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BACKGROUND: Syphilis epidemics among women and men-who-have-sex-with-men (MSM) may be connected, but these connections are poorly understood. Using egocentric network data from a U.S. urban MSM cohort, we examined socio-demographics, behaviors, and syphilis positivity among MSM with (1) direct (MSM who report sex with women, MSMW); (2) indirect (MSM who only report male partners, some of whom are MSMW, MSMO/W); and (3) no (MSM who only report male partners and whose partners only have sex with men, MSMO/O) connection to women. METHODS: Sexually-active MSM aged 18-45 years were administered behavioral and network interviews (recall period: three months) and syphilis/HIV testing. Syphilis positivity was defined as RPR titer >1:8. Modified Poisson regression was used to test for differences across groups. RESULTS: Among 385 MSM, 14.5% were MSMW and 22.3% were MSMO/W. MSMW and MSMO/W were significantly more likely than MSMO/O to report sex behaviors associated with increased syphilis acquisition/transmission risk, including: > 2 sex partners [MSMW aPR:1.28 (0.98-1.68); MSMO/W aPR:1.35 (1.09-1.69)], concurrent sex partners [MSMW aPR:1.50 (1.17-1.92); MSMO/W aPR:1.39 (1.11-1.74)], and for MSMW only, transactional sex [aPR:2.07 (1.11-3.88)]. Syphilis positivity was 16.4% and was lower among MSMW (9.4%) and MSMO/W (14.1%) than MSMO/O (18.5%), but differences were not significant. CONCLUSIONS: There may be considerable connectivity between MSM and female sex partners that could facilitate syphilis transmission, and behaviors that increase acquisition/transmission risk among MSMW and MSMO/W may be distinct from MSMO/O. Future work should focus on examining the context and temporal patterns of sex partnerships among MSMW and MSMO/W.
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Black gay, bisexual, and other men who have sex with men (GBM) are disproportionately affected by HIV and STIs. Safe Spaces 4 Sexual Health (SS4SH), a community-informed, status-neutral HIV/STI testing intervention combines online outreach via geo-social networking apps and social media with mobile van testing. During 2018-2019, we recruited 25 participants for interviews about their perceptions of SS4SH compared to clinic-based testing. Participants were aged 21-65 years (mean 35); 22 (88%) identified as Black/African American; 20 (80%) identified as gay; and 10 (40%) were living with HIV. Interviews were transcribed, coded, and analyzed using a modified thematic constant comparative approach. Five themes emerged; two related to perceptions of online outreach materials (participants were drawn to eye-catching and to-the-point messages and desired more diversity and representation in messages), and three related to preference for the mobile van (participants found SS4SH provided more comfort, more privacy/confidentiality, and increased accessibility and efficiency). GBM is increasingly using geo-social networking apps to meet sexual partners, and tailored online outreach has the potential to reach historically underserved populations. SS4SH is a barrier-reducing strategy that may serve as an entry to a status-neutral approach to services and help reduce stigma and normalize accessing HIV services.
