Immunological Phenomena Research Articles

Japanese Encephalitis Virus infection in South-East Asia: an immuno-epidemiological twist

Background:Japanese encephalitis (JE) is one of the most important zoonotic diseases in a cosmopolitan manner. Japanese encephalitis virus (JEV) infection represents at least 70 % of emerging diseases caused by the mosquito-borne JEV. Nearly 20-30% of case fatality corroborated in JEV infections with 30-50% neurologic and psychiatric disorders. A strong epidemic distribution is observed mainly in South-East Asia, demonstrating typical seasonal characteristics and occasional outbreaks. Depending on the genetic diversity, geographical distribution, and emerging natures of JEV, the disease surveillance, and immunization strategies are also varied. Uncontrolled population growth, haphazard agro-animal farming, and ecological imbalance steer the emergence and reemergence of JEV occurrences. Some murine models elucidate the immunological phenomena of JEV infections, the more detailed pathogenesis depending on the genetic variation is yet to be well defined. And the immune-epidemiological traits also address significant concerns regarding the effective vaccines and immunotherapeutics against JEV infections. Therefore, we summarized some critical notions on molecular epidemiology, immunogenicity, and genetic variance of JEV in South-East Asia.

From Anti-Severe Acute Respiratory Syndrome Coronavirus 2 Immune Response to Cancer Onset via Molecular Mimicry and Cross-Reactivity.

Background and Objectives Whether exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may predispose to the risk of cancer in individuals with no prior cancers is a crucial question that remains unclear. To confirm/refute possible relationships between exposure to the virus and ex novo insurgence of tumors, this study analyzed molecular mimicry and the related cross-reactive potential between SARS-CoV-2 spike glycoprotein (gp) antigen and human tumor-suppressor proteins. Materials and Methods Tumor-associated proteins were retrieved from UniProt database and analyzed for pentapeptide sharing with SARS-CoV-2 spike gp by using publicly available databases. Results An impressively high level of molecular mimicry exists between SARS-CoV-2 spike gp and tumor-associated proteins. Numerically, 294 tumor-suppressor proteins share 308 pentapeptides with the viral antigen. Crucially, the shared peptides have a relevant immunologic potential by repeatedly occurring in experimentally validated epitopes. Such immunologic potential is of further relevancy in that most of the shared peptides are also present in infectious pathogens to which, in general, human population has already been exposed, thus indicating the possibility of immunologic imprint phenomena. Conclusion This article described a vast peptide overlap between SARS-CoV-2 spike gp and tumor-suppressor proteins, and supports autoimmune cross-reactivity as a potential mechanism underlying prospective cancer insurgence following exposure to SARS-CoV-2. Clinically, the findings call for close surveillance of tumor sequelae that possibly could result from the current coronavirus pandemic.

The Role of microRNAs in Pulp Inflammation.

The dental pulp can be affected by thermal, physical, chemical, and bacterial phenomena that stimulate the inflammatory response. The pulp tissue produces an immunological, cellular, and vascular reaction in an attempt to defend itself and resolve the affected tissue. The expression of different microRNAs during pulp inflammation has been previously documented. MicroRNAs (miRNAs) are endogenous small molecules involved in the transcription of genes that regulate the immune system and the inflammatory response. They are present in cellular and physiological functions, as well as in the pathogenesis of human diseases, becoming potential biomarkers for diagnosis, prognosis, monitoring, and safety. Previous studies have evidenced the different roles played by miRNAs in proinflammatory, anti-inflammatory, and immunological phenomena in the dental pulp, highlighting specific key functions of pulp pathology. This systematized review aims to provide an understanding of the role of the different microRNAs detected in the pulp and their effects on the expression of the different target genes that are involved during pulp inflammation.

