The role of CD30 in atopic disease (2001)

The functional role of CD30 has been a matter of debate during the last decade. This molecule has a very distinct expression on lymphoid cells, a fact which indicates a specific immunologic function. The findings that CD30 knockout mice have enlarged thymuses and that CD30 transgenic mice exhibit enhanced killing of thymocytes suggest a role for CD30 in the negative selection in the thymus. However, the function of CD30 in mature T cells is still unknown. CD30 has been associated with T helper (Th) 2 cells and with human disorders dominated by a Th2 type of immune response. This review summarizes the findings on CD30 in atopic disorders, with the focus on atopic dermatitis (AD). The CD30 (Ki-1) surface antigen was originally identified on the tumor cells of Hodgkin's disease, i.e., Hodgkin and Reed-Sternberg cells (1). The monoclonal antibody (mAb) which was produced reacted selectively not only with the Hodgkin and Reed-Sternberg cells, but also with a small but distinct population of cells in lymph nodes and tonsils, as well as scattered CD30+ cells in the bone marrow (1). Further screening for CD30 expression identified CD30/Ki-1 positive non-Hodgkin's lymphoma, and anaplastic large-cell lymphomas (2). It was also found that CD30 is activation dependent, since it is virtually absent on normal resting peripheral blood mononuclear cells (PBMC), but can be induced by mitogen activation, or by infection by viruses such as Epstein-Barr virus (EBV) or human T-cell leukemia viruses (HTLV I and II) (2). Subsequently, it was demonstrated that CD30 is expressed by a subset of CD45RO+ (memory) T cells (3). The CD30 molecule is a type I transmembrane protein of 120 kDa with a 90-kDa nonglycosylated precursor (4) (Table 1, Fig. 1). CD30 was cloned in 1992 and determined to be a member of the tumor necrosis factor receptor (TNF) superfamily (5). It is characterized by six cysteine-rich motifs in the extracellular domain, showing significant homology to the other TNFR family members. In the intracellular parts, however, no homology was found (5) (Fig. 1). The rapidly expanding TNF receptor and ligand families. (modified after Herbein & O’Brien [97]). A soluble form of CD30 (sCD30) has been described (6) (Table 1). This 85/88-kDa molecule is generated when the membrane-bound CD30 protein is cleaved by a zinc metalloproteinase and released from the cell surface (7). The sCD30 shedding can be enhanced by certain anti-CD30 antibodies (8, 9) or by interaction with CD30L+ cells (10). sCD30 can be detected both in vivo, in serum, and in vitro, in cell-culture supernatants of CD30+ cells (6), with a highly sensitive ELISA test kit. Elevated levels of sCD30 have been found in several human disorders, such as various lymphomas and infectious diseases, including Hodgkin's disease and HIV infection (11, 12), while the levels are relatively low in normal healthy subjects. A role for sCD30 as a marker of disease activity and with prognostic significance has been suggested. Indeed, a correlation between disease spread and tumor burden has been shown in Hodgkin's disease patients (11). Furthermore, in patients with HIV infection, a faster progression to AIDS could be demonstrated in patients with elevated sCD30 levels in the early phases of infection (12). The possible immunologic function of sCD30 is not clear. Circulating sCD30 might reflect ongoing biologic events involved in CD30-related diseases. The 26–40-kDa CD30 ligand (CD30L/CD153) has been cloned and shown to be a member of the TNF ligand family (13) (Table 1, Fig. 1). This type II membrane protein is not detectable on resting T cells and macrophages, but it is expressed on both activated T cells and macrophages (13, 14). Furthermore, CD30L expression on resting B cells (15), granulocytes, eosinophils, and neutrophils (16), as well as on various neoplastic cells (17), has been reported. Signal transduction through CD30 has been found to augment proliferation under some circumstances (13), but in other cases to potentiate apoptosis (18). Interestingly, CD30L has been detected in the human thymus. A high expression of CD30L was observed in the outer wall of Hassall's corpuscles, structures in the thymic medulla containing epithelial cells, macrophages, and cell debris, and on epithelial cells in the medullary areas. In addition, CD30 expression was found on CD4+ CD8+ medullary thymocytes, indicating that an interaction between CD30/CD30L could occur in the thymic medulla (19). Indeed, CD30 knockout mice have enlarged thymuses and increased number of thymocytes compared to littermates (20). These data strongly suggest that the CD30/CD30L interaction is involved in the negative selection in the thymus. In our laboratory, we made the novel observation