Biomedical subjects

Mark Peakman

Publications and source records attributed to Mark Peakman.

25 records · Page 2Linked to original sources

PubMed2003

Persistent infection of human microvascular endothelial cells by coxsackie B viruses induces increased expression of adhesion molecules.

Numerous studies indicate that enteroviruses, such as the Coxsackievirus (CV) group, are linked to autoimmune diseases. Virus tropism and tissue access are modulated by vascular endothelial cells (ECs), mainly at the level of the microvasculature. Data on the permissiveness of ECs to CV are, however, scanty and derived from studies on large vessel ECs. To examine the susceptibility of microvascular ECs to infection of group B CV (CVB), human dermal microvascular ECs (HMEC-1) were infected with three CVB strains, and the immunological phenotype of the infected cells was analyzed. All CVB persistently infected the EC cultures without producing overt cytopathic effects. Infected ECs retained endothelial characteristics. Release of infectious particles in cell supernatants persisted for up to 3 mo of culture. Infection up-regulated expression of the adhesion molecules ICAM-1 and VCAM-1, with the highest values detected during the first 30 days of infection (p < 0.05 vs uninfected HMEC-1). CVB infection increased production of the proinflammatory cytokines, IL-6, IL-8, and TNF-alpha, which may account for the enhanced expression of adhesion molecules. Parallel infection of macrovascular HUVEC had less evident effects on induction of ICAM-1 and did not significantly increase expression of VCAM-1. Moreover, mononuclear cell adhesion to CVB-infected HMEC-1 monolayers was increased, compared with uninfected monolayers. These results provide evidence that small vessel ECs can harbor a persistent viral infection, resulting in quantitative modification of adhesion molecule expression, which may contribute to the selective recruitment of subsets of leukocytes during inflammatory immune responses. Furthermore, our data confirm that the behavior against a viral challenge of ECs in large vessels and microvessels may differ.

Cell Adhesion↗

PubMed2003

A systematic review and critical evaluation of the immunology of chronic fatigue syndrome.

OBJECTIVE: Immune dysfunction in patients with chronic fatigue syndrome (CFS) has been widely but inconsistently reported. Traditional reviews of the literature have produced a variety of conclusions. We present the results of the first systematic review of the subject. METHODS: EMBASE, MEDLINE and PSYCHINFO databases were searched, and leading researchers in the field were contacted. Inclusion criteria were applied, and studies were then divided into groups based on the quality of their methodology. Study results were collated and described. RESULTS: Studies ranged widely in quality. There was an inverse association between study quality and finding low levels of natural killer cells, suggesting that the association may be related to study methodology. On the other hand, reports of abnormalities in T cells and cytokine levels were not related to study quality. CONCLUSIONS: The conclusions of this systematic review differ from a recent traditional narrative review of the immunology of CFS. No consistent pattern of immunological abnormalities is identified.

Cytokines↗

PubMed2003

Comparison of cytokine ELISpot assay formats for the detection of islet antigen autoreactive T cells. Report of the third immunology of diabetes society T-cell workshop.

The identification of sensitive assay formats capable of distinguishing islet autoreactive T cells directly ex vivo in blood is a major goal in type 1 diabetes research. Recently, much interest has been shown in the cytokine enzyme linked immunospot assay (CK ELISpot), an assay potentially capable of fulfilling these difficult criteria. To address the utility of this assay in detecting autoreactive T cells, a 'wet' workshop was organized using the same fresh blood sample and coded antigens. Five different laboratories participated, using three distinct CK ELISpot assay formats. Samples from two subjects were pre-tested for responses to sub-optimal concentrations of tetanus toxoid, representing a low frequency recall response, and peptides from diabetes associated autoantigens GAD65, IA-2 and HSP60. All participants measured interferon-gamma production and combinations of interleukins-4, -5, -10 and -13. In the workshop 4 of 5 laboratories detected low frequency recall responses in both subjects and 3 of 5 detected at least one of the autoreactive peptide responses concordant with pre-testing. Significant assay format related differences in sensitivity and signal-to-noise ratio were observed. The results demonstrate the potential for detection of low-level autoreactive T cell responses and identify assay characteristics that will be useful for studies in type 1 diabetes.

Adult↗

PubMed2003

Paraoxonase in Persian Gulf War veterans.