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Pre-exposure prophylaxis (PrEP) is an effective tool in protecting persons from acquiring HIV infection through sex or injection drug use. However, awareness and willingness to use PrEP among Black gay, bisexual, and other men who have sex with men (BMSM) remain suboptimal compared to White MSM (WMSM) in the United States. Our aims were to (1) assess the factors associated with PrEP awareness and willingness to use PrEP among MSM and (2) compare the PrEP perceptions among BMSM versus non-Black MSM. Data were drawn from two cross-sectional behavioral surveys in Baltimore, MD: Behavioral Surveillance Research (BESURE) conducted in 2017, and Safe Spaces 4 Sexual Health (SS4SH), conducted in 2018 and 2019. Descriptive statistics were used to summarize the study population. We used Poisson regression models to identify variables associated with awareness of PrEP and willingness to use PrEP. PrEP perceptions were assessed via 13 items scored on a 5-point Likert scale. Finally, we conducted a post-hoc exploratory bivariate analysis of the relationship between PrEP perception and willingness to use PrEP, stratified by race/ethnicity. A total of 261 MSM participated in this study. Many of the participants were aware of PrEP (75.1%). Factors associated with greater PrEP awareness included having greater than a high school education (aRR 1.22, 95% CI 1.04, 1.43); and earning more than $25,000 annually (aRR 1.24, 95% CI 1.08, 1.42). Participants who had received money in exchange for sex one or more times were less likely to be aware of PrEP (aRR 0.59, 95% CI 0.36, 0.95). More than half of the participants were willing to use PrEP (55.3%). In bivariate and multivariable analyses, demographic or behavioral characteristics were not significantly associated with willingness to use PrEP. Higher agreement with the following statements was associated with lower willingness to use PrEP: "Having to take a pill every day is difficult" (RR 0.89, 95% CI 0.82-0.97) and, "I am concerned about the side effects of PrEP" (RR 0.89, 95% CI 0.82-0.96), and "PrEP is for people who have riskier sex lives than I do" (RR 0.86, 95% CI 0.78-0.95). Conversely, higher willingness to use PrEP was associated with comfortable having sex without a condom (RR 1.11, 95% CI 1.02-1.21), less anxious about sex (RR 1.12, 95% CI 1.02-1.24), and my friends think that I should take PrEP (RR 1.19, 95% CI 1.07-1.32). We found BMSM compared to non-Black MSM had higher mean scores related to taking a daily pill (p = 0.041), concerns about side effects (p = 0.012), concerns about people thinking they had HIV (p = 0.001), concerns about the financial costs of PrEP (p = 0.038) and caution when dealing with healthcare organizations/medical mistrust (p = 0.019). Perceptions with a statistically significant lower score among BMSM versus non-Black MSM included statements such as, comfortable having sex without a condom (p = 0.003) and less anxious about sex (p < 0.001). We conclude HIV prevention strategies, programs, and interventions should be cognizant of PrEP perceptions that facilitate or hinder PrEP uptake in Baltimore City, MD.
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BACKGROUND: Syphilis incidence is increasing among reproductive-aged women, and previous sexually transmitted infections (STIs) are a risk factor for subsequent STIs. This study aimed to determine syphilis incidence after a chlamydia, gonorrhea, or HIV diagnosis, and identify characteristics associated with higher syphilis incidence rates among reproductive-aged women in 1 mid-Atlantic city. METHODS: A retrospective cohort of 85,113 chlamydia, gonorrhea, and HIV diagnoses occurring between 2009 and 2021 and among women aged 13 to 50 years was constructed using public health surveillance data. Cumulative incidence curves were estimated to examine time to early syphilis (i.e., primary, secondary, or early latent) diagnosis, and multivariable analyses determined incidence rate ratios by age (<25 vs. ≥25 years) and number of prior STI diagnoses (0 vs. ≥1) during the study period, stratified by STI. RESULTS: There were 85,113 reportable STI diagnoses and 646 syphilis diagnoses in the cohort. Approximately 1 of 150 chlamydia, 1 of 100 gonorrhea, and 1 of 50 HIV diagnoses were followed by a syphilis diagnosis within 5 years. Cumulative incidence of syphilis differed significantly by STI diagnosis ( P < 0.001). In multivariable analysis, syphilis incidence rates were higher among women diagnosed with ≥1 (vs. 0) prior STI regardless of STI type ( P < 0.05) and among women ≥25 (vs. <25) years old diagnosed with gonorrhea ( P < 0.05). CONCLUSIONS: There were significant differences in syphilis incidence by prior STI type, number of STIs, and age. Our data support targeted screening for syphilis among women with a history of STIs, parwomen with ≥1 prior STI diagnosis, and older women diagnosed with gonorrhea.
