Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity

The immunopathophysiologic development of systemic autoimmunity involves numerous factors through complex mechanisms that are not fully understood. In systemic lupus erythematosus, type I IFN (IFN-I) produced by plasmacytoid dendritic cells (pDCs) critically promotes the autoimmunity through its pleiotropic effects on immune cells. However, the host-derived factors that enable abnormal IFN-I production and initial immune tolerance breakdown are largely unknown. Previously, we found that amyloid precursor proteins form amyloid fibrils in the presence of nucleic acids. Here we report that nucleic acid-containing amyloid fibrils can potently activate pDCs and enable IFN-I production in response to self-DNA, self-RNA, and dead cell debris. pDCs can take up DNA-containing amyloid fibrils, which are retained in the early endosomes to activate TLR9, leading to high IFNα/β production. In mice treated with DNA-containing amyloid fibrils, a rapid IFN response correlated with pDC infiltration and activation. Immunization of nonautoimmune mice with DNA-containing amyloid fibrils induced antinuclear serology against a panel of self-antigens. The mice exhibited positive proteinuria and deposited antibodies in their kidneys. Intriguingly, pDC depletion obstructed IFN-I response and selectively abolished autoantibody generation. Our study reveals an innate immune function of nucleic acid-containing amyloid fibrils and provides a potential link between compromised protein homeostasis and autoimmunity via a pDC-IFN axis.     

Mutated G4P[8] rotavirus associated with a nationwide outbreak of gastroenteritis in Nicaragua in 2005

During February and March 2005, one of the largest national recorded outbreaks of severe acute gastroenteritis occurred in Nicaragua, affecting >or=64,000 individuals and causing >or=56 deaths, predominantly in children under 5 years of age. Through a nationwide laboratory-based study, stool samples were collected and investigated for rotavirus. Of 108 stool samples examined, 72 (67%) were positive for rotavirus. While 69% (50/72) of the positive samples were found in children less than 2 years of age, 50% (6/12) of the adult samples were positive. A mutated G4P[8] strain was the most commonly recognized strain (85%), followed by mixed G strains (8%) and G9P[8] (7%) strains. Phylogenetic analysis of the VP7 gene revealed that the G4 strains belonged to the emerging lineage Ic and was distantly related to the ST3 and VA70 G4 strains. Secondary structure predictions of the VP7 G4 protein revealed an insert of an asparagine residue in position 76, which, combined with additional mutations, surprisingly modified two downstream beta-sheets at amino acid positions 80 to 85 and 115 to 119. The 2005 G4P[8] strain compared to a G4P[8] strain from 2002 had a substitution of an asparagine residue for threonine (Asn-->Thr) at position 96 within antigenic region A, thus eliminating a potential glycosylation site. The mutated G4 virus was introduced in Nicaragua after 2002 and probably emerged from Brazil, Argentina, or Uruguay.     

Separate influences of birth order and gravidity/parity on the development of systemic sclerosis

Objective

Birth order has been valuable in revealing the role of environmental influences on the risk of developing certain diseases such as allergy and atopy. In addition, pregnancy has profound effects on the immune system such as short‐term effects that permit fetal survival as well as longer‐term effects that could influence late‐onset diseases. In order to better evaluate these influences, we studied the association of birth order and gravidity/parity as risk factors for systemic sclerosis (SSc; scleroderma).

Methods

Data regarding SSc cases and their unaffected sibling controls were obtained from the Scleroderma Family Registry and DNA Repository. The case‐sibling design was used to minimize confounding due to differences in age, race, ethnicity, or calendar time. The gravidity/parity analysis was based on sibships with at least one SSc‐affected and one unaffected sister.

Results

Birth order was examined in 974 sibships, comparing SSc cases (n = 987) with their unaffected siblings (n = 3,088). The risk of scleroderma increased with increasing birth order (odds ratio [OR] 1.25, 95% confidence interval [95% CI] 1.06–1.50 for birth order 2–5; OR 2.22, 95% CI 1.57–3.15 for birth order 6–9; and OR 3.53, 95% CI 1.68–7.45 for birth order 10–15). Gravidity/parity was analyzed in 168 sibships (256 unaffected sisters, 172 SSc cases). We found an association between a history of one or more pregnancies and SSc (OR 2.8).

Conclusion

Birth order and pregnancy were independently associated with a higher risk of developing SSc. These findings suggest that immune development in early childhood and/or pregnancy‐associated events, including but not limited to microchimerism, plays a role in SSc susceptibility.     

