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We have shown that cellular inhibitor of apoptosis proteins (cIAPs) impair clearance of hepatitis B virus (HBV) infection by preventing TNF-mediated killing/death of infected cells. A key question, with profound therapeutic implications, is whether this finding can be translated to the development of drugs that promote elimination of infected cells. Drug inhibitors of cIAPs were developed as cancer therapeutics to promote TNF-mediated tumor killing. These drugs are also known as Smac mimetics, because they mimic the action of the endogenous protein Smac/Diablo that antagonizes cIAP function. Here, we show using an immunocompetent mouse model of chronic HBV infection that birinapant and other Smac mimetics are able to rapidly reduce serum HBV DNA and serum HBV surface antigen, and they promote the elimination of hepatocytes containing HBV core antigen. The efficacy of Smac mimetics in treating HBV infection is dependent on their chemistry, host CD4⁺ T cells, and TNF. Birinapant enhances the ability of entecavir, an antiviral nucleoside analog, to reduce viral DNA production in HBV-infected animals. These results indicate that birinapant and other Smac mimetics may have efficacy in treating HBV infection and perhaps, other intracellular infections.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown. Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled. Among the 184 mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated. Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected mutation carriers.

Predominantly antibody deficiency (PAD) is the most prevalent form of primary immunodeficiency, and is characterized by broad clinical, immunological and genetic heterogeneity. Utilizing the current gold standard of whole exome sequencing for diagnosis, pathogenic gene variants are only identified in less than 20% of patients. While elucidation of the causal genes underlying PAD has provided many insights into the cellular and molecular mechanisms underpinning disease pathogenesis, many other genes may remain as yet undefined to enable definitive diagnosis, prognostic monitoring and targeted therapy of patients. Considering that many patients display a relatively late onset of disease presentation in their 2nd or 3rd decade of life, it is questionable whether a single genetic lesion underlies disease in all patients. Potentially, combined effects of other gene variants and/or non-genetic factors, including specific infections can drive disease presentation. In this review, we define (1) the clinical and immunological variability of PAD, (2) consider how genetic defects identified in PAD have given insight into B-cell immunobiology, (3) address recent technological advances in genomics and the challenges associated with identifying causal variants, and (4) discuss how functional validation of variants of unknown significance could potentially be translated into increased diagnostic rates, improved prognostic monitoring and personalized medicine for PAD patients. A multidisciplinary approach will be the key to curtailing the early mortality and high morbidity rates in this immune disorder.

Significance Hepatitis B virus (HBV) causes substantial morbidity and mortality. A large proportion of infected individuals controls infection but does not completely eradicate HBV DNA from the liver, and flares in hepatitis can be precipitated by immunosuppression. A proportion of individuals never controls infection, and these people are at substantial risk of developing liver failure and liver cancer. Current therapies are not effective at eliminating virus, and there is a major interest in developing functional cures for HBV infection. We identified host cell signaling molecules that can restrict the ability to eradicate infected cells. These molecules can be therapeutically targeted, and drugs that interfere with the function of these host cell proteins may be useful therapies to promote clearance of HBV infection. Hepatitis B virus (HBV) infection can result in a spectrum of outcomes from immune-mediated control to disease progression, cirrhosis, and liver cancer. The host molecular pathways that influence and contribute to these outcomes need to be defined. Using an immunocompetent mouse model of chronic HBV infection, we identified some of the host cellular and molecular factors that impact on infection outcomes. Here, we show that cellular inhibitor of apoptosis proteins (cIAPs) attenuate TNF signaling during hepatitis B infection, and they restrict the death of infected hepatocytes, thus allowing viral persistence. Animals with a liver-specific cIAP1 and total cIAP2 deficiency efficiently control HBV infection compared with WT mice. This phenotype was partly recapitulated in mice that were deficient in cIAP2 alone. These results indicate that antagonizing the function of cIAPs may promote the clearance of HBV infection.

