Evidence that emotion mediates social attention in rhesus macaques

Background

Recent work on non-human primates indicates that the allocation of social attention is mediated by characteristics of the attending animal, such as social status and genotype, as well as by the value of the target to which attention is directed. Studies of humans indicate that an individual’s emotion state also plays a crucial role in mediating their social attention; for example, individuals look for longer towards aggressive faces when they are feeling more anxious, and this bias leads to increased negative arousal and distraction from other ongoing tasks. To our knowledge, no studies have tested for an effect of emotion state on allocation of social attention in any non-human species.

Methodology

We presented captive adult male rhesus macaques with pairs of adult male conspecific face images - one with an aggressive expression, one with a neutral expression - and recorded gaze towards these images. Each animal was tested twice, once during a putatively stressful condition (i.e. following a veterinary health check), and once during a neutral (or potentially positive) condition (i.e. a period of environmental enrichment). Initial analyses revealed that behavioural indicators of anxiety and stress were significantly higher after the health check than during enrichment, indicating that the former caused a negative shift in emotional state.

Principle Findings

The macaques showed initial vigilance for aggressive faces across both conditions, but subsequent responses differed between conditions. Following the health check, initial vigilance was followed by rapid and sustained avoidance of aggressive faces. By contrast, during the period of enrichment, the macaques showed sustained attention towards the same aggressive faces.

Conclusions/Significance

These data provide, to our knowledge, the first evidence that shifts in emotion state mediate social attention towards and away from facial cues of emotion in a non-human animal. This work provides novel insights into the evolution of emotion-attention interactions in humans, and mechanisms of social behaviour in non-human primates, and may have important implications for understanding animal psychological wellbeing.     

Genetic substructure in cynomolgus macaques (Macaca fascicularis) on the island of Mauritius

Background

Nonhuman primates are commonly used in biomedical research as animal models of human disease and behavior. Compared to common rodent models, nonhuman primates are genetically, physiologically, behaviorally and neurologically more similar to humans owing to more recent shared ancestry and therefore provide the advantage of greater translational validity in preclinical studies. The cynomolgus macaque (Macaca fascicularis) is one of the most commonly used nonhuman primates in academic and industry settings, yet population genetic research has revealed significant substructure throughout the species distribution that may confound studies. Cynomolgus monkeys introduced to Mauritius specifically have previously been thought to maintain the least genetic heterogeneity of all cynomolgus monkeys, although recent work, including work from our lab, suggests macaques from Mauritius too may harbor cryptic substructure.

Results

To evaluate putative substructure in Mauritian cynomolgus macaques, we designed a panel of 96 single nucleotide polymorphisms based on preliminary findings from previous work to screen 246 of cynomolgus monkeys from two primary suppliers. Results from this study support substructure in Mauritian macaques and suggest a minimum of two populations and maybe three on Mauritius, with moderate admixture.

Conclusion

These findings inform the natural history of these monkeys suggesting either a previously unrecognized physical or ecological barrier to gene flow on Mauritius and/or the breakdown of historic substructure resulting from the history of macaque introduction to the island. These findings are relevant to ongoing research using these models in part because of increased appreciation of segregating common variation with functional effects and may be used to better inform animal selection in preclinical research.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-748) contains supplementary material, which is available to authorized users.     

A non-human primate model for gluten sensitivity

Background and Aims

Gluten sensitivity is widespread among humans. For example, in celiac disease patients, an inflammatory response to dietary gluten leads to enteropathy, malabsorption, circulating antibodies against gluten and transglutaminase 2, and clinical symptoms such as diarrhea. There is a growing need in fundamental and translational research for animal models that exhibit aspects of human gluten sensitivity.

Methods

Using ELISA-based antibody assays, we screened a population of captive rhesus macaques with chronic diarrhea of non-infectious origin to estimate the incidence of gluten sensitivity. A selected animal with elevated anti-gliadin antibodies and a matched control were extensively studied through alternating periods of gluten-free diet and gluten challenge. Blinded clinical and histological evaluations were conducted to seek evidence for gluten sensitivity.

