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Human Immunology Jan 2023Antibody-mediated rejection is a major cause of graft injury and contributes to failure of pig xenografts in nonhuman primates (NHPs). Most 'natural' or elicited... (Review)
Review
BACKGROUND
Antibody-mediated rejection is a major cause of graft injury and contributes to failure of pig xenografts in nonhuman primates (NHPs). Most 'natural' or elicited antibodies found in humans and NHPs are directed against pig glycan antigens, but antibodies binding to swine leukocyte antigens (SLA) have also been detected. Of clinical importance is (i) whether the presence of high levels of antibodies directed towards human leukocyte antigens (HLA) (i.e., high panel-reactive antibodies) would be detrimental to the outcome of a pig organ xenograft; and (ii) whether, in the event of sensitization to pig antigens, a subsequent allotransplant would be at increased risk of graft failure due to elicited anti-pig antibodies that cross-react with human HLA or other antigens.
SUMMARY
A literature review of pig-to-primate studies indicates that relatively few highly-HLA-sensitized humans have antibodies that cross-react with pigs, predicting that most would not be at increased risk of rejecting an organ xenograft. Furthermore, the existing evidence indicates that sensitization to pig antigens will probably not elicit increased alloantibody titers; if so, 'bridging' with a pig organ could be carried out without increased risk of subsequent antibody-mediated allograft failure.
KEY MESSAGE
These issues have important implications for the design and conduct of clinical xenotransplantation trials.
Topics: Animals; Humans; Antigens, Heterophile; Transplantation, Heterologous; Isoantigens; Primates; Antigens; HLA Antigens; Isoantibodies; Graft Rejection
PubMed: 35817653
DOI: 10.1016/j.humimm.2022.06.003 -
BMC Women's Health Jun 2022The optimal management of patients in reproductive endocrinology relies on the accuracy and validity of sex hormone assays. Endogenous or exogenous substances can... (Review)
Review
BACKGROUND
The optimal management of patients in reproductive endocrinology relies on the accuracy and validity of sex hormone assays. Endogenous or exogenous substances can compete with the analyte. This competition can result in interfering errors and falsely indicate elevated serum levels. Obvious interference in estradiol assays appears to occur rarely. Consequently, clinicians who are not familiar with the potential of interference could be misled. In addition to unnecessary investigations and interventions and severe mental stress, falsely elevated estradiol results can result in missed or delayed fertility opportunities.
CASE
A 28-year-old female with pregnancy demand was diagnosed with polycystic ovary syndrome, Hashimoto's thyroiditis and subclinical hypothyroidism. She was found to have persistently elevated levels of serum estradiol in the early follicular phase (between 527 and 642 pg/mL). Screening workup was performed for nearly 11 months to find the causes. Serum tumor biomarkers were normal. Abdominal and pelvic computed tomography were negative for adrenal or adnexal masses. A left mesosalpinx cyst and benign pathological results were achieved by laparoscopic surgery. Hormonal substances and dietary supplements were absent, as determined by dietary records. Ultrasound confirmed follicles could grow slowly and eventually ovulate. Falsely elevated estradiol levels were suspected due to the discrepancy among high estradiol levels, follicle growth and normal gonadotropin levels. Immunological interference by heterophile antibody was finally verified by two competitive chemiluminescent immunoassay platforms (estradiol levels in the early follicle phase: 619 pg/mL, Siemens ADVIA CENTAUR and 60 pg/mL, Beckman, DxI 800). Successful clinical pregnancy was eventually achieved by combining induced ovulation, ultrasound monitoring and intercourse guidance.
CONCLUSIONS
Analytical interference and laboratory error should be suspicious at first when the clinical characteristics contradict the laboratory results of serum hormones. Measuring serum estradiol with another immunoassay platform is an easy and non-time-consuming method to exclude the heterophile interfering.
Topics: Adult; Antibodies, Heterophile; Estradiol; Female; Fertility; Humans; Hypothyroidism; Immunoassay; Pregnancy
PubMed: 35710471
DOI: 10.1186/s12905-022-01828-5 -
Frontiers in Immunology 2022After producing triple (Gal, H-D and Sd)-KO pigs, hyperacute rejection appeared to no longer be a problem. However, the origin of xeno-rejection continues to be a... (Review)
Review
After producing triple (Gal, H-D and Sd)-KO pigs, hyperacute rejection appeared to no longer be a problem. However, the origin of xeno-rejection continues to be a controversial topic, including small amounts of antibodies and subsequent activation of the graft endothelium, the complement recognition system and the coagulation systems. The complement is activated via the classical pathway by non-Gal/H-D/Sda antigens and by ischemia-reperfusion injury (IRI), via the alternative pathway, especially on islets, and via the lectin pathway. The complement system therefore is still an important recognition and effector mechanism in xeno-rejection. All complement regulatory proteins (CRPs) regulate complement activation in different manners. Therefore, to effectively protect xenografts against xeno-rejection, it would appear reasonable to employ not only one but several CRPs including anti-complement drugs. The further assessment of antigens continues to be an important issue in the area of clinical xenotransplantation. The above conclusions suggest that the expression of sufficient levels of human CRPs on Triple-KO grafts is necessary. Moreover, multilateral inhibition on local complement activation in the graft, together with the control of signals between macrophages and lymphocytes is required.
