Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Elimination of Onchocerciasis from Mexico.

BACKGROUND:Mexico is one of the six countries formerly endemic for onchocerciasis in Latin America. Transmission has been interrupted in the three endemic foci of that country and mass drug distribution has ceased. Three years after mass drug distribution ended, post-treatment surveillance (PTS) surveys were undertaken which employed entomological indicators to check for transmission recrudescence. METHODOLOGY/PRINCIPAL FINDINGS:In-depth entomologic assessments were performed in 18 communities in the three endemic foci of Mexico. None of the 108,212 Simulium ochraceum s.l. collected from the three foci were found to contain parasite DNA when tested by polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA), resulting in a maximum upper bound of the 95% confidence interval (95%-ULCI) of the infective rate in the vectors of 0.035/2,000 flies examined. This is an order of magnitude below the threshold of a 95%-ULCI of less than one infective fly per 2,000 flies tested, the current entomological criterion for interruption of transmission developed by the international community. The point estimate of seasonal transmission potential (STP) was zero, and the upper bound of the 95% confidence interval for the STP ranged from 1.2 to 1.7 L3/person/season in the different foci. This value is below all previous estimates for the minimum transmission potential required to maintain the parasite population. CONCLUSIONS/SIGNIFICANCE:The results from the in-depth entomological post treatment surveillance surveys strongly suggest that transmission has not resumed in the three foci of Mexico during the three years since the last distribution of ivermectin occurred; it was concluded that transmission remains undetectable without intervention, and Onchocerca volvulus has been eliminated from Mexico

Interruption of Transmission of <i>Onchocerca volvulus</i> in the Southern Chiapas Focus, México

<div><p>Background</p><p>The Southern Chiapas focus of onchocerciasis in Southern Mexico represents one of the major onchocerciasis foci in Latin America. All 559 endemic communities of this focus have undergone semi-annual mass treatment with ivermectin since 1998. In 50 communities of this focus, ivermectin frequency shifted from twice to four times a year in 2003; an additional 113 communities were added to the quarterly treatment regimen in 2009 to achieve a rapid suppression of transmission.</p> <p>Methodology/Principal findings</p><p>In-depth epidemiologic and entomologic assessments were performed in six sentinel communities (which had undergone 2 rounds of ivermectin treatment per year) and three extra-sentinel communities (which had undergone 4 rounds of ivermectin treatment per year). None of the 67,924 <i>Simulium ochraceum</i> s.l. collected from this focus during the dry season of 2011 were found to contain parasite DNA when tested by polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA), resulting in an upper bound of the 95% confidence interval (95%-ULCI) of the infective rate in the vectors of 0.06/2,000 flies examined. Serological assays testing for <i>Onchocerca volvulus</i> exposure conducted on 4,230 children 5 years of age and under (of a total population of 10,280 in this age group) revealed that 2/4,230 individuals were exposed to <i>O. volvulus</i> (0.05%; one sided 95% confidence interval = 0.08%).</p> <p>Conclusions/Significance</p><p>The in-depth epidemiological and entomological findings from the Southern Chiapas focus meet the criteria for interruption of transmission developed by the international community.</p> </div

Number of individuals with nodules in the Southern Chiapas focus, Mexico, 1995–2010.

<p>Number of individuals with nodules in the Southern Chiapas focus, Mexico, 1995–2010.</p

In-depth epidemiologic assessments in sentinel and extra-sentinel communities of the Southern Chiapas focus.

<p>In-depth epidemiologic assessments in sentinel and extra-sentinel communities of the Southern Chiapas focus.</p

Coverage rate with ivermectin of the eligible population of the Southern Chiapas focus.

<p>The coverage rate, expressed in percent and the 95%-confidence intervals, CIs, surrounding point estimate, with ivermectin of the eligible population of the Southern Chiapas focus, 1995–2011. The line at 85% indicates the coverage needed in a sustained fashion to interrupt transmission.</p

Prevalence of IgG4 antibodies to Ov16 in the focus of Southern Chiapas, México.

<p>Prevalence of IgG4 antibodies to Ov16 in children 10 years of age and under from sentinel, extra-sentinel, and eight other communities, in migrant workers >15 years of age from three coffee fincas and in children 5 years of age and under from 4 districts in the focus of Southern Chiapas, México.</p>*<p>Skin biopsies were taken and tested by PCR; they contained no parasite DNA (unpublished data).</p

Number of new clinical cases of onchocerciasis in the Southern Chiapas focus, México.

<p>The number of new clinical cases of onchocerciasis (individuals diagnosed positive to Mazzotti reaction, nodules, or skin mf for the first time) in the Southern Chiapas focus, from 1989 to 2010.</p

Map of the Southern Chiapas focus, México.

<p>The map of the Southern Chiapas focus shows the six sentinel (marked in yellow) and three extra-sentinel communities (marked in red) and the main rivers and tributaries that might serve as a source of black fly breeding. Map (right) of the Southern Mexico states showing the three onchocerciasis endemic foci.</p

Entomological parameters in the focus of Southern Chiapas, México.

<p>The seasonal <i>S. ochraceum</i> s.l. biting rate is the number of bites per person per season. Prevalence of infective flies is expressed as rate per 2,000 flies examined and seasonal transmission potential is the third-stage larvae per person per season. These entomological parameters were estimated during 2008 through 2011 in the sentinel, extra-sentinel and other communities in the focus of Southern Chiapas.</p>*<p>Value represents point estimate and value in parentheses represents 95%-confidence intervals, CIs (95% upper limit CI when zero) surrounding point estimate.</p