Results

When fed with a gluten-containing diet, gluten-sensitive macaques showed signs and symptoms of celiac disease including chronic diarrhea, malabsorptive steatorrhea, intestinal lesions and anti-gliadin antibodies. A gluten-free diet reversed these clinical, histological and serological features, while reintroduction of dietary gluten caused rapid relapse.

Conclusions

Gluten-sensitive rhesus macaques may be an attractive resource for investigating both the pathogenesis and the treatment of celiac disease.     

Rapid Generation of Human-Like Neutralizing Monoclonal Antibodies in Urgent Preparedness for Influenza Pandemics and Virulent Infectious Diseases

Background

The outbreaks of emerging infectious diseases caused by pathogens such as SARS coronavirus, H5N1, H1N1, and recently H7N9 influenza viruses, have been associated with significant mortality and morbidity in humans. Neutralizing antibodies from individuals who have recovered from an infection confer therapeutic protection to others infected with the same pathogen. However, survivors may not always be available for providing plasma or for the cloning of monoclonal antibodies (mAbs).

Methodology/Principal Findings

The genome and the immunoglobulin genes in rhesus macaques and humans are highly homologous; therefore, we investigated whether neutralizing mAbs that are highly homologous to those of humans (human-like) could be generated. Using the H5N1 influenza virus as a model, we first immunized rhesus macaques with recombinant adenoviruses carrying a synthetic gene encoding hemagglutinin (HA). Following screening an antibody phage display library derived from the B cells of immunized monkeys, we cloned selected macaque immunoglobulin heavy chain and light chain variable regions into the human IgG constant region, which generated human-macaque chimeric mAbs exhibiting over 97% homology to human antibodies. Selected mAbs demonstrated potent neutralizing activities against three clades (0, 1, 2) of the H5N1 influenza viruses. The in vivo protection experiments demonstrated that the mAbs effectively protected the mice even when administered up to 3 days after infection with H5N1 influenza virus. In particular, mAb 4E6 demonstrated sub-picomolar binding affinity to HA and superior in vivo protection efficacy without the loss of body weight and obvious lung damage. The analysis of the 4E6 escape mutants demonstrated that the 4E6 antibody bound to a conserved epitope region containing two amino acids on the globular head of HA.

Conclusions/Significance

Our study demonstrated the generation of neutralizing mAbs for potential application in humans in urgent preparedness against outbreaks of new influenza infections or other virulent infectious diseases.     

Impulsivity and the 5-HTTLPR polymorphism in a non-clinical sample

Background

Impulsivity has been associated with serotonergic system functions. However, few researchers have investigated the relationship between a polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) and the different components of impulsivity in a non-clinical population. The aim of this study was to investigate the relationship between a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and the different components of impulsivity in a non-clinical population.

Methodology/Principal Findings

We administered two neuropsychological tests, the Continuous Performance Task and the Iowa Gambling Task, to 127 healthy participants to measure their levels of motor, attentional and non-planning impulsivity. Then, these participants were grouped by genotype and gender, and their scores on impulsivity measures were compared. There were no significant differences between group scores on attentional, motor and non-planning impulsivity.

Conclusions/Significance

Our results suggest that 5-HTTLPR genotype is not significantly associated with subsets of impulsive behavior in a non-clinical sample when measured by neuropsychological tests. These findings are discussed in terms of the sensitivity of neuropsychological tests to detect impulsivity in a non-clinical population and the role of gender and race in the relationship between the 5-HTTLPR and impulsivity.     

Serotonin differentially regulates short- and long-term prediction of rewards in the ventral and dorsal striatum

Background

The ability to select an action by considering both delays and amount of reward outcome is critical for maximizing long-term benefits. Although previous animal experiments on impulsivity have suggested a role of serotonin in behaviors requiring prediction of delayed rewards, the underlying neural mechanism is unclear.

Methodology/Principal Findings

To elucidate the role of serotonin in the evaluation of delayed rewards, we performed a functional brain imaging experiment in which subjects chose small-immediate or large-delayed liquid rewards under dietary regulation of tryptophan, a precursor of serotonin. A model-based analysis revealed that the activity of the ventral part of the striatum was correlated with reward prediction at shorter time scales, and this correlated activity was stronger at low serotonin levels. By contrast, the activity of the dorsal part of the striatum was correlated with reward prediction at longer time scales, and this correlated activity was stronger at high serotonin levels.

