The push-pull intercrop Desmodium does not repel, but intercepts and kills pests.

Over two decades ago, an intercropping strategy was developed that received critical acclaim for synergizing food security with ecosystem resilience in smallholder farming. The push-pull strategy reportedly suppresses lepidopteran pests in maize through a combination of a repellent intercrop (push), commonly Desmodium spp., and an attractive, border crop (pull). Key in the system is the intercrop's constitutive release of volatile terpenoids that repel herbivores. However, the earlier described volatile terpenoids were not detectable in the headspace of Desmodium, and only minimally upon herbivory. This was independent of soil type, microbiome composition, and whether collections were made in the laboratory or in the field. Furthermore, in oviposition choice tests in a wind tunnel, maize with or without an odor background of Desmodium was equally attractive for the invasive pest Spodoptera frugiperda. In search of an alternative mechanism, we found that neonate larvae strongly preferred Desmodium over maize. However, their development stagnated and no larva survived. In addition, older larvae were frequently seen impaled and immobilized by the dense network of silica-fortified, non-glandular trichomes. Thus, our data suggest that Desmodium may act through intercepting and decimating dispersing larval offspring rather than adult deterrence. As a hallmark of sustainable pest control, maize-Desmodium push-pull intercropping has inspired countless efforts to emulate stimulo-deterrent diversion in other cropping systems. However, detailed knowledge of the actual mechanisms is required to rationally improve the strategy, and translate the concept to other cropping systems.

The Comparative Toxicity, Biochemical and Physiological Impacts of Chlorantraniliprole and Indoxacarb on Mamestra brassicae (Lepidoptera: Noctuidae).

BACKGROUND: The cabbage moth, Mamestra brassicae, is a polyphagous pest that attacks several crops. Here, the sublethal and lethal effects of chlorantraniliprole and indoxacarb were investigated on the developmental stages, detoxification enzymes, reproductive activity, calling behavior, peripheral physiology, and pheromone titer of M. brasssicae. Methods: To assess pesticide effects, the second instar larvae were maintained for 24 h on a semi-artificial diet containing insecticides at their LC10, LC30, and LC50 concentrations. RESULTS: M. brassicae was more susceptible to chlorantraniliprole (LC50 = 0.35 mg/L) than indoxacarb (LC50 = 1.71 mg/L). A significantly increased developmental time was observed with both insecticides at all tested concentrations but decreases in pupation rate, pupal weight, and emergence were limited to the LC50 concentration. Reductions in both the total number of eggs laid per female and the egg viability were observed with both insecticides at their LC30 and LC50 concentrations. Both female calling activity and the sex pheromone (Z11-hexadecenyl acetate and hexadecenyl acetate) titer were significantly reduced by chlorantraniliprole in LC50 concentration. Antennal responses of female antennae to benzaldehyde and 3-octanone were significantly weaker than controls after exposure to the indoxocarb LC50 concentration. Significant reductions in the enzymatic activity of glutathione S-transferases, mixed-function oxidases, and carboxylesterases were observed in response to both insecticides.

Targeted suppression of Dpt-specific B cells in humanized Rag2- γc- mouse model of HDM allergy.

Der p 1 is one of the major allergenic molecules of Dermatophagoides pteronyssinus, causing house dust mite (HDM) allergy. The pathological B cells produce allergen-specific IgE antibodies that mediate the hypersensitivity reaction, therefore the selective elimination of these B cells is a legitimate therapeutic goal in allergy. Chimeric molecule Dp51-72 able to cross-link B cell inhibitory complement receptor type 1 and BCR on Der p 1-specific B cells was constructed. The signalling capabilities of this molecule have been tested on human B cells. A humanized mouse model of HDM allergy has been used to test the in vivo effects of the chimeric molecule administration. Administering the chimeric molecule to immunodeficient Rag2- γc- mice transferred with PBMCs from allergic patients resulted in reduction of allergen-specific IgE antibodies in the sera, and reduced infiltration of immune cells in lung histology preparations. Reduced numbers of human CD45+ and CD4+ cells in the lungs as well as inhibition of mast cell degranulation were also observed. The treatment with Dp51-72 chimera significantly decreased the local levels of anti-Dpt IgE antibodies in the bronchoalveolar lavage fluid (BALF). The binding of the chimeric molecule to tonsillar B cells triggers the tyrosine phosphorylation of 30-32 kDa protein, which is most likely involved in the inhibitory process. Administration of constructed chimeric molecules to humanized mice with developed inflammation resulted in specific suppression of disease-associated IgE antibody-producing cells and preserved lung histology. This effective approach could be further developed into a therapeutic agent for treatment of patients with HDM allergy.