Topics: Animals; Antigens, Heterophile; Complement Activation; Complement System Proteins; Graft Rejection; Humans; Swine; Transplantation, Heterologous
PubMed: 35493484
DOI: 10.3389/fimmu.2022.860165 -
Frontiers in Immunology 2022That Epstein-Barr virus (EBV) infection is associated with systemic lupus erythematosus (SLE) is established. The challenge is to explain mechanistic roles EBV has in...
BACKGROUND
That Epstein-Barr virus (EBV) infection is associated with systemic lupus erythematosus (SLE) is established. The challenge is to explain mechanistic roles EBV has in SLE pathogenesis. Previous studies identify four examples of autoantibody cross-reactions between SLE autoantigens and Epstein-Barr nuclear antigen 1 (EBNA1). For two of these examples, the earliest detected autoantibody specifically cross-reacts with EBNA1; thereby, defined EBNA1 epitopes induce a robust autoantibody response in animals. These results suggest that the autoantibodies initiating the process leading to SLE may emerge from the anti-EBNA1 heteroimmune response. If this hypothesis is true, then anti-EBNA1 responses would be more frequent in EBV-infected SLE patients than in EBV-infected controls. We tested this prediction.
METHODS
We evaluated published East Asian data by selecting those with a positive anti-viral capsid antigen (VCA) antibody immunoglobulin G (IgG) test and determining whether anti-EBNA1 was more common among the EBV-infected SLE cases than among matched EBV-infected controls with conditional logistic regression analysis.
RESULTS
All the qualifying SLE patients (100%) in this dataset were EBV-infected compared to age- and sex-matched controls (92.2%) [odds ratio (OR) = 28.6, 95% CI 6.4-∞, p = 8.83 × 10], confirming the known close association of EBV infection with SLE. Furthermore, virtually all the SLE cases have both anti-VCA IgG and anti-EBNA1 IgG antibodies [124 of 125 (99.2%)], which are more frequently present than in age- and sex-matched EBV-infected controls [232 of 250 (93.2%)] (OR = 9.7, 95% CI 1.5-414, p = 0.0078) for an 89.7% SLE attributable risk from anti-EBNA1, which is in addition to the 100% SLE risk attributable to EBV infection in these data.
CONCLUSIONS
The association of EBV infection with SLE is reconfirmed. The prediction that anti-EBNA1 is more frequent in these SLE cases than in EBV-infected controls is true, consistent with the hypothesis that anti-EBNA1 contributes to SLE. This second EBV-dependent risk factor is consistent with a molecular mimicry model for the generation of SLE, starting with EBV infection, progressing to anti-EBNA1 response; then molecular mimicry leads to anti-EBNA1 antibodies cross-reacting with an SLE autoantigen, causing autoantibody epitope spreading, and culminating in clinical SLE. These results support the anti-EBNA1 heteroimmune response being a foundation from which pathogenic SLE autoimmunity emerges.
Topics: Animals; Antibodies, Heterophile; Antibodies, Viral; Autoantibodies; Autoantigens; Capsid Proteins; Epitopes; Epstein-Barr Virus Infections; Epstein-Barr Virus Nuclear Antigens; Herpesvirus 4, Human; Humans; Immunoglobulin G; Lupus Erythematosus, Systemic; Prevalence
PubMed: 35251022
DOI: 10.3389/fimmu.2022.830993 -
Clinical Medicine (London, England) Jan 2022Cardiac troponin I and T are particularly sensitive and specific markers for cardiomyocyte damage. Myocardial injury can occur due to a discrepancy between oxygen supply...
Cardiac troponin I and T are particularly sensitive and specific markers for cardiomyocyte damage. Myocardial injury can occur due to a discrepancy between oxygen supply and demand (eg coronary artery occlusion and arrhythmias), other cardiac causes (eg pericarditis, myocarditis, cardiac surgery, cardioversion etc) or systemic conditions (eg sepsis, stroke and chronic renal disease). The latest European Society of Cardiology guidelines help to guide clinicians through these different causes. Occasionally troponin concentrations may not fit the clinical presentation and, therefore, other aetiologies should be considered. An under-appreciated basis of a high troponin concentration is a false positive result, which can be attributable to analytical interference from components in the patient's blood. Uncovering this interference can be pivotal to avoid unnecessary and potentially harmful investigations or treatment for patients. We present two cases of false positive troponin results caused by analytical interference. The normal reference range for the assay (Access; Beckman Coulter, High Wycombe, UK) used at our organisation is 0-18 ng/L.