of CD30L+ cells in the fetal part of the placenta. In all the placental specimens studied, CD30L+ cells were detected all over the mesenchymal part of the chorionic villi, in villous stroma, and close to the trophoblast area. Scattered positive cells were also detected in the mesenchymal part of the chorionic plate, in the decidual region, and in umbilical cord tissue (21). From the structure of the CD30L immunoreactive cells in the villous stroma, we concluded that these cells are probably placental macrophages, i.e., Hofbauer cells (22). Indeed, the localization of these cells close to fetal vessels and trophoblasts makes a regulatory function of these cells likely. It is possible that the CD30L expression observed on these placental macrophages plays a role in immune regulation. It is also interesting that the placenta has been proposed to be a site for extrathymic T-cell development (23). Furthermore, a regulatory role for CD30 has been suggested in primary cutaneous CD30+ T-cell lymphomas, in which CD30L was expressed in regressing lesions, but not in growing ones (24). CD30 is preferentially expressed by activated lymphoid cells. In normal peripheral organs, however, CD30 expression is rather low. Resting peripheral blood lymphocytes were found to be negative for CD30. However, one recently published article showed that a variable proportion (3–31%) of circulating T cells in the normal peripheral blood are CD30+, and many of these are CD8+ T cells (25). This variability in results is probably due to the sensitivity of the staining technique. CD30+ cells can also be detected within the parafollicular areas and in the rim of the follicular centers in the lymph nodes (26). In addition, CD30+ cells are found in the medulla of the thymus, mainly around Hassall's corpuscles (19). B cells also express CD30 to a variable extent, as do activated NK cells, endothelial cells, and decidual cells (27–30). sCD30 levels in normal individuals vary, but are usually very low (6–7, 11–12). However, in some studies in which healthy blood donors were used as controls, very high sCD30 levels have been reported (31, 32), most notably in the younger age groups (32). Since CD30 is upregulated after virus infections, the high sCD30 levels in these individuals could be explained by EBV infection (33). In contrast to the low levels of CD30 in healthy individuals, high expression of CD30 has been demonstrated in tumors of the immune system, the malignant lymphomas. CD30 expression is important for the identification of Hodgkin's disease (HD), anaplastic large-cell lymphoma (ALCL), and CD30+ non-Hodgkin's lymphoma. In HD, CD30 is expressed by the giant multi- and mononucleated Hodgkin and Reed-Sternberg cells. The origin of these cells is still unknown (10). Patients with HD also have elevated levels of sCD30 in their blood, in correlation with the clinical features (11). Overexpression of CD30 has also been detected in nonhematolymphoid neoplasms, such as embryonal carcinomas (34), and in some seminomas (35, 36). CD30 also appears to play a role in nonneoplastic diseases. The number of CD30+ cells/levels of sCD30 increases in patients with infectious mononucleosis (33), which is usually caused by EBV. There is overexpression of CD30 also in HIV, hepatitis B, and hepatitis C (12, 37, 38). Moreover, when the expression and release of CD30 were investigated in patients with measles infection, elevated sCD30 levels and an expansion of the CD4+ CD30+ and CD8+ CD30+ cells subsets compared to healthy controls were shown (39). The identification of the two T helper subsets, Th1 and Th2, which each produce a distinct pattern of cytokines, has helped us to understand the mechanisms by which polarized immune responses occur in vivo in various human conditions, and in response to different pathogens. Indeed, Th1 cells are involved in monocyte/macrophage-mediated inflammatory responses, while Th2 cells promote Ig production and enhance eosinophil and mast-cell activation and proliferation (40–42). Th subsets with less differentiated cytokine profiles, designated Th0, usually mediate intermediate effects, depending on the ratio of cytokines produced and the type of target cell (41, 43). It has been shown that during early T-cell activation, the surrounding environment determines the profile of the subsequent T-cell response. IL-4 favors the development of a Th2 response, while IL-12 promotes a Th1 response. Furthermore, it has been suggested that the two subsets counteract each other's development and activities, since Th2-type cytokines (IL-4, IL-10) inhibit Th1 responses, and Th1-type cytokines (IFN-γ) repress the development of Th2 responses (40–42). Strongly polarized human Th1 and Th2 responses not only are involved in protection, but also cause