.02-1.05; P < 0.0001) after accounting for all other predictors. Persons reporting adherence difficulties had significantly greater numbers of outpatient rheumatology and primary care visits, and were more likely to visit the emergency department (OR 1.45, 95% CI 1.04-2.04; P = 0.03).

CONCLUSION

Depression may be an important cause of medication adherence problems, and difficulties with adherence are significantly associated with high-cost service utilization, specifically emergency department visits. In an era of rapidly evolving treatments for lupus, identifying patients at risk for adherence problems may decrease medical expenditures and improve patient outcomes in SLE.

Studies performed using cultured cells indicate that IgE functions not only to trigger degranulation of mast cells following allergen exposure, but also to enhance their survival. Such an influence of IgE on mast cell homeostasis during allergic responses in vivo has not been established. In this study, we show that inhalation of Aspergillus fumigatus extract in mice induced a dramatic rise in IgE accompanied by an increase in airway mast cells. These had an activated phenotype with high levels of FcepsilonRI. Plasma mast cell protease-1 was also increased, indicating an elevated systemic mast cell load. In addition, enhanced levels of IL-5 and eosinophils were observed in the airway. Both mast cell expansion and activation were markedly attenuated in IgE(-/-) animals that are incapable of producing IgE in response to A. fumigatus. The recruitment of eosinophils to the airways was also reduced in IgE(-/-) mice. Analyses of potential cellular targets of IgE revealed that IgE Abs are not required for the induction of mast cell progenitors in response to allergen, but rather act by sustaining the survival of mature mast cells. Our results identify an important role for IgE Abs in promoting mast cell expansion during allergic responses in vivo.