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Infecciones por Chlamydia , Chlamydia , Gonorrea , Infecciones por VIH , Enfermedades de Transmisión Sexual , Sífilis , Femenino , Humanos , Adulto , Anciano , Sífilis/epidemiología , Gonorrea/epidemiología , Estudios Retrospectivos , Baltimore , Infecciones por Chlamydia/epidemiología , Enfermedades de Transmisión Sexual/epidemiología , Infecciones por VIH/epidemiologíaRESUMEN
Despite the identification of the high-incidence red cell antigen Era nearly 40 years ago, the molecular background of this antigen, together with the other 2 members of the Er blood group collection, has yet to be elucidated. Whole exome and Sanger sequencing of individuals with serologically defined Er alloantibodies identified several missense mutations within the PIEZO1 gene, encoding amino acid substitutions within the extracellular domain of the Piezo1 mechanosensor ion channel. Confirmation of Piezo1 as the carrier molecule for the Er blood group antigens was demonstrated using immunoprecipitation, CRISPR/Cas9-mediated gene knockout, and expression studies in an erythroblast cell line. We report the molecular bases of 5 Er blood group antigens: the recognized Era, Erb, and Er3 antigens and 2 novel high-incidence Er antigens, described here as Er4 and Er5, establishing a new blood group system. Anti-Er4 and anti-Er5 are implicated in severe hemolytic disease of the fetus and newborn. Demonstration of Piezo1, present at just a few hundred copies on the surface of the red blood cell, as the site of a new blood group system highlights the potential antigenicity of even low-abundance membrane proteins and contributes to our understanding of the in vivo characteristics of this important and widely studied protein in transfusion biology and beyond.
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Anemia Hemolítica Congénita , Antígenos de Grupos Sanguíneos , Recién Nacido , Humanos , Mutación Missense , Anemia Hemolítica Congénita/genética , Eritrocitos/metabolismo , Canales Iónicos/química , Antígenos de Grupos Sanguíneos/metabolismo , Mecanotransducción CelularRESUMEN
BACKGROUND AND OBJECTIVES: Under the ISBT, the Working Party (WP) for Red Cell Immunogenetics and Blood Group Terminology is charged with ratifying blood group systems, antigens and alleles. This report presents the outcomes from four WP business meetings, one located in Basel in 2019 and three held as virtual meetings during the COVID-19 pandemic in 2020 and 2021. MATERIALS AND METHODS: As in previous meetings, matters pertaining to blood group antigen nomenclature were discussed. New blood group systems and antigens were approved and named according to the serologic, genetic, biochemical and cell biological evidence presented. RESULTS: Seven new blood group systems, KANNO (defined numerically as ISBT 037), SID (038), CTL2 (039), PEL (040), MAM (041), EMM (042) and ABCC1 (043) were ratified. Two (039 and 043) were de novo discoveries, and the remainder comprised reported antigens where the causal genes were previously unknown. A further 15 blood group antigens were added to the existing blood group systems: MNS (002), RH (004), LU (005), DI (010), SC (013), GE (020), KN (022), JMH (026) and RHAG (030). CONCLUSION: The ISBT now recognizes 378 antigens, of which 345 are clustered within 43 blood group systems while 33 still have an unknown genetic basis. The ongoing discovery of new blood group systems and antigens underscores the diverse and complex biology of the red cell membrane. The WP continues to update the blood group antigen tables and the allele nomenclature tables. These can be found on the ISBT website (http://www.isbtweb.org/working-parties/red-cell-immunogenetics-and-blood-group-terminology/).
