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PubMed1994

Complement activation by recombinant HIV-1 glycoprotein gp120.

The mechanism of CD4+ cell depletion in HIV-infected patients is poorly understood. In this study we investigated whether rgp120 can activate the complement system in the absence of anti-gp120 Abs. We found that the complement proteins C4, C3d, C5b-9, and properdin bind to rgp 120-coated CD4+ T cells of healthy individuals when incubated in autologous serum. Activation of the complement system occurred primarily via the classical pathway and was abolished in sera deficient in C1q and C4 as well as in the presence of EDTA. No cell lysis was observed in a lymphocytotoxicity assay using human serum, possibly because of homologous restriction of complement lysis. In contrast, addition of rabbit sera induced lysis of the rgp 120-precoated cells. Cell lysis by rabbit serum was found to be because of naturally occurring IgM anti-gp 120 Abs. The rgp 120, which was immobilized on the surface of microtiter plates activated complement in the absence of lymphocytes. Complement activation by cell-bound HIV-1 envelope glycoprotein gp120 with subsequent opsonization may be relevant for the elimination of noninfected CD4+ T cells in HIV-infected patients.

Amino Acid Sequence↗

PubMed1990

Neutralization of human immunodeficiency virus type 1 by complement occurs by viral lysis.

The ability of complement to inactivate human immunodeficiency virus (HIV) in the presence of specific antibody was evaluated. HIV was treated with complement and/or antibody, and then its titer was determined on the CD4+ H9 cell line. While complement alone had no effect on the HIV titer, complement plus subneutralizing levels of antibody resulted in titer reductions. Complement sources deficient in membrane attack component C5 or C8 did not inactivate antibody-treated HIV, suggesting that neutralization occurred via lysis. This possibility was investigated by assessing release of reverse transcriptase (RT) from the virion. Antibody plus complement, but neither reagent alone, released RT from HIV in a dose-dependent manner. Release of RT did not occur with C5- or C8-deficient sera, also indicating a requirement for membrane attack components. These studies show that complement can neutralize HIV via the classical complement pathway and that this neutralization occurs via C5b-9-mediated viral lysis. Thus, complement may play a major role in resistance to disease by lysing HIV and preventing infection of Fc- and complement receptor-positive cells, as well as CD4+ cells.

Antibody Formation↗

PubMed1997

Sublytic terminal complement attack on myotubes decreases the expression of mRNAs encoding muscle-specific proteins.

Activation of inflammatory and cytotoxic complement effectors that include the C5b-9 complex plays an important pathogenic role in myasthenia gravis, an inflammatory autoimmune disease of the muscle. Altered muscle-specific gene expression has been observed in experimental myasthenic rats. In this study, we have examined the effect of sublytic C5b-9 on myotubes differentiated from C2C12 myoblasts, by generating C5b-9 with C7-deficient serum with or without C7. Within 2 h, C7-deficient serum plus C7, compared with C7-deficient serum alone, induced markedly decreased levels of mRNAs encoding alpha-actin, troponin I slow twitch isoform, acetylcholine receptor alpha, and muscle aldolase A, whereas the heat shock protein 83 mRNA level remained constant, by northern analysis. Because the half-life of the acetylcholine receptor alpha was estimated to be > 8 h, the C5b-9 effect was, in part, due to enhanced mRNA decay. Because C5b-9 also induced c-jun mRNA and reduced the myoD mRNA level, a possible inhibition of muscle gene transcription by C5b-9 was examined in myotubes transfected with troponin promoter-luciferase gene constructs. Luciferase activity was reduced to 50% in response to C5b-9 at 2 h. Thus, C5b-9 appears to inhibit the muscle-specific gene expression by stimulating mRNA decay and by decreasing the transcription process. The data also indicate a possible pathogenic role of C5b-9 in immune-mediated inflammatory muscle disorders in which complement activation has been implicated.

Animals↗

PubMed1997

Involvement of complement components in renal disease.

