scholarly journals Identification of HLA-DR alpha chain residues critical for binding of the toxic shock syndrome toxin superantigen.

1992 ◽  
Vol 176 (6) ◽  
pp. 1779-1784 ◽  
Author(s):  
P Panina-Bordignon ◽  
X T Fu ◽  
A Lanzavecchia ◽  
R W Karr
Keyword(s):  
Toxic Shock Syndrome ◽  
Class Ii ◽  
Antigenic Peptide ◽  
Toxic Shock ◽  
Alpha Chain ◽  
Histocompatibility Complex ◽  
Hla Dr ◽  
Toxic Shock Syndrome Toxin ◽  
Toxin Class ◽  
Staphylococcal Toxic Shock Syndrome

Staphylococcal toxic shock syndrome toxin 1 (TSST-1) binds to major histocompatibility complex class II molecules, and the toxin-class II complexes induce proliferation of T cells expressing V beta 2 sequences. To define the residues involved in TSST-1 binding, a set of transfectants expressing 21 HLA-DR alpha chain mutants were analyzed for their abilities to bind and present TSST-1 and to present an antigenic peptide. Mutations at DR alpha positions 36 and 39 markedly decreased the ability of the DR7 molecule to bind and present TSST-1 but did not affect the ability to present an antigenic peptide. These data indicate that DR alpha residues 36 and 39, predicted to be located on an outer loop, are important in the formation of the TSST-1 binding site on DR molecules.

Defining a novel domain of staphylococcal toxic shock syndrome toxin-1 critical for major histocompatibility complex class II binding, superantigenic activity, and lethality

2000 ◽  
Vol 46 (2) ◽  
pp. 171-179 ◽  
Author(s):  
Winnie WS Kum ◽  
Kevin B Laupland ◽  
Anthony W Chow
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Toxic Shock Syndrome ◽  
Class Ii ◽  
Cytokine Secretion ◽  
Toxic Shock ◽  
Histocompatibility Complex ◽  
Toxic Shock Syndrome Toxin ◽  
Staphylococcal Toxic Shock Syndrome

Staphylococcal toxic shock syndrome toxin-1 (TSST-1) is implicated in the pathogenesis of superantigen-mediated shock. We previously identified TSST-1 residues G31/S32 to be important for major histocompatibility complex (MHC) class II binding, as well as superantigenic and lethal activities. However, the site-directed TSST-1 mutant toxin, G31R, could still induce mitogenesis and low-level TNFalpha secretion, suggesting that additional MHC class II binding sites other than G31/S32 may exist. In the current study, a TSST-1-neutralizing monoclonal antibody, MAb5, was found to inhibit TSST-1 binding to human peripheral blood mononuclear cells, neutralize TSST-1-induced mitogenesis and cytokine secretion, and protect against TSST-1-induced lethality in vivo. Epitope mapping revealed that MAb5 bound to TSST-1 residues 51-56 (T(51-56);51YYSPAF56). Peptide T(51-56) was synthesized and found to also inhibit TSST-1 binding to human monocytes as well as TSST-1-induced mitogenesis, cytokine secretion, and lethality in vivo. This T(51-56) epitope, located within the beta3/beta4 loop, and the previously identified G31/S32 epitope, within the beta1/beta2 loop of TSST-1, are separated within the primary sequence, but spatially juxtaposed to each other. Collectively, these findings suggest that a discontinuous epitope comprising of regions within both the beta1/beta2 and beta3/beta4 loops, are critical for MHC class II binding, and the consequent superantigenic and lethal activities of TSST-1.

scholarly journals Identification of class II major histocompatibility complex and T cell receptor binding sites in the superantigen toxic shock syndrome toxin 1.

1995 ◽  
Vol 181 (6) ◽  
pp. 2229-2235 ◽  
Author(s):  
J M Hurley ◽  
R Shimonkevitz ◽  
A Hanagan ◽  
K Enney ◽  
E Boen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Binding Sites ◽  
Toxic Shock Syndrome ◽  
Cell Receptor ◽  
Class Ii ◽  
Toxic Shock ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Toxic Shock Syndrome Toxin

Superantigens, in association with class II major histocompatibility complex (MHC) molecules, activate T cells bearing particular beta chain variable domains of the T cell receptor (TCR). Unlike conventional peptide antigens, superantigens bind as intact proteins to TCR and MHC molecules outside their peptide binding sites. To characterize these interactions at the molecular level, random point mutations were generated in the gene encoding toxic shock syndrome toxin 1, a bacterial superantigen associated with toxic shock syndrome. Functionally impaired mutants were identified based on their lack of murine and human T cell stimulatory activities, and experiments analyzing binding to human histocompatibility leukocyte antigen-DR molecules differentiated residues involved in MHC from TCR binding. The results showed that the great majority of mutations are clustered in two distinct regions of the toxic shock syndrome toxin 1 molecule. The class II MHC binding site is located in the hydrophobic region of the NH2-terminal domain, and the TCR binding site is primarily in the major central groove of the COOH-terminal domain. These studies provide insight into the interactions necessary for superantigen-mediated disease in humans.