various types of human immunopathologic reactions (44). Human disorders in which a Th1 type of response is believed to predominate include contact dermatitis, multiple sclerosis, rheumatoid arthritis, and unexplained recurrent abortions (45–48). On the other hand, a predominately Th2 type of response has been proposed to be involved in atopic disorders, progression to AIDS in HIV infection, and Omenn's syndrome, as well as in successful pregnancy (45, 49–51) (Table 2). It has been shown that CD30 expression is dependent on activation (52, 53). Exactly what regulates CD30 expression is, however, still unknown. After analysis of CD30 expression in CD4+ T-cell clones, it was suggested that CD30 is preferentially expressed by those identified as Th2 (54, 55). Our own data on allergen-specific T-cell clones contradict the results of Del Prete et al., since we observed that Th1 and Th0, as well as Th2, clones had the ability to express CD30 after activation (53). However, in our data, we noted an extended expression of CD30 and a higher mean fluorescence intensity (MFI) in the clones defined as Th2. Hamann et al. have since confirmed our results by showing, in a large panel of human Th1, Th0, and Th2 clones, that no correlation existed between CD30 expression and Th phenotype (56). Thus, the correlation between CD30 expression and cytokine profile is controversial, and CD30 may not be used as a marker to define the Th2 cell subset. Still, the higher MFI and the extended expression of CD30 in the cells defined as Th2 might suggest an association of molecule with such as Indeed, increased expression of CD30 and the release of soluble have also been found in several the of CD30 was in the target of patients with characterized by Th1 sclerosis, disease, and or Th2 syndrome, sclerosis, and high CD30 expression was detected in the but not in the disorders It has been suggested that is an to a Th2-type pattern in individuals Moreover, large of CD8+ T-cell clones with a Th2-type cytokine pattern were from the blood and of patients with HIV infection In of the overexpression of CD30 in HIV infection, might also an of CD30 in Th2 responses in It has also been shown that CD30 is expressed by decidual cells confirmed these findings when we placenta specimens from atopic and for the of CD30 by CD30 expression was found on the decidual cells, but in the placenta or umbilical cord (21). However, the expression of CD30 in human decidual cells might the environment in the have the function of the Th2 response. The CD30 to Th2 cells and Th2-type of responses is still unknown. However, in mice have results on the of CD30 et al. showed that IL-4 induced CD30 expression on activated CD4+ T cells, while This could the and expression of CD30 on Th2 cells 55). Furthermore, et al. demonstrated that CD30 expression on activated T cells IL-4 or is a inflammatory disease that It is a around of The of are early in of age in and in of the patients have been to in a to the development and of and immunologic The of is on the of and associated clinical including a and of the lesions, as well as a of atopic disease The of is not However, most patients with have elevated levels of and elevated of circulating eosinophils, an increased expression of Th2 cytokines Indeed, a number of studies have demonstrated increased of allergen-specific T cells increased and but in the peripheral blood of patients with of including and are used in the of disease However, studies are to to the of of Th2 responses by the of the different as well as to a between Th1 and Th2 cytokine responses, be the role of CD30 in we from patients with for the of higher levels of sCD30 in the of the patients the controls These results are in with other groups have found increased of sCD30 in both and patients On the other hand, levels of sCD30 were observed in patients with contact dermatitis a which might reflect the response in disease when sCD30 levels in we not significant compared with the healthy controls This is since it has been suggested that is a disease of CD30+ cells in have been reported virtually no CD30+ cells were found in the of patients with (Table et al. compared the CD30 expression in the inflammatory of and lesions, CD30+ cells were found in all from lesions, while CD30 expression was absent or very in the specimens Interestingly, both Th1 and Th2 cytokines have been shown to to the of in depending on the of the The is associated with a of IL-4 and expression while in the and are also expressed Moreover, increased levels of cutaneous antigen T cells CD30 were found in patients with The increased levels of sCD30 in might reflect release by CD30+ cells or by circulating CD30+ T cells. to published the number of CD30+ cells in the as by has been or very in both normal and atopic