Endothelial Dysfunction in Coronavirus disease: A Literature Review

Coronavirus disease (COVID-19), caused by Sars-Cov-2, affects several cell types, including the vascular endothelium, which can lead to immunological phenomena and coagulopathies with vascular and systemic lesions. Thus, the objective was to describe, through a bibliographic review, the endothelial dysfunction induced by coronavirus. The data collected in this study suggest that the lesion of the endothelium caused by the coronavirus leads to cell death and exposure of the vascular glycocalyx, resulting in activation of neutrophils and platelets, with consequent production of cytokines and activation of blood clotting, inducing the formation of thrombi / clots . The consequences are hypoxia and widespread lesions in several organs, resulting in life-threatening patients with COVID-19. Endothelial dysfunction is well established in cardiovascular diseases and diabetes, in such a way that these comorbidities could aggravate the endothelium-induced lesions induced by Sars-Cov-2, with more serious clinical outcomes. Thus, a close relationship was observed between the endothelial dysfunctions induced by COVID-19 and inflammatory and thrombotic events, with worsening of clinical cases and fatal outcomes. Thus, early diagnosis can assist in the therapy that stabilizes the endothelium and reduces thrombotic events, with consequent aggravation and risk of death, especially in patients with chronic cardiovascular diseases and diabetes.

Can molecular mimicry explain the cytokine storm of SARS-CoV-2?: Anin silico approach.

PARP14 and PARP9 play a key role in macrophage immune regulation. SARS‐CoV‐2 is an emerging viral disease that triggers hyper‐inflammation known as a cytokine storm. In this study, using in silico tools, we hypothesize about the immunological phenomena of molecular mimicry between SARS‐CoV‐2 Nsp3 and the human PARP14 and PARP9. The results showed an epitope of SARS‐CoV‐2 Nsp3 protein that contains consensus sequences for both human PARP14 and PARP9 that are antigens for MHC Classes 1 and 2, which can potentially induce an immune response against human PARP14 and PARP9; while its depletion causes a hyper‐inflammatory state in SARS‐CoV‐2 patients.

Direct Evidence for Viral Antigen Presentation during Latent Cytomegalovirus Infection.

Murine models of cytomegalovirus (CMV) infection have revealed an immunological phenomenon known as “memory inflation” (MI). After a peak of a primary CD8+ T-cell response, the pool of epitope-specific cells contracts in parallel to the resolution of productive infection and the establishment of a latent infection, referred to as “latency.” CMV latency is associated with an increase in the number of cells specific for certain viral epitopes over time. The inflationary subset was identified as effector-memory T cells (iTEM) characterized by the cell surface phenotype KLRG1+CD127−CD62L−. As we have shown recently, latent viral genomes are not transcriptionally silent. Rather, viral genes are sporadically desilenced in a stochastic fashion. The current hypothesis proposes MI to be driven by presented viral antigenic peptides encoded by the corresponding, stochastically expressed viral genes. Although this mechanism suggests itself, independent evidence for antigen presentation during viral latency is pending. Here we fill this gap by showing that T cell-receptor transgenic OT-I cells that are specific for peptide SIINFEKL proliferate upon adoptive cell transfer in C57BL/6 recipients latently infected with murine CMV encoding SIINFEKL (mCMV-SIINFEKL), but not in those latently infected with mCMV-SIINFEKA, in which antigenicity is lost by mutation L8A of the C-terminal amino acid residue.

Autoantibodies Against Ubiquitous and Confined Antigens in Patients With Ocular, Neuro-Ophthalmic and Congenital Cerebral Toxoplasmosis.

Toxoplasma gondii infection can trigger autoreactivity by different mechanisms. In the case of ocular toxoplasmosis, disruption of the blood-retinal barrier may cause exposure of confined retinal antigens such as recoverin. Besides, cross-reactivity can be induced by molecular mimicry of parasite antigens like HSP70, which shares 76% identity with the human ortholog. Autoreactivity can be a determining factor of clinical manifestations in the eye and in the central nervous system. We performed a prospective observational study to determine the presence of autoantibodies against recoverin and HSP70 by indirect ELISA in the serum of 65 patients with ocular, neuro-ophthalmic and congenital cerebral toxoplasmosis. We found systemic autoantibodies against recoverin and HSP70 in 33.8% and 15.6% of individuals, respectively. The presence of autoantibodies in cases of OT may be related to the severity of clinical manifestations, while in cases with CNS involvement they may have a protective role. Unexpectedly, anti-recoverin antibodies were found in patients with cerebral involvement, without ocular toxoplasmosis; therefore, we analyzed and proved cross-reactivity between recoverin and a brain antigen, hippocalcin, so the immunological phenomenon occurring in one immune-privileged organ (e.g. the central nervous system) could affect the environment of another (egg. the eye).