Conclusions/Significance

Our results suggest that serotonin controls the time scale of reward prediction by differentially regulating activities within the striatum.     

Elimination of Schistosoma mansoni Adult Worms by Rhesus Macaques: Basis for a Therapeutic Vaccine?

Background

Among animal models of schistosomiasis, the rhesus macaque is unique in that an infection establishes but egg excretion rapidly diminishes, potentially due to loss of adult worms from the portal system via shunts or death by immune attack.

Principal Findings

To investigate this, six rhesus macaques were exposed to Schistosoma mansoni cercariae and the infection monitored until portal perfusion at 18 weeks. Despite a wide variation in worm numbers recovered, fecal egg output and circulating antigen levels indicated that a substantial population had established in all animals. Half the macaques had portal hypertension but only one had portacaval shunts, ruling out translocation to the lungs as the reason for loss of adult burden. Many worms had a shrunken and pallid appearance, with degenerative changes in intestines and reproductive organs. Tegument, gut epithelia and muscles appeared cytologically intact but the parenchyma was virtually devoid of content. An early and intense IgG production correlated with low worm burden at perfusion, and blood-feeding worms cultured in the presence of serum from these animals had stunted growth. Using immunoproteomics, gut digestive enzymes, tegument surface hydrolases and antioxidant enzymes were identified as targets of IgG in the high responder animals.

Significance

It appears that worms starve to death after cessation of blood feeding, as a result of antibody-mediated processes. We suggest that proteins in the three categories above, formulated to trigger the appropriate mechanisms operating in rhesus macaques, would have both prophylactic and therapeutic potential as a human vaccine.     

Ultra-rapid categorization of fourier-spectrum equalized natural images: macaques and humans perform similarly

Background

Comparative studies of cognitive processes find similarities between humans and apes but also monkeys. Even high-level processes, like the ability to categorize classes of object from any natural scene under ultra-rapid time constraints, seem to be present in rhesus macaque monkeys (despite a smaller brain and the lack of language and a cultural background). An interesting and still open question concerns the degree to which the same images are treated with the same efficacy by humans and monkeys when a low level cue, the spatial frequency content, is controlled.

Methodology/Principal Findings

We used a set of natural images equalized in Fourier spectrum and asked whether it is still possible to categorize them as containing an animal and at what speed. One rhesus macaque monkey performed a forced-choice saccadic task with a good accuracy (67.5% and 76% for new and familiar images respectively) although performance was lower than with non-equalized images. Importantly, the minimum reaction time was still very fast (100 ms). We compared the performances of human subjects with the same setup and the same set of (new) images. Overall mean performance of humans was also lower than with original images (64% correct) but the minimum reaction time was still short (140 ms).

Conclusion

Performances on individual images (% correct but not reaction times) for both humans and the monkey were significantly correlated suggesting that both species use similar features to perform the task. A similar advantage for full-face images was seen for both species. The results also suggest that local low spatial frequency information could be important, a finding that fits the theory that fast categorization relies on a rapid feedforward magnocellular signal.     

Association Study of Serotonin Transporter SLC6A4 Gene with Chinese Han Irritable Bowel Syndrome

Objective

Irritable bowel syndrome (IBS) is a common clinical gastrointestinal dysfunction disorders. 5-sertonon (5-hydroxytryptamine, 5-HT) is a very important neurotransmitter, which is involved in gastrointestinal motion and sensation. Solute carrier family 6 member 4 (SLC6A4) gene encode serotonin transporter (SERT) which function is to rapidly reuptake the most of 5-HT. Therefore, it is needed to explore the association between SLC6A4 gene polymorphisms and IBS.

Methods

119 patients and 238 healthy controls were administrated to detect the SLC6A4 gene polymorphisms including 5-HT-transporter-gene-linked polymorphic region (5-HTTLPR), variable number of tandem repeats (VNTRs) and three selected tag Single Nucleotide Polymorphisms (SNPs) rs1042173, rs3794808, rs2020936 by using polymerase chain reaction (PCR) and TaqMan® SNP Genotyping.

