RESUMEN
Autoinflammatory disorders of the innate immune system present with recurrent episodes of inflammation often beginning in early childhood. While there are now more than 30 genetically-defined hereditary fever disorders, many patients lack a clear diagnosis. Many pediatric patients are often grouped with patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome despite failing to meet diagnostic criteria. Here, we categorize these patients as syndrome of undifferentiated recurrent fever (SURF), and identify the unique features which distinguish them from the PFAPA syndrome. SURF patients were more likely to report gastrointestinal symptoms of nausea, vomiting and abdominal pain, and experienced inconsistent responses to on-demand steroid therapy compared to PFAPA patients. For this previously undefined cohort, an optimal course of therapy remains uncertain, with medical and surgical therapies largely driven by parental preference. A subset of patients with SURF underwent tonsillectomy with complete resolution. Flow cytometric evaluation demonstrates leukocytic populations distinct from PFAPA patients, with reduced CD3+ T cell numbers. SURF patient tonsils were predominantly characterized by an IL-1 signature compared to PFAPA, even during the afebrile period. Peripheral blood signatures were similar between groups suggesting that PFAPA and SURF patient tonsils have localized, persistent inflammation, without clinical symptoms. These data suggest that SURF is a heterogenous syndrome on the autoinflammatory disease spectrum.
Asunto(s)
Fiebre/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Inflamación/diagnóstico , Interleucina-1/metabolismo , Linfadenitis/diagnóstico , Faringitis/diagnóstico , Estomatitis Aftosa/diagnóstico , Complejo CD3/metabolismo , Preescolar , Femenino , Fiebre/metabolismo , Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/metabolismo , Enfermedades Autoinflamatorias Hereditarias/metabolismo , Humanos , Inflamación/metabolismo , Linfadenitis/metabolismo , Masculino , Tonsila Palatina/metabolismo , Pediatría , Faringitis/metabolismo , Estomatitis Aftosa/metabolismo , Síndrome , Linfocitos T/metabolismo , Tonsilectomía/métodosRESUMEN
Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome is an inflammatory disorder of childhood classically characterized by recurrent fevers, pharyngitis, stomatitis, cervical adenitis, and leukocytosis. While the mechanism is unclear, previous studies have shown that tonsillectomy can be a therapeutic option with improvement in quality of life in many patients with PFAPA, but the mechanisms behind surgical success remain unknown. In addition, long-term clinical follow-up is lacking. In our tertiary care center cohort, 62 patients with PFAPA syndrome had complete resolution of symptoms after surgery (95.3%). Flow cytometric evaluation demonstrates an inflammatory cell population, distinct from patients with infectious pharyngitis, with increased numbers of CD8+ T cells (5.9% vs. 3.8%, p < 0.01), CD19+ B cells (51% vs. 35%, p < 0.05), and CD19+CD20+CD27+CD38-memory B cells (14% vs. 7.7%, p < 0.01). Cells are primed at baseline with increased percentage of IL-1ß positive cells compared to control tonsil-derived cells, which require exogenous LPS stimulation. Gene expression analysis demonstrates a fivefold upregulation in IL1RN and TNF expression in whole tonsil compared to control tonsils, with persistent activation of the NF-κB signaling pathway, and differential microbial signatures, even in the afebrile period. Our data indicates that PFAPA patient tonsils have localized, persistent inflammation, in the absence of clinical symptoms, which may explain the success of tonsillectomy as an effective surgical treatment option. The differential expression of several genes and microbial signatures suggests the potential for a diagnostic biomarker for PFAPA syndrome.
Asunto(s)
Microambiente Celular/inmunología , Fiebre/inmunología , Linfadenitis/inmunología , Tonsila Palatina/inmunología , Faringitis/inmunología , Estomatitis Aftosa/inmunología , Adolescente , Linfocitos T CD8-positivos/inmunología , Línea Celular , Niño , Preescolar , Femenino , Humanos , Lactante , Inflamación/inmunología , Masculino , Síndrome , Tonsilectomía/métodosRESUMEN
Significantly higher levels of plasma CXCL13 [chemokine (C-X-C motif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4(+) T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS(+) (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.