Neoantigen Cancer Vaccines: Real Opportunity or Another Illusion?

In this communication, we will analyze some important factors and immunological phenomena related to neoantigen cancer vaccines, with particular emphasis on recently published Phase I clinical trials. Several obstacles and issues are addressed that challenge the current paradigm and inquire if neoantigens, which are essentially single-use vaccine candidates, are legitimate targets to induce protective immune responses with regard to the evolving mutational landscape. We also share insights into the striking similarities between cancer and antigenically variable pathogens and suggest that any successful vaccine against either should demonstrate a similar property: efficient induction of a diverse pool of immune cells equipped to prevent immune escape. Hence, to confront antigenic variability directly, we have employed our innovative vaccine concept, Variable Epitope Libraries, composed of large combinatorial libraries of heavily mutated epitopes, as a “universal” vaccine platform. Collectively, we offer critical analyses on key issues, which ultimately reflect on the prospective clinical relevance of personalized neoantigen vaccines which is still undefined.

Pregnancy Outcomes and Child Development Effects of SARS-CoV-2 Infection (PROUDEST Trial): Protocol for a Multicenter, Prospective Cohort Study.

BackgroundA growing body of evidence suggests that SARS-COV-2 infection during pregnancy may affect maternal-fetal outcomes and possibly result in implications for the long-term development of SARS-CoV-2–exposed children.ObjectiveThe PROUDEST (Pregnancy Outcomes and Child Development Effects of SARS-CoV-2 Infection Study) is a multicenter, prospective cohort study designed to elucidate the repercussions of COVID-19 for the global health of mothers and their children.MethodsThe PROUDEST trial comprises 2 prospective, sequential substudies. The PREGNANT substudy will clinically assess the effects of SARS-CoV-2 infection on pregnancy, childbirth, and puerperium from a mechanistic standpoint to elucidate the pregnancy-related inflammatory and immunological phenomena underlying COVID-19. Pregnant women aged 18-40 years who have been exposed (proven with laboratory tests) to SARS-CoV-2 (group A; n=300) will be compared to control subjects with no laboratory evidence of in-pregnancy exposure to the virus (group B; n=300). Subjects exposed to other infections during pregnancy will be excluded. The BORN substudy is a long-term follow-up study that will assess the offspring of women who enrolled in the prior substudy. It will describe the effects of SARS-CoV-2 exposure during pregnancy on children’s growth, neurodevelopment, and metabolism from birth up to 5 years of age. It includes two comparison groups; group A (exposed; n=300) comprises children born from SARS-CoV-2–exposed pregnancies, and group B (controls; n=300) comprises children born from nonexposed mothers.ResultsRecruitment began in July 2020, and as of January 2021, 260 pregnant women who were infected with SARS-CoV-2 during pregnancy and 160 newborns have been included in the study. Data analysis is scheduled to start after all data are collected.ConclusionsUpon completion of the study, we expect to have comprehensive data that will provide a better understanding of the effects of SARS-CoV-2 infection and related inflammatory and immunological processes on pregnancy, puerperium, and infancy. Our findings will inform clinical decisions regarding the care of SARS-CoV-2–exposed mothers and children and support the development of evidence-based public health policies.Trial RegistrationBrazilian Register of Clinical Trials RBR65QXS2; https://ensaiosclinicos.gov.br/rg/RBR-65qxs2International Registered Report Identifier (IRRID)DERR1-10.2196/26477

Thrombocytopenia and Intracranial Venous Sinus Thrombosis after "COVID-19 Vaccine AstraZeneca" Exposure.