Complement Factor H-Related Proteins FHR1 and FHR5 Interact With Extracellular Matrix Ligands, Reduce Factor H Regulatory Activity and Enhance Complement Activation.

Components of the extracellular matrix (ECM), when exposed to body fluids may promote local complement activation and inflammation. Pathologic complement activation at the glomerular basement membrane and at the Bruch's membrane is implicated in renal and eye diseases, respectively. Binding of soluble complement inhibitors to the ECM, including factor H (FH), is important to prevent excessive complement activation. Since the FH-related (FHR) proteins FHR1 and FHR5 are also implicated in these diseases, our aim was to study whether these FHRs can also bind to ECM components and affect local FH activity and complement activation. Both FH and the FHRs showed variable binding to ECM components. We identified laminin, fibromodulin, osteoadherin and PRELP as ligands of FHR1 and FHR5, and found that FHR1 bound to these ECM components through its C-terminal complement control protein (CCP) domains 4-5, whereas FHR5 bound via its middle region, CCPs 3-7. Aggrecan, biglycan and decorin did not bind FH, FHR1 and FHR5. FHR5 also bound to immobilized C3b, a model of surface-deposited C3b, via CCPs 3-7. By contrast, soluble C3, C3(H2O), and the C3 fragments C3b, iC3b and C3d bound to CCPs 8-9 of FHR5. Properdin, which was previously described to bind via CCPs 1-2 to FHR5, did not bind in its physiologically occurring serum forms in our assays. FHR1 and FHR5 inhibited the binding of FH to the identified ECM proteins in a dose-dependent manner, which resulted in reduced FH cofactor activity. Moreover, both FHR1 and FHR5 enhanced alternative complement pathway activation on immobilized ECM proteins when exposed to human serum, resulting in the increased deposition of C3-fragments, factor B and C5b-9. Thus, our results identify novel ECM ligands of FH family proteins and indicate that FHR1 and FHR5 are competitive inhibitors of FH on ECM and, when bound to these ligands, they may enhance local complement activation and promote inflammation under pathological conditions.

Natural Compounds as Target Biomolecules in Cellular Adhesion and Migration: From Biomolecular Stimulation to Label-Free Discovery and Bioactivity-Based Isolation.

Plants and fungi can be used for medical applications because of their accumulation of special bioactive metabolites. These substances might be beneficial to human health, exerting also anti-inflammatory and anticancer (antiproliferative) effects. We propose that they are mediated by influencing cellular adhesion and migration via various signaling pathways and by directly inactivating key cell adhesion surface receptor sites. The evidence for this proposition is reviewed (by summarizing the natural metabolites and their effects influencing cellular adhesion and migration), along with the classical measuring techniques used to gain such evidence. We systematize existing knowledge concerning the mechanisms of how natural metabolites affect adhesion and movement, and their role in gene expression as well. We conclude by highlighting the possibilities to screen natural compounds faster and more easily by applying new label-free methods, which also enable a far greater degree of quantification than the conventional methods used hitherto. We have systematically classified recent studies regarding the effects of natural compounds on cellular adhesion and movement, characterizing the active substances according to their organismal origin (plants, animals or fungi). Finally, we also summarize the results of recent studies and experiments on SARS-CoV-2 treatments by natural extracts affecting mainly the adhesion and entry of the virus.

Robert B. Sim-Tribute.

I met Bob in 1985, when I moved with my family to Oxford for a two-year EMBO fellowship at the MRC Immunochemistry Unit [...].

Label-free real-time monitoring of the BCR-triggered activation of primary human B cells modulated by the simultaneous engagement of inhibitory receptors.

