Role of Superantigens in Dermatology

Abstract

Superantigens are very potent agonists of T-lymphocytes. The superantigenic types of reactions on various subsets of T-lymphocytes are compared with those of classical antigens and aspecific mitogens. The role they could play in skin disease is reviewed with special emphasis to acute and chronic diseases, auto-immunity, immediate type reactions, immunodeficiency, carcinogenesis, psoriasis and other inflammatory cutaneous conditions.

The term “superantigen” has been used for the first time in 1989 by the group of Kappler and Marrack [1,2]. Superantigens are proteins produced by bacteria (mainly streptococci and staphylococci), by mycoplasma, by retroviruses and probably by numerous other viral, bacterial and parasitic micro-organisms. They interfere with the immune system by binding with class II proteins of the major histocompatibility complex (HLA-MHC) present on the antigen presenting cells (APC) on one side and with the variable part of the α-chain (Vα) of the T cell receptor (TCR) on the other side. This binding of superantigen is like a “short circuit” between the two cells resulting in a massive, rapid and exponential proliferation of T-lymphocytes usually followed by death of most stimulated T cells. Moreover, an anergy is usually observed against further stimulations of surviving T cells. However, such an anergy is not specific of superantigenic response and can also be seen for classical nominal antigens, auto-antigens and even for nonspecific mitogens (PWM, PHA, Con A, pertussis toxin). The main characteristic of superantigens as compared to classical antigens is that they do not need maturation processing into antigenic peptides by the proteases in the APC. They are not presented in the groove made by MHC class II on APC and by TCR on T cells but outside this groove on the Vα lateral side. The proportion of T-lymphocytes responding to a nominal antigen is about 1/1000 while the proportion of T-lymphocytes responding to a superantigen reaches 5 to 25 %. As compared to nonspecific mitogens activating all T cells, superantigens display a specificity leading to the proliferation of subsets of T-lymphocytes via Vα chain with a possible contribution of Va chain and a very minor contribution of Dα, Jα and/or Ja. Depending on the subset of stimulated T cells and on the types of cytokines produced, the symptomatology and the syndromes induced are numerous and display a very wide range [3, 4, 5].

According to the stimulated subsets of T cells, different reactions can be observed:

• 1. CD 4⁺T helper: sudden immune reaction (for example: toxic shock syndrome).

• 2. T helper with secondary stimulation ofB-lymphocytes: uncontrolled production of immunoglobulins (for example: staphylococcal scalded skin syndrome).

• 3. CD 8⁺T suppresser: immunosuppressor (for example: AIDS).

• 4. NK cells: carcinogenesis (for example: mammary tumor in mice) [6].

After intense stimulation, a large proliferation can be followed by a desequilibrium between subsets of T lymphocytes due to cell death and apoptosis leading to a secondary immunodepression and a down regulation of Ig mediated and delayed type hypersensitivities. Moreover, the surviving subsets ofT cells are unable to react to further stimulation by other superantigens and also by classical antigens. This mechanism is responsible of a true anergy which is a peripheral tolerance phenomenon [7, 8].

Most of well known superantigens are of exogenous origin;. they are produced by bacteria or viruses. Bacterial superantigens are mainly: 1) Staphyloccus aureus: toxic shock syndrome toxin (TSST1), staphylococcal enterotoxins (SE), exfoliative toxins (ExFT), 2) Streptococcal pyogenic enterotoxins (SPE), 3) Mycoplasma arthritidis mitogen (MAM), 4) Yersinia enterocolica antigen (YEA) and 5) Pseudomonas aeruginosa exotoxin (PE). Viral exogenous superantigens are known for murine leukaemia virus (MuLV), for human immunodeficiency virus (HIV) and for rabies. Molecules produced by viruses could enhance incorporation of the viral genome into the lost cells, increase T cell death and induce immunosuppression by activation of CD 8⁺ T cells. In addition to these infectious agents producing characteristic identified superantigens, many other micro-organiSITIS are most probably able to synthesize molecules with a superantigenic potential. A documentation is already available for toxoplasma gondii and candida albicans [9, 10].