Topics: Biomarkers; Humans; Sepsis; Troponin I
PubMed: 35078800
DOI: 10.7861/clinmed.2021-0633 -
Frontiers in Immunology 2021Amino acid substitutions and deletions in the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can reduce the effectiveness of...
Amino acid substitutions and deletions in the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can reduce the effectiveness of monoclonal antibodies (mAbs). In contrast, heterologous polyclonal antibodies raised against S protein, through the recognition of multiple target epitopes, have the potential to maintain neutralization capacities. XAV-19 is a swine glyco-humanized polyclonal neutralizing antibody raised against the receptor binding domain (RBD) of the Wuhan-Hu-1 Spike protein of SARS-CoV-2. XAV-19 target epitopes were found distributed all over the RBD and particularly cover the receptor binding motives (RBMs), in direct contact sites with the angiotensin converting enzyme-2 (ACE-2). Therefore, in Spike/ACE-2 interaction assays, XAV-19 showed potent neutralization capacities of the original Wuhan Spike and of the United Kingdom (Alpha/B.1.1.7) and South African (Beta/B.1.351) variants. These results were confirmed by cytopathogenic assays using Vero E6 and live virus variants including the Brazil (Gamma/P.1) and the Indian (Delta/B.1.617.2) variants. In a selective pressure study on Vero E6 cells conducted over 1 month, no mutation was associated with the addition of increasing doses of XAV-19. The potential to reduce viral load in lungs was confirmed in a human ACE-2 transduced mouse model. XAV-19 is currently evaluated in patients hospitalized for COVID-19-induced moderate pneumonia in phase 2a-2b (NCT04453384) where safety was already demonstrated and in an ongoing 2/3 trial (NCT04928430) to evaluate the efficacy and safety of XAV-19 in patients with moderate-to-severe COVID-19. Owing to its polyclonal nature and its glyco-humanization, XAV-19 may provide a novel safe and effective therapeutic tool to mitigate the severity of coronavirus disease 2019 (COVID-19) including the different variants of concern identified so far.
Topics: Animals; Antibodies, Heterophile; Antibodies, Viral; Antigenic Variation; Broadly Neutralizing Antibodies; COVID-19; Disease Models, Animal; Epitopes; Humans; Immunization, Passive; Lung; Mice; Protein Interaction Domains and Motifs; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Swine; Viral Load; COVID-19 Serotherapy
PubMed: 34868003
DOI: 10.3389/fimmu.2021.761250 -
Science Translational Medicine Nov 2021Broadly neutralizing antibodies (bNAbs) against HIV-1 develop after prolonged virus and antibody coevolution. Previous studies showed that sequential immunization with a...
Broadly neutralizing antibodies (bNAbs) against HIV-1 develop after prolonged virus and antibody coevolution. Previous studies showed that sequential immunization with a V3-glycan patch germline-targeting HIV-1 envelope trimer (Env) followed by variant Envs can reproduce this process in mice carrying V3-glycan bNAb precursor B cells. However, eliciting bNAbs in animals with polyclonal antibody repertoires is more difficult. We used a V3-glycan immunogen multimerized on virus-like particles (VLPs), followed by boosting with increasingly native-like Env-VLPs, to elicit heterologous neutralizing antibodies in nonhuman primates (NHPs). Structures of antibody/Env complexes after prime and boost vaccinations demonstrated target epitope recognition with apparent maturation to accommodate glycans. However, we also observed increasing off-target antibodies with boosting. Eight vaccinated NHPs were subsequently challenged with simian-human immunodeficiency virus (SHIV), and seven of eight animals became infected. The single NHP that remained uninfected after viral challenge exhibited one of the lowest neutralization titers against the challenge virus. These results demonstrate that more potent heterologous neutralization resulting from sequential immunization is necessary for protection in this animal model. Thus, improved prime-boost regimens to increase bNAb potency and stimulate other immune protection mechanisms are essential for developing anti–HIV-1 vaccines.
Topics: AIDS Vaccines; Animals; Antibodies, Heterophile; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Immunization; Macaca; Polysaccharides; env Gene Products, Human Immunodeficiency Virus
PubMed: 34818054
DOI: 10.1126/scitranslmed.abk1533 -
Journal of the American Board of Family... 2021The accuracy of individual symptoms, signs, and several easily obtainable hematologic parameters for diagnosing infectious mononucleosis (IM) still needs to be... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The accuracy of individual symptoms, signs, and several easily obtainable hematologic parameters for diagnosing infectious mononucleosis (IM) still needs to be confirmed. Improving the diagnosis of IM based on the clinical findings could prompt physicians to identify better which patients need a diagnostic test for IM. This study performed a systematic review to determine the accuracy of symptoms, signs, and hematologic parameters in patients with suspected IM that used heterophile antibody test or viral capsid antigen tests as the reference standard.
