Aminopeptidase N (CD13) is a widely expressed ectoenzyme with functions that do not always depend on its enzymatic activity: an aspect that has been overlooked. Numerous CD13-targeting tools have been developed in the last few years. Several of them are already undergoing clinical trials, and there are promising reports on the effectiveness of others in animal models of disease. However, their efficacy might be obscured by their effects on unrecognized functions of CD13, resulting in unexpected complications. The purpose of this review is (i) to discuss the various functions ascribed to CD13 and the possible mechanisms behind them and (ii) to consider some of the questions that need to be answered to achieve a better understanding of the biological relevance of these functions, a more precise interpretation of the results obtained after their manipulation and a more rational design of CD13-targeting agents.

The atopic march recognizes the increased occurrence of asthma, allergic rhinitis, or both after atopic dermatitis (AD) onset. Mechanisms for developing atopic comorbidities after AD onset are poorly understood but can involve the impaired cutaneous barrier, which facilitates cutaneous sensitization. The association can also be driven or amplified in susceptible subjects by a systemic T H 2-dominant immune response to cutaneous inflammation. However, these associations might merely involve shared genetic loci and environmental triggers, including microbiome dysregulation, with the temporal sequence reflecting tissue-specific peak time of occurrence of each disease, suggesting more of a clustering of disorders than a march. Prospective longitudinal cohort studies provide an opportunity to explore the relationships between postdermatitis development of atopic disorders and potential predictive phenotypic, genotypic, and environmental factors. Recent investigations implicate disease severity and persistence, age of onset, parental atopic history, filaggrin (FLG) mutations, polysensitization, and the nonrural environment among risk factors for development of multiple atopic comorbidities in young children with AD. Early intervention studies to repair the epidermal barrier or alter exposure to the microbiome or allergens might elucidate the relative roles of barrier defects, genetic locus alterations, and environmental exposures in the risk and sequence of occurrence of T H 2 activation disorders. (J

We propose that the normal immunocompetent B cell repertoire is replete with B cells making antibodies that recognize brain antigens. Although B cells that are reactive with self antigen are normally silenced during B cell maturation, the blood–brain barrier (BBB) prevents many brain antigens from participating in this process. This enables the generation of a B cell repertoire that is sufficiently diverse to cope with numerous environmental challenges. It requires, however, that the integrity of the BBBs is uninterrupted throughout life to protect the brain from antibodies that crossreact with microorganisms and brain antigens. Under conditions of BBB compromise, and during fetal development, we think that these antibodies can alter brain function in otherwise healthy individuals.

During inflammation, cell surface adhesion molecules guide the adhesion and migration of circulating leukocytes across the endothelial cells lining the blood vessels to access the site of injury. The transmembrane molecule CD13 is expressed on monocytes and endothelial cells and has been shown to mediate homotypic cell adhesion, which may imply a role for CD13 in inflammatory monocyte trafficking. Here, we show that ligation and clustering of CD13 by mAb or viral ligands potently induce myeloid cell/endothelial adhesion in a signal transduction-dependent manner involving monocytic cytoskeletal rearrangement and filopodia formation. Treatment with soluble recombinant (r)CD13 blocks this CD13-dependent adhesion, and CD13 molecules from monocytic and endothelial cells are present in the same immunocomplex, suggesting a direct participation of CD13 in the adhesive interaction. This concept is strengthened by the fact that activated monocytic cells adhere to immobilized recombinant CD13. Furthermore, treatment with anti-CD13 antibodies in a murine model of peritonitis results in a decrease in leukocyte infiltration into the peritoneum, suggesting a potential role for CD13 in leukocyte trafficking in vivo. Therefore, this work supports a new direction for CD13 biology, where these cell surface molecules act as true molecular interfaces that induce and participate in critical inflammatory cell interactions.

Background: Little is known on the current global prevalence of atopic dermatitis (AD) in the pediatric population.Objective: To estimate the real-world global prevalence of AD in the pediatric population and by disease severity. Methods: This international, cross-sectional, web-based survey of children and adolescents (6 months to <18 years old) was conducted in the following 18 countries:

Homotypic aggregation (HA) of cells plays key roles in physiological and pathological processes, such as embryogenesis, immune responses, angiogenesis, tumor cell invasion, and metastasis. Aminopeptidase N (CD13) has been implicated in most of these phenomena, although its participation has been attributed to its enzymatic activity, while its role as an adhesion molecule has been almost unexplored. Here, we show that certain anti-CD13 monoclonal antibodies induce HA of monocytic U-937 cells, independently of their effect on enzymatic activity. The phenomenon is related to binding to a specific site on the CD13 molecule and is independent of integrins. It is abrogated by low temperature, by the glycolysis inhibitor 2-deoxyglucose, and by inhibitors of tyrosine and mitogen-activated protein kinases. The inhibitor of microtubule polymerization colchicine has a synergistic effect on CD13-mediated aggregation, suggesting an inhibitory role of microtubules in this process. Finally, during HA, CD13 actively redistributes to the zones of cell-cell contact, as determined by live cell imaging studies, demonstrating a direct role of CD13 in the adhesion phenomenon. Together, these data show for the first time the participation of CD13 in monocytic cell adhesion.