The complement system is a critical element of innate immunity whose role in renal physiology and disease is illustrated by the following observations: (1) a deficiency or inhibition of a complement regulatory protein results in renal tissue damage; (2) inhibition of complement activation (with cobra venom factor or sCR1), or in C6-deficient rats, attenuates complement-mediated tissue destruction; and (3) ongoing glomerular disease has been associated with the deposition/expression of complement proteins in glomerular or tubular structures and the excretion of C5b-9 and CD59 proteins. Complement activation by cellulosic membranes results in the production of C5a, which has now been shown to provoke most of the same inflammatory responses observed during hemodialysis. Controlling the dose of C5a given during dialysis, by controlling blood flow rates or membrane types, may have an impact on patient health. Finally, lessons learned in the xenotransplant setting suggest that complement activation can be effectively controlled to limit inflammation (with sCR1 or anti-C5 monoclonal antibodies). Recent developments in this area may lead to new therapeutic approaches to deal with the complex etiology of renal disease.

Animals↗

PubMed1990

Multiple signal messengers generated by terminal complement complexes and their role in terminal complement complex elimination.

The best established function of C5b-9 is the ability to lyse or kill cells after assembly in the plasma membrane. In addition to this cytolytic function, increasing evidence suggests that C5b-9 also stimulate a variety of cell functions in vitro. Relatively little is known about the C5b-9 signals responsible for cell activation other than a transient increase in cytosolic Ca2+ primarily due to Ca2+ influx that have been determined in a cell population. In this report, signal messenger generation in Ehrlich cells by the sublytic terminal complement complexes (TCC), C5b-9, C5b-8, and C5b-7, was further examined, as well as the role of signal messengers in stimulating elimination of TCC from the cell surface. Changes in cytosolic Ca2+ were monitored in individual cells after a single dose of C5b-9 by digital imaging fluorescence microscopy that revealed oscillations in cytosolic Ca2+ over a period of 10 min. Sublytic C5b-9 substantially increased protein kinase C (PKC) activity at an external Ca2+ concentration of 1.5 mM. C5b-9-mediated PKC activation could be inhibited by 60 to 80% when external Ca2+ was reduced to 0.015 mM. C5b-8, but not C5b-7, activated PKC to a lesser extent. C5b-8 and C5b-7 also stimulated an increase in cAMP. Rapid elimination of TCC known to be stimulated by Ca2+ signal was partially inhibited by protein kinase inhibitors, H-7 and to a lesser extent by HA1004, suggesting a role for PKC in the elimination response. TCC elimination was not accelerated by agents that increase cAMP.

Calcium↗

PubMed1990

Measurement of complement activation products in patients with chronic rheumatic diseases.

Measurement of the complement activation products C1s:C1-inh, C3bP and C5b-9 by ELISA in plasma samples from normals, rheumatoid arthritis (RA) and systemic lupus erythematosis (SLE) patients showed significantly elevated levels in the two patient groups (P less than 0.0001 for C1s:C1-inh, C3bP and C5b-9) compared to normals. In seropositive RA patients there were significant correlations between the levels of the three complement activation complexes and IgM-RF, IgG-RF and IgA-RF. However, IgM-RF did not interfere with any of the ELISA systems. Mean levels of C1s:C1-inh, C3bP and C5b-9 were the same in paired plasma and synovial fluids; however, C3bP levels in the paired samples did not correlate with one another by rank. Our conclusions are that: (a) elevated plasma levels of these complement activation products are detectable in rheumatic diseases; (b) plasma levels of these complement activation products are related to Rheumatoid factor (RF) levels in seropositive RA patients; and (c) IgM-RF does not influence these solid-phase ELISA procedures.

Antibodies↗

PubMed1978

The structural events associated with the attachment of complement components to cell membranes in reactive lysis.

Electron microscopic study of the events occurring at the cell membrane during reactive lysis by complement, showed that a foliaceous particle was formed at the C5b-7 stage, that enlarged to a particle with a variable number of arms at the C5b-8 stage. Up to this point, no typical complement lesions were found. At the C5b-9 stages, the particles were completely converted to typical complement lesions, i.e. hollow cylinders projecting from the cell membrane and partly penetrating it. C5b-9 complexes assembled in the fluid phase did not show the typical structure of the lesions, but were amorphous masses of fibres.

Complement C5↗

PubMed1992

Immune damage to the mesangium: antibody- and complement-mediated stimulation and destruction of mesangial cells.