Endogenous superantigens have been identified in mice. The minor antigen of immune stimulation (AgMIS) is coded by an endogenous provirus. The murine mammary tumor virus (MMTV) is transmitted by mendelian heredity and probably by breast feeding. Its expression at birth leads to a negative selection of reactive T-lymphocytes. In adults, it induces a stimulation of subsets of T cells followed by relative anergy. Its integration near a proto-oncongen is responsible for the mammary tumor [6, 10, 11]. It could playa partial role in auto-immune reaction induction through the production of IgG by activated B-lymphocytes or by reaction between TCR present on active T-lymphocytes and auto-antigens present in their peripheral homing location [6, 12]. The equivalent of MMTV has not yet been found in man but superantigenic mechanisms’ could well be involved in viral induced carcinogenesis, in auto-immune diseases and in congenital immunodeficiency.

In dermatology, diseases and syndromes with superantigenic pathogenicity are ITIOSt probably very numerous. Apart from well-defined superantigen diseases, many inflammatory skin disorders are associated with bacterial parasitic colonies that could secrete superantigens. Superantigeris actions are probably involved, at least in part, in the etiology or at least in some of the pathogenic mechanisms of such disorders [4, 6, 10].

We present in the list below several dermatological conditions with possible superantigenic pathogenicity:

• 1. Acute skin diseases caused by bacterial superantigenic toxins or by viral superantigens: infectious toxic dermatitis in menstrual and non menstrual toxic shock syndrome, toxic dermatitis in pseudo-toxic shock syndrome induced by Yersinia or pseudomonas, staphylococcal scalded skin syndrome, scarlet fever, erysipelas, cellulitis, fasciitis, purpura in septicemia, cutaneous symptoms ofendocarditis, rabies.

• 2. Auto-immune chronic skin diseases: erythema marginatium in rheumatic fever, skin lesions of rheumatoid polyarthritis, Kawasaki’s syndrome, lupus-like syndrome (lichenoid chronic graft versus host disease, mycoplasma arthritidis arthritis, lichen planus, acroscleroderma, mixed connective tissue disease).

• 3. Modifications of dermatoses induced by hypersensitivity reactions: inhibition of IgE mediated hypersensitivity through the skin in contact urticaria; flare-up after staphylococcal infection in atopic dermatitis; eczema vaccinatum, eczema herpeticum, Kaposi-Juliusberg’s syndromes in atopic dermatitis; down regulation of delayed type hypersensitivity in contact dermatitis with inhibition of reaction to of patch tests.

• 4. Various vasculitis with dermatological symptoms during infections with special attention to sudden IgA mediated necrotizing vasculitis following infection by streptococci, staphylococci, clostridiurnperfringens and pseudomonas aeruginosa.

• 5. Neoplasic disorders in the pathogenicity of which viruses could act as superantigens beeing expressed near proto-oncogens. A documentation is already available for Kaposi’s sarcoma (classical Mediterranean, endemic African and HIV associated), Burkitt’s tumor, cutaneous T cell lymphoma (CTCL) such as Worringer Kolopp’s disease (pagetoid reticulosis), mycosis fungoides, Sezary’s syndrome and probably several forms of leukaemias.

• 6. Genetically pre-existing diseases in which superantigens can induce the onset, aggravate and induce relapses. Psoriasis comprises possibilities to be mediated e.a. by superantigens. This could specially be the case in poststreptoccal guttate psoriasis, all kinds of pustular psoriasis (Barber, Milian-Katchoura-Lapiere, von Zumbusch) in exfoliative psoriatic erythroderma, in pustular psoriatic erythroderma. All these forms of psoriasis display a very rapid evolution. So could also be impetigo herpetiformis which should however be distinguished from pustular psoriasis of pregnancy.

• 7. Many syndromes of immuno-deficiency are a direct and/or indirect consequence of superantigenicity such as in several leukaemias and in AIDS. Secondary immunodeficiency by various superantigenic mechanisms: direct action on CD 8⁺ T cell suppressors, gaps produced in T cells by negative selection ofVß specific subsets of T cells after initial expansion of specific T cells.

In conclusion, apart from a few well known superantigenic diseases, several syndromes begin to be substantiated as superantigenic. Many questions still remain unanswered and the superantigenic function is far from being elucidated. Among working hypothesis are auto-immune diseases, nummular dermatitis, seborrheic dermatitis and most of the “ide” reactions.