Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers

Background: 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 CTLA4 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.Methods: Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 CTLA4 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled.Results: Among the 184 CTLA4 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 CTLA4 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.Conclusion: 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 CTLA4 mutation carriers

Pro-apoptotic therapies for the treatment of Mycobacterium tuberculosis infection

© 2017 Dr. Samar OjaimiOne third of the world’s population is infected with Mycobacterium tuberculosis (Mtb). Tuberculosis (TB) has killed more than 1 billion people over the past two hundred years, surpassing mortality caused by all other pandemics and epidemics combined. Despite a concerted global effort to reduce transmission, Mtb infects an estimated 10.4 million people and kills 1.4 million people each year. Managing this condition is becoming increasingly challenging because Mtb is fast becoming resistant to all first line antibiotic therapies. Novel interventions beyond iterations on antibiotics are required. Understanding host-Mtb interactions, with a view to targeting host signalling pathways that the organism is reliant upon, is a tenable approach to combatting this deadly disease. Host cells are intolerant of intracellular organisms and consequently Mtb must prevent a cell from dying so that it has time to propagate and disseminate. Exactly how it does so is controversial and poorly understood. In my work, I sought to understand the role of apoptosis in Mtb disease pathogenesis. I dissected the role of the extrinsic apoptotic pathway and associated key molecular components including inhibitor of apoptosis (IAP) proteins. I also examined the role of the intrinsic apoptotic pathway and associated Bcl-2 family of proteins. I found that Mtb infected mouse and human macrophages showed major aberrations in the protein expression levels of IAP and Bcl-2 family molecules such that the stoichiometry of these proteins strongly favoured cell survival. I infected mice that were deficient in the three major mammalian IAPs (cIAP1, cIAP2 andXIAP) and found that in the absence of cIAP1, and to a lesser extent cIAP2, Mtb infected macrophages died and disease pathogenesis was strikingly altered. I then sought to reprogram the extrinsic apoptotic pathway to promote death of Mtb infected cells by using a clinical stage drug inhibitor of cIAPs. I was able to optimise a dosing regimen of the cIAP antagonist, birinapant, that proved efficacious in killing Mtb infected macrophages and in reducing bacterial loads in various strains of mice and in mice engrafted with a human immune system. An examination of the intrinsic cell death pathway also proved very interesting. Again, I used a combination of gene-targeted mice and clinical stage drugs to antagonise the function of several Bcl-2 family pro-survival proteins. Interfering with Bcl-xL function had no effect on Mtb disease pathogenesis whilst antagonising the function of Bcl-2 made the disease worse. Notably, as little as a 50% reduction in Mcl-1 function, examined using Mcl-1+/- mice, produced an improvement in Mtb infection outcomes. Given the success in defining targetable host cell pathways involved in TB pathogenesis, I next investigated if these insights were applicable to latent Mtb infection. A large proportion of people infected with Mtb may not progress to overt disease but remain latently infected and can reactivate disease under certain circumstances. There are well defined indications for treating some people who are latently infected. Treatment of latent infection suffers from the same shortcomings as treatment of active disease. I found that birinapant could be optimised to also impact on latent infection. The significance of my work includes providing valuable insights into how apoptosis plays a critical role in determining Mtb infection and disease outcomes. I believe that my work, for the first time, has identified the key molecular components that regulate cell survival / apoptosis signalling during Mtb infection. The importance and implications of these findings are underscored by my preclinical studies showing that these host cell molecules and pathways can be targeted using clinical stage drugs to promote clearance of Mtb infection and disease

Is Receptor-Interacting Protein Kinase 3 a Viable Therapeutic Target for Mycobacterium tuberculosis Infection?

The dwindling list of antimicrobial agents exhibiting broad efficacy against clinical strains of Mycobacterium tuberculosis (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 Ripk3 deletion, nor did this affect production of the pro-inflammatory cytokine IL-1β, both in vitro and in vivo. 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

Is Receptor-Interacting Protein Kinase 3 a Viable Therapeutic Target for Mycobacterium tuberculosis Infection?

The dwindling list of antimicrobial agents exhibiting broad efficacy against clinical strains of Mycobacterium tuberculosis (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 Ripk3 deletion, nor did this affect production of the pro-inflammatory cytokine IL-1β, both in vitro and in vivo. 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

Impact of a spleen registry on optimal post-splenectomy vaccination and care

Objective: To evaluate quality of patient knowledge and rates of adherence to guidelines amongst splenectomised patients registered to the Spleen Australia registry. Method: Registrants recruited for assessment of residual splenic function post-splenectomy also underwent an assessment of quality of knowledge and a review of their long-term management. Eligible patients were ≥ 18 years of age, registered to the Spleen Australia clinical registry and had been splenectomised at least 1 year prior to their visit. Quality of knowledge was assessed using a validated questionnaire used in similar studies. Receipt of immunisations was validated by record review. Chemoprophylaxis use was self-reported by patients. Adherence was evaluated using Australian guidelines. Results: 77 patients were evaluated for education and adherence. 58% were female, mean age was 58 years, and median duration since splenectomy was 14 years. Most common indications for splenectomy were trauma and haematological conditions. 77% had good knowledge of key educational points to reduce chances of infection. Adherence to immunisations varied with poor adherence to vaccines introduced after 2010. Only 6 patients were adherent to all recommended immunisations. Increasing duration since registration was associated with poorer 13vPCV (p = 0.008) and 4vMenCV adherence (p = 0.001). Over 70% either currently or had previously used daily chemoprophylaxis and 66% had a supply of emergency antibiotics. Conclusions: Although registrants are receiving initial and booster vaccinations, they do not receive newly recommended vaccines. In order to maintain long-term adherence, we recommend streamlining health information systems, improving awareness strategies and improving financial access to vaccinations in the community with additional awareness of the activities of the registry

Vitamin D deficiency impacts on expression of toll-like receptor-2 and cytokine profile: a pilot study

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 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

presentation_1_Is Receptor-Interacting Protein Kinase 3 a Viable Therapeutic Target for Mycobacterium tuberculosis Infection?.PDF

<p>The dwindling list of antimicrobial agents exhibiting broad efficacy against clinical strains of Mycobacterium tuberculosis (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 Ripk3 deletion, nor did this affect production of the pro-inflammatory cytokine IL-1β, both in vitro and in vivo. 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.</p

Vancomycin-associated drug reaction with eosinophilia and systemic symptoms syndrome

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but potentially life-threatening multi-system disorder characterised by the delayed onset of fever, rash and internal organ involvement following the administration of a drug. We report three definite cases of vancomycin-associated DRESS syndrome occurring and review the literature regarding this syndrome