Asunto(s)
Biomarcadores/sangre , Quimiocina CXCL13/sangre , Quimiocina CXCL13/inmunología , Centro Germinal/inmunología , Animales , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , Humanos , Ganglios Linfáticos/inmunología , Macaca , Ratones Endogámicos C57BL , VacunaciónRESUMEN
Detection of Ag-specific CD4(+) T cells is central to the study of many human infectious diseases, vaccines, and autoimmune diseases. However, such cells are generally rare and heterogeneous in their cytokine profiles. Identification of Ag-specific germinal center (GC) T follicular helper (Tfh) cells by cytokine production has been particularly problematic. The function of a GC Tfh cell is to selectively help adjacent GC B cells via cognate interaction; thus, GC Tfh cells may be stingy cytokine producers, fundamentally different from Th1 or Th17 cells in the quantities of cytokines produced. Conventional identification of Ag-specific cells by intracellular cytokine staining relies on the ability of the CD4(+) T cell to generate substantial amounts of cytokine. To address this problem, we have developed a cytokine-independent activation-induced marker (AIM) methodology to identify Ag-specific GC Tfh cells in human lymphoid tissue. Whereas Group A Streptococcus-specific GC Tfh cells produced minimal detectable cytokines by intracellular cytokine staining, the AIM method identified 85-fold more Ag-specific GC Tfh cells. Intriguingly, these GC Tfh cells consistently expressed programmed death ligand 1 upon activation. AIM also detected non-Tfh cells in lymphoid tissue. As such, we applied AIM for identification of rare Ag-specific CD4(+) T cells in human peripheral blood. Dengue, tuberculosis, and pertussis vaccine-specific CD4(+) T cells were readily detectable by AIM. In summary, cytokine assays missed 98% of Ag-specific human GC Tfh cells, reflecting the biology of these cells, which could instead be sensitively identified by coexpression of TCR-dependent activation markers.
Asunto(s)
Biomarcadores/sangre , Linfocitos T CD4-Positivos/inmunología , Técnicas Inmunológicas/métodos , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Citocinas/análisis , Citocinas/biosíntesis , Ensayo de Immunospot Ligado a Enzimas , Citometría de Flujo , Centro Germinal/citología , Centro Germinal/inmunología , HumanosRESUMEN
A range of current candidate AIDS vaccine regimens are focused on generating protective HIV-neutralizing Ab responses. Many of these efforts rely on the rhesus macaque animal model. Understanding how protective Ab responses develop and how to increase their efficacy are both major knowledge gaps. Germinal centers (GCs) are the engines of Ab affinity maturation. GC T follicular helper (Tfh) CD4 T cells are required for GCs. Studying vaccine-specific GC Tfh cells after protein immunizations has been challenging, as Ag-specific GC Tfh cells are difficult to identify by conventional intracellular cytokine staining. Cytokine production by GC Tfh cells may be intrinsically limited in comparison with other Th effector cells, as the biological role of a GC Tfh cell is to provide help to individual B cells within the GC, rather than secreting large amounts of cytokines bathing a tissue. To test this idea, we developed a cytokine-independent method to identify Ag-specific GC Tfh cells. RNA sequencing was performed using TCR-stimulated GC Tfh cells to identify candidate markers. Validation experiments determined CD25 (IL-2Rα) and OX40 to be highly upregulated activation-induced markers (AIM) on the surface of GC Tfh cells after stimulation. In comparison with intracellular cytokine staining, the AIM assay identified >10-fold more Ag-specific GC Tfh cells in HIV Env protein-immunized macaques (BG505 SOSIP). CD4 T cells in blood were also studied. In summary, AIM demonstrates that Ag-specific GC Tfh cells are intrinsically stingy producers of cytokines, which is likely an essential part of their biological function.
