Hyperimmunoglobin E syndrom: a sign of TH1/TH2 imbalance?

ARTICLE

Hyperimmunoglobulin E syndrome (HIES) is a congenital disorder characterized by high serum IgE, chronic eczematoid dermatitis, and recurrent infections particularly of the skin and the respiratory tract [1]. The most common bacterial pathogen in this disease is Staphylococcus aureus. Abnormality of neutrophil chemotaxis has been described in many cases of this syndrome, now it is suggested that this is a resultant event [2]. Elevation of specific IgE antibody to S. aureus was relatively specific in this disorder [3]. Recently TH1/TH2 imbalance has been thought to be involved in HIES. We report on a boy with HIES, whose cytokine profile of circulating CD4⁺ T cells was also examined by intracellular cytokine staining and flow cytometry.

Case report

A patient was first referred to our hospital for papules and vesiculopapules chiefly on the face and recurrent skin abscesses at 3 years of age in November 1995. He began to develop pruritic vesiculopapules on the face and scalp at the age of six months, which was thought to be atopic dermatitis. He also had recurrent episodes of skin abscesses and oral thrush. He was found to have an extremely elevated serum immunoglobulin E concentration.

Physical examination did not reveal a coarse face. There were many milliary-sized follicular vesiculopapules and pustules on erythematous bases which were distributed symmetrically on the forehead, jaws, cheeks, and around the eyes (Fig. 1). Some papules had central umbilication and most were eroded and encrusted. Similar vesiculopapules were scattered on the scalp and trunk. The morphology and distribution of the eruption were not typical of atopic dermatitis. Erythematous lesions with scale, crust, and slight exudate were also found around external auditory meatus. In addition, there were thumb-sized, dome-shaped, skin-colored abscesses on the left hand (Fig. 2) and right oral angle, without tenderness or fever.

A 3 mm punch biopsy specimen was taken from the vesiculopapules on the cheek (Fig. 3). Eosinophil-rich infiltration involved the hair follicles and the follicles were slightly destroyed. Perivascular, perifollicular and follicular infiltration with many lymphocytes and eosinophils were also present. Vasculitis was absent. These findings were compatible with eosinophilic pustular folliculitis.

Laboratory examinations showed a peripheral leukocyte count of 19,600/µl with 7% eosinophils. Serum IgE was elevated at 59,514 IU/ml. Specific IgE antibody to Staphylococcus aureus was positive. The neutrophil chemotaxis value measured with Boyden's chamber method was less than 70% compared with 3 healthy controls, but other functions of neutrophils were normal. Lymphocyte blastogenic response to phytohemagglutinin and concanavalin A was not reduced. Delayed hypersensitivity skin tests using candida and streptokinase-streptodornase were negative and tuberculin was false-positive. Only 2,4-dinitro-1-chlorobenzene was strongly positive. Bacterial culture of pustules and abscesses of skin yielded S. aureus.

We also examined cytokine profiles of circulating CD4⁺ T cells using intracellular cytokine staining and flow cytometry. Peripheral blood mononuclear cells (PBMC) were separated from fresh heparinized venous blood by centrifugation over a Ficoll-Hypaque (Creder Lane, Ontario, Canada) density gradient, and stimulated with 20 mg/ml phorbol myristate acetate (Sigma, St. Louis, MO) and 2 mg/ml ionomycin (Sigma, St. Louis, MO). Followed by incubation at 37š C, they were stained with PerCP-conjugated mouse anti human CD4 monoclonal antibody (SK3, Becton Dickinson, Mountain View, CA). They were fixed with 4% paraformaldehyde for 20 min. Cells were washed and pre-incubated for 10 min in PBS (1% FCS) containing 0.5% saponin (Sigma, St. Louis, MO). Then, cells were incubated with phycoerythrin (PE)-conjugated mouse anti human interleukin-4 (IL-4) monoclonal antibody (8D4-8, Pharmingen, San Diego, CA) and PE-conjugated mouse anti human interferon-gamma (IFN- gamma) monoclonal antibody (4S.B3, Pharmingen, San Diego, CA) respectively. After washing twice, flow cytometric analysis was performed by FACScan flow cytometry with LYSIS II software (Becton Dickinson, Mountain View, CA). An analysis gate was set on CD4⁺ population in flow cytometry. The results showed that the ratio of IL-4⁺ cells was not different compared with a healthy control (Table I). However, the ratio of IFN- gamma⁺ cells was significantly reduced (Fig. 4 and Table I). Furthermore, we have examined cytokine profiles of circulating CD4⁺ T cells in 20 normal subjects and obtained nearly the same results as the control above (data not shown).