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Antígenos de Grupos Sanguíneos , COVID-19 , Eritrocitos , Humanos , Antígenos de Grupos Sanguíneos/genética , Transfusión Sanguínea , Inmunogenética , Pandemias , Eritrocitos/inmunologíaRESUMEN
BACKGROUND: Urban Black gay, and bisexual men (MSM) bear a disproportionate burden of HIV in the U.S. Mental health is a barrier to adherence to both antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP). The objective was to determine the association between psychological distress and ART or PrEP adherence among urban Black MSM. METHODS: Using data from a four-year prospective cohort study, adherence to ART was defined as > 95% and PrEP was defined as > 80% of doses taken in the past 30 days. Psychological distress measures included difficulty sleeping; feeling anxious; suicidality; feeling sad or depressed; feeling sick, ill, or not well in the past 3 months; high (vs. low) overall psychological distress was classified as above the median value. Associations were examined using Chi-square, Fisher's exact tests, and logistic regression. RESULTS: Among 165 Black MSM, 44.2% (73) reported high psychological distress. 65.3% (47/72) of participants living with HIV and 39.8% (37/93) of HIV negative participants were ART or PrEP adherent, respectively. Education was significantly associated with PrEP adherence (p = 0.038). Non-injection drug use in the past 3 months (p = 0.008), difficulty sleeping (p = 0.010), feeling anxious (p = 0.003), and feeling sad or depressed (p < 0.001), and overall psychological distress (p < 0.001) were significantly associated with ART adherence. High psychological distress was significantly associated with a reduced odds of ART adherence (aOR 0.23; 95% CI = 0.08-0.70) adjusting for age and non-injection drug use. CONCLUSIONS: Increased psychological distress was significantly associated with ART nonadherence and may represent an important barrier to viral suppression.
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Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Distrés Psicológico , Minorías Sexuales y de Género , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Homosexualidad Masculina/psicología , Humanos , Masculino , Cumplimiento de la Medicación , Estudios ProspectivosRESUMEN
BACKGROUND: Black men who have sex with men (MSM) carry the greatest burden of new HIV diagnoses in the United States. Ending the HIV epidemic requires strategic, culturally specific approaches to target factors contributing to persistent HIV disparities. SETTING: Safe Spaces 4 Sexual Health (SS4SH), a community-informed HIV/sexually transmitted infection (STI) testing strategy combining mobile van testing with online outreach, was implemented over a 14-month period from 2018 to 2019 in Baltimore, MD. METHODS: We evaluated the reach of MSM at high risk with high acquisition or transmission risk by SS4SH mobile van combined with online outreach as compared with the Baltimore City Health Department's venue-based mobile van (with no online outreach) operating during the same period based on the following HIV/STI testing outcome measures: (1) number of MSM HIV or STI tested, (2) new HIV diagnosis rate, (3) percent with new syphilis diagnosis, (4) percent at high risk for HIV acquisition, and (5) percent people living with HIV at high risk for transmission. RESULTS: Over a 14-month period, SS4SH HIV/STI tested 151 MSM. Of these, 74% were Black and the mean age was 34 (SD = 10, range = 19-68). Seven percent (10/148) were new HIV diagnoses, and 10% (13/130) were diagnosed with syphilis. The Baltimore City Health Department's venue-based mobile van strategy yielded 53% (231) more MSM (71% Black, mean age 38, SD = 14, range = 15-74), but the HIV/syphilis positivity rate was significantly lower: 0.5% new HIV diagnosis rate (P < 0.001) and 0.5% with syphilis diagnosis (P < 0.001). CONCLUSIONS: Our findings suggest SS4SH combing online outreach with mobile van testing may be more effective at reaching high-risk Black MSM than venue-based mobile testing.