Asunto(s)
Biomarcadores/análisis , Infecciones por VIH/inmunología , Técnicas Inmunológicas/métodos , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Citocinas/análisis , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Citometría de Flujo , Centro Germinal/citología , Centro Germinal/inmunología , Humanos , Macaca mulattaRESUMEN
"Strep throat" is highly prevalent among children, yet it is unknown why only some children develop recurrent tonsillitis (RT), a common indication for tonsillectomy. To gain insights into this classic childhood disease, we performed phenotypic, genotypic, and functional studies on pediatric group A Streptococcus (GAS) RT and non-RT tonsils from two independent cohorts. GAS RT tonsils had smaller germinal centers, with an underrepresentation of GAS-specific CD4+ germinal center T follicular helper (GC-TFH) cells. RT children exhibited reduced antibody responses to an important GAS virulence factor, streptococcal pyrogenic exotoxin A (SpeA). Risk and protective human leukocyte antigen (HLA) class II alleles for RT were identified. Lastly, SpeA induced granzyme B production in GC-TFH cells from RT tonsils with the capacity to kill B cells and the potential to hobble the germinal center response. These observations suggest that RT is a multifactorial disease and that contributors to RT susceptibility include HLA class II differences, aberrant SpeA-activated GC-TFH cells, and lower SpeA antibody titers.
Asunto(s)
Anticuerpos Antibacterianos/inmunología , Streptococcus/fisiología , Tonsilitis/inmunología , Tonsilitis/microbiología , Adolescente , Alelos , Linfocitos B/inmunología , Diferenciación Celular , Niño , Susceptibilidad a Enfermedades , Femenino , Centro Germinal/inmunología , Granzimas/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Inmunoglobulina G/metabolismo , Masculino , Recurrencia , Superantígenos/metabolismo , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
OBJECTIVES/HYPOTHESIS: The goal of this study is to retrospectively compare the long-term, 10 year, outcomes of surgical versus medical management of young children with chronic rhinosinusitis. STUDY DESIGN: This is a retrospective, age-matched, cohort outcome study performed at a tertiary-care hospital. METHODS: Two groups of young children (2-5 yr old) with chronic rhinosinusitis were treated with endoscopic sinus surgery or medically managed and evaluated 10 years after their initial therapy. Of the 131 eligible patients, 67 could be located and consented to participate in the study. Six symptoms (day cough, night cough, irritability or crankiness, headaches, nasal airway obstruction, and purulent rhinorrhea) were used to assess the outcome of their treatment. RESULTS: Children undergoing endoscopic sinus surgery had more significant disease as noted on the computed tomography (CT) scans. Their symptom severity, however, was similar. When individual symptoms were compared, there were no statistically significant differences between the surgically and medically managed groups. When the mean was controlled for baseline symptom severity and CT severity, there was statistical improvement in nasal airway obstruction and decreased rhinorrhea. There was a trend toward improvement in cough, but this was not statistically significant. Parenteral assessment of improvement (change) in symptoms (P = .001) and their degree of satisfaction with treatment (P = .005) was significantly higher in the surgically managed group. CONCLUSIONS: Children who have chronic rhinosinusitis improve in their symptoms of nasal airway obstruction and purulent discharge if they undergo surgery. Parents of young children with chronic rhinosinusitis appear to be more satisfied with the outcome of surgical management than medical management when assessed 10 years later.