METHODS
The PubMed database was searched for all relevant articles. Two reviewers reviewed all studies in parallel and assessed the quality of the selected studies using the quality assessment of diagnostic accuracy studies 2 (QUADAS-2) criteria. The pooled measures of diagnostic performance were calculated by bivariate meta-analysis for each clinical finding, which included sensitivity, specificity, likelihood ratios, the diagnostic odds ratios, and the area under the receiver operating characteristic curve.
RESULTS
Seventeen studies were included in our final analysis. The prevalence of IM ranged from 2.1% to 80% among prospective cohort studies. The presence of splenomegaly (positive likelihood ratio [LR+], 2.39; 95% confidence interval [CI], 1.11-5.51), palatal petechiae (LR+, 1.32-11.40), posterior cervical lymphadenopathy (LR+, 3.16; 95% CI, 1.45-5.20), and axillary or inguinal cervical lymphadenopathy (LR+, 3.05; 95 CI, 1.85-4.70) were moderately useful for ruling in IM. The most helpful hematologic parameters for ruling in IM include lymphocytes greater than 4 × 10/L and greater than 40% to 50%, or atypical lymphocytes greater than 40%. A combination of lymphocytes greater than 50% and atypical lymphocytes greater than 10% (LR+, 50.40; 95% CI, 8.43-162) was also found to be helpful to rule in disease. Most of the clinical findings have limited diagnostic value in ruling out the disease when absent.
CONCLUSIONS
Although most symptoms and signs were unhelpful, the likelihood of IM is appreciably increased by several examination findings. Hematologic parameters were more accurate than symptoms and signs. Since most clinical findings have limited diagnostic value in ruling out the disease, physicians should not rely on the absence of any individual symptom or clinical sign for ruling out IM.
Topics: Diagnostic Tests, Routine; Humans; Infectious Mononucleosis; Neck; Prospective Studies; ROC Curve; Sensitivity and Specificity
PubMed: 34772769
DOI: 10.3122/jabfm.2021.06.210217 -
CJC Open Jul 2021A 78-year-old woman presented twice with high sensitivity troponin I (hs-TnI) elevation. Two cardiac catheterizations showed nonocclusive coronary artery disease, and 2...
A 78-year-old woman presented twice with high sensitivity troponin I (hs-TnI) elevation. Two cardiac catheterizations showed nonocclusive coronary artery disease, and 2 cardiac magnetic resonance imaging scans were normal. With these investigations unable to explain the troponin I (hs-TnI) elevation, alternate troponin samples were sent to check for assay interference. Results from these troponin assays were low. With the patient having elevated rheumatoid factor as a potential contributor to assay interference, the lab reanalyzed the samples using heterophile antibody blocking tubes, revealing lower hs-TnI levels. This case serves as a reminder to consider assay interference when the clinical picture is inconsistent with ischemia.
PubMed: 34401704
DOI: 10.1016/j.cjco.2021.02.014 -
Annals of Laboratory Medicine Jan 2022Immunoassays are powerful qualitative and quantitative analytical techniques. Since the first description of an immunoassay method in 1959, advances have been made in... (Review)
Review
Immunoassays are powerful qualitative and quantitative analytical techniques. Since the first description of an immunoassay method in 1959, advances have been made in assay designs and analytical characteristics, opening the door for their widespread implementation in clinical laboratories. Clinical endocrinology is closely linked to laboratory medicine because hormone quantification is important for the diagnosis, treatment, and prognosis of endocrine disorders. Several interferences in immunoassays have been identified through the years; although some are no longer encountered in daily practice, cross-reaction, heterophile antibodies, biotin, and anti-analyte antibodies still cause problems. Newer interferences are also emerging with the development of new therapies. The interfering substance may be exogenous (e.g., a drug or substance absorbed by the patient) or endogenous (e.g., antibodies produced by the patient), and the bias caused by interference can be positive or negative. The consequences of interference can be deleterious when clinicians consider erroneous results to establish a diagnosis, leading to unnecessary explorations or inappropriate treatments. Clinical laboratories and manufacturers continue to investigate methods for the detection, elimination, and prevention of interferences. However, no system is completely devoid of such incidents. In this review, we focus on the analytical interferences encountered in daily practice and possible solutions for their detection or elimination.
Topics: Antibodies; Biotin; Cross Reactions; Hormones; Humans; Immunoassay
PubMed: 34374345
DOI: 10.3343/alm.2022.42.1.3