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Infecciones por VIH , Salud Sexual , Minorías Sexuales y de Género , Enfermedades de Transmisión Sexual , Sífilis , Adulto , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Homosexualidad Masculina , Humanos , Masculino , Conducta Sexual , Parejas Sexuales , Enfermedades de Transmisión Sexual/diagnóstico , Enfermedades de Transmisión Sexual/epidemiología , Enfermedades de Transmisión Sexual/prevención & control , Sífilis/diagnóstico , Sífilis/epidemiologíaRESUMEN
BACKGROUND: CD151 is a cell-surface molecule of the tetraspanin family. Its lateral interaction with laminin-binding integrin É3ß1 is important for podocyte adhesion to the glomerular basement membrane (GBM). Deletion of Cd151 in mice induces glomerular dysfunction, with proteinuria and associated focal glomerulosclerosis, disorganisation of GBM and tubular cystic dilation. Despite this, CD151 is not routinely screened for in patients with nephrotic-range proteinuria. We aimed to better understand the relevance of CD151 in human kidney disease. METHODS: Next-generation sequencing (NGS) was used to detect the variant in CD151. Electron and light microscopy were used to visualise the filtration barrier in the patient kidney biopsy, and immunoreactivity of patient red blood cells to anti-CD151/MER2 antibodies was performed. Further validation of the CD151 variant as disease-causing was performed in zebrafish using CRISPR-Cas9. RESULTS: We report a young child with nail dystrophy and persistent urinary tract infections who was incidentally found to have nephrotic-range proteinuria. Through targeted NGS, a novel, homozygous truncating variant was identified in CD151, a gene rarely reported in patients with nephrotic syndrome. Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement. Immunofluorescence of patient kidney tissue demonstrated that CD151 was significantly reduced, and we did not detect immunoreactivity to CD151/MER2 on patient red blood cells. CRISPR-Cas9 depletion of cd151 in zebrafish caused proteinuria, which was rescued by injection of wild-type CD151 mRNA, but not CD151 mRNA containing the variant sequence. CONCLUSIONS: Our results indicate that a novel variant in CD151 is associated with nephrotic-range proteinuria and microscopic haematuria and provides further evidence for a role of CD151 in glomerular disease. Our work highlights a functional testing pipeline for future analysis of patient genetic variants. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Enfermedades Renales , Podocitos , Animales , Niño , Humanos , Membrana Basal Glomerular/patología , Integrina alfa3beta1 , Enfermedades Renales/genética , Enfermedades Renales/complicaciones , Laminina/genética , Podocitos/patología , Proteinuria/etiología , ARN Mensajero , Tetraspanina 24/genética , Pez CebraRESUMEN
BACKGROUND: The impact of coronavirus disease 2019 (COVID-19) mitigation measures on sexually transmitted infection (STI) transmission and racial disparities remains unknown. Our objectives were to compare sex and drug risk behaviors, access to sexual health services, and STI positivity overall and by race during the COVID-19 pandemic compared with pre-pandemic among urban sexual minority men (MSM). METHODS: Sexually active MSM aged 18-45 years were administered a behavioral survey and STI testing every 3-months. Participants who completed at least 1 during-pandemic (April 2020-December 2020) and 1 pre-pandemic study visit (before 13 March 2020) that occurred less than 6 months apart were included. Regression models were used to compare during- and pre-pandemic visit outcomes. RESULTS: Overall, among 231 MSM, reports of more than 3 sex partners declined(pandemic-1: adjusted prevalence ratio 0.68; 95% confidence interval: .54-.86; pandemic-2: 0.65, .51-.84; pandemic-3: 0.57, .43-.75), substance use decreased (pandemic-1: 0.75, .61-.75; pandemic-2: 0.62, .50-.78; pandemic-3: 0.61, .47-.80), and human immunodeficiency virus/preexposure prophylaxis care engagement (pandemic-1: 1.20, 1.07-1.34; pandemic-2: 1.24, 1.11-1.39; pandemic-3: 1.30, 1.16-1.47) increased. STI testing decreased (pandemic-1: 0.68, .57-.81; pandemic-2: 0.78, .67-.92), then rebounded (pandemic-3: 1.01, .87-1.18). Nei-ther Chlamydia (pandemic-2: 1.62, .75-3.46; pandemic-3: 1.13, .24-1.27) nor gonorrhea (pandemic-2: 0.87, .46 1.62; pandemic-3: 0.56, .24-1.27) positivity significantly changed during vs pre-pandemic. Trends were mostly similar among Black vs. non-Black MSM. CONCLUSIONS: We observed sustained decreases in STI risk behaviors but minimal change in STI positivity during compared with pre-pandemic. Our findings underscore the need for novel STI prevention strategies that can be delivered without in-person interactions.
