Pathogenesis Of Pustulosis Palmaris Et Plantaris Research Articles

Presence of keratin-specific antibody-forming cells in palatine tonsils of patients with pustulosis palmaris et plantaris (PPP) and its correlation with prognosis after tonsillectomy

Conclusion: Keratin-specific immune responses in tonsils may be associated with the pathogenesis of pustulosis palmaris et plantaris (PPP). Evaluation of keratin-specific immune responses in tonsils might be useful to predict the effectiveness of tonsillectomy for patients with PPP. Objectives: The aim of the present study was to clarify the role of keratin-specific immune responses in the pathogenesis of PPP in tonsils. It has been reported that anti-keratin antibodies in serum were higher in patients with PPP and decreased after tonsillectomy, indicating that anti-keratin antibodies might be generated in tonsils. Methods: In order to demonstrate the presence of keratin-specific immune responses in tonsils, the numbers of keratin-specific antibody-forming cells (AFCs) in tonsillar and peripheral blood lymphocytes were examined by enzyme-linked immunospot assay. The prognosis of PPP was compared after tonsillectomy. Results: The numbers of keratin-specific IgM and IgG AFCs in tonsils and of IgG AFCs in peripheral blood were significantly increased in patients with PPP. The numbers of keratin-specific IgG AFCs in peripheral blood correlated positively with tonsil and serum IgG antibodies specific to keratin. Our data show that a good prognosis in patients with PPP depended on the numbers of keratin-specific IgG and IgM AFCs in peripheral blood and the levels of keratin-specific IgG antibodies in serum being significantly decreased 6 months after tonsillectomy.

Up-Regulation of ß1 Integrin on Tonsillar T Cells and its Induction by In Vitro Stimulation with α-streptococci in Patients with Pustulosis Palmaris et Plantaris

Pustulosis palmaris et plantaris (PPP) is a tonsil-related disease that can be cured with tonsillectomy. Recent immunological studies have shown that hyperactivation of tonsillar T cells is caused by a hyperimmune response to α-streptococci; recruitment of the T cells to lesions may be involved in the pathogenesis of PPP. ß1 integrin, expressed on T cells, not only provides a costimulatory signal for T-cell activation but also facilitates the accumulation of T cells in inflammatory skin lesions. In this study, we found that expression of ß1 integrin on both tonsillar and peripheral blood CD4-positive T cells was higher in PPP patients than in non-PPP patients. In vitro stimulation with α-streptococcal antigen significantly enhanced ß1 integrin expression on tonsillar CD4-positive T cells in PPP patients, but not in non-PPP patients. The chemotactic response of tonsillar CD4-positive T cells to vascular cell adhesion molecule-1, the ß1 integrin ligand, was significantly better in PPP patients than in non-PPP patients. The percentage of ß1 integrin-positive peripheral blood CD4-positive T cells decreased after tonsillectomy in PPP patients. The numbers of ß1 integrin-positive T cells and the expression of vascular cell adhesion molecule-1 were more elevated in plantar PPP skin lesions than in normal skin. These results suggest that ß1 integrin may play a key role in the pathogenesis of PPP.

掌蹠膿疱症における扁桃摘出術についてのアンケート調査―耳鼻咽喉科医および皮膚科医からみた考え方―

Today, pustulosis palmaris et plantaris (PPP) is widely accepted to be one of the tonsil-related diseases because tonsillectomy is quite effective in curing this condition. In addition, many fundamental findings have been reported which suggest that the tonsil plays a key role in the pathogenesis of PPP. However, criteria for the operation for PPP have not been established yet, so a common opinion of tonsillectomy for PPP has not been obtained from both dermatologists and otolaryngologists. In this study, we conducted a questionnaire survey to determine the current situation of tonsillectomy for PPP. Questionnaires were sent to otolaryngology and dermatology departments of the university hospitals in Japan. The results revealed that a deep relation between PPP and the tonsils was recognized by many otolaryngologists, however, the majority of dermatologists seemed to feel that the tonsils played a small role in the pathogenesis of PPP. To reduce the perception gap regarding the relationship between PPP and the tonsils among otolaryngologists and dermatologists, criteria regarding tonsillectomy for PPP need to be established.