Genetic susceptibility to symptomatic norovirus infection in Nicaragua

Host genetic resistance to Norovirus (NoV) has been observed in challenge and outbreak studies in populations from Europe, Asia, and USA. In this study, we have investigated if histo‐blood group antigens can predict susceptibility to diarrhea caused by NoV in Nicaragua, Central America, and if this can be reflected in antibody‐prevalence and titer to NoV among individuals with different histo‐blood group antigen phenotypes. Investigation of 28 individuals infected with NoV and 131 population controls revealed 6% of non‐secretors in the population and nil non‐secretors among patients infected with NoV, suggesting that non‐secretors may be protected against NoV disease in Nicaragua. Surprisingly, 25% of the population was Lewis negative (Le^a?b?). NoV infections with genogroup I (GI) and GII occurred irrespective of Lewis genotype, but none of the Lewis a positive (Le^{a + b?}) were infected. The globally dominating GII.4 virus infected individuals of all blood groups except AB (n = 5), while the GI viruses (n = 4) infected only blood type O individuals. Furthermore, O blood types were susceptible to infections with GI.4, GII.4, GII.7, GII.17, and GII.18‐Nica viruses, suggesting that secretors with blood type O are susceptible (OR = 1.52) and non‐secretors resistant. The overall antibody‐prevalence to NoV GII.3 VLP was 62% with the highest prevalence among blood type B carriers (70%) followed by A (68%) and O (62%). All four investigated individuals carrying blood type AB were antibody‐negative. Among secretors, 63% were antibody‐positive compared to 33% among non‐secretors (P = 0.151). This study extends previous knowledge about the histo‐blood group antigens role in NoV disease in a population with different genetic background than North American and European. J. Med. Virol. 81:728–735, 2009 © 2009 Wiley‐Liss, Inc.     

Association of the PTPN22 R620W polymorphism with anti-topoisomerase I- and anticentromere antibody-positive systemic sclerosis

OBJECTIVE: To determine any associations of the PTPN22 R620W single-nucleotide polymorphism (SNP) with systemic sclerosis (SSc) or with anticentromere antibody (ACA)-positive or anti-topoisomerase I (anti-topo I) antibody-positive SSc, in a case-control study of US white, black, Hispanic, and Choctaw Indian individuals. METHODS: A total of 850 white, 130 black, 120 Hispanic, and 20 Choctaw Indian patients with SSc were compared with 430 white, 164 black, 146 Hispanic, and 76 Choctaw Indian control subjects, respectively. All subjects were living in the US. PTPN22 SNP (rs2476601) genotyping was performed by TaqMan 5' allelic discrimination assay and pyrosequencing. RESULTS: The PTPN22 CT/TT genotype showed significant association with anti-topo I antibody-positive SSc in white patients (odds ratio [OR] 2.21, 95% confidence interval [95% CI] 1.3-3.7) and with ACA-positive white patients with SSc (OR 1.70, 95% CI 1.1-2.7). Frequency of the PTPN22*T allele also showed significant association with anti-topo I antibody-positive SSc in white patients (OR 2.03, 95% CI 1.3-3.2). When data for patients in the 3 ethnic groups (black, white, and Hispanic) were combined, a significant association with both genotype and allele frequencies was observed, suggesting a trend toward association in ACA-positive and anti-topo I antibody-positive SSc. Stepwise logistic regression analysis (controlled for the confounding effects of sex and race) showed that the PTPN22 CT/TT genotype was associated with a significantly higher risk of SSc compared with the CC genotype (for patients with SSc, OR 1.64, 95% CI 1.2-2.2; for ACA-positive patients with SSc, OR 1.63, 95% CI 1.0-2.6; for anti-topo I antibody-positive SSc, OR 2.33, 95% CI 1.5-3.7). CONCLUSION: Our results indicate that the PTPN22 R620W polymorphism is associated with ACA-positive and anti-topo I antibody-positive subsets of SSc and represents a risk factor in both white patients and black patients. The association of subsets of SSc with the PTPN22 R620W polymorphism further strengthens the classification of SSc within the spectrum of autoimmune diseases and strongly suggests the involvement of common susceptibility genes and similarly disordered immunoregulatory pathways.     

Correlation analysis of twin data with repeated measures based on generalized estimating equations

Repeated measures allow additional tests of common assumptions in twin correlation analysis. Analysis of log serum triglyceride level in NHLBI male twins using generalized estimating equations disclosed that the mean and variance shifted across exams, presumably because of changes in laboratory practice. © 1993 Wiley-Liss, Inc.     

