Margaret Conacher

Interleukin‐18 plays a role in both the alum‐induced T helper 2 response and the T helper 1 response induced by alum‐adsorbed interleukin‐12

Previous studies have shown that the antigen‐specific T helper 2 (Th2) response induced by alum adjuvants is interleukin (IL)‐4 independent. As a role for IL‐18 in Th2 induction has recently been described, in addition to its role in enhancing Th1 responses, we have studied the Th2 response induced by ovalbumin (OVA) adsorbed to alum in wild‐type and IL‐18‐deficient mice. Our results indicate that while endogenous IL‐18 facilitates alum‐induced IL‐4 production, OVA‐specific immunoglobulin G1 (IgG1) and IgE production remain unaffected. Furthermore, antigen‐specific Th1 responses induced with alum/IL‐12‐adsorbed OVA were demonstrated to be highly IL‐18 dependent. Despite these observations, injection of BALB/c mice with exogenous IL‐18 adsorbed to alum/OVA did not alter IL‐4 or interferon‐γ production by T cells and had little effect on the relative production of IgG1/IgG2a antibody subclasses compared with alum/OVA inoculated mice. However, the previously described synergism between IL‐12 and IL‐18 in Th1 induction was evident as the Th1‐promoting activity of alum/IL‐12 against adsorbed OVA was greatly augmented by the coadministration of IL‐18. These results indicate that while alum‐induced IL‐18 can facilitate Th2 induction, the addition of exogenous IL‐18 cannot further enhance the alum‐induced Th2 response.

A Novel Dendritic Cell-Induced Model of Erosive Inflammatory Arthritis: Distinct Roles for Dendritic Cells in T Cell Activation and Induction of Local Inflammation

Transferring collagen-pulsed, bone marrow-derived dendritic cells (DCs) into congenic DBA/1 recipient mice produced arthritis in joints adjacent to the site of DC transfer and could be inhibited by treatment with TNF antagonists. Disease was Ag specific, as transfer of control, unpulsed DCs, or DCs pulsed with OVA did not produce arthritis. In contrast to other experimental arthritis models, DC-induced arthritis localized to the site of injection and did not spontaneously generalize to uninvolved joints, despite the demonstration of circulating collagen-reactive T cells. Similarly, transfer of T cells primed by collagen/DCs was not sufficient to produce arthritis in recipient mice. In collagen/DC-primed mice however, disease could be induced in uninvolved joints by local administration of noncollagen-pulsed DCs and this could be reduced through TNF inhibition. Similarly, injection of collagen/DC-primed mice with low-dose TNF also resulted in local induction of arthritis, as did administration of TNF to mice receiving T cells from collagen/DC but not OVA/DC-primed mice. Thus, we have demonstrated for the first time that administration of collagen-pulsed mature DCs is sufficient for the induction of arthritis. Furthermore, this disease process is mediated through both adaptive and innate effects of DCs; first, priming of autoreactive T cells and, second, induction of local inflammation via mediators such as TNF.

Oral immunisation with peptide and protein antigens by formulation in lipid vesicles incorporating bile salts (bilosomes).

The ability of non-ionic surfactant vesicles to induce systemic immune responses in mice following oral immunisation was studied using a standard antigen (bovine serum albumin), a synthetic measles peptide and an influenza sub-unit vaccine. The effectiveness of this formulation was significantly increased by incorporating bile salts (in particular deoxycholate) into the formulation. We have named the resulting vesicles bilosomes. We found that the most effective immunisation protocol was to give two doses of vaccine three days apart and then repeat this protocol two weeks later. Following this method, preparation of measles peptide in bilosomes produced a specific cell mediated response, as measured by splenocyte proliferation and IL-2 production. Of particular significance, these studies demonstrate that oral administration of bilosomes incorporating the influenza sub-unit vaccine could induce as potent an antibody response as the parenterally administered vaccine containing the same quantity of antigen. In addition, the Th1/Th2 balance, as measured by antibody subclasses, was similar whether animals were immunised by the oral or the parenteral vaccine route. As bilosomes are prepared from naturally occurring lipids and have no apparent toxicity associated with their use, they represent a useful modification of conventional lipid vesicle based systems for the oral delivery of proteins and peptides.