Expression of cutaneous lymphocyte-associated antigen (CLA) in tonsillar T-cells and its induction by in vitro stimulation with alpha- streptococci in patients with pustulosis palmaris et plantaris (PPP)

Pustulosis palmaris et plantaris (PPP) is known to be a one of the tonsil-related diseases because tonsillectomy is quite effective in curing this condition. However etiological association between tonsils and PPP have not fully clarified yet. Cutaneous lymphocyte-associated antigen (CLA) is known to be a specific homing receptor that facilitates T-cell migration into skin. In this study, we investigated the expression of CLA on T-cells in tonsil, peripheral blood, and skin from patients with PPP. Two-color flow cytometric and two-color immunohistological analyses revealed that the numbers of CLA/CD3 double-positive cells in freshly isolated tonsillar mononuclear cells (TMC) and in tonsillar tissues were significantly higher in patients with PPP than in patients without PPP ( P < 0.01, each). In vitro stimulus with α-streptococcal antigens enhanced CLA expression of tonsillar T-cells and TGF-β production of TMC in patients with PPP ( P < 0.01, each), but did not in patients without PPP. In peripheral blood from PPP patients, the number of the CLA/CD3 double-positive cells significantly decreased at 6 months after tonsillectomy ( P < 0.05). The CLA/CD3 double-positive cells and the postcapillary venule that expressed with a ligand of CLA, E-selectin, were found more frequently in the plantar skin from patients with PPP as compared to that from healthy volunteers ( P < 0.01, each). These data suggest that a novel immune response to α- streptococci may enhance CLA expression on tonsillar T-cells through TGF-β production in patients with PPP, resulting in moving of CLA-positive tonsillar T-cells to skin and tissue damages. This may play a key role in pathogenesis of PPP.

Increase of activated T-cells and up-regulation of Smad7 without elevation of TGF-beta expression in tonsils from patients with pustulosis palmaris et plantaris

Pustulosis palmaris et plantaris (PPP) is known to be a skin disease related to tonsillitis, because the pustulosis often become exacerbated during acute tonsillitis and disappears after tonsillectomy. However, etiology of PPP remains unclear. In this study, we investigated the activation of tonsillar T-cell from PPP patients. Furthermore, we analyzed expressions of cytotoxic T-lymphocyte antigen-4 (CTLA4) that is a co-stimulatory molecule for inhibition of T-cell activation and of Smad7 that is a regulatory factor of TGF-beta intracellular signaling. For 47 Japanese patients with PPP who had tonsillectomy, the skin lesion was improved in 87% of PPP patient at 12 months after tonsillectomy. In quantitative immunohistologic analysis, T-cell nodules on tonsillar tissues from PPP patients were more expanded than those from the patients with obstructive sleep apnea syndrome (OSAS) ( P = 0.015), and there was a positive correlation between the enlargement and clinical improvement ( r = 0.422, P = 0.021). Flow cytometric analysis showed that the numbers of CD4+CD25+ and CD4+CD29+ cells in tonsils from PPP patients increased significantly compared to those from OSAS patients ( P = 0.017, P = 0.016, respectively). Using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting analyses with CD3+ tonsillar lymphocytes, we found that both expressions of Smad7 mRNA and protein were enhanced in PPP patients compared with OSAS patients ( P = 0.03, P = 0.02, respectively), but expression of TGF-beta mRNA was not different between 2 groups. Although mRNA expression of CTLA4 was reduced in PPP patients compared with OSAS patients ( P = 0.04), the CTLA4 surface protein expression was not different between 2 groups. These data suggest that helper T-cells are frequently activated in tonsils from PPP patients, and this activation may be related to unresponsiveness of TGF-beta1 by overexpression of Smad7. Such hyper-activation of T-cell may increase the risk of elicitation of self-reactive T-cell, being associated with pathogenesis of PPP.

