Browsing by Subject "Antibodies"
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Item B Quiet: Autoantigen-Specific Strategies to Silence Raucous B Lymphocytes and Halt Cross-Talk with T Cells in Type 1 Diabetes(MDPI, 2021-01-06) Felton, Jamie L.; Conway, Holly; Bonami, Rachel H.; Pediatrics, School of MedicineIslet autoantibodies are the primary biomarkers used to predict type 1 diabetes (T1D) disease risk. They signal immune tolerance breach by islet autoantigen-specific B lymphocytes. T-B lymphocyte interactions that lead to expansion of pathogenic T cells underlie T1D development. Promising strategies to broadly prevent this T-B crosstalk include T cell elimination (anti-CD3, teplizumab), B cell elimination (anti-CD20, rituximab), and disruption of T cell costimulation/activation (CTLA-4/Fc fusion, abatacept). However, global disruption or depletion of immune cell subsets is associated with significant risk, particularly in children. Therefore, antigen-specific therapy is an area of active investigation for T1D prevention. We provide an overview of strategies to eliminate antigen-specific B lymphocytes as a means to limit pathogenic T cell expansion to prevent beta cell attack in T1D. Such approaches could be used to prevent T1D in at-risk individuals. Patients with established T1D would also benefit from such targeted therapies if endogenous beta cell function can be recovered or islet transplant becomes clinically feasible for T1D treatment.Item CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance(Springer Nature, 2019-09-27) Chen, Yuhong; Yu, Mei; Zheng, Yongwei; Fu, Guoping; Xin, Gang; Zhu, Wen; Luo, Lan; Burns, Robert; Li, Quan-Zhen; Dent, Alexander L.; Zhu, Nan; Cui, Weiguo; Malherbe, Laurent; Wen, Renren; Wang, Demin; Microbiology and Immunology, School of MedicineMany autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.Item Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation(National Academy of Sciences, 2017-01-17) McEwan, William A.; Falcon, Benjamin; Vaysburd, Marina; Clift, Dean; Oblak, Adrian L.; Ghetti, Bernardino; Goedert, Michel; James, Leo C.; Pathology and Laboratory Medicine, School of MedicineAlzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubule-associated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived. Here, we show that when misfolded tau assemblies enter the cell, they can be detected and neutralized via a danger response mediated by tau-associated antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21). We developed fluorescent, morphology-based seeding assays that allow the formation of pathological tau aggregates to be measured in situ within 24 h in the presence of picomolar concentrations of tau seeds. We found that anti-tau antibodies accompany tau seeds into the cell, where they recruit TRIM21 shortly after entry. After binding, TRIM21 neutralizes tau seeds through the activity of the proteasome and the AAA ATPase p97/VCP in a similar manner to infectious viruses. These results establish that intracellular antiviral immunity can be redirected against host-origin endopathogens involved in neurodegeneration.Item HIV infection drives IgM and IgG3 subclass bias in Plasmodium falciparum-specific and total immunoglobulin concentration in Western Kenya(BioMed Central, 2019-08-30) Odhiambo, Eliud O.; Datta, Dibyadyuti; Guyah, Bernard; Ayodo, George; Ondigo, Bartholomew N.; Abong’o, Benard O.; John, Chandy C.; Frosch, Anne E. P.; Pediatrics, School of MedicineBACKGROUND: HIV infection is associated with more frequent and severe episodes of malaria and may be the result of altered malaria-specific B cell responses. However, it is poorly understood how HIV and the associated lymphopenia and immune activation affect malaria-specific antibody responses. METHODS: HIV infected and uninfected adults were recruited from Bondo subcounty hospital in Western Kenya at the time of HIV testing (antiretroviral and co-trimoxazole prophylaxis naïve). Total and Plasmodium falciparum apical membrane antigen-1 (AMA1) and glutamate rich protein-R0 (GLURP-R0) specific IgM, IgG and IgG subclass concentrations was measured in 129 and 52 of recruited HIV-infected and uninfected individuals, respectively. In addition, HIV-1 viral load (VL), CD4+ T cell count, and C-reactive protein (CRP) concentration was quantified in study participants. Antibody levels were compared based on HIV status and the associations of antibody concentration with HIV-1 VL, CD4+ count, and CRP levels was measured using Spearman correlation testing. RESULTS: Among study participants, concentrations of IgM, IgG1 and IgG3 antibodies to AMA1 and GLURP-R0 were higher in HIV infected individuals compared to uninfected individuals (all p < 0.001). The IgG3 to IgG1 ratio to both AMA1 and GLURP-R0 was also significantly