Psoriasis is an illness resulting from the activation of certain subpopulations of T lymphocytes

[|In view of the recent publication by Zenz et al. (Psoriasis-like skin
disease and arthritis caused by inducible epidermal deletion of Jun
proteins. Nature. 2005 Sep 15;437(7057):369-75.) the abrogation of
JunB/activator protein 1 (AP-1) in keratinocytes may trigger
chemokine/cytokine expression, which recruits neutrophils and
macrophages to the epidermis thereby contributing to the phenotypic
changes observed in psoriasis. These data do support the hypothesis
that epidermal alterations are sufficient to initiate both skin lesions
and arthritis in psoriasis.|auteur192]

[|Here I agree – psoriasis is maintained by T cells!|auteur195]

[|While the immunopathogenesis of psoriasis is driving new drug development with antigen presenting cells (APC)-T-cell interaction with a host of cytokines, particularly TNF-? and IL 12/23 implicated, what I believe the next focus of our research needs to be is antigen presentation. This is well-discussed in #6, ie activation of certain subpopulations of T lymphocytes. In addition to antigens, super antigens, or ultra antigens mentioned, I do believe the role of drugs in triggering psoriasis, ie beta-blockers, lithium, could be proved to be a fruitful line of investigation. Certainly, laboratories exist in the world, ie here in Dallas under the supervision of Jacques Banchereau, PhD, a Frenchman and world leader in antigen presenting cells, which could pave the way for better understanding of this complex disease.|auteur215]

Whether a basic defect does exist at the level of skin cells and possibly fibroblasts, it has been perfectly demonstrated that the T lymphocytes play a major role in maintaining the disease (photo 1). This is based on three main lines of argument:

• triggering of psoriasis in a non-psoriatic person after bone-marrow grafting taken from a subject suffering from psoriasis;
• triggering of a clinical and histological psoriatic lesion after grafting on the immuno-tolerant mouse of a non involved psoriatic skin, followed by an injection of activated psoriatic T lymphocytes;
• the efficacy of numerous immunosuppressive drugs inhibiting T lymphocyte activation in psoriasis treatment. This argument is more flimsy because, although it is true that cyclosporine is remarkably effective, other immunosuppressants are less efficient. Moreover, cyclosporine has various cellular targets and, in addition to its action on T lymphocytes, it might conceivably be capable of inhibiting the secretion of certain cytokines by the skin cells. Its action on fibroblast activation has not been specifically studied.

The field of immunological research remains thus wide open in the sphere of psoriasis. Research is currently expanding to identify, in functional terms, the T lymphocytes migrating into a psoriasis plaque. There is a need to identify the molecules attracting and activating these lymphocytes in the skin, to identify the cytokines released by these lymphocytes and to understand how they maintain proliferation and epidermal inflammation. In particular, there is a need to research the antigens, superantigens and/or autoantigens that might be initiating this torrent of activation. Amongst these antigens, research is currently turning towards bacterial and viral antigens. Part of the HPV 5 genome has been found in many psoriatic lesions. Moreover, the incidence of psoriasis is higher in HIV-positive subjects. Similarly, antigens of streptococcal and staphylococcal origin might shoulder some responsibility for the lymphocytic activation of the psoriatic plaque.

Whatever the interest in such research might be, it should not end in some conceptual abuse, the most frequent being to classify psoriasis among the autoimmune disorders, when it is nothing like it. Immunosuppressants are not effective in all the patients. This immunological research should not slow down research on the anomalies present in the structural cells of the skin.

One of the most interesting fields of research at the moment relates to the study of innate defence mechanisms. These mechanisms are expressed not only by adaptive immunity cells but also by keratinocytes, macrophages and neutrophils. They may even be more important for psoriasis than adaptive immunity.

A different research pathway consists of studying the interactions between lymphocytes and skin cells. Recently, we have observed that psoriatic fibroblasts activate CD4 lymphocytes more effectively than normal fibroblasts, and that CD4 lymphocytes stemming from psoriatics activate fibroblasts more effectively than non-psoriatic CD4 lymphocytes.

Therefore, the most likely scenario is that CD4 lymphocytes accumulated in the dermis after any cutaneous aggression powerfully activate psoriatic fibroblasts and these activated fibroblasts activate the CD4 lymphocytes in return. This self-activating loop ends in the release of cytokines responsible for epidermal proliferation. Furthermore, the same hyperreactivity is likely to be expressed at keratinocyte level. All genetic and environmental events resulting in an increase of the pro-inflammatory cytokine production by the epidermis and by the inflammatory cells would thus be capable of triggering the appearance of psoriasis. These events vary and some of them are beginning to be identified: release of neurotransmitters at times of stress, presence of viral antigens, existence of varied genotypes leading, via the activation of various transduction pathways, to a cytokinic response heightened in response to stress. If this hypothesis is confirmed, psoriasis is certainly a syndrome, and a variety of different physiopathological pathways can result in this same clinical and histological expression.