We diagnosed this patient as HIES by clinical appearance and laboratory findings. Sulfomethoxazole and trimethoprim were administered at a dose of 40 mg/kg/day and 8 mg/kg/day respectively, and ascorbic acid was combined to stimulate neutrophil function. He gradually improved and subcutaneous abscesses and oral thrush have not been found since the institution of the treatment.

Discussion

Job's syndrome was reported in 1966 and this is considered to be the first report of HIES [4]. Buckley et al. reported two boys with eczematoid rashes, coarse faces, cold abscesses and recurrent sinopulmonary infections with Staphylococcus and Hemophilus, which contributed to the description of this disorder [5]. It was subsequently proved that the abscesses observed in most patients are not "cold" [6] and that specific IgE antibody to Staphylococcus aureus is elevated in this syndrome [3]. There have been many reports of HIES from the pediatric field, however histological findings were not mentioned in most reports. Several reports described the presence of "subacute to chronic dermatitis" [7, 8] and only one case was accompanied with "vasculitis" [9]. However the histology of our case, similar to eosinophilic pustular folliculitis, has not been reported. Eosinophilic pustular folliculitis (Ofuji's disease) was first reported by Ofuji in 1970 [10] and the spectrum of this disease has expanded since its initial description. In 1994, Margo and Crowson reported patients who did not fall within the accepted clinical spectrum of eosinophilic pustular folliculitis, but their histopathological changes were compatible with eosinophilic folliculitis [11]. They called this histopathology an eosinophilic pustular follicular reaction, and insisted that it is not exclusive to eosinophilic folliculitis. They also suggested that eosinophilic pustular follicular reaction may reflect a TH1/TH2 imbalance due to a specific T cell dysfunction, as such T cell dysfunctions are known to occur in atopic dermatitis, diabetes, HIV infection, and with anticonvulsant drug therapy. It is suggested that TH2 is dominant in this histological reaction.

Since IFN- gamma secreted chiefly from TH1, and IL-4 secreted chiefly from TH2 play a central role in controlling the isotype switch to IgE, we examined cytokine profiles of circulating CD4⁺ T cells by intracellular cytokine staining and flow cytometry. Decrease of CD4⁺IFN- gamma⁺ cells was found. Several reports have shown decreased IFN- gamma production by PBMC of patients with HIES [12, 13]. Der Prete et al. reported that a significant difference was not found between patients with this condition and controls, in the ability of PBMC to produce IL-4. However, production of IFN- gamma by PBMC of patients was much reduced compared to controls. Other investigators have reported that stimulated PBMC from patients with HIES yielded a larger amount of IL-4 than controls but the increase was relatively small, at a 3-fold increase. It was also reported that administration of IFN- gamma to HIES patients decreased in vitro IgE production and serum IgE [14]. Thus reports of decreased production of IFN- gamma and/or elevated production of IL-4 are perhaps common and it is thought that TH2 dominant imbalance of TH1/TH2 may involve the onset of HIES, though IFN- gamma has been described as having no significant effect on spontaneous in vitro IgE synthesis of PBMC from HIES patients, and secretion of IL-4 and IFN- gamma by PBMC in vitro did not show significant difference between patients with HIES and normal controls [15]. Our examination using intracellular cytokine staining and flow cytometry showed a decrease of CD4⁺IFN- gamma⁺ cells. We think that this cytokine profile and histopathology of EPER support the hypothesis that HIES is caused by TH1/TH2 imbalance.

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