Recurrent respiratory papillomatosis (RRP) commonly affects the upper airways, and lung parenchymal involvement is extremely rare. We present a case of adult‐onset laryngotracheal RRP with lung parenchymal involvement that progressed despite systemic bevacizumab and ultimately required a left lower lobectomy. Histological features were characteristic of a squamous papilloma. Unusually, parenchymal involvement was present, with solid intra‐alveolar nests cradled by preserved alveolar septa. Cytologic atypia and keratinisation were present; however, the absence of stromal desmoplasia and invasion precluded a diagnosis of squamous cell carcinoma and made overall classification challenging in this case. This case highlights the complexity of managing RRP with pulmonary involvement, particularly when disease progression persists despite systemic therapy such as systemic bevacizumab. Recurrent respiratory papillomatosis (RRP) commonly affects the upper airways, and lung parenchymal involvement is extremely rare. We present a case of adult‐onset laryngotracheal RRP with confirmed distal dissemination that progressed despite systemic bevacizumab, ultimately requiring surgical resection. This case highlights the complexity of managing RRP with pulmonary involvement, particularly when disease progression persists despite systemic therapy with limited efficacious options, highlighting the need for more robust clinical trials.

Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the cohort. Our data are largely consistent with the experience of other centers internationally, with clear areas for improvement, including reducing diagnostic delay for patients with PADs. It is likely that these challenges will be in part overcome by continued advances in implementation of genomic sequencing for diagnosis of PADs, and with that opportunities for targeted treatment of non-infectious complications.

The dwindling list of antimicrobial agents exhibiting broad efficacy against clinical strains of (Mtb) has forced the medical community to redefine current approaches to the treatment of tuberculosis (TB). Host receptor-interacting protein kinase 3 (RIPK3) has been flagged recently as a potential target, given that it is believed to regulate necroptosis-independent signaling pathways, which have been implicated in exacerbating several inflammatory conditions and which reportedly play a role in the necrosis of Mtb-infected macrophages. To examine the therapeutic potential of inhibiting RIPK3, we infected RIPK3-deficient mice with aerosolized Mtb. We found that the loss of RIPK3 did not alter overall disease outcomes, with deficient animals harboring similar bacterial numbers in the lungs and spleens compared to their wild-type counterparts. Mtb-infected macrophages were not rescued from dying by deletion, nor did this affect production of the pro-inflammatory cytokine IL-1β, both and . Infiltration of immune cells into the lungs, as well as the activation of adaptive immunity, similarly was not overtly affected by the loss of RIPK3 signaling. Collectively, our data argue against a role of RIPK3 in mediating pathological inflammation or macrophage necrosis during Mtb disease pathogenesis and thus suggest that this host protein is unlikely to be an attractive therapeutic target for TB.

Background Vitamin D is believed to play an important role outside the endocrine system in the regulation of the immune system, and in cellular proliferation and differentiation. The aim of the study was to investigate the impact of vitamin D levels on innate immunity. Methods Participants for this prospective, longitudinal study were recruited amongst otherwise healthy staff of a large hospital in Victoria, Australia. Those fulfilling the inclusion criteria, including a vitamin D level of <50 nmol/L, were supplemented. Using flow cytometry, expression of the innate immune receptors TLR2, TLR4 and CD86 was measured on peripheral blood mononuclear cells (PBMCs) collected prior to vitamin D treatment and then at 1 and 3 months. Additonally, PBMCs at each timepoint were stimulated with specific TLR ligands and resultant supernatants were assayed for the cytokines TNFα, IL-6, IFN-α and IP-10. Results In participants whose vitamin D level was >100 nmol/L post supplementation (n=11), TLR2 expression on PBMCs increased significantly, with no change noted in TLR4 or CD86 expression. Stimulation of vitamin D deficient samples with TLR ligands produced a number of proinflammatory cytokines, which were significantly reduced upon vitamin D normalisation. In patients whose levels returned to a deficient level at 3 months despite ongoing low-level supplementation, an increase in the pro-inflamamtory state returned. This suggests that vitamin D may play an important role in ensuring an appropriate baseline pro-inflammatory state. Conclusions This ex-vivo pilot study adds clinical evidence supporting a possibly important role for vitamin D in innate immunity. If confirmed, this unique clinical study has potentially significant implications for the treatment of a variety of inflammatory conditions, where achieving optimal vitamin D levels may help reduce inflammation.