The deposition of immune complexes in the tissue results in complement activation leading to the formation of the lytic C5b-9 complex. Tissue cells are relatively resistant to complement attack due to cellular mechanisms such as removing C5b-9 from the surface and the expression of membrane proteins, which regulate complement activation and attack on the cell surface. Hence, cell killing is not an important consequence of complement activation on nucleated cells. On the other hand, the sublethal C5b-9-membrane interaction leads to various cellular responses, among them the synthesis of eicosanoids, cytokines, matrix-degrading proteases, and extracellular matrix, resulting in the modification of cell proliferation, leukocyte function, matrix degradation, and the formation of scar tissue. Thus, the complement-dependent immune damage is caused by secondary mediators, either derived from leukocytes or mesangial cells, rather than by a direct C5b-9-mediated killing.

Animals↗

PubMed1980

Membrane attack complex of complement: a structural analysis of its assembly.

This study was conducted to gain insight into the process of assembly of the membrane attack complex (MAC) of complement through structural analysis. Four intermediate complexes and the MAC were examined by electron microscopy and by sucrose density-gradient ultracentrifugation. The C5b-6 complex has a sedimentation rate of 11S, an elongated, slightly curved shape and dimensions of 160 x 60 x 60 A. At protein concentrattions greater than 1 mg/ml, and physiologic ionic strength and pH, the complex forms paracrystals that have the appearance of parallel strands. Equimolar quantities of C5b-6 and C7 mixed in the absence of lipids or detergents give rise to C5b-7 protein micelles which are soluble in aqueous media and have a sedimentation rate of 36S, suggesting a tetrameric composition. Ultrastructurally, C5b-7 protein micelles consist of four half-rings, each measuring 200 x 50 A, which are connected to one another by short stalks extending from the convex side of the half-rings. C5b-7 bound to dioleoyl lecithin (DOL) vesicles has a similar ultrastructural appearance. After extraction with deoxycholate (DOC), C5b-7 has a sedimentation velocity of 36S which further suggests the occurrence of C5b-7 in the form of tetrameric protein micelles. Attachment of C8 to vesicle-bound C5b-7 results in dissociation of the protein micelles. An individual C5b-8 complex appears as a half-ring attached to the DOL-vesicle via a 100-A-long and 30-A-wide stalk. After extraction from the DOL-vesicles with DOC, C5b-8 has a sedimentation velocity of approximately 18S. Binding of C9 to DOL-vesicle bound C5b-8 induces the formation of the typical ultrastructural complement lesions. C5b-9 extracted from the vesicles with DOC has a sedimentation rate of 33S, which is characteristic of the C5b-9 dimer. It is concluded that dimerization is a function of C9. C5b-9 monomers are visualized when a single C5b-9 complex or an odd number of complexes were bound per DOL-vesicle. The C5b-9 monomer has an ultrastructural appearance that is theoretically expected of a half-dimer: a 200- x 50-A half-ring which is attached to the DOL-vesicle by a 100- x 80-A appendage. Extracted with DOC, the C5b-9 monomer has a sedimentation rate of 23S. At a higher multiplicity of MAC per DOL-vesicle, large structural defects in the lipid bilayer are seen which are attributed to direct physical destruction of membranes by the known lipid-binding capacity of the MAC. It is proposed that protein micelle formation at the C5b-7 stage of MAC assembly and dissociation of these micelles upon binding of C8 are events that facilitate dimerization of C5b-9 and thus MAC formation.

Binding Sites↗

PubMed2000

Blockade of complement inhibits obliterative bronchiolitis in rat tracheal allografts.

The role of complement activation in the development of obliterative bronchiolitis, a manifestation of chronic lung allograft rejection, was investigated in the heterotopic rat tracheal allograft model. An increase in intragraft complement components C3 and C5b-9 (membrane attack complex) as well as IgM and IgG deposits were demonstrated during the progressive loss of respiratory epithelium and airway occlusion in nontreated allografts compared with syngeneic grafts. A 7-d treatment with recombinant human soluble complement receptor type 1 (sCR1; 20 mg/kg/d, intraperitoneal), an inhibitor of both the classic and alternative complement pathways, significantly decreased epithelial necrosis and intragraft neutrophil infiltration, and reduced obliterative changes by 40%. Immunohistochemical analysis of the grafts showed that sCR1 treatment significantly decreased early C5b-9 and IgG deposits, neutrophil chemoattractant IL-8 immunoreactivity, and ICAM-1 expression. Treatment with sCR1 was associated with increased staining for Th2 cytokines, in particular IL-10, with concomitant downregulation of IL-2 and TNF-alpha immunoreactivity. In contrast, sCR1 treatment did not affect the number of graft-infiltrating CD4(+) and CD8(+) T cells, CD45(+) B cells, ED1(+) and ED3(+) macrophages, or immune activation with expression of IL-2Ralpha or MHC class II. In conclusion, this is the first study to demonstrate that blockade of complement activation attenuates the development of OB and suggests that in addition to T cell-driven responses, humoral and antigen-independent immune responses also operate in the disease process. A blockade of complement activation renders the chemokine milieu unattractive to neutrophils and also modulates the alloimmune response toward Th2 cytokines, which may have an antiproliferative role in fibroproliferative disorders.

