The Impact of Altitude at Birth on Perinatal Respiratory Support for Neonates with Trisomy 21.

OBJECTIVE: Both high altitude and trisomy 21 (T21) status can negatively impact respiratory outcomes. The objective of this study was to examine the association between altitude and perinatal respiratory support in neonates with T21 compared with those without T21. STUDY DESIGN: This retrospective cohort study used the United States all-county natality files that included live, singleton, in-hospital births from 2015 to 2019. Descriptive statistics for neonates with and without the primary outcome of sustained assisted ventilation (>6 hours) were compared using t-tests and Chi-squared analyses. Multivariable logistic regression was used to determine the association between respiratory support and the presence of T21, and included an interaction term to determine whether the association between respiratory support and the presence of T21 was modified by elevation at delivery. RESULTS: A total of 17,939,006 neonates, 4,059 (0.02%) with T21 and 17,934,947 (99.98%) without, were included in the study. The odds of requiring sustained respiratory support following delivery were 5.95 (95% confidence interval [CI]: 5.31, 6.66), 4.06 (95% CI: 2.39, 6.89), 2.36 (95% CI: 1.64, 3.40), and 5.04 (95% CI: 1.54, 16.54) times as high for neonates with T21 than without T21 when born at low, medium, high, and very high elevations, respectively. The odds of requiring immediate ventilation support following delivery were 5.01 (95% CI: 4.59, 5.46), 5.90 (95% CI: 4.16, 8.36), 2.86 (95% CI: 2.15, 3.80), and 12.08 (95% CI: 6.78, 21.51) times as high for neonates with T21 than without T21 when born at low, medium, high, and very high elevation, respectively. CONCLUSION: Neonates with T21 have increased odds of requiring respiratory support following delivery when compared with neonates without T21 at all categories of altitude. However, the odds ratios did not increase monotonically with altitude which indicates additional research is critical in understanding the effects of altitude on neonates with T21. KEY POINTS: · Neonates with T21 have an increased need for perinatal respiratory support at all altitudes.. · The odds of needing perinatal respiratory support did not increase monotonically with elevation.. · Additional research is critical to understanding the effects of altitude on neonates with T21..

T-cell trafficking plays an essential role in tumor immunity.

Distinct populations of effector memory T cells use different homing receptors to traffic to the skin and gut. Whether tissue-selective T cells are needed for early rejection of a neoplasm growing in these tissues remains an open question. We chose to study an allogeneic tumor model because growth of such a fully mismatched tumor would signify a profound immune deficit. We implanted allogeneic tumor cells in the skin or gut of mice deficient in either α(1,3) fucosyltransferases IV and VII, enzymes critical for generating E-selectin ligands on skin-homing T cells, or ß7 integrin, a component of the α4ß7 integrin ligand for the mucosal adressin MAdCAM. During the first 9 days after tumor implantation, FucTVII-/- mice showed a profoundly impaired capacity to reject tumors growing in the skin, but readily rejected tumors implanted in the gut. Rejection of tumors in the skin was even more impaired in mice deficient in both FucTIV and FucTVII. This impairment was corrected by infusion of T cells from normal mice. By contrast, ß7 integrin-/- mice showed profoundly impaired rejection of tumors in the gut, but no defect in the skin tumor rejection. These differences were unrelated to antigen recognition or effector function of T cells, since all strains of mice were capable of generating tumor-specific CTLs in vitro against the tumor cell line used in vivo. These results demonstrate that T-cell homing defects in vivo impair immune surveillance of peripheral epithelial tissues in a specific and selective fashion.

Activation of human vascular endothelium in melanoma metastases induces ICAM-1 and E-selectin expression and results in increased infiltration with effector lymphocytes.