Results

There were significant difference for 5-HTTLPR between IBS and control groups (X2 = 106.168, P<0.0001). In control group, genotypes were mainly L/L (58.4%), however, the genotypes in IBS were S/S (37.8%). The significant difference was shown in D-IBS subjects when compared to the controls (X² = 50.850, P<0.0001) for 5-HTTLPR. For STin2 VNTR, rs1042173, rs3794808, and rs2020936 polymorphisms, there were no any significant differences between IBS and control groups. There were no statistical significantly haplotypes for 5-HTTLPR, VNTRs and the three SNPs between IBS and controls.

Conclusion

The S allele in 5-HTTLPR was a susceptible allele with Chinese Han IBS, but other associations of VNTRs, three selected Tag SNPs and positive haplotype with IBS were not found. It is indicated that much research are needed to study the relationship between other polymorphisms in SLC6A4 gene and IBS.     

Serotonin transporter gene variation, infant abuse, and responsiveness to stress in rhesus macaque mothers and infants

A functional polymorphism in the promoter region of the serotonin transporter (5-HTTLPR) gene has been associated with variation in anxiety and hypothalamus-pituitary-adrenal (HPA) axis function in humans and rhesus macaques. Individuals carrying the short allele are at a higher risk for developmental psychopathology, and this risk is magnified in short allele carriers who have experienced early life stress. This study investigated the relationship between 5-HTTLPR allelic variation, infant abuse, and behavioral and hormonal responses to stress in rhesus macaques. Subjects were 10 abusive mothers and their infants, and 10 nonabusive mother-infant pairs. Mothers and infants were genotyped for the rh5-HTTLPR, and studied in the first 6 months of infant life. For mothers and infants, we measured social group behavior, behavioral responses to handling procedures, and plasma concentrations of ACTH and cortisol under basal conditions and in response to stress tests. The proportion of individuals carrying the short rh5-HTTLPR allele was significantly higher among abusive mothers than controls. Among mothers and infants, the short allele was associated with higher basal cortisol levels and greater hormonal stress responses in the infants. In addition, infants who carried the short rh5-HTTLPR allele had higher anxiety scores than infants homozygous for the long allele. The rh5-HTTLPR genotype also interacted with early adverse experience to impact HPA axis function in the infants. These results are consistent with those of previous studies which demonstrate associations between serotonergic activity and anxiety and stress reactivity, and add additional evidence suggesting that genetic variation in serotonergic function may contribute to the occurrence of abusive parenting in rhesus macaques and modulate emotional behavior and HPA axis function.     

Better Than I Thought: Positive Evaluation Bias in Hypomania

Background

Mania is characterised by increased impulsivity and risk-taking, and psychological accounts argue that these features may be due to hypersensitivity to reward. The neurobiological mechanisms remain poorly understood. Here we examine reinforcement learning and sensitivity to both reward and punishment outcomes in hypomania-prone individuals not receiving pharmacotherapy.

Method

We recorded EEG from 45 healthy individuals split into three groups by low, intermediate and high self-reported hypomanic traits. Participants played a computerised card game in which they learned the reward contingencies of three cues. Neural responses to monetary gain and loss were measured using the feedback-related negativity (FRN), a component implicated in motivational outcome evaluation and reinforcement learning.

Results

As predicted, rewards elicited a smaller FRN in the hypomania-prone group relative to the low hypomania group, indicative of greater reward responsiveness. The hypomania-prone group also showed smaller FRN to losses, indicating diminished response to negative feedback.

Conclusion

Our findings indicate that proneness to hypomania is associated with both reward hypersensitivity and discounting of punishment. This positive evaluation bias may be driven by aberrant reinforcement learning signals, which fail to update future expectations. This provides a possible neural mechanism explaining risk-taking and impaired reinforcement learning in BD. Further research will be needed to explore the potential value of the FRN as a biological vulnerability marker for mania and pathological risk-taking.     

Human Faces Are Slower than Chimpanzee Faces

Background

While humans (like other primates) communicate with facial expressions, the evolution of speech added a new function to the facial muscles (facial expression muscles). The evolution of speech required the development of a coordinated action between visual (movement of the lips) and auditory signals in a rhythmic fashion to produce “visemes” (visual movements of the lips that correspond to specific sounds). Visemes depend upon facial muscles to regulate shape of the lips, which themselves act as speech articulators. This movement necessitates a more controlled, sustained muscle contraction than that produced during spontaneous facial expressions which occur rapidly and last only a short period of time. Recently, it was found that human tongue musculature contains a higher proportion of slow-twitch myosin fibers than in rhesus macaques, which is related to the slower, more controlled movements of the human tongue in the production of speech. Are there similar unique, evolutionary physiologic biases found in human facial musculature related to the evolution of speech?