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COVID-19 , Infecciones por VIH , Minorías Sexuales y de Género , Enfermedades de Transmisión Sexual , COVID-19/epidemiología , Infecciones por VIH/epidemiología , Homosexualidad Masculina , Humanos , Masculino , Pandemias , Conducta Sexual , Enfermedades de Transmisión Sexual/epidemiología , Enfermedades de Transmisión Sexual/prevención & controlRESUMEN
Young Black gay, bisexual and other men who have sex with men (YBMSM) carry a disproportionate HIV burden perpetuated by exposure to sexual networks with higher untreated HIV prevalence and incidence. In Baltimore, these sexual networks include high utilization of geosocial networking apps (GSN-apps). Our prior work suggests these apps can be important access points for targeted interventions like PrEP. To inform online PrEP outreach we explored YBMSM GSN-app users' exposure to and discussions about PrEP while navigating apps. We actively recruited YBMSM (n=17) age 18-24 from the GSN-app most frequently reported by newly diagnosed HIV-infected MSM in Baltimore. Participants were recruited through direct messaging within the GSN-app while logged-on in high HIV transmission areas. Participants completed 60-90 minute semi-structured interviews, which were analyzed using a 3-stage analytic coding strategy. While some participants had not heard of PrEP, the majority described mentions or conversations about PrEP on GSN-apps. Three themes emerged: (1) Mistrust of PrEP, (2) Association with sexual promiscuity, and (3) Concerns about lack of protection from other STIs. Proper messaging, accurate information, and education are needed to account for the negative perceptions that surround PrEP; otherwise, continued underuse among YBMSM will expand rather than reduce HIV disparities.
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BACKGROUND: In the context of increasing syphilis rates, particularly among Black men who have sex men (MSM), the objectives were to determine the associations between methamphetamine (meth) use and syphilis and HIV positivity, and to identify sex partner meeting venues as potential intervention access points among Black MSM in a mid-Atlantic US city. METHODS: This study is an ongoing longitudinal cohort study. Participants were recruited from clinical and nonclinical settings and included sexually active MSM aged 18 to 45 years. The baseline visit included a behavioral survey and testing for syphilis, HIV, gonorrhea, and chlamydia. Logistic regression analyses were used for hypothesis testing. RESULTS: Among 359 MSM completing baseline, 74.4% (268) Black MSM were included; 31% (84) were aged 24 to 29 years, 43.7% (117) reported unprotected anal intercourse at last sex, and 15.3% (41) reported meth use in the past 3 months. Sixteen percent (43) had syphilis, 46.6% (125) were living with HIV, and 19.0% (51) had gonorrhea and/or chlamydia. Meth use was associated with sexual and drug risk behaviors and HIV, but not syphilis. In adjusted analyses, meth use increased the odds of HIV positivity by 6.43 (95% confidence interval, 2.30-17.98) and syphilis positivity by 2.57 (95% confidence interval, 1.23-5.37). Four online sex partner meeting venues were associated with meth use and HIV, whereas syphilis was associated with one. CONCLUSIONS: Among Black MSM, meth use and syphilis positivity were associated with more than 6-fold and almost 3-fold increased adjusted odds of HIV positivity, respectively. Four specific sex partner meeting venues may be important access points for HIV/sexually transmitted infection and substance use prevention.