Today, there is an intense demand for lab-on-a-chip and tissue-on-a-chip applications in basic cell biological research and medical diagnostics. A particular challenge is the implementation of advanced biosensor techniques in point-of-care testing utilizing human primary cells. In this study, a resonant waveguide grating (RWG)-based label-free optical biosensor technique has been applied for real-time monitoring of the integrated responses of primary human tonsillar B cells initiated by B cell receptor (BCR) and modified by FcγRIIb and CR1 engagement. The BCR-triggered biosensor responses of resting and activated B cells were revealed to be specific and dose-dependent, in some cases with strong donor dependency. Targeted inhibition of Syk attenuated the label-free biosensor response upon BCR stimulation. Indifferent protein human serum albumin (HSA) did not interfere with the recorded signal to BCR stimulation. Simultaneous engagement of BCR and FcγRIIb modulated the kinetic signal of the cells. Activated and resting B cells exhibited different response profiles upon simultaneous engagement of BCR and CR1. This advanced approach has the potential to decipher interfering signaling events in human B cells, manage differences between activated and resting B cell states, helping to understand the actual integrated response of these immune cells, and could be useful in the point-of-care diagnostic testing on human primary cells.

BCR activated CLL B cells use both CR3 (CD11b/CD18) and CR4 (CD11c/CD18) for adhesion while CR4 has a dominant role in migration towards SDF-1.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the western world. In previous studies, various proportion of patients was found to carry CD11b+ or CD11c+ B cells whose presence was an unfavourable prognostic factor. The exact mechanism however, how these receptors contribute to the pathogenesis of CLL has not been revealed so far. Here we analysed the role of CD11b and CD11c on B cells of CLL patients in the adhesion to fibrinogen and in the migration towards stromal cell derived factor-1 (SDF-1) and studied the role of CR4 in the adherence of the CD11c+ B cell line BJAB. We observed that both CR3 and CR4 mediate adhesion of the malignant B cells. Moreover, we found, that CR4 was strongly involved in the migration of the leukemic cells towards the chemoattractant SDF-1. Our data suggest that CR3 and CR4 are not only passive markers on CLL B cells, but they might contribute to the progression of the disease. Since the role of SDF-1 is prominent in the migration of CLL cells into the bone marrow where their survival is supported, our findings help to understand how the presence of CD11c on leukemic B cells can worsen the prognosis of chronic lymphocytic leukaemia.

New aspects in the regulation of human B cell functions by complement receptors CR1, CR2, CR3 and CR4.

The involvement of complement in the regulation of antibody responses has been known for long. By now several additional B cell functions - including cytokine production and antigen presentation - have also been shown to be regulated by complement proteins. Most of these important activities are mediated by receptors interacting with activation fragments of the central component of the complement system C3, such as C3b, iC3b and C3d, which are covalently attached to antigens and immune complexes. This review summarizes the role of complement receptors interacting with these ligands, namely CR1 (CD35), CR2 (CD21), CR3 (CD11b/CD18) and CR4 (CD11c/CD18) expressed by B cells in health and disease. Although we focus on human B lymphocytes, we also aim to call the attention to important differences between human and mouse systems.

Autoantibodies Against the Complement Regulator Factor H in the Serum of Patients With Neuromyelitis Optica Spectrum Disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS), characterized by pathogenic, complement-activating autoantibodies against the main water channel in the CNS, aquaporin 4 (AQP4). NMOSD is frequently associated with additional autoantibodies and antibody-mediated diseases. Because the alternative pathway amplifies complement activation, our aim was to evaluate the presence of autoantibodies against the alternative pathway C3 convertase, its components C3b and factor B, and the complement regulator factor H (FH) in NMOSD. Four out of 45 AQP4-seropositive NMOSD patients (~9%) had FH autoantibodies in serum and none had antibodies to C3b, factor B and C3bBb. The FH autoantibody titers were low in three and high in one of the patients, and the avidity indexes were low. FH-IgG complexes were detected in the purified IgG fractions by Western blot. The autoantibodies bound to FH domains 19-20, and also recognized the homologous FH-related protein 1 (FHR-1), similar to FH autoantibodies associated with atypical hemolytic uremic syndrome (aHUS). However, in contrast to the majority of autoantibody-positive aHUS patients, these four NMOSD patients did not lack FHR-1. Analysis of autoantibody binding to FH19-20 mutants and linear synthetic peptides of the C-terminal FH and FHR-1 domains, as well as reduced FH, revealed differences in the exact binding sites of the autoantibodies. Importantly, all four autoantibodies inhibited C3b binding to FH. In conclusion, our results demonstrate that FH autoantibodies are not uncommon in NMOSD and suggest that generation of antibodies against complement regulating factors among other autoantibodies may contribute to the complement-mediated damage in NMOSD.