Methodology/Prinicipal Findings

Using myosin immunohistochemistry, we tested the hypothesis that human facial musculature has a higher percentage of slow-twitch myosin fibers relative to chimpanzees (Pan troglodytes) and rhesus macaques (Macaca mulatta). We sampled the orbicularis oris and zygomaticus major muscles from three cadavers of each species and compared proportions of fiber-types. Results confirmed our hypothesis: humans had the highest proportion of slow-twitch myosin fibers while chimpanzees had the highest proportion of fast-twitch fibers.

Conclusions/significance

These findings demonstrate that the human face is slower than that of rhesus macaques and our closest living relative, the chimpanzee. They also support the assertion that human facial musculature and speech co-evolved. Further, these results suggest a unique set of evolutionary selective pressures on human facial musculature to slow down while the function of this muscle group diverged from that of other primates.     

The Influence of 5-HTTLPR Genotype on the Association between the Plasma Concentration and Therapeutic Effect of Paroxetine in Patients with Major Depressive Disorder

Introduction

The efficacy of treatment with selective serotonin reuptake inhibitors in patients with major depressive disorder (MDD) can differ depending on the patient''s serotonin transporter-linked polymorphic region (5-HTTLPR) genotype, and the effects of varying plasma concentrations of drugs can also vary. We investigated the association between the paroxetine plasma concentration and clinical response in patients with different 5-HTTLPR genotypes.

Methods

Fifty-one patients were enrolled in this study. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate patients at 0, 1, 2, 4, and 6 weeks. The patients'' paroxetine plasma concentrations at week 6 were measured using high-performance liquid chromatography. Additionally, their 5-HTTLPR polymorphisms (alleles S and L) were analyzed using a polymerase chain reaction with specific primers. We divided the participants into two groups based on their L haplotype: the SS group and the SL and LL group. We performed single and multiple regression analyses to investigate the associations between MADRS improvement and paroxetine plasma concentrations or other covariates for each group.

Results

There were no significant differences between the two groups with regard to demographic or clinical data. In the SS group, the paroxetine plasma concentration was significantly negatively correlated with improvement in MADRS at week 6. In the SL and LL group, the paroxetine plasma concentration was significantly positively correlated with improvement in MADRS at week 6 according to the results of the single regression analysis; however, it was not significantly correlated with improvement in MADRS at week 6 according to the results of the multiple regression analysis.

Conclusion

Among patients with MDD who do not respond to paroxetine, a lower plasma concentration or a lower oral dose of paroxetine might be more effective in those with the SS genotype, and a higher plasma concentration might be more effective in those with the SL or LL genotype.     

Improved xenobiotic metabolism and reduced susceptibility to cancer in gluten-sensitive macaques upon introduction of a gluten-free diet

Background

A non-human primate (NHP) model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta).

Methodology

Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD) and gluten-containing (GD) diets, as described previously. Pin-head-sized biopsies, obtained non-invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies),targeting expression of over 20,000 genes.

Principal Findings

When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories - cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin-collagen deposition, neuronal and unknown function - this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function) and actin-collagen-matrix metalloproteinases (MMP) genes.

Conclusions/Significance

A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research.     

Decreased dengue replication and an increased anti-viral humoral response with the use of combined Toll-like receptor 3 and 7/8 agonists in macaques

Background

Pathogenic versus protective outcomes to Dengue virus (DENV) infection are associated with innate immune function. This study aimed to determine the role of increased TLR3- and TLR7/8-mediated innate signaling after Dengue infection of rhesus macaques in vivo to evaluate its impact on disease and anti-DENV immune responses.