A role of skin homing receptor on tonsillar T-cells from patients with pustulosis palmaris et plantaris

We investigated the expression of cutaneous lymphocyte antigen (CLA) on tonsillar T-cells from patients with pustulosis palmaris et plantaris (PPP). Two-color immunohistologic analysis was used for CLA expression in tonsillar tissues. Two-color flow cytometric analysis was performed for CLA expression on tonsillar T-cells at freshly isolated and α-streptococcal antigen stimulus conditions. Enzyme-linked immunosorbent assay (ELISA) was employed for the measurement of IL-6 and TGF-β levels in the culture supernatant fluids of tonsillar lymphocytes stimulated by α-streptococcal antigens. Two-color immunohistologic analysis and two-color flow cytometry revealed that the numbers of CLA-positive tonsillar CD3-cells in tissue and freshly isolated condition were significantly higher in patients with PPP than those in patients with non-PPP. Stimulation of α-streptococcal antigens from S. mitis and S. salivalius statistically increased CLA-positive CD3-cells in PPP, but did not in non-PPP. The stimulation of S. sanguis and S. salivalius antigen also increased TGF-β production by tonsillar lymphocytes from PPP, but did not from non-PPP. These results suggest that hyper-immune response to α-streptococci may increase CLA expression of tonsillar T-cells through TGF-β production, and it may play a key role in the pathogenesis of PPP.

The role of palatine tonsil in the pathogenesis of pustulosis palmaris et plantaris

Pustulosis palmaris et plantaris (PPP) is a skin disease considered to be caused by a focal infection of the palatine tonsils. We studied patients with PPP, recurrent tonsillitis and tonsillar hypertrophy, from whom tonsillar mononuclear cells (TNMC) and peripheral blood mononuclear cells (PBMC) were isolated; PBMC were collected again 6 months after surgery. The number of keratin-specific antibody-forming cells (AFC) in TNMC was found to be greater than those in PBMC as determined by ELISPOT assays, and were increased in patients with PPP when compared with patients with recurrent tonsillitis or tonsillar hypertrophy. In patients showing a remarkable improvement of PPP, the number of keratin-specific IgA AFC in TNMC was higher than in those who showed no improvement in their skin lesions. Further, the numbers of keratin-specific IgG AFC in PBMC were significantly decreased after surgery in patients with a good prognosis. The present results demonstrated the presence of keratin-specific immune responses in palatine tonsils. Further, keratin-specific IgA and IgG immune response in tonsils and peripheral blood were significantly correlated with the prognosis of PPP. Together, these findings suggest that keratin-specific immune responses in palatine tonsils might be associated with the pathogenesis of PPP.

Exacerbation of pustulosis palmaris et plantaris after topical application of metals accompanied by elevated levels of leukotriene B4 in pustules

<h2>Abstract</h2> <b>Background:</b> Pustulosis palmaris et plantaris (PPP) is a chronic inflammatory disease consisting of polymorphonuclear leukocyte infiltration, and is often exacerbated by focal infections such as tonsillitis. In some cases, metal allergy has been reported. <b>Objective:</b> The purpose of this study was to evaluate (1) the significance of metal allergy in the formation of pustules, and (2) the participation of leukotriene (LT) B₄ in the formation of pustules of PPP. <b>Methods:</b> Patch tests with metals were performed on 7 patients with PPP, and both pustular and plasma levels of LTB₄ were measured in these 7 patients before and 48 hours after metal patch tests. <b>Results:</b> Palmoplantar pustules were exacerbated after the metal patch tests in all 7 patients. The mean levels of LTB₄ in plasma and pustules of the volar surface at 48 hours after the metal patch tests were significantly higher than those before the metal patch tests. <b>Conclusion:</b> Metals can be important in the pathogenesis of PPP by contributing to the induction of high LTB₄ concentration in the pustules. (J Am Acad Dermatol 2000;42:1021–5.)

Exacerbation of pustulosis palmaris et plantaris after topical application of metals accompanied by elevated levels of leukotriene B4 in pustules

Background: Pustulosis palmaris et plantaris (PPP) is a chronic inflammatory disease consisting of polymorphonuclear leukocyte infiltration, and is often exacerbated by focal infections such as tonsillitis. In some cases, metal allergy has been reported. Objective: The purpose of this study was to evaluate (1) the significance of metal allergy in the formation of pustules, and (2) the participation of leukotriene (LT) B4 in the formation of pustules of PPP. Methods: Patch tests with metals were performed on 7 patients with PPP, and both pustular and plasma levels of LTB4 were measured in these 7 patients before and 48 hours after metal patch tests. Results: Palmoplantar pustules were exacerbated after the metal patch tests in all 7 patients. The mean levels of LTB4 in plasma and pustules of the volar surface at 48 hours after the metal patch tests were significantly higher than those before the metal patch tests. Conclusion: Metals can be important in the pathogenesis of PPP by contributing to the induction of high LTB4 concentration in the pustules. (J Am Acad Dermatol 2000;42:1021–5.)

