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Cross-reactivity between allergens and human proteins could have a clinical impact in allergic diseases. Blo t 13 is an allergen from the mite Blomia tropicalis, which belongs to the fatty acid binding protein (FABP) family and has structural homology with human FABPs. This work aimed to map B cell epitopes on Blo t 13 and to identify epitopes involved in cross-reactivity with human heart FABP (FABP3) and adipocyte FABP (FABP4). Sera from 25 patients with house dust mite (HDM) allergy that were sensitized to Blo t 13 were used for testing the reactivity of immunoglobulin E (IgE) and IgG to FABP. The epitope mapping of Blo t 13 was performed using overlapping peptides, and cross-reactivity between Blo t 13 and human FABP was analyzed using human sera and anti-Blo t 13 monoclonal antibodies. IgE antibodies to all FABPs were detected in 14/25 serum samples, and IgG was detected in 25/25 serum samples. The cross-reactivity of Blo t 13 was 42% with FABP3 and 48% with FABP4. Two IgE-binding regions were identified in Blo t 13; one between residues 54 and 72 (the main cross-reacting region) and another between residues 111 to 129. Our results suggest that exposure to the Blo t 13 allergen could induce an auto-reactive response to endogenous FABP in allergic patients sensitized to Blo t 13.

Key Points Fatty acid-binding proteins (FABPs) are versatile proteins that can modulate lipid fluxes, trafficking, signalling and metabolism Fatty acid-binding protein, adipocyte (FABP4) regulates metabolic and inflammatory pathways, and in mouse models its inhibition can improve type 2 diabetes mellitus and atherosclerosis FABP4 is actively secreted by adipocytes and its levels are increased in obesity; in humans, elevated circulating FABP4 levels are associated with obesity, metabolic disease and cardiac dysfunction Circulating FABP4 is secreted through a vesicular pathway and has pleiotropic roles that include the stimulation of hepatic glucose production Targeting FABP4 offers a novel therapeutic approach for the treatment of many metabolic diseases The signalling components of hormonal FABP4 and determinants of FABP-mediated functions in the context of specific lipid or other cargo are issues that must be addressed in future research Fatty acid-binding proteins (FABPs) improve the solubility of fatty acids. Here, Hotamisligil and Bernlohr describe the structure and function of FABPs in the control of fatty acid metabolism and obesity. The authors focus on FABP4 and FABP5, the most abundant FABPs in adipose tissue, and discuss how targeting these proteins might be exploited to treat metabolic diseases. Intracellular and extracellular interactions with proteins enables the functional and mechanistic diversity of lipids. Fatty acid-binding proteins (FABPs) were originally described as intracellular proteins that can affect lipid fluxes, metabolism and signalling within cells. As the functions of this protein family have been further elucidated, it has become evident that they are critical mediators of metabolism and inflammatory processes, both locally and systemically, and therefore are potential therapeutic targets for immunometabolic diseases. In particular, genetic deficiency and small molecule-mediated inhibition of FABP4 (also known as aP2) and FABP5 can potently improve glucose homeostasis and reduce atherosclerosis in mouse models. Further research has shown that in addition to their intracellular roles, some FABPs are found outside the cells, and FABP4 undergoes regulated, vesicular secretion. The circulating form of FABP4 has crucial hormonal functions in systemic metabolism. In this Review we discuss the roles and regulation of both intracellular and extracellular FABP actions, highlighting new insights that might direct drug discovery efforts and opportunities for management of chronic metabolic diseases.

