review Haematologica 1995; 80:161-175 LEUKOCYTE CD11/CD18 INTEGRINS: BIOLOGICAL AND CLINICAL RELEVANCE Antonino Mazzone, Giovanni Ricevuti Dipartimento di Medicina Interna e Terapia Medica, Università di Pavia, IRCCS Policlinico S. Matteo, Pavia, Italy ABSTRACT The integrin family consists of a series of related Ͱͱ heterodimers (subunits of 95,000-200,000 Mw) involved in a variety of cell-matrix and cell-cell adhesion functions. Leukocyte adhesion has biological importance in numerous processes involving host defense. The CD11/CD18 integrins are differentiated antigens which play a critical role in this mechanism. CD11a/CD18 are apparent on early progenitors of all myeloid and erythroid cells. CD11b/CD18 and CD11c/CD18 are more restricted antigens normally expressed on monocytes, macrophages, PMN and natural killer cells. Activated granulocytes and monocytes express far more CD11b/CD18 than the other two antigens: 6 to 8҂105 CD11b/CD18 molecules appear on maximally activated granulocytes. These integrins and in particular the ͱ2 subunit are lacking in a genetic disease. On the other hand, they are funda- mental in numerous physiological processes and in various hematological and cardiovascular dis- eases. The biochemical characterization and behavior of the CD11/CD18 complex in various clini- cal conditions are the subject of this review. Key words: CD11/CD18, integrins, leukocytes ell adhesion molecules play an important role in leukocyte-endothelial cell interac- ͱ1 subfamily (also called VLA proteins) each 1-3 ͱ Ctions. In the immune system these contain the 1 subunit in association with one molecules encourage leukocyte-endothelial cell of at least nine different Ͱ subunits. In the ͱ2 interactions and orchestrate many other types of subfamily, there are three distinct Ͱ subunits cell interactions through a variety of adhesion which associate with ͱ2 (CD11/CD18). The receptors belonging to evolutionarily distant other groups associated with the ͱ3-ͱ8 sub- genesuperfamilies,including integrins, selectins, families have various roles and functions.13-15 immunoglobulin-like molecules and cad- This review will focus on recent studies con- herins.4-10 Adhesion molecules coordinate the cerning the structure and function of leukocyte various phases of leukocyte adherence to resting CD11/CD18 receptors and their clinical signifi- or inflamed endothelium in a stepwise fashion cance. through a regulated mechanism of ligand bind- ing. This typically includes qualitative changes in receptor avidity,11 quantitative increases in CD11/CD18 structure receptor surface expression following inflamma- Various studies and reviews17-25 have deter- tory challenges, and transient activation of mined the structure of leukocyte CD11/CD18 reversible pathways of leukocyte-endothelium adhesion molecules: a family of cell-surface gly- interaction.12-14 The integrins have been orga- coproteins, consisting of 3 heterodimers sharing nized into eight distinct subfamilies based on ͱ a common ͱ subunit (CD18) with a distinct Ͱ subunit associations (Table 1). Members of the subunit (CD11a, CD11b, CD11c), called inte- Correspondence: Antonino Mazzone, M.D., Dipartimento di Medicina Interna e Terapia Medica, Patologia Medica I, Università di Pavia, IRCCS Policlinico S. Matteo, p. le Golgi 2, 27100 Pavia, Italy. Tel. international +39.382.388499. Fax. international +39.382.526341. Received February 2, 1994; accepted January 9, 1995. 162 A. Mazzone et al. Table 1. The integrin families. ative granules, and in other granules which are mobilized to the cell surface by inflammatory Leukocytes CD11/CD18 mediators.1,2,15,36-43 In resting conditions, each ͱ1 ͱ2 ͱ3 ͱ4 ͱ5 ͱ6 ͱ7 ͱ8 granulocyte in a normal subject bears 6-7,000 CD11/CD18 molecules; after stimulation this Ͱ1-Ͱ9 ͰL ͰIIb Ͱ6 ͰV ͰV Ͱ4 ͰV number can increase many times, probably as a ͰV ͰM ͰV ͰIEL result of mobilization of reserve molecules ͰX ͰLRI stored in the granules.3 Whereas CD11a/CD18 are constitutively expressed on the plasma mem- brane and are not up-regulated, CD11b/CD18 grins. The three Ͱ chains of the CD11/CD18 can be up-regulated several fold from intracellu- family have molecular weights of 177 kD lar granules by chemotactic factors such as C5a, (CD11a, LFA-1), 165 kD (CD11b, CR3), and interleukin-8, platelet activating factor, f-MLP 150 kD (CD11c, p150, 95), and are the products and others chemoattractants,15 causing a marked 24 of three separate genes. Linking of the Ͱ and ͱ2 increase in adhesion that is completely inhibited subunit precursors occurs in the Golgi appara- by monoclonal antibodies against either the ͰM tus, and the assembled receptors are then trans- or the ͱ2 subunit of CD11b/CD18 receptors. ported to the cell surface or to intracellular stores.25 Distribution of CD11/CD18 in immune cells The cDNA sequences encoding the Ͱ and ͱ2 CD11a/CD18 were first described as receptors subunits have been cloned.22,25,26 The Ͱ subunit that encourage the adhesion of cytotoxic T cells has a long extracellular domain, a transmem- to their targets.1,5,13 