Background Annual influenza vaccination is recommended to all individuals over 6 months of age, including predominantly antibody deficiency (PAD) patients. Vaccination responses are typically evaluated by serology, and because PAD patients are by definition impaired in generating IgG and receive immunoglobulin replacement therapy (IgRT), it remains unclear whether they can mount an antigen‐specific response. Objective To quantify and characterise the antigen‐specific memory B (Bmem) cell compartment in healthy controls and PAD patients following an influenza booster vaccination. Methods Recombinant hemagglutinin (HA) from the A/Michigan/2015 H1N1 (AM15) strain with an AviTag was generated in a mammalian cell line, and following targeted biotinylation, was tetramerised with BUV395 or BUV737 streptavidin conjugates. Multicolour flow cytometry was applied on blood samples before and 28 days after booster influenza vaccination in 16 healthy controls and five PAD patients with circulating Bmem cells. Results Recombinant HA tetramers were specifically recognised by 0.5–1% of B cells in previously vaccinated healthy adults. HA‐specific Bmem cell numbers were significantly increased following booster vaccination and predominantly expressed IgG1. Similarly, PAD patients carried HA‐specific Bmem cells, predominantly expressing IgG1. However, these numbers were lower than in controls and did not increase following booster vaccination. Conclusion We have successfully identified AM15‐specific Bmem cells in healthy controls and PAD patients. The presence of antigen‐specific Bmem cells could offer an additional diagnostic tool to aid in the clinical diagnosis of PAD. Furthermore, alterations in the number or immunophenotype of HA‐specific Bmem cells post‐booster vaccination could assist in the evaluation of immune responses in individuals receiving IgRT. We here developed an extensive flowcytometry panel to examine influenza‐specific memory B cells using fluorescently labeled recombinant haemagglutinin (HA) tetramers. Influenza‐specific memory B cells were predominantly IgG1+, and these were increased following booster vaccination in healthy controls, but not in patients with predominantly antibody deficiency.

Background Daclizumab is a humanized monoclonal antibody that blocks CD25, the high affinity alpha subunit of the interleukin-2 receptor. Daclizumab therapy targets T regulatory cell and activated effector T cell proliferation to suppress autoimmune disease activity, in inflammatory conditions like relapsing and remitting multiple sclerosis. Here, we present the first report of agranulocytosis with daclizumab therapy in a patient with relapsing and remitting multiple sclerosis. Case presentation Our patient was a 24-year-old Australian female with a clinical history of atopy, lymphocytic enteritis complicated by B12 deficiency, relapsing and remitting multiple sclerosis, recurrent lower respiratory tract infections, vulval/cervical intraepithelial neoplasia and melanoma. She was commenced on daclizumab therapy after failing several lines of treatment for relapsing and remitting multiple sclerosis. During a hospital admission for lymphocytic enteritis, she was incidentally diagnosed with combined immunodeficiency with hypogammaglobulinaemia and declined proposed regular intravenous immunoglobulin infusions. Following six months of daclizumab therapy, our patient presented to hospital with febrile neutropenia. No clear infective cause was found, despite numerous investigations. However, bone marrow biopsy revealed agranulocytosis with an apparent maturation block at the myeloblasts stage. Neustrophil recovery occurred following cessation of daclizumab and the initiation of T cell immunosuppressive agents including systemic corticosteroids and methotrexate. The patient was further investigated for combined immunodeficiency and whole exome sequencing revealed a novel heterozygous missense variant in cytotoxic T lymphocyte antigen 4 ( CTLA4 ), leading to a diagnosis of CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI). Conclusion This case demonstrates that autoimmune disease may be the presenting feature of primary immunodeficiency and should be appropriately investigated prior to the commencement of immunotherapy. Genetic clarification of underlying primary immunodeficiency may provide critical clinical information that alters the safety of the proposed treatment strategy.