The molecular basis for the propensity of a small number of environmental proteins to provoke allergic responses is largely unknown. Herein, we report that mite group 13 allergens of the fatty acid-binding protein (FABP) family are sensed by an evolutionarily conserved acute-phase protein, serum amyloid A1 (SAA1), that promotes pulmonary type 2 immunity. Mechanistically, SAA1 interacted directly with allergenic mite FABPs (Der p 13 and Blo t 13). The interaction between mite FABPs and SAA1 activated the SAA1-binding receptor, formyl peptide receptor 2 (FPR2), which drove the epithelial release of the type-2-promoting cytokine interleukin (IL)-33 in a SAA1-dependent manner. Importantly, the SAA1–FPR2–IL-33 axis was upregulated in nasal epithelial cells from patients with chronic rhinosinusitis. These findings identify an unrecognized role for SAA1 as a soluble pattern recognition receptor for conserved FABPs found in common mite allergens that initiate type 2 immunity at mucosal surfaces. Smole and colleagues show that the soluble pattern recognition receptor serum amyloid A (SAA) recognizes several mite allergenic proteins, including Der p 13 and Blo t 13, which are conserved fatty acid-binding proteins. Such FABP–SAA1 binding triggers epithelial cell release of the type-2-promoting cytokine IL-33, which in turn drives IL-13 production and allergic syptoms.

Many different Schistosoma antigens have been evaluated as vaccine candidates, including the recombinant form of the Schistosoma mansoni 14-kDa fatty acid-binding protein (rSm14). However, recombinant proteins often lack intrinsic immunostimulatory activity, a limitation that can be addressed by using vaccine formulations that contain adjuvants. In this work, we describe the immune response triggered by rSm14, a vaccine candidate against schistosomiasis currently under clinical trial, formulated with either (i) Monophosphoryl Lipid A (MPLA), (ii) MPLA/Alum, or (iii) Freund's adjuvant. rSm14/MPLA and rSm14/MPLA/Alum formulations induced increased frequency of effector and memory CD4+ T and central memory CD8+ T cells, respectively. Both formulations induced significant production of rSm14-specific IgG and IgG1 antibodies, which could recognize the protein's native form. The rSm14/Freund's formulation elicited a robust immune response characterized by increased levels of IFN-γ, TNF, IgG, IgG1, and IgG2c antibodies, and expansion of memory B cell. These soluble factors have been implicated in the efficacy of Sm14-based vaccines. Despite inducing both humoral and cellular immune responses, the different formulations did not impact worm burden and the number of eggs trapped in the liver and intestine. Altogether, our findings indicate a limitation in the use of the molecules assessed in this study, such as IFN-γ, TNF, and specific antibodies, as correlates of protection and vaccine efficacy.

Background Breast cancer is the most common cancer in women diagnosed in the U.S. and worldwide. Obesity increases breast cancer risk without clear underlying molecular mechanisms. Our studies demonstrate that circulating adipose fatty acid binding protein (A-FABP, or FABP4) links obesity-induced dysregulated lipid metabolism and breast cancer risk, thus potentially offering a new target for breast cancer treatment. Methods We immunized FABP4 knockout mice with recombinant human FABP4 and screened hybridoma clones with specific binding to FABP4. The potential effects of antibodies on breast cancer cells in vitro were evaluated using migration, invasion, and limiting dilution assays. Tumor progression in vivo was evaluated in various types of tumorigenesis models including C57BL/6 mice, Balb/c mice, and SCID mice. The phenotype and function of immune cells in tumor microenvironment were characterized with multi-color flow cytometry. Tumor stemness was detected by ALDH assays. To characterize antigen-antibody binding capacity, we determined the dissociation constant of selected anti-FABP4 antibodies via surface plasmon resonance. Further analyses in tumor tissue were performed using 10X Genomics Visium spatial single cell technology. Results Herein, we report the generation of humanized monoclonal antibodies blocking FABP4 activity for breast cancer treatment in mouse models. One clone, named 12G2, which significantly reduced circulating levels of FABP4 and inhibited mammary tumor growth, was selected for further characterization. After confirming the therapeutic efficacy of the chimeric 12G2 monoclonal antibody consisting of mouse variable regions and human IgG1 constant regions, 16 humanized 12G2 monoclonal antibody variants were generated by grafting its complementary determining regions to selected human germline sequences. Humanized V9 monoclonal antibody showed consistent results in inhibiting mammary tumor growth and metastasis by affecting tumor cell mitochondrial metabolism. Conclusions Our current evidence suggests that targeting FABP4 with humanized monoclonal antibodies may represent a novel strategy for the treatment of breast cancer and possibly other obesity- associated diseases.