皮膚科から見た掌せき膿ほう症とへん桃病巣感染症

It is widely accepted by otolaryngologists in Japan that the palatine tonsil is typically the site of focal infection in cases of pustulosis palmaris et plantaris (PPP). Numerous reports have indicated that about 80% of PPP cases are successfully treated by tonsillectomy. It is thus important to know how dermatologists treat PPP patients, especially in investigations of focal infection. Questionnaires were sent to 577 dermatologists in the Kinki district and 238 answers were analyzed. Dermatologists tended to treat PPP patients first with corticosteroid ointment and secondly with tonsillectomy. However the questionnaires revealed that tonsillectomy was performed on an average of 1.5 patients per year as treatment for PPP. Examination of focal infection, was carried out by about 70% of the dermatologists only in severe cases. Regarding the pathogenesis of PPP, 97% of the dermatologists agreed that PPP may be the result of tonsillar focal infection. However, almost all of them indicated that the percentage of patients in which the tonsil plays a role in the pathogenesis of PPP is less than 50%. The majority of dermatologists seem to feel that tonsillar focal infection plays a small part in the pathogenesis of PPP. On the basis of this study, it is stressed that we as otolaryngologists, should more clearly communicate the role of focal infections in dermatological disorders such as PPP and educate dermatologists regarding the very high curative rate of PPP by tonsillectomy.

Increased Interleukin-6, Interferon-? and Tumour Necrosis Factor-a Production by Tonsillar Mononuclear Cells Stimulated with Alpha-Streptococci in Patients with Pustulosis Palmaris et Plantaris

In vitro cytokine production by tonsillar mononuclear cells under culture conditions with or without lyophilized streptococcal antigens was measured by enzyme-linked immunosorbent assay (ELISA). Under culture conditions without any stimulus, a certain amount of interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, and interleukin (IL)-6, was detected in the supernatant culture fluids from all 29 donors tested and just detectable levels of IL-1alpha and IL-2 were identified in 5 of 12 donors tested; but IL-4 and IL-5 were not detected in any supernatants from 21 donors tested. In 16 patients with pustulosis palmaris et plantaris (PPP), all three alpha-streptococcal antigens from Streptococcus, (S.) sanguis, S. salivarius and S. mitis induced production of IL-6. IFN-gamma and TNF-alpha by tonsillar mononuclear cells at a significant level. However, no significant induction of such cytokines by alpha-streptococcal stimulus was seen in 13 donors without PPP. No significant difference in cytokine production by tonsillar mononuclear cells was seen between the PPP and non-PPP subjects, when stimulated with S. pyogenes, Staphylococcus aureus Cowan I and pokeweed mitogen. In the experiments using tonsillar cell subsets, the cytokine inductions by alpha-streptococcal stimulus were found in monocyte-depleted cells as well as in purified T-cells. but not in B-cells. These data suggest that IL-6, IFN-gamma and TNF-alpha may play an important role in immunological reactions in the tonsils and that a hyper-immune response to some of alpha-streptococcal antigens through increased production of such cytokines by tonsillar mononuclear cells, to which T-cells mainly contribute, may play a key role in the pathogenesis of PPP.

