Immune Phenomena in Myeloid Neoplasms: An “Egg or Chicken” Question

Immune phenomena are increasingly reported in myeloid neoplasms, and include autoimmune cytopenias/diseases and immunodeficiency, either preceding or complicating acute myeloid leukemia, myelodysplastic syndromes (MDS), chronic myeloproliferative neoplasms, and bone marrow failure (BMF) syndromes. Autoimmunity and immunodeficiency are the two faces of a dysregulated immune tolerance and surveillance and may result, along with contributing environmental and genetic factors, in an increased incidence of both tumors and infections. The latter may fuel both autoimmunity and immune activation, triggering a vicious circle among infections, tumors and autoimmune phenomena. Additionally, alterations of the microbiota and of mesenchymal stem cells (MSCs) pinpoint to the importance of a permissive or hostile microenvironment for tumor growth. Finally, several therapies of myeloid neoplasms are aimed at increasing host immunity against the tumor, but at the price of increased autoimmune phenomena. In this review we will examine the epidemiological association of myeloid neoplasms with autoimmune diseases and immunodeficiencies, and the pivotal role of autoimmunity in the pathogenesis of MDS and BMF syndromes, including the paroxysmal nocturnal hemoglobinuria conundrum. Furthermore, we will briefly examine autoimmune complications following therapy of myeloid neoplasms, as well as the role of MSCs and microbiota in these settings.

Immune-Related Hub Genes and the Competitive Endogenous RNA Network in Alzheimer’s Disease

Background: The pathogenesis of Alzheimer’s disease (AD) involves various immune-related phenomena; however, the mechanisms underlying these immune phenomena and the potential hub genes involved therein are unclear. An understanding of AD-related immune hub genes and regulatory mechanisms would help develop new immunotherapeutic targets. Objective: The aim of this study was to explore the hub genes and the mechanisms underlying the regulation of competitive endogenous RNA (ceRNA) in immune-related phenomena in AD pathogenesis. Methods: We used the GSE48350 data set from the Gene Expression Omnibus database and identified AD immune-related differentially expressed RNAs (DERNAs). We constructed protein–protein interaction (PPI) networks for differentially expressed mRNAs and determined the degree for screening hub genes. By determining Pearson’s correlation coefficient and using StarBase, DIANA-LncBase, and Human MicroRNA Disease Database (HMDD), the AD immune-related ceRNA network was generated. Furthermore, we assessed the upregulated and downregulated ceRNA subnetworks to identify key lncRNAs. Results: In total, 552 AD immune-related DERNAs were obtained. Twenty hub genes, including PIK3R1, B2M, HLA-DPB1, HLA-DQB1, PIK3CA, APP, CDC42, PPBP, C3AR1, HRAS, PTAFR, RAB37, FYN, PSMD1, ACTR10, HLA-E, ARRB2, GGH, ALDOA, and VAMP2 were identified on PPI network analysis. Furthermore, upon microRNAs (miRNAs) inhibition, we identified LINC00836 and DCTN1-AS1 as key lncRNAs regulating the aforementioned hub genes. Conclusion: AD-related immune hub genes include B2M, FYN, PIK3R1, and PIK3CA, and lncRNAs LINC00836 and DCTN1-AS1 potentially contribute to AD immune-related phenomena by regulating AD-related hub genes.

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.

The S1P–S1PR Axis in Neurological Disorders—Insights into Current and Future Therapeutic Perspectives

Sphingosine 1-phosphate (S1P), derived from membrane sphingolipids, is a pleiotropic bioactive lipid mediator capable of evoking complex immune phenomena. Studies have highlighted its importance regarding intracellular signaling cascades as well as membrane-bound S1P receptor (S1PR) engagement in various clinical conditions. In neurological disorders, the S1P–S1PR axis is acknowledged in neurodegenerative, neuroinflammatory, and cerebrovascular disorders. Modulators of S1P signaling have enabled an immense insight into fundamental pathological pathways, which were pivotal in identifying and improving the treatment of human diseases. However, its intricate molecular signaling pathways initiated upon receptor ligation are still poorly elucidated. In this review, the authors highlight the current evidence for S1P signaling in neurodegenerative and neuroinflammatory disorders as well as stroke and present an array of drugs targeting the S1P signaling pathway, which are being tested in clinical trials. Further insights on how the S1P–S1PR axis orchestrates disease initiation, progression, and recovery may hold a remarkable potential regarding therapeutic options in these neurological disorders.