Revisiting the Coreceptor Function of Complement Receptor Type 2 (CR2, CD21); Coengagement With the B-Cell Receptor Inhibits the Activation, Proliferation, and Antibody Production of Human B Cells.

The positive coreceptor function of complement receptor type 2 [CR2 (CD21)] on B cells is generally accepted, although its role in the enhancement of antibody production had only been proven in mice. The importance of this phenomenon prompted reinvestigation of the functional consequences of coclustering CD21 and the B cell receptor (BCR) on primary human cells. We found that, at non-stimulatory concentrations of anti-IgG/A/M, coclustering the BCR and CR2 enhanced the Ca2+ response, while activation marker expression, cytokine production, proliferation, and antibody production were all inhibited upon the coengagement of CR2 and BCR on human B cells. Thus, the "textbook dogma" claiming that C3d acts as an adjuvant to enhance humoral immunity is relevant only to mice and not to humans.

Insect chemical ecology: chemically mediated interactions and novel applications in agriculture.

Insect chemical ecology (ICE) evolved as a discipline concerned with plant-insect interactions, and also with a strong focus on intraspecific pheromone-mediated communication. Progress in this field has rendered a more complete picture of how insects exploit chemical information in their surroundings in order to survive and navigate their world successfully. Simultaneously, this progress has prompted new research questions about the evolution of insect chemosensation and related ecological adaptations, molecular mechanisms that mediate commonly observed behaviors, and the consequences of chemically mediated interactions in different ecosystems. Themed meetings, workshops, and summer schools are ideal platforms for discussing scientific advancements as well as identifying gaps and challenges within the discipline. From the 11th to the 22nd of June 2018, the 11th annual PhD course in ICE was held at the Swedish University of Agricultural Sciences (SLU) Alnarp, Sweden. The course was made up of 35 student participants from 22 nationalities (Fig. 1a) as well as 32 lecturers. Lectures and laboratory demonstrations were supported by literature seminars, and four broad research areas were covered: (1) multitrophic interactions and plant defenses, (2) chemical communication focusing on odor sensing, processing, and behavior, (3) disease vectors, and (4) applied aspects of basic ICE research in agriculture. This particular article contains a summary and brief synthesis of these main emergent themes and discussions from the ICE 2018 course. In addition, we also provide suggestions on teaching the next generation of ICE scientists, especially during unprecedented global situations.

Activated Human Memory B Lymphocytes Use CR4 (CD11c/CD18) for Adhesion, Migration, and Proliferation.

Complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) of myeloid cells are known for long to participate in actin linked functions like phagocytosis, adhesion, and migration. The expression and role of these two ß2-integrins however, in human B lymphocytes have only scarcely been studied so far, although it has been shown recently that CD11c+ B cells are mainly memory cells. In our systematic study we investigated B cells isolated from tonsils and peripheral blood of healthy donors. We found, that while only 5% of resting tonsillar B cells expressed CD11c, their number increased up to 26% after 3 days of BCR stimulation. Lower, but still remarkable percentage of B lymphocytes were positive for CD11c after stimulation via TLR9 alone or via TLR9 and BCR simultaneously. At the same time, we detected no significant expression of CD11b on resting or activated tonsillar B cells. Blood B lymphocytes showed a similar expression pattern of both ß2-integrins. We demonstrated that CD11c molecules appearing on the surface of B cells are newly synthesized, reaching the number of 9,500 per activated B cell. We found that CR4 expressing B cells belong to the memory pool and the increase of CD11c expression on tonsillar B cells upon BCR mediated activation occurs parallel with class switching. Analysis of the function of CD11c revealed, that this ß2-integrin contributes to the adhesion and migration of activated B lymphocytes. We also demonstrated that the CR4 mediated adhesion promotes the proliferation of the BCR activated cells. Our studies are the first to demonstrate that CD11c expressed on BCR-activated human B cells are not only passive markers but functional drivers of memory B cell responses.