Background: As of 8 April 2021, a total of 2.9 million people have died with or from the coronavirus infection causing COVID-19 (Corona Virus Disease 2019). On 29 January 2021, the European Medicines Agency (EMA) approved a COVID-19 vaccine developed by Oxford University and AstraZeneca (AZD1222, ChAdOx1 nCoV-19, COVID-19 vaccine AstraZeneca, Vaxzevria, Covishield). While the vaccine prevents severe course of and death from COVID-19, the observation of pulmonary, abdominal, and intracranial venous thromboembolic events has raised concerns. Objective: To describe the clinical manifestations and the concerning management of patients with cranial venous sinus thrombosis following first exposure to the “COVID-19 vaccine AstraZeneca”. Methods: Patient files, laboratory findings, and diagnostic imaging results, and endovascular interventions of three concerning patients were evaluated in retrospect. Results: Three women with intracranial venous sinus thrombosis after their first vaccination with “COVID-19 vaccine AstraZeneca” were encountered. Patient #1 was 22 years old and developed headaches four days after the vaccination. On day 7, she experienced a generalized epileptic seizure. Patient #2 was 46 years old. She presented with severe headaches, hemianopia to the right, and mild aphasia 13 days after the vaccination. MRI showed a left occipital intracerebral hemorrhage. Patient #3 was 36 years old and presented 17 days after the vaccination with acute somnolence and right-hand hemiparesis. The three patients were diagnosed with extensive venous sinus thrombosis. They were managed by heparinization and endovascular recanalization of their venous sinuses. They shared similar findings: elevated levels of D-dimers, platelet factor 4 antiplatelet antibodies, corona spike protein antibodies, combined with thrombocytopenia. Under treatment with low-molecular-weight heparin, platelet counts normalized within several days. Conclusion: Early observations insinuate that the exposure to the “COVID-19 vaccine AstraZeneca” might trigger the expression of antiplatelet antibodies, resulting in a condition with thrombocytopenia and venous thrombotic events (e.g., intracranial venous sinus thrombosis). These patients’ treatment should address the thrombo-embolic manifestations, the coagulation disorder, and the underlying immunological phenomena.

Progress in the Management of Smoldering Multiple Myeloma.

Smoldering multiple myeloma (SMM) is defined as an asymptomatic clonal proliferation of pre-malignant plasma cells and an increased risk of progression to multiple myeloma (MM) relative to monoclonal gammopathy of undetermined significance. Whether patients with SMM should be treated prior to development of symptomatic disease is fiercely debated and is a highly active area of research. The ECOG E3A06 study demonstrated that early treatment with lenalidomide significantly reduced the risk of progression to MM compared to observation in patients with high risk SMM. The IMWG recently validated a risk stratification model to include cytogenetics and a personalized risk calculator for individual patients. Beyond this, molecular genomic aberrations and immunological phenomena that promote progression from asymptomatic disease to MM have been recently characterized and may help to more precisely identify patients who are most suitable for early intervention. As highly effective and tolerable therapies for plasma cell disorders evolve, the field is approaching a paradigm shift that involves the adoption of intervention for patients with SMM who are at high risk for progression to symptomatic myeloma in order to prevent morbidity and mortality. This review highlights our current understanding of the biology of patients with SMM, clarifies the rationale for early intervention, and summarizes early results of various treatment strategies for patients with high-risk smoldering myeloma.

Activated CD4+ T cells and CD14hiCD16+ monocytes correlate with antibody response following influenza virus infection in humans

SummaryThe failure to mount an antibody response following viral infection or seroconversion failure is a largely underappreciated and poorly understood phenomenon. Here, we identified immunologic markers associated with robust antibody responses after influenza virus infection in two independent human cohorts, SHIVERS and FLU09, based in Auckland, New Zealand and Memphis, Tennessee, USA, respectively. In the SHIVERS cohort, seroconversion significantly associates with (1) hospitalization, (2) greater numbers of proliferating, activated CD4+ T cells, but not CD8+ T cells, in the periphery during the acute phase of illness, and (3) fewer inflammatory monocytes (CD14hiCD16+) by convalescence. In the FLU09 cohort, fewer CD14hiCD16+ monocytes during early illness in the nasal mucosa were also associated with the generation of influenza-specific mucosal immunoglobulin A (IgA) and IgG antibodies. Our study demonstrates that seroconversion failure after infection is a definable immunological phenomenon, associated with quantifiable cellular markers that can be used to improve diagnostics, vaccine efficacy, and epidemiologic efforts.