Still, in a by et al., a mean of of CD30+ CD4+ CD45RO+ from patients was a higher for the controls It was also demonstrated that the number of CD30+ cells with the number of cells in the Interestingly, was an correlation between the of cells and cells Elevated sCD30 levels have also been found in patients with but not in patients with disorders et al. showed that a number of CD4+ T cells from atopic atopic or healthy controls express CD30. also demonstrated an correlation between production and the of CD4+ CD30+ cells in from both atopic and (Table Moreover, Del Prete et al. reported a small number of CD4+ CD30+ cells in the of of six atopic donors during the while virtually no CD4+ CD30+ cells were detected the These CD4+ CD30+ cells were specific and produced Th2-type cytokines et al. not significant in sCD30 levels when a of patients with atopic disorders with controls et al. investigated the expression of CD30 from patients with and compared it with that of A significant expression in the of the atopic patients was Interestingly, a correlation between CD30 and levels was also a which might a functional role for CD30 in the response in patients In a of with and also with the found higher sCD30 levels in controls, while the levels of IL-12 in were not different from controls In sCD30 levels were also in with However, the sCD30 levels in these patients were not higher in In had elevated levels of IL-12 from patients with et al. found a significant number of T cells CD30 Furthermore, et al. reported a higher number of cells in the of patients with in controls There is still no marker to The of CD30 as a biologic to disease activity in or as a of atopic disease has been Since the levels of CD30+ cells in the of both atopic and individuals are very the of which are detected in has been used to the association with clinical in atopic In our laboratory, we investigated the between the of sCD30 and levels in a of However, we found no significant we between sCD30 levels and the clinical which was by the of a to the In with our data, et al., et al., observed no between sCD30 and in patients with was correlation found between sCD30 and levels in patients with other atopic (32). In a between the of sCD30 and disease activity in has been described et al. reported a correlation between the number of CD30+ CD4+ CD45RO+ circulating T cells in patients and clinical and peripheral eosinophil However, not a between sCD30 levels and clinical findings the that can various have significant including The designated has also as a in with were for with the was an in the clinical with levels of and as well as eosinophil protein However, no significant in sCD30 was noted in the different during correlation between of sCD30 and disease or levels was found However, the correlation with disease activity was in a by for to contact with of the patients as a The in both with a in patients with Interestingly, sCD30 levels the in both with a significant after This may that is a to a in sCD30 but that after these levels do reflect the clinical Moreover, et al., et al., demonstrated sCD30 levels in patients with that were with with clinical it has been reported that in patients with and for 2 the with the of CD30+ cells within the T-cell subset In the results from different that patients with have elevated levels of sCD30 in their blood compared to healthy Still, the correlation between CD30 and clinical is a In some the levels of sCD30 with disease while a correlation with has not been sCD30 in with other be as a marker in the of and to disease The of high levels of sCD30 in cord blood can the development of or in early has been However, when et al. investigated the levels of sCD30 in the cord blood of the age of had disease, found no between sCD30 in cord blood and the subsequent development of disease In a we have investigated sCD30 levels in from cord from with atopic and from with (21). The results showed no significant in sCD30 between the two groups of However, the levels of sCD30 in cord blood, of were relatively high compared to the of sCD30 in the (21). Interestingly, sCD30 in cord blood with sCD30 our of sCD30 has not been However, one could be that the sCD30 levels also the The mechanisms that the to the a tissue and it through pregnancy to are still not However, studies in suggest that a of to a successful of is the production of certain cytokines (IL-4, and IL-10) and and in the which has been shown to promote a in the of cytokine from a and a Th2-type might that the Th2 environment surrounding the during pregnancy is the cause of the elevated sCD30 levels observed in Indeed, et al. have shown that a the Th1 pattern when the immune in the growing and that is with sCD30 levels In addition, sCD30 levels were in a of healthy in a of healthy