A study of risk factors for acquisition of Epstein‐Barr virus and its subtypes

BACKGROUND Risk factors for primary infection with Epstein-Barr virus (EBV) and its subtypes have not been fully investigated. METHODS Questionnaires and serum samples from a total of 2006 students who entered Edinburgh University in 1999-2000 were analyzed to examine risk factors for EBV seropositivity, both overall and by EBV type. RESULTS The prevalence of EBV seropositivity was significantly increased among females, older students, those who had lived in tropical countries, those with siblings, and those who were sexually active, particularly if they had had numerous sex partners. Risk was lower (1) among students who always used a condom than among those who had sexual intercourse without one and (2) among female oral-contraceptive users than among sexually active nonusers. Risk factors for type 1 EBV infection were similar to those for EBV overall. No associations were found between nonsexual risk factors and type 2 infection. Sexual activity increased the risk of type 2 infection, but the increase in risk with number of sex partners was less consistent than for type 1 infections. Dual infection was uncommon, but the patterns of risk appeared to be similar to those of type 1 infection. CONCLUSION This study provides further evidence that EBV may be sexually transmitted and some suggestion that the risk factors for type 1 and type 2 infection differ.

Epstein-Barr Virus Can Establish Infection in the Absence of a Classical Memory B-Cell Population

ABSTRACT Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that persists in the body for life after primary infection. The primary site of EBV persistence is the memory B lymphocyte, but whether the virus initially infects naïve or memory B cells is still disputed. We have analyzed EBV infection in nine cases of X-linked hyper-immunoglobulin M (hyper-IgM) syndrome who, due to a mutation in CD40 ligand gene, do not have a classical, class-switched memory B-cell population (IgD− CD27+). We found evidence of EBV infection in 67% of cases, which is similar to the infection rate found in the general United Kingdom population (60 to 70% for the relevant age range). We detected EBV DNA in peripheral blood B cells and showed in one case that the infection was restricted to the small population of nonclassical, germinal center-independent memory B cells (IgD+ CD27+). Detection of EBV small RNAs, latent membrane protein 2, and EBV nuclear antigen 3C expression in peripheral blood suggests full latent viral gene expression in this population. Analysis of EBV DNA in serial samples showed variability over time, suggesting cycles of infection and loss. Our results demonstrate that short-term EBV persistence can occur in the absence of a germinal center reaction and a classical memory B-cell population.

Role of the HLA System in the Association Between Multiple Sclerosis and Infectious Mononucleosis

OBJECTIVE To determine whether multiple sclerosis (MS) and infectious mononucleosis (IM) share common HLA associations. DESIGN A prospective cohort study was conducted from October 1, 1999, through September 30, 2003. SETTING University of Edinburgh Richard Verney Health Centre, Edinburgh, Scotland. PATIENTS Participants included 179 individuals who underwent asymptomatic Epstein-Barr virus seroconversion and 175 patients who developed IM. INTERVENTION Genotyping for 5 classical HLA loci (HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1). MAIN OUTCOME MEASURE Diagnosis of IM and allele frequency. RESULTS Allelic analysis showed that HLA-DRB1*01:01 was significantly associated with the development of IM (odds ratio, 3.2; P < .001). Patients with IM and HLA-DRB1*01:01 had a lower Epstein-Barr virus viral load compared with those without the allele (median, 783 vs 7366 copies/10(6) peripheral blood mononuclear cells; P = .03). CONCLUSION HLA-DRB1*01:01 is protective against developing MS; thus, a common genetic basis between IM and MS is not supported.