Comparison of sexual and drug use behaviors between female sex workers in Tijuana and Ciudad Juarez, Mexico

Female sex workers (FSWs) have been documented to have high rates of sexually transmitted diseases and HIV in many parts of the world. However, little work has been done to characterize the prevalence of these infections along the U.S.-Mexican border, where sexual tourism and culturally sanctioned sex work among nationals is widespread. The objective of this study was to compare differences in background characteristics, HIV risk behaviors, drug use, and sexually transmitted infection/HIV prevalence between FSWs who participated in a behavioral risk intervention in two U.S.-Mexican border cities. Baseline data were collected from March 2004 through September 2005. Data from 295 FSWs were compared between Tijuana and Ciudad (Cd.) Juarez. Among 155 FSWs in Tijuana and 140 in Cd. Juarez, HIV seroprevalence was 4.8% and 4.9%, respectively. FSWs in Cd. Juarez were more likely to test positive for active syphilis (31.3%) compared with Tijuana (11.8%) but did not differ in terms of the prevalence of gonorrhea and chlamydia. FSWs in both sites reported high levels of unprotected sex and use of drugs; however, FSWs in Cd. Juarez were more likely than those in Tijuana to ever have injected drugs (75% vs. 25%, p <.001). Heroin and cocaine use and injection drug use were significantly more common in Cd. Juarez, whereas methamphetamine use was more common in Tijuana. Injection of vitamins was common in both cities. Logistic regression analyses suggested that being younger, working in Cd. Juarez, and using heroin or cocaine were independently associated with active syphilis infection. In Tijuana, methamphetamine use was strongly associated with active syphilis infection. These preliminary results suggest that risk profiles for HIV/sexually transmitted infection among FSWs in these two Mexico-U.S. border cities differ, suggesting a need to tailor interventions to the specific needs in each city.     

Predictors of everyday functioning among older Mexican Americans vs. Anglo-Americans with schizophrenia

OBJECTIVE: We assessed clinical, demographic, and cognitive predictors of everyday functioning in Mexican American and Anglo-American outpatients with schizophrenia. METHOD: Three groups of participants aged 40 years and over with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder were compared: 79 Anglo-Americans, 24 Mexican American patients who chose to be tested in English, and 33 Mexican American patients who preferred Spanish. The study was conducted from October 2001 to July 2004. RESULTS: On demographic, clinical, cognitive, and functional measures, Anglo-American participants were generally similar to Mexican American participants who opted for being tested in English. Mexican American participants who preferred Spanish were significantly different from the other 2 groups on several measures, including everyday functioning performance. To determine the predictors of everyday functioning, separate regression analyses were conducted for each of the 3 groups. Cognitive ability consistently accounted for the greatest proportion of variance in performance regardless of ethnicity, language preference, or education. Among the Mexican American participants, level of acculturation was the second strongest predictor of everyday functioning when the group was examined as a whole; however, acculturation was not a significant predictor when controlling for language preference. CONCLUSION: Cognitive performance and language preference (a proxy for acculturation) may play a particularly important role in predicting ability to perform everyday tasks. Further studies to better understand the potential impact of ethnicity, culture, education, and language on everyday functioning may help develop more specific and culture-sensitive intervention strategies for different ethnic groups.     

A Qualitative Exploration of Female Sex Work in Tijuana, Mexico

Previous research has documented high rates of STDs and increased risk of HIV infection among female sex workers (FSWs) in Mexico; however, little is known about the sexual risk behaviors of this population. The purpose of this study was to explore work history, context of sex work, sexual risk practices, client characteristics, attitudes toward condoms, and potential barriers to condom use in a sample of FSWs in Tijuana, Mexico. Analysis of qualitative data from 25 FSWs revealed that most women entered the sex trade at a young age ( M = 23 years), primarily as a result of financial need. Forty percent were single mothers supporting children. Women worked an average of 6-7 days per week; work shifts ranged from 4 to 13 hr per day. Clients were both Mexican and foreign (mostly American and Asian), and ranged in age from 18 to 80 years. Positive aspects of the job included flexible work hours and good income. Negative aspects of sex work included risks associated with physical assault, diseases, and unwanted pregnancies. Most clients did not want to use a condom and many offered additional money for unprotected sex. FSWs did not like to use condoms because they were perceived as uncomfortable. Most FSWs did not negotiate the use of condoms, had a low knowledge regarding the proper use of condoms, and were reticent to report their own unsafe sex practices. These results suggest the need to develop culturally appropriate safer sex interventions for FSWs in Mexican border cities.