A study of MHC class I binding viral and host derived peptides and natural killer cell function

Natural killer (NK) cells are a key component of innate immunity and have been implicated in determining the outcome of HCV infection in both genetic and functional studies. The last two decades have seen significant advances in the understanding of NK cell regulation with the discovery of a multitude of activating and inhibitory receptors. CD94:NKG2A operates in tandem with the polymorphic killer cell immunoglobulin-like receptors (KIR) and Ly49 systems to inhibit NK cells, however it is not clear as to the benefits of having two distinct inhibitory receptor:ligand systems. Down regulation or modification of MHC class I expression is a key feature of NK cell recognition of virus infected cells. However, viruses can subvert this mechanism of NK cell surveillance by encoding peptides that can bind to MHC class I. The aim of this thesis is to further our understanding of the interaction between viral and host derived MHC class I binding peptides and their effect on NK cell inhibition. By using an MHC deficient cell line, we have shown that HCV core35-44 peptide is capable of enhancing cell surface expression of MHC class I (HLA-C and HLA-E). Although this peptide stabilises HLA-E, the HLA-E:HCV core35-44 complex alone is insufficient to inhibit at NKG2A positive NK cells. However, in the presence of HLA-E binding MHC class I signal peptides, HCV core35-44 has a synergistic effect in suppressing the NKG2A+ NK cell population. Peptides derived from other viruses such as EBV and HIV, and the stress related peptide derived from heat shock protein 60 also augment inhibition of NKG2A+ NK cells, but only when in the presence of MHC class I signal peptides. This augmentation is caused by recruitment of the non-signalling CD94 molecule to the immune synapse in the absence of its inhibitory signalling partner NKG2A. Thus CD94 can function independently as an enhancer of inhibition. The augmentation of inhibition of CD94:NKG2A by non-inhibitory peptides, contrasts with antagonism of inhibition of KIR by low affinity peptide:MHC complexes. We also show that KIR+ and NKG2A+ NK cells respond with differing stoichiometries to MHC class I down-regulation. Thus peptide selectivity and MHC class I sensitivity of natural killer cell receptors provides a rationale for the evolution of two distinct inhibitory systems for MHC class I.Open Acces

Report: Fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn’s disease

Abstract We present the case of a 28 year old lady with refractory Crohn's Disease treated with infliximab throughout her pregnancy. Her baby was born healthy and received a Bacillus Calmette-Guérin (BCG) vaccine aged 3 months. Soon after this the infant became unwell and died aged 4.5 months. At post-mortem the cause of death was attributed to an unusual complication of the BCG vaccine, known as disseminated BCG. BCG vaccination is contraindicated in individuals who are receiving immunosuppressive drugs. We recommend physicians should exercise caution before such vaccines are used in infants born to mothers taking anti-TNF therapies or other potentially immunosuppressive IgG1 antibodies. © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. Case report This case is of a 28 year old Caucasian lady diagnosed with pan-colitis and erythema nodosum secondary to Crohn's Disease (CD) in 2001. She was treated early on with mesalazine and azathioprine at a dose of 2 mg per kg bodyweight but experienced recurrent flare-ups requiring repeated courses of prednisolone with eventual loss of response. In 2004, infliximab 5 mg/kg was commenced with initial good symptomatic benefit but subsequent loss of response. Therefore, in 2006 the dose of infliximab was increased to 10 mg/kg every eight weeks. In 2008 she became pregnant. The pros and cons of continuing infliximab were discussed at length with the patient. Due the severity and corticosteroid refractory nature of her CD, the benefits of maintaining remission with infliximab was felt to outweigh the risks of foetus exposure to the drug. She consented to continue eightweekly infusions of infliximab 10 mg/kg as monotherapy for CD. Her disease remained in remission during pregnancy and in July 2008 she gave birth to a healthy baby boy. The baby was born at 36 + 3 gestation via spontaneous vaginal deliver

Natural killer cells and hepatitis C: action and reaction

In 1989, hepatitis C virus (HCV) was first identified as the infectious agent responsible for human non-A, non-B hepatitis. Two decades later, HCV remains a global public health problem with a suboptimal response rate to treatment and the absence of a protective vaccine. Recent work has highlighted the influence of the innate immune system, and in particular natural killer cells, on the outcome and pathology of HCV infection. These cells are considerably more complex than was originally thought and their role in viral infections is currently being unravelled. This review summarises our emerging understanding of natural killer cells in HCV infection

Natural killer cells: integrating diversity with function

The key role of natural killer cells in many aspects of the immune response is now being recognized. The last decade has seen an exponential increase in our understanding of the workings of these cells. Receptor diversity is crucial in allowing natural killer cells to respond effectively to a variety of different pathogens. This article reviews aspects of natural killer cell diversity that combine to generate populations of functional natural killer cells that exist within both the individual and throughout the population at large

NK receptors: it's all in the name

We read with interest the paper by Muhanna et al on natural killer cells, their role in ameliorating liver fibrosis and in particular the role of inhibitory receptors for major histocompatibility complex (MHC) class I.1 We would like to clarify the often confusing terminology of inhibitory receptors for natural killer cells

Recurrent Campylobacter jejuni Infection in an Immunodeficient Patient Treated with Repeated Faecal Microbiota Transplant (FMT)—A Case Report

There is limited evidence to guide successful treatment of recurrent Campylobacter infection in patients with common variable immunodeficiency (CVID) already managed on regular immunoglobulin therapy. The role of faecal microbiota transplant (FMT) is uncertain. We report a case of recurrent Campylobacter jejuni infection in a patient with CVID treated with repeated FMT with 18 months of symptom resolution prior to relapse