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Infecciones por VIH , Metanfetamina , Minorías Sexuales y de Género , Enfermedades de Transmisión Sexual , Sífilis , Negro o Afroamericano , Infecciones por VIH/epidemiología , Homosexualidad Masculina , Humanos , Estudios Longitudinales , Masculino , Conducta Sexual , Parejas Sexuales , Enfermedades de Transmisión Sexual/epidemiología , Sífilis/epidemiologíaRESUMEN
Each year, blood transfusions save millions of lives. However, under current blood-matching practices, sensitization to non-self-antigens is an unavoidable adverse side effect of transfusion. We describe a universal donor typing platform that could be adopted by blood services worldwide to facilitate a universal extended blood-matching policy and reduce sensitization rates. This DNA-based test is capable of simultaneously typing most clinically relevant red blood cell (RBC), human platelet (HPA), and human leukocyte (HLA) antigens. Validation was performed, using samples from 7927 European, 27 South Asian, 21 East Asian, and 9 African blood donors enrolled in 2 national biobanks. We illustrated the usefulness of the platform by analyzing antibody data from patients sensitized with multiple RBC alloantibodies. Genotyping results demonstrated concordance of 99.91%, 99.97%, and 99.03% with RBC, HPA, and HLA clinically validated typing results in 89 371, 3016, and 9289 comparisons, respectively. Genotyping increased the total number of antigen typing results available from 110 980 to >1 200 000. Dense donor typing allowed identification of 2 to 6 times more compatible donors to serve 3146 patients with multiple RBC alloantibodies, providing at least 1 match for 176 individuals for whom previously no blood could be found among the same donors. This genotyping technology is already being used to type thousands of donors taking part in national genotyping studies. Extraction of dense antigen-typing data from these cohorts provides blood supply organizations with the opportunity to implement a policy of genomics-based precision matching of blood.
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Donantes de Sangre , Transfusión Sanguínea , Genotipo , Humanos , Isoanticuerpos , Estudios ProspectivosRESUMEN
The clinically important MAM blood group antigen is present on haematopoietic cells of all humans except rare MAM-negative individuals. Its molecular basis is unknown. By whole-exome sequencing we identify EMP3, encoding epithelial membrane protein 3 (EMP3), as a candidate gene, then demonstrate inactivating mutations in ten known MAM-negative individuals. We show that EMP3, a purported tumour suppressor in various solid tumours, is expressed in erythroid cells. Disruption of EMP3 by CRISPR/Cas9 gene editing in an immortalised human erythroid cell line (BEL-A2) abolishes MAM expression. We find EMP3 to associate with, and stabilise, CD44 in the plasma membrane. Furthermore, cultured erythroid progenitor cells from MAM-negative individuals show markedly increased proliferation and higher reticulocyte yields, suggesting an important regulatory role for EMP3 in erythropoiesis and control of cell production. Our data establish MAM as a new blood group system and demonstrate an interaction of EMP3 with the cell surface signalling molecule CD44.
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Antígenos de Grupos Sanguíneos/genética , Proliferación Celular , Células Eritroides/citología , Glicoproteínas de Membrana/genética , Antígenos de Grupos Sanguíneos/química , Antígenos de Grupos Sanguíneos/metabolismo , Plaquetas/metabolismo , Células Cultivadas , Membrana Eritrocítica/metabolismo , Células Eritroides/metabolismo , Humanos , Receptores de Hialuranos/metabolismo , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , Modelos Moleculares , Mutación , Fenotipo , Unión Proteica , Secuenciación del ExomaRESUMEN
BACKGROUND AND OBJECTIVES: The Mi(a+) GP(B-A-B) hybrid phenotypes occur with a prevalence of 2%-23% across Southeast Asia. While the s antigen is alleged to be altered, no evidence for specific variants is known. Screening using a monoclonal IgM anti-s mistyped six S-s+ RBC units as S-s-. Further, alloanti-s was identified in an S+s+ patient. Our objective was to investigate the s antigen further. MATERIALS AND METHODS: DNA from 63 Thai blood donor samples PCR-positive for a GYP(B-A-B) hybrid was sequenced with primers spanning GYPB exons 3-4. Flow cytometry was used for semiquantitative analysis of s expression and correlated with the glycophorin genotype. RESULTS: DNA sequencing showed that GYP*Mur was carried by 56/63 samples (88·9%) of which 5/56 lacked normal GYPB: three of these were GYP*Mur homozygotes, one was a compound heterozygote carrying GYP*Mur and a GYP*Bun-like allele (designated GYP*Thai), and the fifth sample carried GYP*Mur and another GYP*Bun-like allele. Seven samples (7/63) were GYP*Thai heterozygotes. IgM monoclonal anti-s (P3BER) did not react with the s antigen carried by GP.Mur or GP.Bun, whereas two IgG anti-s showed enhanced reactivity. CONCLUSIONS: We confirmed that GYP*Mur is the most frequent variant in Thai blood donors and also identified GYP*Thai with a frequency of 1·1%. We showed that s antigen on Mi(a+) GP(B-A-B) hybrids is qualitatively altered and should be considered when selecting reagents for phenotyping where such hybrids are prevalent, endemically and in blood centres worldwide.