Serum paraoxonase (PON1) is responsible for the metabolism of organophosphates in serum, and PON1 activity is a major determinant of their toxicity in humans. There have been reports linking lowered PON1 activity to physical symptoms after deployment to the Persian Gulf War (PGW) of 1990 to 1991. Therefore, the object of this study was to determine (1) whether PON1 activity was decreased among symptomatic PGW veterans compared with asymptomatic PGW veterans and (2) to determine whether PGW veterans as a whole had lower PON1 activity compared with other military control groups. This was a case control study nested in occupational cohort study of military personnel. Four groups of military personnel were identified from a large epidemiological study of health effects of deployment to the PGW and Bosnia: (1) symptomatic PGW veterans, n = 115; (2) healthy PGW veterans, n = 95; (3) symptomatic Bosnia peacekeeping veterans, n = 52; and (4) symptomatic nondeployed military controls, n = 85. The main outcome measures were PON1 activity and genotype for PON1-55 and -192. We found significant differences in PON1 activity among these four groups, and although the two Gulf groups did not differ in PON1 activity, those deployed to the Gulf had significantly lower PON1 activity compared with the non-PGW groups (median difference = 70.9; 95% CI: 20.2, 121.5, P = 0.012). These differences were not explained by a range of potential confounders, or differences in PON1 coding region polymorphisms. PON1 activity is reduced in PGW veterans compared with military control groups. The effect is independent of ill health in PGW veterans.

Adult↗

PubMed2003

Processing and presentation of the islet autoantigen GAD by vascular endothelial cells promotes transmigration of autoreactive T-cells.

Type 1 diabetes is characterized by T-cell infiltration of the islets of Langerhans and abundant HLA class II molecule expression on islet endothelial cells (ECs). The specificity of infiltrating T-cells for islet autoantigens has been amply demonstrated in animal models, and is implicit in human diabetes, but the processes regulating endothelial transmigration of islet autoantigen-specific T-cells into islets are not known. We examined the ability of ECs expressing HLA class II molecules to process and present the islet autoantigen GAD65 and examined the effects of presentation on transmigration of GAD65-specific T-cells. Primary cultures of human vascular ECs expressing the DRB1*0401 (VEC1) and DRB1*0301 (VEC2) genotypes were established and de novo expression of HLA class II molecules induced with interferon-gamma. Under these conditions, VEC1 efficiently processed and presented whole GAD65 to the HLA-DR4-restricted murine T-cell hybridoma T33.1 that recognizes the 274-286 epitope of GAD65. Using a transwell system, we examined the effect of GAD65 presentation on migration of GAD65-specific T-cells across EC monolayers. Migration of T33.1 hybridoma cells and of the human T-cell clone, PM1#11 (recognizes GAD65 epitope 339-352 presented by HLA-DR3) across VEC1 and VEC2, respectively, were greatly enhanced in the presence of GAD65, commencing more rapidly and achieving a higher peak migration at 3 h. Migrated PM1#11 cells retained full proliferative capacity. These results support the hypothesis that presentation of autoantigens by islet endothelium in vivo could promote transmigration of circulating islet autoantigen-specific T-cells primed in regional lymph nodes against islet autoantigens.

Amino Acid Sequence↗

PubMed2002

Characterization of the T-cell response to coxsackievirus B4: evidence that effector memory cells predominate in patients with type 1 diabetes.

Most of the evidence linking enterovirus (EV) infection with the development and/or acceleration of type 1 diabetes is indirect. Few studies have examined T-cell responses to these viruses, and therefore the nature of the viral targets and the immune cells involved in antiviral responses remain unclear. In the present study, we examined the characteristics of the T-cell response to the EV Coxsackievirus B4 (CVB4) in patients with type 1 diabetes and healthy control subjects. We find that CVB4-specific T-cells preferentially target the envelope proteins VP1, VP2, and VP3, and that the response to these and other CVB4 proteins differs markedly in type 1 diabetic patients compared with nondiabetic control subjects. The frequency of T-cell proliferative responses against VP2 was significantly reduced in type 1 diabetic patients compared with control subjects, especially in patients tested near to diagnosis (P < 0.001). In contrast, median levels of gamma-interferon (IFN-gamma) production by T-cells in response to the CVB4 antigens tested were generally high in new-onset type 1 diabetic patients, who produced significantly higher levels in response to VP3 compared with healthy subjects (P < 0.05) and patients with long-standing disease (P < 0.05). New-onset type 1 diabetic patients also had higher levels in response to P2C compared with healthy subjects (P < 0.005) and to VP2 compared with patients with long-standing disease (P < 0.05). These results suggest that the quality of the immune response to CVB4 antigens differs significantly between type 1 diabetic patients and control subjects, with a predominance of primed effector (IFN-gamma-producing) memory cells near to disease diagnosis. The data are consistent with the notion that the diagnosis of type 1 diabetes is associated with recent or persistent exposure to EV antigens.

Adult↗

PubMedDate not supplied

Enteroviruses and type 1 diabetes.

The development of type 1 diabetes mellitus (T1DM) has been linked to exposure to environmental triggers, with Enteroviruses (EV) historically considered the prime suspects. Early serological studies suggested a link between EV infections and the development of T1DM and, though controversial, have been bolstered by more recent studies using more sensitive techniques such as direct detection of the EV genome by RT-PCR in peripheral blood. In this review, we consider the weight of evidence that EV can be considered a candidate trigger of T1DM, using three major criteria: (1) is EV infection associated with clinical T1DM, (2) can EV trigger the development of autoimmunity and (3) what would explain the putative association?

Autoimmune Diseases↗