In T and B lymphocytes all brane domain and a short cytoplasmic CD11/CD18-dependent functions such as 27-32 domain. The ͱ2 subunit has a highly con- mitogen, antigen and alloantigen induced pro- served cysteine-rich region which gives it a rigid liferation, T-cell-mediated cytotoxicity, B-cell tertiary structure.33-36 The divalent cations Ca2+ aggregation, and Ig production are inhibited by and Mg2+ are essential in the stabilization and anti-CD11a/CD18 MoAbs, supporting the fact function of the Ͱͱ complex.33 The gene encoding that CD11a/CD18 are the only heterodimers 3 the ͱ2 subunit has been mapped on chromo- normally apparent on these cells. Moreover, some 21 band 21q22, which is a breakpoint in CD11a/CD18 have recently been shown to play chromosomal translocation t(3;21)(q26;q22) a role in strengthening the adhesion of T lym- associated with the blast phase of chronic phocytes to dendritic cells. Effective adhesion myeloid leukemia.32 All three Ͱ subunits have with a dendritic cell appears to be a requirement been localized to bands p11-p13.1 on chromo- for the stimulation of resting T cells.5 Both T some 16. Inversions in translocations involving cells and dendritic cells express CD11a/CD18; this region have been reported in patients with CD11c also mediates some lymphocyte adhe- acute myelomonocytic leukemia (AMMoL).31-34 sive functions, e.g. it contributes to the conju- Whether the Ͱ and ͱ2 subunit genes are actually gated formation of some cytotoxic T-cell clones involved in these chromosomal rearrangements and their targets. Neutrophil-mediated inflam- remains to be shown. A comparison of the pri- matory responses depend on adherence to mary structure of the Ͱ and ͱ2 subunits of endothelium, migration into an inflammatory leukocyte adhesion receptors with extracellular site, and the release of toxic products by neu- matrix receptors demonstrates strong homolo- trophils.1,3,8 gies between the two groups of receptors. All Unstimulated neutrophils demonstrate a base- have a heterodimeric Ͱ-ͱ2 structure and recog- line level of spontaneous adherence to cultured nize the RGD (arginine-glycine-aspartic acid) endothelial monolayers in vitro. In contrast to sequence in the adhesive proteins.24,35,36 In neu- unstimulated adherence, enhanced adherence in trophils CD11b/CD18 integrins are found in a response to neutrophil mediators is almost large intracellular pool, in myeloperoxidase neg- entirely leukocyte integrin-dependent, mainly Leukocyte CD11/CD18 163 CD11b, with a variable contribution from (CD54) expression on a wide range of cells, and CD11a.9 Under conditions of endothelial activa- its up-regulation during cell activation and tion, however, neutrophil adhesion is only part- inflammation point to an important role in ly dependent on the leukocyte integrin family; leukocyte immune responses, lymphocyte traffic this time CD11a plays a major part but all three and tissue localization. ICAM-1 also functions as members have a cooperative effect.44 Trans- a receptor for rhinoviruses. ICAM-2 is also pre- endothelial migration of neutrophils appears to sent in endothelial cells, the U937 monocytic cell be heavily dependent on leukocyte integrins, line and B and T lymphoblastoid lines, but unlike even at high flow rates, and requires the syner- ICAM-1, its basal expression is high and not gistic action of CD11a and CD11b.8 affected by cytokines.52-58 There is some evidence CD11c/CD18 are expressed on monocytes, to suggest that under certain conditions ICAM-1 macrophages, and on a subpopulation of cyto- can function as a ligand for CD11/CD18.59,60 This toxic cells, and appear to be important in medi- is also true for CD11b/CD18, which binds with a ating several types of adhesive interactions for region of complement protein C3bi containing monocytes. In fact, antibodies to CD11c also RGD. A study testing the ability of CD11b/CD18 interfere with several functions of human to bind with RGD-containing ligands found that monocytes, including random and directed macrophages are able to bind erythrocytes coated migration, and adhesion to endothelial mono- with a 21-amino-acid peptide from C3bi that layers.1,5,8,9,13,15 contained this sequence. Although CD11b/CD18 were originally described as a receptor for C3bi, Ligands recognized by members of the more recent work has identified several addition- CD11/CD18 family al ligands for these receptors.61 CD11b/CD18 ICAM-1 (CD54), a major ligand for CD11a, bind with protein gp63 on the surface of leish- was initially identified by raising monoclonal mania and promote the internalization of this antibodies to cells from patients with a congeni- intracellular parasite.62 Surfaces coated with the tal deficiency of leukocyte integrin expression protein fibrinogen are also recognized by (see Table 2). Another ligand for CD11a, ICAM- CD11b/CD18, and this receptor may therefore 2 was cloned by screening a cDNA library from promote the adhesion of neutrophils to clots and endothelial cells.15,44-51 The regulation of ICAM-1 the subsequent digestion of fibrin.