SARS-CoV-2 infection is a major global public health concern with incompletely understood pathogenesis. The SARS-CoV-2 spike (S) glycoprotein comprises a highly conserved free fatty acid binding pocket (FABP) with unknown function and evolutionary selection advantage 1 , 2 . Deciphering FABP impact on COVID-19 progression is challenged by the heterogenous nature and large molecular variability of live virus. Here we create synthetic minimal virions (MiniVs) of wild-type and mutant SARS-CoV-2 with precise molecular composition and programmable complexity by bottom-up assembly. MiniV-based systematic assessment of S free fatty acid (FFA) binding reveals that FABP functions as an allosteric regulatory site enabling adaptation of SARS-CoV-2 immunogenicity to inflammation states via binding of pro-inflammatory FFAs. This is achieved by regulation of the S open-to-close equilibrium and the exposure of both, the receptor binding domain (RBD) and the SARS-CoV-2 RGD motif that is responsible for integrin co-receptor engagement. We find that the FDA-approved drugs vitamin K and dexamethasone modulate S-based cell binding in an FABP-like manner. In inflammatory FFA environments, neutralizing immunoglobulins from human convalescent COVID-19 donors lose neutralization activity. Empowered by our MiniV technology, we suggest a conserved mechanism by which SARS-CoV-2 dynamically couples its immunogenicity to the host immune response. Staufer et al. provide a protocol for preparation of synthetic minimal virions (MiniV) of SARS-CoV-2, mimicking viral structure and allowing for precise investigation of receptor binding mechanism. They find that the highly conserved free fatty acid binding pocket (FABP) can function as an allosteric regulator, enabling adaptation of immunogenicity via binding of proinflammatory free fatty acids and mediating the spike open to-closed equilibrium.

•First clinical test of a schistosomiasis vaccine in humans for safety and immunogenicity.•Formulation with glucopyranosyl lipid A (GLA) adjuvant in an oil-in-water emulsion.•High tolerability shown with specific IgG response and absence of IgE response.•CD4+ T cells producing TNFα and IL-2 emerged with few multi-functional TH1 cells.•The Phase 1 trial shows this schistosomiasis vaccine as safe and strongly immunogenic. Safety and immunogenicity of a recombinant 14kDa, fatty acid-binding protein(FABP) from Schistosoma mansoni (rSm14) were evaluated through an open, non-placebo-controlled, dose-standardized trial, performed at a single research site. The vaccine was formulated with glucopyranosyl lipid A (GLA) adjuvant in an oil-in-water emulsion (SE) and investigated in 20 male volunteers from a non-endemic area for schistosomiasis in the state of Rio de Janeiro, Brazil. Fifty microgram rSm14 with 10μg GLA-SE (rSm14/GLA-SE)/dose were given intramuscularly three times with 30-day intervals. Participants were assessed clinically, biochemically and immunologically for up to 120 days. Participants were screened for inclusion by physical examination, haematology and blood chemistry; then followed to assess adverse events and immunogenicity. Sera were tested for IgG (total and isotypes) and IgE. T cell induction of cytokines IL-2, IL-5, IL-10, IFNγ and TNFα was assessed by Milliplex kit and flow cytometry. The investigational product showed high tolerability; some self-limited, mild adverse events were observed during and after vaccine administration. Significant increases in Sm14-specific total IgG, IgG1 and IgG3 were observed 30 days after the first vaccination with specific IgG2 and IgG4 after 60 days. An increase in IgE antibodies was not observed at any time point. The IgG response was augmented after the second dose and 88% of all vaccinated subjects had developed high anti-Sm14 IgG titres 90 days after the first injection. From day 60 and onwards, there was an increase in CD4+ T cells producing single cytokines, particularly TNFα and IL-2, with no significant increase of multi-functional TH1 cells. Clinical trial data on tolerability and specific immune responses after vaccination of adult, male volunteers in a non-endemic area for schistosomiasis with rSm14/GLA-SE, support this product as a safe, strongly immunogenic vaccine against schistosomiasis paving the way for follow-up Phase 2 trials. Study registration ID: NCT01154049 at http://www.clinicaltrials.gov.