Fungal Volatiles as Olfactory Cues for Female Fungus Gnat, Lycoriella ingenua in the Avoidance of Mycelia Colonized Compost.

The chemical signatures emitted by fungal substrates are key components for mycophagous insects in the search for food source or for suitable oviposition sites. These volatiles are usually emitted by the fruiting bodies and mycelia. The volatiles attract fungivorous insects, like flowers attract pollinators; certain flowers mimic the shape of mushroom fruiting bodies and even produce a typical mushroom odor to exploit on fungus-insect mutualism. There are numerous insects which are mycophagous or eat fungi additionally, but only a few are considered a threat in agriculture. Lycoriella ingenua is one of the most serious pests in mushroom cultivation worldwide. Here we attempt to examine the role of environmental volatiles upon behavioral oviposition preference. In two-choice bioassays, fungus gnats preferred uncolonized compost compared to colonized compost but preferred colonized compost against nothing. However, when colonized compost was paired against distilled water, no significant choice was observed. The comparison of fresh casing material and mycelium colonized casing material resulted in no significant preference. From colonized compost headspace, three antennally active volatiles were isolated by gas chromatography coupled with electroantennography and subsequently identified with gas chromatography coupled mass spectrometry as 1-hepten-3-ol, 3-octanone and 1-octen-3-ol. In behavioral assays the addition of said synthetic volatiles to uncolonized compost separately and in combination to mimic colonized compost resulted in avoidance. We thus partially elucidate the role of fungal volatiles in the habitat seeking behavior of Lycoriella ingenua.

Novel opioid-neurotensin-based hybrid peptide with spinal long-lasting antinociceptive activity and a propensity to delay tolerance development.

The behavioral responses exerted by spinal administration of the opioid-neurotensin hybrid peptide, PK23, were studied in adult male rats. The antinociceptive effect upon exposure to a thermal stimulus, as well as tolerance development, was assessed in an acute pain model. The PK23 chimera at a dose of 10 nmol/rat produced a potent pain-relieving effect, especially after its intrathecal administration. Compared with intrathecal morphine, this novel compound was found to possess a favourable side effect profile characterized by a reduced scratch reflex, delayed development of analgesic tolerance or an absence of motor impairments when given in the same manner, though some animals died following barrel rotation as a result of its i.c.v. administration (in particular at doses higher than 10 nmol/rat). Nonetheless, these results suggest the potential use of hybrid compounds encompassing both opioid and neurotensin structural fragments in pain management. This highlights the enormous potential of synthetic neurotensin analogues as promising future analgesics.

Essential Oil Headspace Volatiles Prevent Invasive Box Tree Moth (Cydalima perspectalis) Oviposition-Insights from Electrophysiology and Behaviour.

The box tree moth (Cydalima perspectalis Walker) is an invasive species in Europe causing severe damage both in natural and ornamental boxwood (Buxus spp.) vegetation. Pest management tactics are often based on the use of chemical insecticides, whereas environmentally-friendly control solutions are not available against this insect. The application of essential oils may provide effective protection against oviposition and subsequent larval damage. Oviposition deterrence of cinnamon, eucalyptus and lavender essential oils was tested on female C. perspectalis in behavioural bioassays. Our results indicate that all the studied essential oils may be adequate deterrents; however, cinnamon oil exhibited the strongest effect. To determine the physiologically active compounds in the headspace of the essential oils, gas chromatography coupled with electroantennography recordings were performed in parallel with gas chromatography-mass spectrometry to identify the volatile constituents. In addition, the release rates of various components from vial-wick dispensers were measured during the oviposition bioassay. These results may serve as a basis for the development of a practical and insecticide-free plant protection method against this invasive moth species.

The differential role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in the adherence, migration and podosome formation of human macrophages and dendritic cells under inflammatory conditions.