higher in HIV-infected individuals (p = 0.02). In HIV-infected participants, HIV-1 VL and CRP were weakly correlated with AMA1 and GLURP-R0 specific IgM and IgG1 concentrations and total (not antigen specific) IgM, IgG, IgG1, and IgG3 concentrations (all p < 0.05), suggesting that these changes are related in part to viral load and inflammation. CONCLUSIONS: Overall, HIV infection leads to a total and malaria antigen-specific immunoglobulin production bias towards higher levels of IgM, IgG1, and IgG3, and HIV-1 viraemia and systemic inflammation are weakly correlated with these changes. Further assessments of antibody affinity and function and correlation with risk of clinical malaria, will help to better define the effects of HIV infection on clinical and biological immunity to malaria.Item Immunobiological barriers to xenotransplantation(Elsevier, 2015-11) Cooper, David K. C.; Ekser, Burcin; Tector, A. Joseph; Department of Surgery, IU School of MedicineBinding of natural anti-pig antibodies in humans and nonhuman primates to carbohydrate antigens expressed on the transplanted pig organ, the most important of which is galactose-α1,3-galactose (Gal), activate the complement cascade, which results in destruction of the graft within minutes or hours, known as hyperacute rejection. Even if antibody is removed from the recipient's blood by plasmapheresis, recovery of antibody is associated with acute humoral xenograft rejection. If immunosuppressive therapy is inadequate, the development of high levels of T cell-dependent elicited anti-pig IgG similarly results in graft destruction, though classical acute cellular rejection is rarely seen. Vascular endothelial activation by low levels of anti-nonGal antibody, coupled with dysregulation of the coagulation-anticoagulation systems between pigs and primates, leads to a thrombotic microangiopathy in the graft that may be associated with a consumptive coagulopathy in the recipient. The most successful approach to overcoming these barriers is by genetically-engineering the pig to provide it with resistance to the human humoral and cellular immune responses and to correct the coagulation discrepancies between the two species. Organs and cells from pigs that (i) do not express the important Gal antigen, (ii) express a human complement-regulatory protein, and (iii) express a human coagulation-regulatory protein, when combined with an effective immunosuppressive regimen, have been associated with prolonged pig graft survival in nonhuman primates.Item Methodological aspects of anti-human leukocyte antigen antibody analysis in solid organ transplantation(Baishideng Publishing Group Inc., 2014-09-24) Lobashevsky, Andrew L.; Department of Medicine, IU School of MedicineDonor human leukocyte antigen (HLA)-specific antibodies (DSA) play an important role in solid organ transplantation. Preexisting IgG isotype DSA are considered a risk factor for antibody mediated rejection, graft failure or graft loss. The post-transplant development of DSA depends on multiple factors including immunogenicity of mismatched antigens, HLA class II typing of the recipient, cytokine gene polymorphisms, and cellular immunoregulatory mechanisms. De novo developed antibodies require special attention because not all DSA have equal clinical significance. Therefore, it is important for transplant clinicians and transplant immunologists to accurately characterize DSA. In this review, the contemporary immunological techniques for detection and characterization of anti-HLA antibodies and their pitfalls are described.Item Population Point Prevalence of SARS-CoV-2 Infection Based on a Statewide Random Sample — Indiana, April 25–29, 2020(Department of Health and Human Services, Centers for Disease Control and Prevention, 2020-07-24) Menachemi, Nir; Yiannoutsos, Constantin T.; Dixon, Brian E.; Duszynski, Thomas J.; Fadel, William F.; Wools-Kaloustian, Kara K.; Needleman, Nadia Unruh; Box, Kristina; Caine, Virginia; Norwood, Connor; Weaver, Lindsay; Halverson, Paul K.; Health Policy and Management, School of Public HealthDuring April 25–29, 2020, Indiana conducted statewide random sample testing of persons aged ≥12 years to assess prevalence of active infection and presence of antibodies to SARS-CoV-2; additional nonrandom sampling was conducted in racial and ethnic minority communities to better understand the impact of the virus in certain racial and ethnic minority populations.Item Seroprevalence of antibodies to SARS-CoV-2 among blood donors in the early month of the pandemic in Saudi Arabia(Elsevier, 2020) Banjar, Ayman; Al-Tawfiq, Jaffar A.; Alruwaily, Amaal; Alserehi, Haleema; Al-Qunaibet, Ada; Alaswad, Rehab; Almutlaq, Hind; Almudaiheem, Abdullah; Khojah, Abdullah T.; Alsaif, Faisal; Almolad, Shaza