Pathogenesis of COVID-19 and multi-system inflammatory syndrome in children

World health organization declared COVID-19 caused by SARS CoV-2 virus as a pandemic in early 2020. The target cells facilitating viral entry are ACE-2 receptor bearing cells like bronchial epithelial cells and pneumocytes. Children pose a less risk compared to adults in acquiring this disease and mortality in them is low due to protective pathogenesis. Children with COVID-19 are also at risk of developing unique immunological phenomena, known as multi-system inflammatory syndrome in children. MIS-C is considered to be hyperimmune state resulting from cytokine storm and circulating immune complexes. This mini-review reflects the most recent understanding of the pathogenesis in children with special emphasis on MIS-C.

A Case of Unremitting Cellulitis in a Lung Transplant Recipient: What is the Infectious Etiology?

<h3>Introduction</h3> <i>Mycobacterium chelonae</i> is a rare, non-tuberculous mycobacterium that is highly pathogenic in immunosuppressed patients. Herein, we describe a chronic presentation of cellulitis which was later biopsy-proven as <i>M. chelonae</i> in a lung transplant recipient. <h3>Case Report</h3> A 61-year-old female bilateral lung transplant recipient presented 15-months post-transplant with multiple erythematous cutaneous lesions of the right arm. She had a 3-month history of waxing and waning cutaneous lesions that had not fully cleared despite antibiotic therapy. The first transplant year was eventful with two episodes of acute cellular rejection necessitating high-dose corticotherapy. Dermatological biopsy performed in a prior visit demonstrated features consistent with dermatitis. Autoimmune etiologies were ruled out, and the patient reported no history of trauma or other nidus of entry for infection. At the time of the current presentation, we observed nodular changes to the cutaneous lesions, which necessitated repeat biopsy, revealing granulomatous infiltrate (Figure 1). Acid-fast staining was positive, and <i>M. chelonae</i> was properly identified. Given her immunosuppressed state, the patient was started on multidrug antibiotic therapy, guided by antibiogram. Skin showed some improvement on observation, however, one large, nodular cutaneous lesion persisted. Decision was made to perform excision in effort to reduce bacterial growth burden. Subsequent biopsy findings were negative, likely a result of immunological phenomenon. She ultimately finished multidrug treatment with complete resolution of skin nodules. <h3>Summary</h3> This case underlines the role of corticotherapy and immunosuppression as a major risk factor for atypical infections, such as <i>M. chelonae</i>, in lung transplant recipients. Eradication can be difficult as demonstrated, and thus early recognition and multidrug antibiotic therapy are the cornerstone for management in this population.

Possible correlation of electrochemiluminescence based numerical cut off index value with concentration of anti-SARS-CoV-2 antibody: Is it worth reporting?

Background: Many laboratories are reporting a numerical cutoff index value (COI) value for most anti-SARS-CoV-2 qualitative tests. These numerical values in patients’ report ultimately created great confusion in the public and physicians, therefore this study was designed to evaluate the correlation of electrochemiluminescence (ECLIA) based numerical COI values with quantitative ELISA of anti-SARS-CoV-2 antibody.Design and Methods: Two hundred and twenty-eight (228) recovered COVID-19 patients were included; their serum samples were analyzed by quantitative ELISA and ECLIA for anti-SARSCOV- 2 antibodies.Results: One hundred and seventy-three (75.8%) patients tested positive by ECLIA and ELISA assay and thirty-seven (6.2%) were tested negative by both methods. A weak positive correlation (r=0.37) was found between numerical COI value of ECLIA with ELISA concentration, which was statistically significant with p<0.001. All values were dispersed on scatter plot and there was no significant linear relationship between ECLIA and ELISA assay.Conclusions: As both testing techniques are base upon the same immunological phenomena of detecting antibodies against nucleocapsid protein. We suggest that COI values are not meant to describe the immunity level of the individuals thus the physicians should not consider it as a quantitative value for antibody levels in COVID-19 patients.Significance for public healthMany laboratories in Pakistan are reporting numerical COI values, which ultimately created great confusion among the patients and physicians. These values are, used indiscriminately and wrongly compared to other testing systems which were in general intended to be used for quantitative analysis of the antibodies developed in the persons exposed to the virus. There had been obvious misunderstanding in the public including the healthcare sector when these different techniques were used indiscriminately without a proper orientation towards the utility and limitations of a given testing system. As a result, the different numerical COI values which were included in the laboratory reports of the test created a great havoc and raised suspicions about the certainty of the diagnostic techniques. This correlation is important because this number game has been talk of the town and lay person uses them to get the idea of one's own immunity status.