CR3 and CR4, the leukocyte specific ß2-integrins, involved in cellular adherence, migration and phagocytosis, are often assumed to have similar functions. Previously however, we proved that under physiological conditions CR4 is dominant in the adhesion to fibrinogen of human monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs). Here, using inflammatory conditions, we provide further evidence that the expression and function of CR3 and CR4 are not identical in these cell types. We found that LPS treatment changes their expression differently on MDMs and MDDCs, suggesting a cell type specific regulation. Using mAb24, specific for the high affinity conformation of CD18, we proved that the activation and recycling of ß2-integrins is significantly enhanced upon LPS treatment. Adherence to fibrinogen was assessed by two fundamentally different approaches: a classical adhesion assay and a computer-controlled micropipette, capable of measuring adhesion strength. While both receptors participated in adhesion, we demonstrated that CR4 exerts a dominant role in the strong attachment of MDDCs. Studying the formation of podosomes we found that MDMs retain podosome formation after LPS activation, whereas MDDCs lose this ability, resulting in a significantly reduced adhesion force and an altered cellular distribution of CR3 and CR4. Our results suggest that inflammatory conditions reshape differentially the expression and role of CR3 and CR4 in macrophages and dendritic cells.

Utilization of complement receptors in immune cell-microbe interaction.

The complement system is a major humoral component of immunity and is essential for the fast elimination of pathogens invading the body. In addition to its indispensable role in innate immunity, the complement system is also involved in pathogen clearance during the effector phase of adaptive immunity. The fastest way of killing the invader is lysis by the membrane attack complex, which is formed by the terminal components of the complement cascade. Not all pathogens are lysed however and, if opsonized by a variety of molecules, they undergo phagocytosis and disposal inside immune cells. The most important complement-derived opsonins are C1q, the first component of the classical pathway, MBL, the initiator of the lectin pathway and C3-derived activation fragments, including C3b, iC3b and C3d, which all serve as ligands for their corresponding receptors. In this review, we discuss how complement receptors are utilized by various immune cells to tackle invading microbes, or by pathogens to evade host response.

Complement Receptor Type 1 (CR1, CD35), the Inhibitor of BCR-Mediated Human B Cell Activation, Differentially Regulates TLR7, and TLR9 Induced Responses.

The complement system and Toll-like receptors (TLRs) are essential contributors of innate immunity. Separate activation of these systems has been shown to play a role in initiating and shaping the adaptive immune response, however the modulation of various B cell functions by the simultaneous involvement of these two systems has not yet been uncovered. We demonstrate here that occupancy of complement receptor type 1 (CR1, CD35) by its natural, complement component C3-derived ligand significantly and dose dependently reduces the TLR9-induced expression of activation markers, cytokine production, proliferation, and antibody production by human B cells, but has no effect on the TLR7-induced functions. The synergistic response to the simultaneous engagement of either TLR9 or TLR7 along with the BCR however, is significantly inhibited by CR1 occupancy. Our findings imply that both under physiological and pathological conditions, when complement- and TLR-activating microbial and damage products are present in the B cell environment, the cooperation between CR1 and TLR7 or TLR9 provides additional levels of the regulation of human B cell functions.

Non-identical twins: Different faces of CR3 and CR4 in myeloid and lymphoid cells of mice and men.

Integrins are cell membrane receptors that are involved in essential physiological and serious pathological processes. Their main role is to ensure a closely regulated link between the extracellular matrix and the intracellular cytoskeletal network enabling cells to react to environmental stimuli. Complement receptor type 3 (CR3, αMß2, CD11b/CD18) and type 4 (CR4, αXß2, CD11c/CD18) are members of the ß2-integrin family expressed on most white blood cells. Both receptors bind multiple ligands like iC3b, ICAM, fibrinogen or LPS. ß2-integrins are accepted to play important roles in cellular adhesion, migration, phagocytosis, ECM rearrangement and inflammation. Several pathological conditions are linked to the impaired functions of these receptors. CR3 and CR4 are generally thought to mediate overlapping functions in monocytes, macrophages and dendritic cells, therefore the potential distinctive role of these receptors has not been investigated so far in satisfactory details. Lately it has become clear that a functional segregation has evolved between the two receptors regarding phagocytosis, cellular adhesion and podosome formation. In addition to their tasks on myeloid cells, the expression and function of CR3 and CR4 on lymphocytes have also gained interest recently. The picture is further complicated by the fact that while these ß2-integrins are expressed by immune cells both in mice and humans, there are significant differences in their expression level, functions and the pathological consequences of genetic defects. Here we aim to summarize our current knowledge on CR3 and CR4 and highlight the functional differences between these receptors, involving their expression in myeloid and lymphoid cells of both men and mice.