The role of the co-receptors 2B4/CD48 in allergic eosinophilic airway inflammation

Abstract

Eosinophils have a pivotal role in the pathogenesis of allergic airway disorders. They express a variety of receptors involved in their activation. Recently, the role of the CD2 Ig superfamily of receptors in eosinophilic inflammation, especially 2B4 and CD48, has been explored in allergic rhinitis and asthma. In recent years, there has been increasing evidence suggesting that these two molecules have an important role in allergic airway disorders. In this article, the most recently acquired data on the role of CD48 and 2B4 in allergic airway disorders are reviewed.

• eosinophil
• 2B4
• CD48
• CD2
• allergic rhinitis
• asthma

Eosinophils are bone marrow-derived, blood circulating granulocytes with a typical bi-lobed nucleus and cytoplasmatic granules (1, 2).

In recent years, there has been an increased awareness regarding the role of the eosinophil in several physiologic and pathologic processes. The eosinophils have an important role in the pathogenesis of allergic airway diseases (3–5).

Eosinophils express a variety of receptors for different agonists which may activate them in their pathophysiological environment. For example, they express receptors for IgA, IgG, cytokines, chemokines, PRRS, and complement components (6). Activation of eosinophils results in secretion of specific crystalloid granule proteins such as major basic protein (MBP), eosinophil peroxidase (EPO), eosinophil-derived neurotoxin, eosinophil cationic protein, arachidonic acid metabolites, and cytokines (3, 6).

Recently, the role of the CD2 subfamily receptors on eosinophils has been investigated in allergic airway diseases and in atopic dermatitis. Two of these molecules, 2B4 and CD48, considered to have an important role in the pathophysiology of these disorders, are gaining increasing attention (7).

This review will discuss key evidence from animal models and from human clinical trials which may show the role and the importance of these molecules in the pathogenesis of allergic airway disease.

CD2 subfamily of receptors

Recently, the expression and function of the CD2 subfamily of receptors, especially 2B4 and CD48, has been widely explored in allergic airway disorders. The CD2 subfamily of eosinophilic receptors include CD2, CD48, 2B4 (CD244), CD150 (SLAM), CD229, BCM-like membrane, SF2001, NTB-A, and CS1 (7, 8).

CD48 is a glycosylphosphatidylinositol-anchored protein belonging to the CD2 subfamily. It is expressed mainly in hematopoietic cells and exists in both membrane-associated and soluble forms. It is a low-affinity ligand for CD2 and is implicated as an important co-stimulatory molecule in lymphocyte activation. CD48 has a broad immunologic role (7, 9).

In addition, CD48 is a high-affinity ligand for 2B4. CD48-2B4 interactions can modulate T cells, B cells, and natural killer (NK) cell functions and cross-talk. It is involved in cellular activation, co-stimulation, and adhesion of these cells (7, 10). The absence of functional 2B4-CD48 interactions impairs NK cell cytotoxic response and IFN-γ release on tumour target exposure.

CD48 cross-linking on human eosinophils triggers release of eosinophil granule proteins, cytokines, and chemokines.

2B4 is a cell surface glycoprotein of the CD2 subfamily. 2B4 is expressed on NK cells, CD^{8 +} T cells, and myeloid cells. Engagement of 2B4 on NK cells with specific antibodies or with its ligand CD48 enhances NK cell–mediated cytotoxicity (7, 10, 11).

Recent studies suggest that 2B4 and CD48 have an important role in eosinophil pathology. Data suggest that 2B4 is an activating receptor on human eosinophils. Cross-linking of 2B4 triggers eosinophil degranulation and cytokine release, and induce cytotoxicity towards CD48⁺tumour cells (12–14).

Munitz et al. (7) showed that cross-linking of 2B4 caused eosinophils to release EPO, a member of the haloperoxidase family, which catalyses the perioxidative oxidation of halides and pseudohalides. Once EPO is released, it can elicit several effects, some of which are protective, and others are destructive. In addition, cross-linking of 2B4 triggers IFN-γ and IL-4 release from eosinophils.

The demonstration that 2B4 activation on eosinophils can elicit both EPO and IL-4, as well as IFN-γ, raises the possibility that the function of 2B4 on eosinophils has a broad immunological importance and can contribute to eosinophil effector functions in both Th1- and Th2-like responses (7).

In the same study, it was demonstrated that the activation of eosinophils via 2B4 caused cytotoxic effects towards malignant cells.

2B4/CD48 in eosinophilic airway inflammation

Allergic rhinitis (AR) is the most common type of chronic rhinitis, affecting 10–20% of the population. Evidence suggests that the prevalence of the disorder is increasing.

In the past, AR was considered to be a disorder localized to the nose and nasal passages, but current evidence indicates that it may represent a component of a systemic airway disease involving the entire respiratory tract. Evidence has shown that allergen provocation of the upper airways leads not only to a local inflammatory response, but also to inflammatory processes in the lower airways. This is supported by the fact that rhinitis and asthma frequently coexist (15–18).