Animals↗

PubMed1988

Complement activation occurs through both classical and alternative pathways prior to onset and resolution of adult respiratory distress syndrome.

We have previously reported that plasma concentrations of the terminal complement (C) complex (TCC), C5b-9, increased significantly 2 days prior to onset of adult respiratory distress syndrome (ARDS) and also 1 day preceding its resolution. To determine the pathway of complement activation that preceded development and resolution of this acute inflammatory lung injury in septic patients, we quantified the C1rC1s-C1 inhibitor complex and the C3bP complex, which are generated following activation of classical and alternative complement pathways, respectively. Two days prior to diagnosis of ARDS, the plasma C1rC1s-C1 inhibitor complex and C3bP complex levels increased 22 and 14%, respectively. Furthermore, significant correlations were identified between concentrations of the TCC and C1rC1s-C1 inhibitor complex (r = 0.73, P = 0.003) and also with the levels of the TCC and C3bP complex (r = 0.81, P = 0.002) before onset of ARDS. Equally of interest, the C1rC1s-C1 inhibitor complex and C3bP complex concentrations increased 68 and 35%, respectively, 1 day before resolution of ARDS. Similarly, significant elevations of TCC concentrations preceding resolution of ARDS correlated with C1rC1s-C1 inhibitor complex (r = 0.66, P = 0.02) and also with C3bP complex (r = 0.72, P = 0.002) levels. Our results indicate that both the classical and alternative complement pathways are activated prior to onset of ARDS and also before its resolution in septic patients.

Complement Activating Enzymes↗

PubMed1990

Localization and molecular modelling of the membrane-inserted domain of the ninth component of human complement and perforin.

Upon interaction with the membrane-bound C5b-8 complex, the ninth component of complement (C9) unfolds and inserts into the membrane of cells on which surface complement has been activated. Consequently C9 oligomerization occurs and transmembrane channels of varying sizes are formed. The domain of the unfolded protein interacting with the cell membrane has so far not been identified since, unlike many integral membrane proteins, the C9 sequence does not contain a continuous stretch of hydrophobic amino acids. We studied the interaction of C9 with the lipid bilayer using the membrane-restricted photoaffinity label 3-(trifluoromethyl)-3-(m[125I]iodophenyl)diazirine (125I-TID). C9 was assembled on liposomes and after photoactivation, several labeled and non-labeled peptides, obtained by chemical and enzymatic cleavage or the 125I-TID-labeled C9, were analyzed. The segment from 176 to 345 was identified as the region containing the membrane-interacting structure. By means of secondary structure predictions, we identified two amphipathic alpha-helices (292-308 and 313-333) separated by a turn (309-312). Based on these results, we constructed a molecular model for the membrane-spanning region of C9. By analogy, we also constructed a model for this domain in perforin/cytolysin, a pore-forming protein found in the cytoplasmic granules of cytotoxic T-lymphocytes.

Affinity Labels↗

PubMed2001

Mannose-binding lectin accelerates complement activation and increases serum killing of Neisseria meningitidis serogroup C.

The capacity for different lipo-oligosaccharide (LOS) sialylation patterns of Neisseria meningitidis serogroup C to influence the binding and function of the innate humoral component, mannose-binding lectin (MBL), was investigated. By use of flow cytometry and immunogold electron microscopy, a clinical isolate with reduced endogenous LOS sialylation was found to bind more MBL than did strains with higher endogenous sialylation. MBL binding was reduced but not ablated if the same strain was allowed to exogenously sialylate its LOS structures after incubation with cytidine-5'-monophospho-neuraminic acid. MBL binding led to an increased rate of complement activation, with enhanced deposition of the complement components C4 and C5b-9, and this correlated with an increase in bactericidal activity. LOS sialylation appears to be an important determinant of MBL binding to N. meningitidis and can modulate complement-dependent killing of the bacterium. These findings could explain the observed susceptibility to meningococcal disease of individuals genetically deficient in MBL.