Dietary obesity is regarded as a problem worldwide, and it has been revealed the strong linkage between obesity and allergic inflammation. Fatty acid-binding protein 5 (FABP5) is expressed in lung cells, such as alveolar epithelial cells (ECs) and alveolar macrophages, and plays an important role in infectious lung inflammation. However, we do not know precise mechanisms on how lipid metabolic change in the lung affects allergic lung inflammation. In this study, we showed that Fabp5 −/− mice exhibited a severe symptom of allergic lung inflammation. We sought to examine the role of FABP5 in the allergic lung inflammation and demonstrated that the expression of FABP5 acts as a novel positive regulator of ST2 expression in alveolar ECs to generate retinoic acid (RA) and supports the synthesis of RA from type II alveolar ECs to suppress excessive activation of innate lymphoid cell (ILC) 2 during allergic lung inflammation. Furthermore, high-fat diet (HFD)-fed mice exhibit the downregulation of FABP5 and ST2 expression in the lung tissue compared with normal diet (ND)-fed mice. These phenomena might be the reason why obese people are more susceptible to allergic lung inflammation. Thus, FABP5 is potentially a therapeutic target for treating ILC2-mediated allergic lung inflammation.

The mechanisms underlying gestational diabetes mellitus (GDM) and their impact on maternal and child immunity remain unclear. We hypothesize that gut microbiome alterations and increased small intestinal permeability contribute to GDM. Intestinal fatty acid-binding protein (I-FABP) leakage and elevated IgA/IgG against beta-lactoglobulin may indicate mucosal damage and may serve as biomarkers. This study evaluated I-FABP and IgA/IgG levels against beta-lactoglobulin in mothers with and without GDM (n=100) and in their children (n=87 at time point 1 (TP1), n=79 at time point 2 (TP2). Levels of antibody to (DSM20083, DSM20086) and (DSM20213) were assessed using flow cytometry. I-FABP was measured using the Hycult Biotech ELISA Kit, and IgA/IgG levels to beta-lactoglobulin were measured using in-house ELISA. I-FABP and IgA/IgG levels did not significantly differ between mothers with and without GDM. However, children at TP1 had significantly higher I-FABP, IgA and IgG levels to beta-lactoglobulin than their mothers (p<0.01). In children, both I-FABP and IgA levels to beta-lactoglobulin declined with age (p<0.05). The children of mothers with GDM had higher IgA levels to beta-lactoglobulin (p=0.004). I-FABP was inversely correlated with IgA to in GDM mothers (p<0.002). Breastfeed children had higher beta-lactoglobulin IgA/IgG levels (p=0.02), but I-FABP levels did not differ regarding the length of breastfeeding. Higher I-FABP and IgA levels to beta-lactoglobulin in children suggest increased intestinal permeability compared to adults. Only IgA to beta-lactoglobulin was significantly elevated in the children of mothers with GDM.

Both innate and adaptive immune cells are critical players in autoimmune destruction of insulin-producing β cells in type 1 diabetes. However, the early pathogenic events triggering the recruitment and activation of innate immune cells in islets remain obscure. Here we show that circulating fatty acid binding protein 4 (FABP4) level was significantly elevated in patients with type 1 diabetes and their first-degree relatives and positively correlated with the titers of several islet autoantibodies. In nonobese diabetic (NOD) mice, increased FABP4 expression in islet macrophages started from the neonatal period, well before the occurrence of overt diabetes. Furthermore, the spontaneous development of autoimmune diabetes in NOD mice was markedly reduced by pharmacological inhibition or genetic ablation of FABP4 or adoptive transfer of FABP4-deficient bone marrow cells. Mechanistically, FABP4 activated innate immune responses in islets by enhancing the infiltration and polarization of macrophages to proinflammatory M1 subtype, thus creating an inflammatory milieu required for activation of diabetogenic CD8+ T cells and shift of CD4+ helper T cells toward Th1 subtypes. These findings demonstrate FABP4 as a possible early mediator for β cell autoimmunity by facilitating crosstalk between innate and adaptive immune cells, suggesting that pharmacological inhibition of FABP4 may represent a promising therapeutic strategy for autoimmune diabetes.