Asunto(s)
Rinitis/cirugía , Sinusitis/cirugía , Preescolar , Enfermedad Crónica , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Estudios Retrospectivos , Rinitis/diagnóstico por imagen , Índice de Severidad de la Enfermedad , Sinusitis/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
OBJECTIVE: Food allergies in childhood have been found to vary in frequency from 6% to 8% in the general population. Previous studies indicate milk allergy affects approximately 2.5% of infants and egg allergy has been estimated at 1.6% to 2.6%. Numerous allergists believe that the prevalence of food allergies is rising, similar to the rise in other atopic conditions. Prior studies have demonstrated that food-specific IgE is a useful test for diagnosing symptomatic allergies to certain foods, including milk and eggs, and could decrease the need to perform cumbersome multiple double-blind, placebo-controlled food challenges in children based on history alone. The purpose of this study was to determine the prevalence of food allergies and elevated IgE in a consecutive series of pediatric otolaryngology patients. STUDY DESIGN AND SETTING: ImmunoCap studies were drawn in a 2-year series of children undergoing ENT procedures of bilateral myringotomy with tubes (BMT) with or without adenoidectomy or tonsillectomy or adenoidectomy alone between 2001 and 2003. Sera was analyzed for increased total IgE antibodies, as well as specific IgE antibodies to antigens, including milk, egg, beef, and environmental allergens. A positive patient history or family history of allergy were documented. RESULTS: A total of 242 patients were assessed. Of the study population, milk allergy was found in 10.7%; egg white allergy was found in 5.0%. The prevalence of elevated IgE among participants was 11.2%. The overall food allergy prevalence was 14.5%. CONCLUSIONS: Although we cannot imply causality, the study demonstrated an increased prevalence of food allergy in children undergoing ENT procedures, specifically milk and eggs, than in previous population studies. EBM RATING: C-4.
Asunto(s)
Hipersensibilidad a los Alimentos/epidemiología , Inmunoglobulina E/sangre , Enfermedades Otorrinolaringológicas/complicaciones , Adolescente , Anticuerpos Antiidiotipos/sangre , Niño , Preescolar , Femenino , Hipersensibilidad a los Alimentos/sangre , Hipersensibilidad a los Alimentos/complicaciones , Humanos , Inmunoglobulina E/inmunología , Lactante , Masculino , Prevalencia , Estudios Retrospectivos , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE: The Waldeyer's ring, comprised of the nasopharyngeal tonsil (adenoid), the paired tubal tonsils, the paired palantine tonsils, and the lingual tonsil, is arranged in a circular orientation around the wall of the throat. This orientation allows direct contact between the tissues of the Waldeyer's ring and inhaled or ingested material, which may contain potential antigenic substances. Previous studies involving the tissues of the Waldeyer's ring have been focused on the adaptive immune system, with little consideration toward the innate immune system. Since studies have demonstrated that the adenoids and tonsils are capable of producing proinflammatory cytokines, we postulate that toll-like receptors (TLRs), which recognize components of pathogenic organisms, may be involved in the immune response in these tissues. TLRs are innate pattern recognition receptors, which produce proinflammatory cytokines and chemokines upon ligation. In this pilot study, we address expression of TLRs, which are vital components of the innate immune system, in adenoid and tonsil tissue. METHODS: To determine whether TLRs are expressed in the human adenoid and palantine tonsils, we utilized endpoint RT-PCR and real time RT-PCR. Endpoint PCR was performed on all tissue obtained from adenotonsillectomy patients. Real time RT-PCR was performed only on adenoid tissue. RESULTS: All of the ten TLRs examined are expressed in the adenoid and tonsil tissue with varying band intensities. TLR3, TLR7, TLR8, and TLR9 expression is highly variable between patients. CONCLUSIONS: TLRs are expressed in human adenoid and tonsil tissue, and may play a vital role in the immunological outcomes of these tissues.