Nasal and/or blood eosinophilia is a hallmark of the pathophysiology of allergic airway disorders such as AR, asthma, and chronic rhinosinusitis. Accumulation of the eosinophils in the inflamed airway, with subsequent activation of their cytotoxic granule proteins released by the proper stimuli, is believed to contribute to nasal hyper-responsiveness and to tissue damage (3). Accumulating evidence had established that eosinophils largely contribute to the development of airway remodelling in asthma (19–21).

El-shazly et al. (22) demonstrated that 2B4 molecule expression had increased after a single nasal allergen challenge in eosinophils obtained from AR patients.

In another study by Zeddou et al. (23) on AR patients sensitized against house dust mite (HDM), a single nasal allergen challenge with the HDM allergen has resulted in a clear increase in the percentage of eosinophils expressing intracellular CD48 in all tested patients. Another interesting observation in this study was that 20% of patients whose nasal allergy was worsened by asthma and nasal polyps demonstrated an increase in surface CD48 expression. These patients also had a high eosinophil peripheral blood count (8–10%). Consistent with the results of Munitz et al. (7), this may reflect a phenotype effect, since Munitz et al. had demonstrated CD48 surface expression in atopic asthmatics, and in eosinophils obtained from nasal polyps.

These results may indicate a possible role for the dynamic expression of CD48 in the pathophysiology of AR and highlight CD48 as a useful marker for the severity of eosinophilic inflammation (7).

CD48 may have a potential role in mediating eosinophil adhesion. This may be concluded from the observation that blockage of CD48 inhibits eotaxin-induced eosinophil adhesion to collagen IV in a dose-dependent fashion (23).

CD48 expression was found to be increased in tissue and in blood eosinophils obtained from asthmatic donors. Strengthening the role of CD48 in allergic airway diseases is the finding that CD48 is increased in lungs of allergen challenged mice (13, 24).

CD48 was shown to be up-regulated in two murine models of allergic eosinophilic airway inflammation. This was demonstrated by quantitative microarray analysis, which revealed that mRNA expression of CD48, but not CD2 or 2B4, was significantly increased in both ovalbumin (OVA) and aspergillus-induced allergic eosinophilic airway inflammation models (7).

Another demonstration of the importance of CD48 is the finding that neutralization of CD48 in allergen-induced murine models abrogated eosinophilic inflammation, TH2 and pro-inflammatory cytokine expression, lung inflammation, mucous production, and smooth muscle hyperplasia. This was also seen in histological analysis of eosinophilic lung inflammation. Anti-CD48-treated mice had a striking reduction in several parameters of lung inflammation (13).

Furthermore, experiments with anti-CD48, anti-CD2, and anti-2B neutralizing monoclonal antibodies (mABs) demonstrate that CD48 is critically involved in allergic eosinophilic airway inflammation (7).

These effects of anti-CD48 treatment are only partially dependent on interactions with CD2 expressed on lymphocytes, as anti-CD2 treatment induced a relatively modest effect (13).

In addition, OVA-challenged mice displaced increased IL-4, IL-5, IL-13, TNF-γ, and eotaxin levels. However, neutralization of CD48 showed a pronounced reduction of these cytokines (73–93% decrease) (7).

An important role of CD48 in eosinophil activation was shown in atopic dermatitis. The skin of atopic dermatitis patients showed a striking increase of eosinophil-associated CD48 expression (25).

2B4 seems to have an important role as a stimulating signal for eosinophils trafficking. This was demonstrated by an atopic dermatitis murine model, in which 2B4 −/− mice showed hampered eosinophils infiltration (26).

Another function of eosinophils is cytotoxicity towards several malignant cells. Eosinophils have been documented to be elevated in peripheral blood and/or to infiltrate the tissue in some malignant disorders. In addition, they have been shown to display direct and indirect anti-tumour effect both in vitro and in vivo. 2B4 was found to trigger eosinophil cytotoxicity towards malignant cells, as it does in NK cells (12).

A recent study by Levi-Schaffer et al. (unpublished data) demonstrated that both the leukocytes membrane CD48 (mCD48) and the soluble form of this protein (sCD48) are elevated in asthmatic patients. The authors concluded that CD48 in peripheral blood may be a potential biomarker for asthma and may eventually serve as a therapeutic target for this disease.

The results of the above studies indicate that CD48 and/or CD48-2B4 may be used as a novel target for therapeutic modalities in airway allergy and may be of important value in monitoring allergic eosinophilic inflammation.

Conclusion

Eosinophils have a pivotal role in allergic airway diseases. The studies summarised in this review have shown evidence of the important function of 2B4/CD48 molecules, which are critical for the function of eosinophils in these diseases. These molecules may be targeted pharmacologically, thus providing new medications for allergic airway diseases. Of course, more research needs to be carried out.

Conflict of interest and funding

The authors have not received any funding or benefits from industry or elsewhere to conduct this study.