Karim; Alqahtani, Saeed; AlJurayyan, Abdullah; Alotaibi, Abdullah; Almalki, Safar; Abuhaimed, Yousef; Alkhashan, Abdullah; Alfaifi, Amal; Alabdulkareem, Khaled; Jokhdar, Hani; Assiri, Abdullah; Almudarra, Sami; Medicine, School of MedicineBackground: Serologic testing provides better understanding of SARS-CoV-2 prevalence and its transmission. This study was an investigation of the prevalence of antibodies to SARS-CoV-2 among blood donors in Saudi Arabia. Objective: To estimate the seroprevalence of anti-SARS-CoV-2 antibodies among blood donors in Saudi Arabia during the early phase of the COVID-19 pandemic. Methods: Serology results and epidemiological data were analyzed for 837 adult blood donors, with no confirmed SARS-CoV-2 infection, in Saudi Arabia from 20th to 25th May 2020. Seroprevalence was determined using electrochemical immunoassay to detect anti-SARS-CoV-2 antibodies. Results: The overall seroprevalence of anti-SARS-CoV-2 antibodies was 1.4% (12/837). Non-citizens had higher seroprevalence compared with citizens (OR 13.6, p = 0.001). Secondary education was significantly associated with higher seroprevalence compared with higher education (OR 6.8, p = 0.005). The data showed that the highest seroprevalence was in Makkah (8.1%). Uisng Makkah seroprevalence as the reference, the seroprevalence in other areas was: Madinah 4.1% (OR 0.48, 95% CI 0.12-1.94), Jeddah 2.3% (OR 0.27, 95% CI 0.31-2.25), and Qassim 2.9 % (OR 0.34, 95% CI 0.04-2.89) and these were not statistically different from seroprevalence in the Makkah region. Conclusions: At the early months of the COVID-19 pandemic in Saudi Arabia, the seroprevalence of antibodies to SARS-CoV-2 among blood donors was low, but was higher among non-citizens. These findings may indicate that non-citizens and less educated individuals may be less attentive to preventive measures. Monitoring seroprevalence trends over time require repeated sampling.Item Seroprevalence of SARS-CoV-2 Antibodies Among Healthcare Workers With Differing Levels of COVID-19 Patient Exposure(Cambridge University Press, 2020-08-03) Hunter, Benton R.; Dbeibo, Lana; Weaver, Christopher; Beeler, Cole; Saysana, Michele; Zimmerman, Michelle; Weaver, Lindsay; Emergency Medicine, School of MedicineHealthcare employees were tested for antibodies against SARS-CoV-2. Among 734 employees, the prevalence of SARS-CoV-2 antibodies was 1.6%. Employees with heavy COVID-19 exposure had similar antibody prevalence as those with limited or no exposure. Guidelines for PPE use seem effective for preventing COVID-19 infection in healthcare workers.Item Viral shedding and antibody response in 37 patients with MERS-coronavirus infection(Oxford, 2016-11) Corman, Victor M.; Albarrak, Ali M.; Omrani, Ali Senosi; Albarrak, Mohammed M.; Farah, Mohamed Elamin; Almasri, Malak; Muth, Doreen; Sieberg, Andrea; Meyer, Benjamin; Assiri, Abdullah M.; Binger, Tabea; Steinhagen, Katja; Lattwein, Erik; Al-Tawfiq, Jaffar; Müller, Marcel A.; Drosten, Christian; Memish, Ziad A.; Department of Medicine, IU School of MedicineBackground. The Middle East respiratory syndrome (MERS) coronavirus causes isolated cases and outbreaks of severe respiratory disease. Essential features of the natural history of disease are poorly understood. Methods. We studied 37 adult patients infected with MERS coronavirus for viral load in the lower and upper respiratory tracts (LRT and URT, respectively), blood, stool, and urine. Antibodies and serum neutralizing activities were determined over the course of disease. Results. One hundred ninety-nine LRT samples collected during the 3 weeks following diagnosis yielded virus RNA in 93% of tests. Average (maximum) viral loads were 5 × 106 (6 × 1010) copies/mL. Viral loads (positive detection frequencies) in 84 URT samples were 1.9 × 104 copies/mL (47.6%). Thirty-three percent of all 108 serum samples tested yielded viral RNA. Only 14.6% of stool and 2.4% of urine samples yielded viral RNA. All seroconversions occurred during the first 2 weeks after diagnosis, which corresponds to the second and third week after symptom onset. Immunoglobulin M detection provided no advantage in sensitivity over immunoglobulin G (IgG) detection. All surviving patients, but only slightly more than half of all fatal cases, produced IgG and neutralizing antibodies. The levels of IgG and neutralizing antibodies were weakly and inversely correlated with LRT viral loads. Presence of antibodies did not lead to the elimination of virus from LRT. Conclusions. The timing and intensity of respiratory viral shedding in patients with MERS closely matches that of those with severe acute respiratory syndrome. Blood viral RNA does not seem to be infectious. Extrapulmonary loci of virus replication seem possible. Neutralizing antibodies do not suffice to clear the infection.