Asunto(s)
Tonsila Faríngea/inmunología , Tonsila Palatina/inmunología , Receptores Toll-Like/análisis , Adolescente , Niño , Preescolar , Electroforesis en Gel de Agar , Humanos , Inmunidad Innata/inmunología , Lactante , Mediadores de Inflamación/análisis , Proyectos Piloto , ARN/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor Toll-Like 1/análisis , Receptor Toll-Like 2/análisis , Receptor Toll-Like 3/análisis , Receptor Toll-Like 4/análisis , Receptor Toll-Like 7/análisis , Receptor Toll-Like 8/análisis , Receptor Toll-Like 9/análisisRESUMEN
Follicular helper T cells (Tfh cells) are required for T cell help to B cells, and BCL6 is the defining transcription factor of Tfh cells. However, the functions of BCL6 in Tfh cells have largely remained unclear. Here we defined the BCL6 cistrome in primary human germinal center Tfh cells to assess mechanisms of BCL6 regulation of CD4 T cells, comparing and contrasting BCL6 function in T and B cells. BCL6 primarily acts as a repressor in Tfh cells, and BCL6 binding was associated with control of Tfh cell migration and repression of alternative cell fates. Interestingly, although some BCL6-bound genes possessed BCL6 DNA-binding motifs, many BCL6-bound loci were instead characterized by the presence of DNA motifs for AP1 or STAT. AP1 complexes are key positive downstream mediators of TCR signaling and external stimuli. We show that BCL6 can directly bind AP1, and BCL6 depends on AP1 for recruitment to BCL6-binding sites with AP1 motifs, suggesting that BCL6 subverts AP1 activity. These findings reveal that BCL6 has broad and multifaceted effects on Tfh biology and provide insight into how this master regulator mediates distinct cell context-dependent phenotypes.
Asunto(s)
Diferenciación Celular/inmunología , Proteínas de Unión al ADN/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Secuencias de Aminoácidos , Linfocitos B/citología , Linfocitos B/inmunología , Sitios de Unión , Diferenciación Celular/genética , Proteínas de Unión al ADN/genética , Femenino , Humanos , Masculino , Proteínas Proto-Oncogénicas c-bcl-6 , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/inmunología , Linfocitos T Colaboradores-Inductores/citología , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/inmunologíaRESUMEN
OBJECTIVE: We sought to determine whether functional endoscopic sinus (FES) surgery performed in children with chronic rhinosinusitis alters facial growth. STUDY DESIGN AND SETTING: This was a retrospective age-matched cohort outcome study performed at a tertiary care hospital. RESULTS: Sixty-seven children participated. There were 46 boys and 21 girls, and the mean age was 3.1 years at presentation and 13.2 years at follow-up. There were 46 children who underwent FES surgery and 21 children who did not undergo FES surgery. Quantitative anthropomorphic analysis was performed using 12 standard facial measurements. A facial plastic expert performed qualitative facial analysis. Both quantitative and qualitative analyses showed no statistical significance in facial growth between children who underwent FES surgery and those who did not undergo FES surgery. CONCLUSIONS: In this study, there was no evidence that FES surgery affected facial growth. SIGNIFICANCE: These results will aid physicians when discussing with parents the risks of FES surgery.
Asunto(s)
Endoscopía/métodos , Huesos Faciales/crecimiento & desarrollo , Rinitis/cirugía , Sinusitis/cirugía , Antropometría , Estudios de Casos y Controles , Desarrollo Infantil/fisiología , Preescolar , Enfermedad Crónica , Estudios de Cohortes , Intervalos de Confianza , Endoscopía/efectos adversos , Femenino , Humanos , Modelos Lineales , Masculino , Probabilidad , Pronóstico , Valores de Referencia , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
Branchial cleft cysts, sinuses, and fistulas are the most common congenital lateral neck lesions in children. They arise as a result of an abnormal development of the branchial arches and their corresponding ectoderm-lined branchial clefts. Of these diverse anomalies, second branchial cleft lesions are the most common, accounting for approximately 95% of all branchial arch pathologies. We describe what is to the best of our knowledge the first reported case of an ectopic tooth in a branchial cleft anomaly. The patient was a young girl who had other congenital abnormalities and syndromic features and who was eventually diagnosed with Townes-Brocks syndrome. We describe the clinical presentation, management, pathologic analysis, and postoperative outcomes of this case, and we present a brief review of Townes-Brocks syndrome.