Methodology/Principal Findings

TLR3 and TLR7/8 agonists (emulsified in Montanide) were administered subcutaneously to rhesus macaques at 48 hours and 7 days after DENV infection. The Frequency and activation of myeloid dendritic cells, plasmacytoid dendritic cells, and B cells were measured by flow cytometry while the serum levels of 14 different cytokines and chemokines were quantified. Adaptive immune responses were measured by DENV-specific antibody subtype measurements. Results showed that the combined TLR agonists reduced viral replication and induced the development of a proinflammatory reaction, otherwise absent in Dengue infection alone, without any clear signs of exacerbated disease. Specifically, the TLR-induced response was characterized by activation changes in mDC subsets concurrent with higher serum levels of CXCL-10 and IL-1Ra. TLR stimulation also induced higher titers of anti-DENV antibodies and acted to increase the IgG2/IgG1 ratio of anti-DENV to favor the subtype associated with DENV control. We also observed an effect of DENV-mediated suppression of mDC activation consistent with prior in vitro studies.

Conclusions/Significance

These data show that concurrent TLR3/7/8 activation of the innate immune response after DENV infection in vivo acts to increase antiviral mechanisms via increased inflammatory and humoral responses in rhesus macaques, resulting in decreased viremia and melioration of the infection. These findings underscore an in vivo protective rather than a pathogenic role for combined TLR3/7/8-mediated activation in Dengue infection of rhesus macaques. Our study provides definitive proof-of-concept into the mechanism by which DENV evades immune recognition and activation in vivo.     

Astrocyte Atrophy and Immune Dysfunction in Self-Harming Macaques

Background

Self-injurious behavior (SIB) is a complex condition that exhibits a spectrum of abnormal neuropsychological and locomotor behaviors. Mechanisms for neuropathogenesis could include irregular immune activation, host soluble factors, and astrocyte dysfunction.

Methods

We examined the role of astrocytes as modulators of immune function in macaques with SIB. We measured changes in astrocyte morphology and function. Paraffin sections of frontal cortices from rhesus macaques identified with SIB were stained for glial fibrillary acidic protein (GFAP) and Toll-like receptor 2 (TLR2). Morphologic features of astrocytes were determined using computer-assisted camera lucida.

Results

There was atrophy of white matter astrocyte cell bodies, decreased arbor length in both white and gray matter astrocytes, and decreased bifurcations and tips on astrocytes in animals with SIB. This was combined with a five-fold increase in the proportion of astrocytes immunopositive for TLR2.

Conclusions

These results provide direct evidence that SIB induces immune activation of astrocytes concomitant with quantifiably different morphology.     

Visualization of Transepithelial Passage of the Immunogenic 33-Residue Peptide from α-2 Gliadin in Gluten-Sensitive Macaques

Background

Based on clinical, histopathological and serological similarities to human celiac disease (CD), we recently established the rhesus macaque model of gluten sensitivity. In this study, we further characterized this condition based on presence of anti-tissue transglutaminase 2 (TG2) antibodies, increased intestinal permeability and transepithelial transport of a proteolytically resistant, immunotoxic, 33-residue peptide from α₂-gliadin in the distal duodenum of gluten-sensitive macaques.

Methodology/Principal Findings

Six rhesus macaques were selected for study from a pool of 500, including two healthy controls and four gluten-sensitive animals with elevated anti-gliadin or anti-TG2 antibodies as well as history of non-infectious chronic diarrhea. Pediatric endoscope-guided pinch biopsies were collected from each animal''s distal duodenum following administration of a gluten-containing diet (GD) and again after remission by gluten-free diet (GFD). Control biopsies always showed normal villous architecture, whereas gluten-sensitive animals on GD exhibited histopathology ranging from mild lymphocytic infiltration to villous atrophy, typical of human CD. Immunofluorescent microscopic analysis of biopsies revealed IgG+ and IgA+ plasma-like cells producing antibodies that colocalized with TG2 in gluten-sensitive macaques only. Following instillation in vivo, the Cy-3-labeled 33-residue gluten peptide colocalized with the brush border protein villin in all animals. In a substantially enteropathic macaque with “leaky” duodenum, the peptide penetrated beneath the epithelium into the lamina propria.

Conclusions/Significance

The rhesus macaque model of gluten sensitivity not only resembles the histopathology of CD but it also may provide a model for studying intestinal permeability in states of epithelial integrity and disrepair.