Acute-Phase Proteins↗

PubMed1998

Antisulfatide polyneuropathy: antibody-mediated complement attack on peripheral myelin.

Increased titers of circulating antisulfatide antibodies are consistently associated with a variety of chronic axonal and demyelinating polyneuropathy syndromes. Previous studies have shown that the pattern of antisulfatide binding to neural tissues correlates with the type of neuropathy. This suggests a possible role for antisulfatide antibodies in inducing peripheral nerve dysfunction, although their exact contribution to the pathogenesis of neuropathy is still unknown. We examined sural nerve biopsy specimens from two patients with sensorimotor and small fiber sensory neuropathy associated with high titers of IgM monoclonal antibodies to sulfatide. Electrophysiological and pathological findings were consistent with predominant demyelination in the patient with sensorimotor involvement, whereas evidence of demyelination was obtained only by teased fiber examination in the other patient. The ultrastructural study disclosed in both cases the presence of myelinated fibers with widely spaced myelin, due to a separation of leaflets of the intraperiod lines. Immunocytochemistry, performed on frozen sections, demonstrated the presence of IgM and complement product C3d bound to myelin sheaths of almost all fibers. Few fibers were immunoreactive for complement components C1q and C5. In addition, the terminal complement complex neoantigen C5b-C9, not associated with S protein, was detected on some myelinated fibers. The results suggest that, at the least in some forms of demyelinating neuropathy associated with antisulfatide antibodies, pathological changes are complement mediated. Our data further confirm previous clinical and experimental observations that complement activation initiates separation of myelin intraperiod lines.

Aged↗

PubMed2002

Expression of the C5a receptor (CD88) on granulocytes and monocytes in patients with severe sepsis.

INTRODUCTION: Treatment of patients with severe sepsis with agents antagonising the effects of C5a has been proposed based on beneficial effects in animal experiments and in vitro studies demonstrating upregulation of the C5a receptor (CD88) on granulocytes by endotoxin. MATERIALS AND METHODS: CD88 expression on leukocytes from 12 patients with severe sepsis or septic shock was analysed by flow cytometer, and serum complement factors C3a and C5b-9 were measured by enzyme immunoassay techniques. RESULTS: The granulocyte CD88 expression on day 1 was lowered (36; range, 2-59) in comparison with controls (63; range, 25-88) (P < 0.001), despite complement activation, while the monocyte CD88 expression was unchanged. The receptor reduction correlated significantly to the APACHE II score (r2 = 0.35, P < 0.05). The recovery of CD88 expression was slow. DISCUSSION: In contrast to the findings in animals, it is concluded that granulocyte CD88 expression is reduced at the time when the diagnosis of severe sepsis or septic shock can clinically be made. The reason for this needs further investigation but it may be due to a previous complement activation or to cytokine effects.

APACHE↗

PubMed1996

Amplification of the inflammatory response: adhesion molecules associated with platelet/white cell responses.