The Potential Role of Regulatory B Cells in Idiopathic Membranous Nephropathy.

Regulatory B cells (Breg) are widely regarded as immunomodulatory cells which play an immunosuppressive role. Breg inhibits pathological autoimmune response by secreting interleukin-10 (IL-10), transforming growth factor-β (TGF-β), and adenosine and through other ways to prevent T cells and other immune cells from expanding. Recent studies have shown that different inflammatory environments induce different types of Breg cells, and these different Breg cells have different functions. For example, Br1 cells can secrete IgG4 to block autoantigens. Idiopathic membranous nephropathy (IMN) is an autoimmune disease in which the humoral immune response is dominant and the cellular immune response is impaired. However, only a handful of studies have been done on the role of Bregs in this regard. In this review, we provide a brief overview of the types and functions of Breg found in human body, as well as the abnormal pathological and immunological phenomena in IMN, and propose the hypothesis that Breg is activated in IMN patients and the proportion of Br1 can be increased. Our review aims at highlighting the correlation between Breg and IMN and proposes potential mechanisms, which can provide a new direction for the discovery of the pathogenesis of IMN, thus providing a new strategy for the prevention and early treatment of IMN.

Deciphering the Immunological Phenomenon of Adaptive Natural Killer (NK) Cells and Cytomegalovirus (CMV).

Natural killer (NK) cells play a significant and vital role in the first line of defense against infection through their ability to target cells without prior sensitization. They also contribute significantly to the activation and recruitment of both innate and adaptive immune cells through the production of a range of cytokines and chemokines. In the context of cytomegalovirus (CMV) infection, NK cells and CMV have co-evolved side by side to employ several mechanisms to evade one another. However, during this co-evolution the discovery of a subset of long-lived NK cells with enhanced effector potential, increased antibody-dependent responses and the potential to mediate immune memory has revolutionized the field of NK cell biology. The ability of a virus to imprint on the NK cell receptor repertoire resulting in the expansion of diverse, highly functional NK cells to this day remains a significant immunological phenomenon that only occurs in the context of CMV. Here we review our current understanding of the development of these NK cells, commonly referred to as adaptive NK cells and their current role in transplantation, infection, vaccination and cancer immunotherapy to decipher the complex role of CMV in dictating NK cell functional fate.

IMMUNE EFFECTS OF STEREOTACTIC ABLATIVE RADIATION THERAPY IN PATIENTS WITH MALIGNANT TUMORS: LITERATURE REVIEW

The purpose of the study was to conduct a systematic analysis of the data available in the modern literature on the systemic (abscopal) effects in radiation therapy, which are mediated by immunological phenomena.Material and Methods.A structured search for articles published in peer-reviewed journals between January 2000 and February 2019 was conducted using MEDLINE database. The review included data from registered clinical trials at Clinicaltrials.gov, showing the results of the combined use of immunotherapy and radiation therapy.Results. There is an opinion that the systemic effect of radiotherapy is mediated by immunological phenomena. In connection with the recent data, there is a growing interest in the combined use of immunotherapy with radiation therapy in order to increase the efficacy of systemic therapy. However, the incidence of abscopal effects after standard radiation treatment is very low. In this regard, stereotactic ablative radiotherapy, due to its high immunogenic potential, low toxicity and short duration of the treatment, is apparently an attractive partner for immunotherapy in patients with metastatic disease.Conclusion. In view of the variety of the immunological effects of radiotherapy, further studies of the effect of radiation therapy on the immune system of cancer patients are needed, and the use of various combinations of immunotherapy and radiation therapy should be continued. All this, ultimately, will help improve the survival rates of cancer patients.

