Predominance of Type 1 cytokines and decreased number of

CD4+CD25+ high T regulatory cells in peripheral blood of

patients with recurrent aphthous ulcerations.

 

Natalia Lewkowicz^a, Przemysaw Lewkowicz^b,Magorzata Banasik^b,

Anna Kurnatowska^a, Henryk Tchórzewski^b

 

a) Department of Periodontal and Oral Mucosal Diseases, Medical University of Lodz, Pomorska Street 251, 92-213 Lodz, Poland

b) Department of Clinical Immunology, Institute of Polish Mother’s Memorial Hospital, Rzgowska Street 281/289, 93-338 Lodz, Poland

 

Abstract (link to PubMed Abstract)

Recurrent aphthous ulcerations (RAU) are a chronic inflammatory disease with evidence of inappropriate immune response. Previous studies have suggested cell-mediated activation of immune response towards common micro-organisms of oral cavity in RAU. In this investigation, we explored cytokine production by peripheral blood mononuclear cells (PBMC) and T regulatory cell population in blood of active and remission RAU patients as crucial factors for maintenance of peripheral tolerance. Ten patients with minor RAU and 12 healthy individuals were selected for the study. Cytokine levels were analysed in supernatants using Cytometric Bead Array Kit for flow cytometry and ELISA. We have demonstrated increased production of Type 1 cytokines IL-2, IFN-_ and TNF-_ as well as IL-5, IL-6 and IL-8 by peripheral blood mononuclear cells in RAU. In contrast, IL-10 and TGF-_ anti-inflammatory cytokine production was decreased in RAU patients compared

to healthy individuals. Moreover, we have found that CD4+CD25+ high T regulatory cell proportion was decreased in RAU and represented 3.58±0.654% of CD4+ T cells in active RAU, 4.66±0.561% of CD4+ T cells in remission RAU, whereas in healthy controls CD4+CD25+ high T cells represented 7.30±1.238% of CD4+ T cells (p < 0.001). Thus, the obtained results indicate that disproportion in cytokine production may be contributing factor in the pathogenesis ofRAU. Alteration in the number of CD4+CD25+ high T regulatory cells inRAUmay additionally influence the development of the disease.We propose that imbalance in pro- and anti-inflammatory cytokine network may lead to the breakdown of peripheral tolerance in RAU and the excessive immune response towards harmless micro-organisms colonized oral mucosa or self-antigens.

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Editor Comment:

Regulatory T cells (Treg) have gained recent prominence through its association with increased susceptibility to several clinically important human inflammatory diseases as for example Crohn's disease (CD).

 

A key suppressor role has recently been ascribed to the natural CD4+CD25+ regulatory T cells.  Impaired regulatory function of these cells may lead to the development of autoimmune disease and aggravated pathogen-induced inflammation in otherwise normal hosts. Although widely acknowledged to play a role in the maintenance of self-tolerance, recent studies indicate that Treg can be activated and expanded against bacterial, viral and parasite antigens in vivo.

 

Recurrent aphthous ulcers (RAU) may have an immunogenetic background owing to cross-reactivity with Streptococcus sanguis or heat shock protein. In a recent published study by Lewkowicz et al. (Immunology Letters 99 (2005) 57–62) it was suggested that inadequate suppression by Treg may lead to excessive immune activation towards microorganisms which may play a role in the development of RAS. Based on the results the authors also proposed that imbalance in pro- and anti-inflammatory cytokine network may lead to the breakdown of peripheral tolerance in RAU and the excessive immune response towards harmless microorganisms colonized oral mucosa or self-antigens.

 

Imbalance in the cytokine profile has previously been reported for RAU and is confirmed by the present paper. However, a suppression of Treg in RAU patients is demonstrated for the firs time. This result suggests that regulatory T-cells are incapable to exert inhibitory effects on autoreactivity which may have implication for the development of RAU. Although, the immunological impairments have gained acceptance in the aetiology of RAU, the main question remains – why are these aphthous ulcers recurrent? Obviously, other factors have to be involved in parallel with immunologic disturbances to contract RAU.