Since pregnancy to be a with a immune response and since recurrent abortions might be due to a Th1 the of sCD30 were determined in from with normal pregnancy and from with recurrent However, no significant was shown between the groups a which that sCD30 be used as a marker to pregnancy CD30 and CD30L to the rapidly expanding TNF receptor and ligand that are involved in immune regulation. the of the TNFR family are and the factor the antigen and (Fig. 1). The family are very in their extracellular but are in the intracellular The family of TNF factor CD30 and (Fig. 1). It is believed that the of the TNF ligand family are and mediate their by of the receptor the cell surface It has been shown that the ligand family can biologic responses, including activation, and cell the function of interaction in human allergen-specific Th cells, we used anti-CD30 It has been shown that antibody has i.e., the ability to a response in a and CD30 receptor In our we activated human allergen-specific Th clones of Th1 and Th2 type with as a with observed an increased production of in the Th1 clones, and of IL-4 and in the clones defined as Th2, after compared to cytokine production after with the antibodies Our that the anti-CD30 by can as a positive in activated T cells by the in both Th1 and Th2 clones These data to with those by Del Prete et al. described an in cytokine production only in Th2 cells, and not in Th1 cells. These also demonstrated a development of Th2 cells after CD30 of interaction induced a the Th1 phenotype It has been demonstrated in various cells that activation with anti-CD30 or with cells CD30L on their can effects, from proliferation to cell The mechanisms by which CD30 these are However, the have been to the of the target of and The may also be explained by of CD30 transduction through a family of we the surface expression of CD30 by in the after to the anti-CD30 were in the number of CD30+ cells after However, the CD30 mean fluorescence intensity (MFI) was in all the clones after to compared to the studies have made it that some anti-CD30 antibodies the release of inhibit it This could be explained by the induced by a certain the CD30 to while antibody may the site the CD30 and inhibit Since our results elevated levels of sCD30 in supernatants after CD30 it is that induced of the membrane-bound CD30 also in our The immunologic function of sCD30 is still not clear. It is not the elevated sCD30 levels associated with several human disorders (12, the activated of these immune or sCD30 plays an role in the immune response. It has been shown that sCD30 can to the CD30L on peripheral blood lymphocytes sCD30 may not be to CD30L and a but of the interaction by sCD30 could CD30 It has been shown in human T-cell that of CD30 the activation of studies a role for CD30 in HIV infection It has been reported that of CD30 on CD4+ T cells to activation and enhanced HIV The role of interaction in the mechanisms in is still an CD30 or sCD30 have a role in the by or the Th2 responses in disease, or the overexpression of CD30 and the release of soluble reflect the Th2 response in and Th2 cells are believed to play an important role in the and of the response by the production of certain IL-4 and promote the production of antibodies by B the and activation of and the of cells and The expression of CD30 on cells and the CD30 expression on CD4+ cells suggest an of CD30 in the Our results showing enhanced cytokine production after CD30 suggest that CD30 plays a role as a positive of T-cell immune responses Indeed, the function of CD30 as an important molecule in immune responses has been suggested The of is, for unknown the atopic are and The phenotype is dependent not only on but also on and after The mechanisms involved in the reactions are only is still unknown. It is however, that the cytokines produced by Th2 cells, and play an important role in the as promote the production of antibodies by B cells, cause the and activation of eosinophils, and the of cells and The CD30 molecule has been to be preferentially expressed by T cells cytokines However, the correlation between CD30 and a certain cytokine profile is still (52, and the be that CD30 be used as a marker to Th2 cells. Still, increased expression of and the release of soluble has been found in several the atopic groups have reported elevated levels of sCD30 and increased expression of CD30+ cells in the of patients (31, In some of the a between the levels of of CD30+ cells and clinical has been has a correlation between CD30 and been is still no marker to disease activity in analysis of CD30+ cells could be a to the of and the levels of sCD30 may function as an marker for of disease activity and after I for of the This was by from the the and the and the for the for and the for and