HLA-DR polymorphisms influencein vivoresponses to staphylococcal toxic shock syndrome toxin-1 in a transgenic mouse model

HLA ◽  
2016 ◽  
Vol 89 (1) ◽  
pp. 20-28 ◽  
Author(s):  
A. Krogman ◽  
A. Tilahun ◽  
C. S. David ◽  
V. R. Chowdhary ◽  
M. P. Alexander ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Toxic Shock Syndrome ◽  
Transgenic Mouse Model ◽  
Toxic Shock ◽  
Hla Dr ◽  
Toxic Shock Syndrome Toxin ◽  
Staphylococcal Toxic Shock Syndrome

scholarly journals Sequences in both class II major histocompatibility complex alpha and beta chains contribute to the binding of the superantigen toxic shock syndrome toxin 1.

1992 ◽  
Vol 175 (5) ◽  
pp. 1301-1305 ◽  
Author(s):  
N S Braunstein ◽  
D A Weber ◽  
X C Wang ◽  
E O Long ◽  
D Karp
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Toxic Shock Syndrome ◽  
Cell Receptor ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Toxic Shock ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Toxic Shock Syndrome Toxin

Class II major histocompatibility complex (MHC) molecules present peptides derived from processed antigen to antigen-specific CD4-positive T cells. In addition, class II molecules bind with high affinity another class of antigens, termed superantigens. T cell stimulation by superantigens depends almost exclusively on the V beta segment expressed by the T cell receptor (TCR). Mapping of the superantigen binding site on class II molecules should provide valuable information on how MHC and TCR molecules interact. Recombinant mouse I-A class II molecules expressed on transfected L cells were analyzed for their ability to bind the toxic shock syndrome toxin 1. Polymorphic residues in the alpha helices of both the alpha and beta chains of I-A contributed to quantitative toxin binding, suggesting that the toxin binds to either a combinatorial or a conformational site on class II MHC molecules.

Receptors for toxic shock syndrome toxin-1 and staphylococcal enterotoxin A on human blood monocytes

1992 ◽  
Vol 38 (9) ◽  
pp. 937-944 ◽  
Author(s):  
Raymond H. See ◽  
Gerald Krystal ◽  
Anthony W. Chow
Keyword(s):  
T Lymphocytes ◽  
Toxic Shock Syndrome ◽  
Staphylococcal Enterotoxin ◽  
Human Monocytes ◽  
Staphylococcal Enterotoxin A ◽  
Blood Monocytes ◽  
Toxic Shock ◽  
Hla Dr ◽  
Toxic Shock Syndrome Toxin ◽  
Staphylococcal Toxic Shock Syndrome

Staphylococcal toxic shock syndrome toxin-1 (TSST-1) as well as staphylococcal enterotoxin A (SEA) and B (SEB) have recently been shown to bind directly to the class II major histocompatibility antigen, HLA-DR. Whereas others have characterized TSST-1 and SEA binding to HLA-DR on transfected L cells or B lymphoma cell lines, we sought evidence for direct binding of TSST-1 and SEA to HLA-DR on purified human monocytes. A single class of high-affinity receptors was found for both TSST-1 (dissociation constant (Kd) 40 nM, 3.4 × 104 receptors per cell) and SEA (Kd 12 nM, 3.2 × 104 receptors per cell) on normal human monocytes. Affinity cross-linking of 125I-labeled toxins to monocytes revealed the presence of two membrane protein subunits with molecular masses consistent with the α and β chains of human HLA-DR (35 and 28 kDa, respectively). The anti-HLA-DR monoclonal antibody L243, but not L203 or 2.06, inhibited radiolabeled toxin binding to human monocytes and neutralized the mitogenic response of human T lymphocytes to both toxins. However, L243 was consistently more effective in blocking radiolabeled TSST-1 than SEA binding to human monocytes from the same donors, suggesting that TSST-1 and SEA may be binding to overlapping epitopes rather than to the same epitope on HLA-DR. Because TSST-1 and SEB bind to distinct epitopes on HLA-DR and because SEA cross competes with both TSST-1 and SEB on the HLA-DR receptor, we postulate that SEA occupies a binding site within HLA-DR that overlaps both TSST-1 and SEB. Future studies focused on receptor-mediated binding of these toxins to human monocytes and T lymphocytes from normal donors and toxic shock syndrome patients may reveal the underlying anomalies that predispose particular individuals to toxic shock syndrome. Key words: monocytes, staphylococcal toxic shock syndrome toxin-1, receptors, HLA-DR, staphylococcal enterotoxin A.

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