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Alelos , Glicoforinas/genética , Mutación , Donantes de Sangre , Antígenos de Grupos Sanguíneos/genética , Duplicación de Gen , Humanos , Análisis de Secuencia de ADN , TailandiaRESUMEN
CONCLUSIONS: This report is part of a series reporting the proceedings from the International Society of Blood Transfusion (ISBT) Working Party on Immunohaematology Workshop on the Clinical Significance of Red Blood Cell Alloantibodies. The aim of the workshop was to review information regarding the clinical significance of alloantibodies to red blood cell antigens recognized by the ISBT. The first 12 systems will be covered in this report. It is understandable that many of the most clinically important antibodies are directed toward antigens found in the blood group systems discovered earlier in history. The ABO system was the first to be discovered and remains the most clinically important regarding transfusion.
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Sistema del Grupo Sanguíneo ABO , Protestantismo , Antígenos de Grupos Sanguíneos , Transfusión Sanguínea , Eritrocitos , Humanos , IsoanticuerposRESUMEN
Sda is a high-frequency carbohydrate histo-blood group antigen, GalNAcß1-4(NeuAcα2-3)Galß, implicated in pathogen invasion, cancer, xenotransplantation and transfusion medicine. Complete lack of this glycan epitope results in the Sd(a-) phenotype observed in 4% of individuals who may produce anti-Sda. A candidate gene (B4GALNT2), encoding a Sda-synthesizing ß-1,4-N-acetylgalactosaminyltransferase (ß4GalNAc-T2), was cloned in 2003 but the genetic basis of human Sda deficiency was never elucidated. Experimental and bioinformatic approaches were used to identify and characterize B4GALNT2 variants in nine Sd(a-) individuals. Homozygosity for rs7224888:Tâ¯>â¯C dominated the cohort (nâ¯=â¯6) and causes p.Cys466Arg, which targets a highly conserved residue located in the enzymatically active domain and is judged deleterious to ß4GalNAc-T2. Its allele frequency was 0.10-0.12 in different cohorts. A Sd(a-) compound heterozygote combined rs7224888:Tâ¯>â¯C with a splice-site mutation, rs72835417:Gâ¯>â¯A, predicted to alter splicing and occurred at a frequency of 0.11-0.12. Another compound heterozygote had two rare nonsynonymous variants, rs148441237:Aâ¯>â¯G (p.Gln436Arg) and rs61743617:Câ¯>â¯T (p.Arg523Trp), in trans. One sample displayed no differences compared to Sd(a+). When investigating linkage disequilibrium between B4GALNT2 variants, we noted a 32-kb block spanning intron 9 to the intergenic region downstream of B4GALNT2. This block includes RP11-708H21.4, a long non-coding RNA recently reported to promote tumorigenesis and poor prognosis in colon cancer. The expression patterns of B4GALNT2 and RP11-708H21.4 correlated extremely well in >1000 cancer cell lines. In summary, we identified a connection between variants of the cancer-associated B4GALNT2 gene and Sda, thereby establishing a new blood group system and opening up for the possibility to predict Sd(a+) and Sd(aâ) phenotypes by genotyping.