病巣性へん桃炎における免疫組織学的研究 画像解析による定量的検索

The purpose of this study was to clarify the mechanism of tonsillar focal infections such as pustulosis palmaris et plantaris (PPP), especially the role of tonsil on it. In 88 cases of various tonsillar diseases, i.e., PPP, chronic tonsillitis, and sleep apnea syndrome, distribution of immunocompetent cells, i.e., B cells having various immunoglobulin isotypes (IgG, IgM, IgA, IgD, IgE, IgA1, and IgA2) on their surfaces and T cell subsets, helper/inducer (CD4+) T cell and suppressor/cytotoxic (CD8+) T cell were investigated immunohistologically using monoclonal antibodies and ABC method. The proportion of the immunocompetent cells in four anatomical sites in tonsil (germinal center, mantle zone, interfollicular area, and subepithelial area) were quantitatively studied by the image analyzer (CUE-2, Olympus, USA) and compared among various age groups and among three groups of tonsillar diseases. The difference of immunocompetent cells in tonsils between the effective group (showing marked improvement of skin lesions of PPP after tonsillectomy) and the not-effective group (showing no improvement of skin lesions after tonsillectomy) was also investigated. The results were summarized as follows. 1) Every type of Ig-positive cells in tonsils was decreased in proportion to age, especially the changes of IgG-, IgM-, and IgD-positive cells were inversely proportional to age with statistical significance. On the other hand, changes to T cell subsets with age were smaller in comparison with those of Ig-positive cells, especially the proportion of CD4-positive cells showed almost no changes in accordance with age. 2) Eighty percent of cases with PPP were classified into the effective group, whereas only 20% of them into the not-effective group. 3) IgG-, IgM-, and IgD-positive cells in tonsils of PPP were found to be significantly increased in the effective group compared to the not-effective group. In addition, in the effective group, CD4-positive cells were significantly increased in the interfollicular area and the subepithelial area of the tonsil. These results indicate that the image analysis will be a breakthrough in quantitative study on the immunohistology of the tonsil and give us useful informations in terms of the mechanism of tonsillar focal infections, i.e., immunological abnormalities in tonsils may play one of the important roles in the pathogenesis of PPP.

掌せき膿ほう症患者へん桃リンパ球のレンサ球菌に対する免疫応答に関する研究

The purpose of this study was to clarify the etiological role of immune responses in tonsillar lymphocytes of the patients with pustulosis palmaris et plantaris (PPP). In order to determine their immune response to S. pyogenes T4, S. pyogenes T12, S mitis, S. salivarius, S. sanguis I, S. sanguis II and S. pneumoniae, tonsillar lymphocytes from patients with PPP, CT, and sleep apnea syndrome (control) were cultured with formalinized streptococcal cellular antigens. Blastoid transformation was investigated by [3H] -thymidine uptake, while antistreptococcal antibody production were measured by an enzyme-linked immunosorbent assay (ELISA). The results were as follows. 1. Tonsillar lymphocytes from PPP patients underwent blastoid transformation and accelerated the production of immunoglobulin G following the addition of S. sanguis I, S. sanguis II S. mitis, S. pyogenes T4, and S. pyogenes T12, while those form CT patients and controls did so only with S. pyogenes T4 and S. pyogenes T12. 2. The spontaneous production of specific IgG against various streptococci, including S. sanguis I, S. sanguis II and S. mitis by tonsillar lymphocytes from patients with PPP was already higher than that from CT patients and controls. The specific IgM production was also increased above that in PPP patients without any antigens. 3. S. sanguis I, S. sanguis II and S. salivarius antigens stimulated antigen-specific IgM production in tonsillar lymphocytes from PPP patients. 4. The levels of specific IgG production against S. sanguis I and S. sanguis II by tonsillar lymphocytes from PPP patients showed a relationship with the serum levels of the PPP patients. These results suggested that the sensitization of alpha-streptococci, especially S. sanguis, in the tonsillar lacunae may lead to the specific production of anti-S. sanguis antibodies in patients with PPP, and these may be involved in the pathogenesis of PPP.

Pustulosis Palmaris Et Plantaris: With Reference to the Cross-Reactivity between Tonsillar Epithelium Antigen and Skin Antigen

Though it is well known that pustulosis palmaris et plantaris (PPP) is one of skin diseases caused by focal infection of the tonsils, its etiology remains unknown. The purpose of this study was to elucidate the role of the tonsils in the pathogenesis of PPP, by using histological and immunological techniques. Our findings were as follows: The common histological findings in tonsillar lacunae of patients with PPP were pus plugs, pronounced infiltration of polymorphonuclear cells and mononuclear cells, desquamation of keratinized squamous cells, uneven thickness of the epithelium, and inflammation of the subepithelial area. By applying Arthur's method, skin extracts of sole (S) and epithelial extracts of tonsillar lacunae (T) were prepared as antigens for rabbit immunization. Cross-reactivity between skin extract of sole and epithelial extract of tonsils was tested using the Ouchterlony technique. Anti-T antisera reacted to both T and S. Anti-S antisera reacted similarly to T and S. Direct and indirect immunofluorescence studies using anti-T and anti-S antisera revealed positive staining either in the lacunal epithelium of tonsil or in the corneous, granular and papillary layers of sole. As regards the pathogenesis, it is suggested that the antigenic modification of tonsillar epithelium caused by various stimuli produces cells and/or antibodies so as to challenge against skins.