Cardiopulmonary bypass (CPB) causes leukocyte and platelet activation, resulting in upregulation of the adhesion receptor CD11b/CD18 on leukocytes and upregulation of P-selectin, the adhesion receptor that binds the activated platelet to polymorphonuclear neutrophils (PMNs) and monocytes. Our laboratory has studied the expression of activation-dependent adhesion receptors during in vivo CPB. Both PMN and monocyte CD11b were upregulated during CPB but with differing time courses. Peak PMN CD11b levels occurred at the end of the hypothermic phase of bypass, whereas monocyte CD11b levels increased steadily throughout the course of CPB, peaked at 2-4 h after CPB, and remained significantly elevated as late as 18-24 h post CPB. The percentage of P-selectin-positive platelets increased significantly during bypass, peaking around the end of bypass and remaining elevated in the early post-bypass period. The level then returned to normal by 18 h post-bypass. Monocyte-platelet binding paralleled the increase in P-selectin-positive platelets during bypass and similarly remained elevated in the post-bypass period. PMN-platelet binding also increased but peaked early during CPB. Upregulation of these adhesive receptors and formation of platelet-leukocyte conjugates may influence the prothrombotic activity of monocytes and the proinflammatory activity of PMNs in the post-CPB period. Our laboratory has developed an in vitro model of extracorporeal circulation, and recirculation of blood on this circuit results in significant activation of PMNs and monocyte CD11b expression, increasing progressively over time. Likewise, the percentage of P-selectin-positive platelets increased and was paralleled by the formation of leukocyte-platelet conjugates comparable to the pattern found in vivo. Generation of the complement fragments C5a and the C5b-9 membrane-attack complex may contribute to platelet P-selectin expression and formation of leukocyte-platelet conjugates during CPB. The in vitro model has been used to test the cellular effects of complement inhibition employing a monoclonal antibody that blocks cleavage of C5 into C5a and C5b to determine the role of early vs. late complement components in the cellular activation induced by CPB. Preliminary results demonstrate that blockage of the formation of C5a and the C5b-9 membrane-attack complex during simulated extracorporeal circulation effectively inhibits platelet and PMN activation and the formation of leukocyte-platelet conjugates.

Blood Platelets↗

PubMed1983

Human monocyte spreading induced by activated factor B of the complement alternative pathway: differential effects of Fab' and F(ab')2 antibody fragments directed to C5, C6, and C7.

Human peripheral blood mononuclear phagocytes are induced by activated Factor B (Bb) of the complement alternative pathway to undergo morphological shape changes in vitro which have been described as "spreading." The spreading reaction induced by Bb has previously been shown to depend upon the enzymatic activity of Bb and to be inhibited by Fab' antibody fragments directed to C5 (but not anti-C3 Fab'). The possibility that Bb may exert its effect on monocytes by initiating assembly of terminal complement complexes comprised of C5b, 6, 7, C5b-8, or C5b-9 was addressed in the present study. The effects were tested of Fab' and F(ab')2 antibody fragments directed to C5, C6, C7, and C8 and to neoantigens expressed in the assembling terminal complement complexes on the monocyte spreading reaction induced by Bb. Differential effects of monovalent Fab' and divalent F(ab')2 antibody fragments were observed. Anti-C5, C6, and C7 Fab' were found to inhibit the spreading reaction induced by Bb in an immunologically specific manner. Divalent F(ab')2 fragments directed to these same proteins (but not to C3, C4, C8, or C9) induced monocyte spreading in the complete absence of Bb or other recognized inducing agents. Monocyte spreading induced by hybridoma immunoglobulin (Ig) directed to C5 and C7 was found to be correlated with the binding of 10(6) molecules Ig per cell. These findings support the notion that C5, C6, and C7 (or an analogous system of cellular proteins) are associated with the surface of human peripheral blood monocytes and that these proteins may play a role in certain reactions by which mononuclear phagocytes are induced to altered states of cellular physiology.

Antibodies, Anti-Idiotypic↗

PubMed2000

Cleavage of the fifth component of complement and generation of a functionally active C5b6-like complex by human leukocyte elastase.

Activation by complement C3/C5 convertases of the fifth component of human complement, C5, leads to two active cleavage products: C5a, a chemotactic peptide, and C5b, the activated form of C5. Human leukocyte elastase (HLE) has long been known to also release from C5 a chemotactic, C5a-like fragment. This, however, cannot be identical with C5a, since HLE does not cleave peptide bonds at the carboxyl group of arginine, the cleavage site that separates C5a and C5b after the exposure to the complement convertases. Therefore, the question arose whether HLE is capable of releasing a functionally C5b-like product from C5. The results show that this is, indeed, so. Treatment of human C5 with HLE in the presence of C6 leads to the formation on an active C5b6-like complex that lyses non-sensitized guinea pig red cells upon addition of the terminal components C7, C8, and C9. However, since C6 is highly sensitive to the hydrolytic action of HLE, the yield of the activation complex is rather low. The results offer a third possibility for the activation of C5: 1) classical cleavage at Arg74 by complement convertases, 2) oxidation of methionine residues without cleavage, and, as shown here, 3) cleavage by elastase at (a) site(s) distal from Arg74. The three procedures may modulate the relative yield of the two activities generated from C5, C5a-like and C5b-like effects.

Animals↗