Hepatitis-Associated Glomerulonephritis

Viral hepatitis can be associated with extrahepatic manifestations, including kidney injury, mainly glomerulonephritis (GN). The physiopathology of GN is of particular interest because some immune responses, triggered by viral infections, can harm the glomerulus, either via deposition of immune complexes, auto-immune phenomena, or through cytopathogenic effects. This chapter describes the epidemiology of hepatitis A-, B-, C-, and E-associated GN; the clinical and biological presentations; the histological patterns; and management regimens. Few cases of hepatitis A- or hepatitis E-associated GN have been reported. Cryoglobulinemic membranoproliferative glomerulonephritis is the most common type of GN diagnosed in patients infected by the hepatitis C virus. Patients infected by hepatitis B mainly develop membranous nephritis. Viral clearance using antiviral therapies, when available, is necessary to improve kidney outcomes.

The Integrated Immunological Signature of Refractory Cytopenia of Childhood (RCC)

Refractory cytopenia of childhood (RCC) is the most common subtype of childhood myelodysplastic syndrome (MDS). Clinical and laboratory evidence suggest a T-cell mediated pathophysiology in a subset of adult patients with low-grade MDS.Recently, it was shown that in RCC, indicators of an immune-mediated pathophysiology are frequently present. These indicators included the presence of minor paroxysmal nocturnal haemoglobinuria (PNH) clones and T cell receptor (TCR) β-chain variable (Vβ) domain (TCRVβ) skewing. In addition, aberrant immunophenotypes are frequently identified in RCC patients. It is however still unknown to what extend these immune phenomena concomitantly occur in low-grade MDS. Therefore, in the current study we integrated the presence of minor PNH clones, TCRVβ skewing and immunophenotypic aberrancies in a large international cohort of 72 RCC patients. Small PNH clones were present in 31 cases (43%), TCRVβ skewing in 30 cases (42%), and immunophenotypic aberrancies in 43 cases (60%). In only 9 patients (13%) all these three were present. Two parameters were present in 25 patients (35%), and 27 patients (38%) displayed only one parameter. In 11 patients (15%) none of the three characteristics was present. The most prominent parameter was the presence of an aberrant immunophenotype, which was associated with TCRVβ skewing (n=18) or the presence of PNH clones (n= 20) in a subset of the patients. Hypocellular RCC patients with a small PNH clone (>0.1%) were more likely to respond to IST than PNH negative patients (88% versus 40% of patients responded at six months, respectively, P=0.038). From the current study we could not predict the strongest predictable value of combined parameters, with respect to response on immunosuppressive therapy (IST) in RCC patients, as only 23 patients were treated with IST. We conclude that RCC patients frequently show immunological aberrancies, but that the presence of and combination with PNH and TCRVB skewing is rather heterogeneous. However, our study underscores the fact that in RCC, which might be challenging to diagnose based on morphology only due to hypoplasia, bone marrow immunophenotyping by flow cytometry, combined with either TCRVβ skewing or the presence of PNH clones, may be of important diagnostic value. Future studies in extended RCC series are required to build a prediction model for response to immunosuppressive therapy. Figure 1. Venn diagram depicting the overlap between flow cytometric aberrant immunophenotype, PNH clones and TCRVβ skewing in RCC. Figure 1. Venn diagram depicting the overlap between flow cytometric aberrant immunophenotype, PNH clones and TCRVβ skewing in RCC. Disclosures Langerak: Roche: Other: Lab services in the field of MRD diagnostics provided by Dept of Immunology, Erasmus MC (Rotterdam); In Vivo Scribe: Patents & Royalties: Licensing of IP and Patent on BIOMED-2-based methods for PCR-based Clonality Diagnostics. DAKO: Patents & Royalties: Licensing of IP and Patent on Split-Signal FISH. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL.

Acute Disseminated Encephalomyelitis following Seasonal Influenza Vaccination in an Elderly Patient

ABSTRACTAlthough such occurrences are rare, it should be recognized that certain vaccines might trigger serious neurological immune phenomena such as Guillain-Barre syndrome, seizures, cranial neuropathy, and acute disseminated encephalomyelitis (ADEM). Here we report on an elderly woman with ADEM following seasonal influenza vaccination who recovered after plasma exchange.