Asunto(s)
Anomalías Múltiples/diagnóstico , Ano Imperforado/diagnóstico , Región Branquial/anomalías , Anomalías Craneofaciales/diagnóstico , Pérdida Auditiva Sensorineural/diagnóstico , Enfermedades Faríngeas/diagnóstico , Pulgar/anomalías , Erupción Ectópica de Dientes/diagnóstico , Anomalías Múltiples/patología , Anomalías Múltiples/cirugía , Ano Imperforado/patología , Ano Imperforado/cirugía , Región Branquial/patología , Región Branquial/cirugía , Niño , Anomalías Craneofaciales/patología , Anomalías Craneofaciales/cirugía , Femenino , Estudios de Seguimiento , Pérdida Auditiva Sensorineural/patología , Pérdida Auditiva Sensorineural/cirugía , Humanos , Enfermedades Faríngeas/patología , Enfermedades Faríngeas/cirugía , Pulgar/patología , Pulgar/cirugía , Erupción Ectópica de Dientes/patología , Erupción Ectópica de Dientes/cirugía , Resultado del TratamientoRESUMEN
AIM: To demonstrate safely with the use of polymethyl methacrylate (PMMA) microspheres in the infraorbital eyelid area using a deliberate conservative injection in the treatment of rhytids. METHODS: A retrospective case series of 289 patients in an outpatient cosmetic dermatology clinic evaluated and treated by one senior provider (NM) of infraorbital rhytids with PMMA from December 2010 to March 2011. Statistical analysis was performed for race, skin type, history of hypertrophic scar, autoimmunity, history of "sensitive skin" and history of prior procedures such as prior facelift, rhinoplasty, and blepharoplasty. RESULTS: Two hundred ninety-one patients underwent at least 1-6 injections of PMMA microspheres into bilateral under eye area. Early complications were edema and ecchymosis. Late complications were identified in 4 of 289 patients who developed small granulomas. All patients who developed granulomas had had a previous lower blepharoplasty (P = 0.00). A history of "sensitive skin" was approaching statistical significance (P = 0.15). CONCLUSION: This study has shown that PMMA microsphere injection is a safe subdermal technique in the correction of infraorbital rhytids. Safety was demonstrated in 289 patients with only 4 minor complications of small lateral granuloma which all resolved within 4 weeks after intralesion triamcinolone injection. However, this is an off-label use of a permanent filler not approved for use in the infraorbits and significant caution must be taken with full disclosure to the patient leading to informed consent. Caution in PMMA microsphere injection should be given in the patient with prior blepharoplasty. The advantage of PMMA microsphere is that the result seems to be predictable and natural.
Asunto(s)
Materiales Biocompatibles/administración & dosificación , Microesferas , Pacientes Ambulatorios , Polimetil Metacrilato/administración & dosificación , Envejecimiento de la Piel/efectos de los fármacos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Materiales Biocompatibles/efectos adversos , Cara , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Polimetil Metacrilato/efectos adversos , Rejuvenecimiento , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Short latency linear vestibular sensory evoked potentials (VsEPs) provide a means to objectively and directly assess the function of gravity receptors in mammals and birds. The importance of this functional measure is illustrated by its use in studies of the genetic basis of vestibular function and disease. Head motion is the stimulus for the VsEP. In the bird, it has been established that neurons mediating the linear VsEP respond collectively to the rate of change in linear acceleration during head movement (i.e. jerk) rather than peak acceleration. The kinematic element of motion responsible for triggering mammalian VsEPs has not been characterized in detail. Here we tested the hypothesis that jerk is the kinematic component of head motion responsible for VsEP characteristics. VsEP amplitudes and latencies changed systematically when peak acceleration level was held constant and jerk level was varied from â¼0.9-4.6 g/ms. In contrast, responses remained relatively constant when kinematic jerk was held constant and peak acceleration was varied from â¼0.9 to 5.5 g in mice and â¼0.44 to 2.75 g in rats. Thus the mammalian VsEP depends on jerk levels and not peak acceleration. We conclude that kinematic jerk is the adequate stimulus for the mammalian VsEP. This sheds light on the behavior of neurons generating the response. The results also provide the basis for standardizing the reporting of stimulus levels, which is key to ensuring that response characteristics reported in the literature by many laboratories can be effectively compared and interpreted.