CD13/aminopeptidase N is a transmembrane peptidase that is induced in the vasculature of solid tumors and is a potent angiogenic regulator. Here, we demonstrate that CD13 controls endothelial cell invasion in response to the serum peptide bradykinin by facilitating signal transduction at the level of the plasma membrane. Inhibition of CD13 abrogates bradykinin B 2 receptor internalization, leading to the attenuation of downstream events such as bradykinin-induced activation of Cdc42 and filopodia formation, and thus affects endothelial cell motility.Investigation into mechanisms underlying this block led us to focus on B 2 R internalization via membrane-dependent mechanisms. Membrane disruption by depletion of cholesterol or trypsinization halts B 2 R internalization, invasion, and filopodia formation, which can be recovered with addition of cholesterol. However, this functional recovery is severely impaired in the presence of CD13 antagonists, and the distribution of membrane proteins is disordered in treated cells, suggesting a role for CD13 in plasma membrane protein organization. Finally, exogenous expression of wild-type but not mutant CD13 further alters protein distribution, suggesting peptidase activity is required for CD13's regulatory activity. Therefore, CD13 functions as a novel modulator of signal transduction and cell motility via its influence on specific plasma membrane organization, thus regulating angiogenesis. IntroductionBradykinin has long been recognized as a component of an array of potent serum factors that maintain and regulate tissue perfusion by controlling the integrity of endothelial cells. This nonapeptide is the principal effector of the kallikrein-kinin system which functions in many normal and disease-related processes including pain perception, vascular homeostasis, smooth muscle contraction, coagulation, and fibrinolysis (reviewed in Blaukat 1 and Prado et al 2 ). Recently, bradykinin and its kininogen precursor have been implicated in angiogenesis, where the ischemic environment stimulates bradykinin production. In this setting, bradykinin acts immediately as a vasodilator to increase tissue perfusion and later as a long-term angiogenic stimulator. [3][4][5][6][7][8] CD13 is a cell-surface peptidase that was originally defined as a myeloid-specific hematopoietic marker. 9 More recently, however, we have shown that while normal endothelial cells are CD13 Ϫ , neovessels in developing tumors express high levels of CD13. 10 This induction is mediated at the transcriptional level in response to angiogenic stimuli in the tumor microenvironment 11 through signals transduced via the Ras/MAPK pathway. 12 Additional data support the notion that CD13 peptidase activity is required for endothelial invasion and morphogenic phases of tumor neovessel formation. 11 CD13's role as a regulator of angiogenesis is clear: CD13 rescues angiogenesis in the presence of inhibitors of the Ras/MAPK pathway, 12 and CD13 inhibition prevents tumor growth. 10 However, the precise mechanisms mediating CD13'...

Aminopeptidase N (E.C. 3.4.11.2) is a membrane-bound metalloproteinase expressed in many tissues. Although its cytoplasmic portion has only eight amino acids, cross-linking of CD13 by monoclonal antibodies (mAb) has been shown to trigger intracellular signaling. A functional association between CD13 and receptors for immunoglobulin G (FcgammaRs) has been proposed. In this work, we evaluated possible functional interactions between CD13 and FcgammaRs in human peripheral blood monocytes and in U-937 promonocytic cells. Our results show that during FcgammaR-mediated phagocytosis, CD13 redistributes to the phagocytic cup and is internalized into the phagosomes. Moreover, modified erythrocytes that interact with the monocytic cell membrane through FcgammaRI and CD13 are ingested simultaneously, more efficiently than those that interact through the FcgammaRI only. Also, co-cross-linking of CD13 with FcgammaRI by specific mAbs increases the level and duration of Syk phosphorylation induced by FcgammaRI cross-linking. Finally, FcgammaRI and CD13 colocalize in zones of cellular polarization and coredistribute after aggregation of either of them. These results demonstrate that CD13 and FcgammaRI can functionally interact on the monocytic cell membrane and suggest that CD13 may act as a signal regulator of FcgammaR function.