Super antigen (SAG) is microbial protein of 22 – 29 Daltons in size and are potent stimulators of the immune cells. They are produced by bacteria, viruses and mycoplasma
SAG bind simulataneously to specific Vβ regions of T cell receptors and to the α chain of MHC class II molecules.
SAG’s require no antigen processing.
Types of SAG
Exogenous – soluble proteins secreted by bacteria and a variety of exotoxins
Endogenous – cell membrane proteins encoded by certain viruses that infect mammalian cells
T cell SAG – binds directly to Vβdomain of TCR and MHC II receptor outside the conventional antigen binding site
B cell SAG – interacts with B cell receptor (Ig) at the variable region of heavy chain / light chainoutside the conventional antigen binding site
Super antigen toxins
Staphylococcal SAG –
Staphylococcal enterotoxin A, B, C, D, E, G, H, I, J (most studied A, B and TSST1 )
Peptostreptococcus magnus – Protein L (B cell SAG)
Mechanism of action
In classical response antigen is processed by antigen presenting cell and an epitope from a protein antigen acts as a bridge between the HLA complex of antigen presenting cell and TCR. Only a small proportion of T cells become activated particularly after a co-stimulatory signal is produced by the APC. Response is highly regulated to limit the harmful response
Super antigen response
T-cell SAG
binds directly to TCR and MHC class II receptor outside the conventional antigen binding site thus bypassing the restrictive features of conventional antigen processing
SAG binds to Vβ domain of TCR where Vβ refers to variable region of β peptide. Thus SAG can stimulate all T cells bearing particular Vβ designation. Thus they can stimulate 20 – 30% of the total lymphocytes in an individual
MHC – II positive cells are required for SAG induced T cell activation, but it is not MHC –II restrictive and binding of MHC –II receptor determines susceptibility of an individual to the particular SAG
B cell SAG
B cell SAG interacts with variable region of heavy/ light chain outside the conventional antigen binding site, thus activating B cells in a VH selective manner
SAG interaction and effects
T cell SAG
Massive T cell activation and release of cytokines eg. TNF α, IL-2, IL-6, IFN-γ in large amounts resulting in capillary leak and systemic shock
There is biphasic response after SAG stimulation of T cels with T-cell derived initial peak of IL-2, TNF-α followed by second peak from macrophage – derived cytokines
Deletion – initially Vβ specific T cell expansion followed by Vβ specific clonal deletion of T cells
Anergy – hypo responsive state of T cell to an antigen in the absence of appropriate co-stimulatory signal
T cell dependent B cell activation – characterized by polyclonal IgM and IgG production, enhancing humoral immunity via antigen specific CD4+ T cells
Cytotoxicity – Cytotoxic T cell mediated cytotoxicity against MHC class II positive cells known as SAG dependent cell – mediated cytotoxicity (SDCC). Activation induced cell death (AICD). SAG dependent auto killing
Induction of autoimmune status
Autoimmune state may result from indiscriminate Vβ specific expansion that amplifies the clone that manifests cross reactivity towards endogenous antigen and loss of self tolerance. This persists even after SAG stimuli ceases
SAG increases the expression of Glucocorticoid receptor β and are associated with decreased corticosteroid response
Other effects –
Stimulates lymphocyte locomotion
Neutrophilic recruitment to the site of infection
Emesis
Augmentation of endotoxin activity
Recruitment of T cells, B cells and APC ‘s at the site of infection
Activation of B cells and APCs further augment the cytokine release
B cell SAG
B cell SAG binds to serum Ig and leads to the formation of large amount of immune complexes. Such immune complexes activate the complement pathyway and inflict tissue injury
B cell SAG bind to surface Ig on the mast cells and basophils resulting in the release of pro-inflammatory mediators
T cell independent VH specific B cell activation and proliferation, followed by clonal deletion and prolonged suppression of antibody production
Endogenous super antigens
Endogenous SAG are cell membrane proteins encoded by certain viruses that infect mammalian cells
In humans endogenous SAG is encoded by env gene of human endogenous retrovirus (HERV). Exact significance of endogenous SAG is not known
Endogenous SAG stimulate T cell in Vβ in a selective manner to support viral replication and plays a role in pathogenesis of EB virus infections, HIV infections, CMV infections and IDDM.
SAG are powerful cell mitogens and causes Toxic shock syndrome.
Treatment
Removal of source of SAG. For eg.
Draining the abscess
Early and adequate antibacterial therapy
Supportive care for shock
Immunomodulatory drugs for various SAG associated diseases.
Reference
V Hemalatha, P Srikanth, M Mallika. Superantigens – concepts, clinical disease and therapy. Indian Journal of Medical Microbiology, (2004) 22 (4):204-211
