Biomedical subjects

Martin Llewelyn

Publications and source records attributed to Martin Llewelyn.

4 recordsLinked to original sources

PubMed2006

The TCR Vbeta signature of bacterial superantigens spreads with stimulus strength.

Superantigens (Sags) induce large-scale stimulation of T lymphocytes by a mechanism distinct from conventional antigen presentation, involving direct MHC binding and stimulation of TCR families based on Vbeta gene usage. The specific Vbeta targets of a given Sag have, since the earliest studies in murine models, been considered a hallmark of that toxin. Bacterial Sags are implicated in the aetiology of a wide range of human diseases, although their role has been most clearly defined in toxic shock syndrome. While Sags have been defined by the Vbeta-specific changes in T cell repertoire they induce, human studies of in vitro stimulation or analysis of cells from infected patients have produced inconsistent findings. Here we have evaluated the contribution of HLA allelic polymorphisms and strength of stimulus to this response. We show that there are differences in binding and presentation of the staphylococcal Sag, staphylococcal enterotoxin A (SEA), by different HLA-DR alleles. We also show that the TCR Vbeta response, previously thought to be a fixed property defining a given Sag, varies with stimulus strength such that a broader repertoire of response is seen at higher concentrations or following presentation by high-binding class II types. Responses of human Vbeta8 and Vbeta1 to SEA, Vbeta5 to SEB and of Vbeta12 and Vbeta13 to streptococcal pyrogenic exotoxin A are absolutely dependent on stimulus strength. These findings have important implications for heterogeneity in the response to Sags and the consequent differences in susceptibility to severe toxic shock.

Antigen Presentation↗

PubMed2005

Human leukocyte antigen class II haplotypes that protect against or predispose to streptococcal toxic shock.

In the United States, 1.5-5.2/100,000 persons develop invasive Streptococcus pyogenes infections each year, and approximately 10%-20% of these patients go on to develop streptococcal toxic shock syndrome (STSS). Patients who develop STSS usually present with generalized erythema, conjunctivitis, and confusion. Fulminant cardiovascular shock develops over a period of a few hours, accompanied by multiorgan failure. Between 20% and 40% of patients with STSS die, compared with approximately 10% of patients with invasive streptococcal disease without STSS.

HLA Antigens↗

PubMed2004

HLA class II polymorphisms determine responses to bacterial superantigens.

The excessive immunological response triggered by microbial superantigens has been implicated in the etiology of a wide range of human diseases but has been most clearly defined for the staphylococcal and streptococcal toxic shock syndromes. Because MHC class II presentation of superantigens to T cells is not MHC-restricted, the possibility that HLA polymorphisms could influence superantigenicity, and thus clinical susceptibility to the toxicity of individual superantigens, has received little attention. In this study, we demonstrate that binding of streptococcal and staphylococcal superantigens to HLA class II is influenced by allelic differences in class II. For the superantigen streptococcal pyrogenic exotoxin A, class II binding is dependent on DQ alpha-chain polymorphisms such that HLA-DQA1*01 alpha-chains show greater binding than DQA1*03/05 alpha-chains. The functional implications of differential binding on T cell activation were investigated in various experimental systems using human T cells and murine Vbeta8.2 transgenic cells as responders. These studies showed quantitative and qualitative differences resulting from differential HLA-DQ binding. We observed changes in T cell proliferation and cytokine production, and in the Vbeta specific changes in T cell repertoire that have hitherto been regarded as a defining feature of an individual superantigen. Our observations reveal a mechanism for the different outcomes seen following infection by toxigenic bacteria.

Amino Acid Sequence↗

PubMed2002

Superantigens: microbial agents that corrupt immunity.

Microbial superantigens are a family of protein exotoxins that share the ability to trigger excessive and aberrant activation of T cells. The best characterised are the staphylococcal enterotoxins and the streptococcal pyrogenic exotoxins that trigger the staphylococcal and streptococcal toxic shock syndromes. It is now apparent that superantigens have a wider role in the pathology of infectious diseases than has previously been appreciated. Staphylococcus aureus and Streptococcus pyogenes together produce 19 different superantigens. The range of microorganisms known to produce superantigens has expanded to include Gram negative bacteria, mycoplasma, and viruses. Research is beginning to shed light on the more subtle parts these molecules play in causing disease and to produce some real possibilities for specific treatment of superantigen-induced toxicity. We aim to highlight these new developments and review the science behind these fascinating molecules.

Animals↗