S2401 Hidden Immune Complexes: A Rare Case of Renal Failure Secondary to Hepatitis C Following Sustained Virologic Response

INTRODUCTION: Patients with cleared Hep C may still experience extrahepatic immunologic phenomena. CASE DESCRIPTION/METHODS: A 63 year-old woman with hepatitis C cirrhosis presented with a 20-pound weight gain and edema refractory to diuretics. She had been treated with sofosbuvir and ribavirin in 2013 with sustained virologic response (SVR) and was listed for liver transplant. She was hemodynamically stable and had 4+ pitting lower extremity edema. There was no jugular venous distention, crackles, or ascites. Labs showed sodium of 122 and creatinine of 1.43 compared to 137 and 0.61 three months prior, respectively, low complement levels and antinuclear antibody titer 1:320. Urine studies noted 6 gm of protein with protein/creatinine ratio of 6.3, 11–25 RBC, sodium 11, and osmolality 188. She was treated aggressively with diuretics with improvement of hyponatremia, but renal function worsened. She subsequently underwent a renal biopsy which revealed mesangial proliferation, foot process effacement, endocapillary proliferation, and immunofluorescence positive for C3, IgG, IgA, C1q, kappa, and lambda, all consistent with membranoproliferative glomerulonephritis (MPGN). Autoimmune causes including lupus, occult infections, dysproteinemias, and lymphoma were ruled out which raised the question of HCV as the etiology despite curative therapy. She underwent liver transplantation a week later and received mycophenolate and tacrolimus with marked improvement in renal function. DISCUSSION: MPGN is an uncommon cause of renal failure that can be complement- or mmune complex-mediated. The latter is most commonly associated with hepatitis C virus (HCV), although it can also be seen with hepatitis B. Our patient did not have any etiologies of secondary MPGN other than chronic HCV treated remotely. Given SVR, HCV was not initially thought to be a contributing factor. However, one previous study confirmed the presence of HCV-antigen-specific immune complexes without virions in 56.6% of patients involved who had spontaneous or treatment-induced clearance of HCV. Furthermore, another study demonstrated persistent HCV-associated cryoglobulinemic glomerulonephritis in those who achieved SVR with direct-acting antiviral therapy and postulated this may be due to residual rheumatoid factor-producing B-cell clones. This suggests that despite resolution of HCV and absence of ongoing viral replication, the accompanying immunologic phenomena may persist. Therefore, treated HCV should not be dismissed as potential cause of MPGN.

Significance of Anti-Nuclear Antibodies and Cryoglobulins in Patients with Acute and Chronic HEV Infection.

Background: Hepatitis E virus (HEV) has been associated with immunological phenomena. Their clinical significance, however, still needs to be clarified, that is, whether cryoglobulins or autoantibodies impact overt disease in HEV-infected individuals. To better understand, we analyzed these different immune phenomena in three cohorts, each representing different types of HEV infection. Methods: The cohorts included: (i) immunocompetent patients with acute hepatitis E, (ii) immunosuppressed patients with chronic hepatitis E, and (iii) individuals with asymptomatic HEV infection. Together, they consisted of 57 individuals and were studied retrospectively for the presence of anti-nuclear antibodies (ANAs), cryoglobulins, and serum total IgG. They were then compared with a control cohort of 17 untreated patients with chronic hepatitis B virus (HBV) infection or hepatitis C virus (HCV) infection. Results: Thirteen (23%) were immunocompetent patients with acute hepatitis E (median alanine aminotransferase (ALT) = 872 U/L), 15 (26%) were immunosuppressed patients with chronic hepatitis E (median ALT = 137 U/L), and 29 (51%) were blood donors with asymptomatic HEV infection (median ALT = 35 U/L). Overall, 24% tested positive for elevated ANA titers of >1:160, and 11% presented with a specific ANA pattern. ANA detection was not associated with the type of HEV infection, IgG levels, sex, or age. All individuals tested negative for anti-mitochondrial antibodies, anti-neutrophil cytoplasmic antibodies, liver-kidney microsomal antibodies, anti-myeloperoxidase-, and anti-proteinase-3 antibodies. Five patients (9%) tested positive for cryoglobulins. Notably, cryoglobulinemia was present in overt hepatitis E (Groups (i) and (ii); one acute and four chronic HEV infections), but was not present in any of the asymptomatic blood donors (p = 0.02). The frequency of cryoglobulins and elevated ANAs did not differ significantly between HEV and HBV/HCV patients. Conclusion: In line with findings on HBV and HCV infections, we frequently observed detection of ANAs (24%) and cryoglobulins (9%) in association with HEV infections. The presence of cryoglobulins was limited to patients with overt hepatitis E. We add to the findings on the immune phenomena of hepatitis E.