Lymphocytic infiltration into melanoma tissue is an important prerequisite for effective antitumoral immunity. However, analysis of human metastatic melanoma has shown that leucocyte adhesion receptor expression on melanoma blood vessels is very low or absent, thereby impairing the entry of cytotoxic lymphocytes into tumor tissue. We hypothesized that adhesion molecules can be induced on melanoma vasculature allowing better infiltration of cytotoxic lymphocytes. Quantitative real-time PCR and immunofluorescence staining indicated that the adhesion molecules ICAM-1 (CD54) and E-selectin (CD62E) can be significantly induced by intralesional application of TNF alpha in tissue from human melanoma metastases either in vitro or in vivo when grafted onto immunodeficient NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ) mice that preserved human vessels. Furthermore, activated human autologous CD3+ lymphocytes were injected intravenously into mice bearing melanoma xenografts treated with TNF-α or PBS in addition to the leucocyte chemoattractant TARC (CCL17). Significantly increased numbers of CD8+ cells were detected in TNF-α-treated melanoma metastases compared with PBS-treated controls. In addition, tumor cell apoptosis was enhanced and melanoma cell proliferation reduced as shown by TUNEL assay and KI-67 staining. We conclude that adhesion molecules can be induced on human melanoma vasculature resulting in significantly improved homing of activated autologous cytotoxic T cells to melanoma tissue and inhibition of melanoma cell proliferation. These observations should be considered when designing protocols for immunotherapy of malignant melanoma.

IL-1R Type 1-Deficient Mice Demonstrate an Impaired Host Immune Response against Cutaneous Vaccinia Virus Infection.

The IL-1 superfamily of cytokines and receptors has been studied extensively. However, the specific roles of IL-1 elements in host immunity to cutaneous viral infection remain elusive. In this study, we applied vaccinia virus (VACV) by scarification to IL-1R1 knockout mice (IL-1R1-/-) and found that these mice developed markedly larger lesions with higher viral genome copies in skin than did wild-type mice. The phenotype of infected IL-1R1-/- mice was similar to eczema vaccinatum, a severe side effect of VACV vaccination that may develop in humans with atopic dermatitis. Interestingly, the impaired cutaneous response of IL-1R1-/- mice did not reflect a systemic immune deficiency, because immunized IL-1R1-/- mice survived subsequent lethal VACV intranasal challenge, or defects of T cell activation or T cell homing to the site of inoculation. Histologic evaluation revealed that VACV infection and replication after scarification were limited to the epidermal layer of wild-type mice, whereas lack of IL-1R1 permitted extension of VACV infection into dermal layers of the skin. We explored the etiology of this discrepancy and determined that IL-1R1-/- mice contained significantly more macrophages and monocyte-derived dendritic cells in the dermis after VACV scarification. These cells were vulnerable to VACV infection and may augment the transmission of virus to adjacent skin, thus leading to larger skin lesions and satellite lesions in IL-1R1-/- mice. These results suggest new therapeutic strategies for treatment of eczema vaccinatum and inform assessment of risks in patients receiving IL-1 blocking Abs for treatment of chronic inflammatory disorders.

Staged development of long-lived T-cell receptor αß TH17 resident memory T-cell population to Candida albicans after skin infection.

BACKGROUND: Candida albicans is a dimorphic fungus to which human subjects are exposed early in life, and by adulthood, it is part of the mycobiome of skin and other tissues. Neonatal skin lacks resident memory T (TRM) cells, but in adults the C albicans skin test is a surrogate for immunocompetence. Young adult mice raised under specific pathogen-free conditions are naive to C albicans and have been shown recently to have an immune system resembling that of neonatal human subjects. OBJECTIVE: We studied the evolution of the adaptive cutaneous immune response to Candida species. METHODS: We examined both human skin T cells and the de novo and memory immune responses in a mouse model of C albicans skin infection. RESULTS: In mice the initial IL-17-producing cells after C albicans infection were dermal γδ T cells, but by day 7, αß TH17 effector T cells were predominant. By day 30, the majority of C albicans-reactive IL-17-producing T cells were CD4 TRM cells. Intravital microscopy showed that CD4 effector T cells were recruited to the site of primary infection and were highly motile 10 days after infection. Between 30 and 90 days after infection, these CD4 T cells became increasingly sessile, acquired expression of CD69 and CD103, and localized to the papillary dermis. These established TRM cells produced IL-17 on challenge, whereas motile migratory memory T cells did not. TRM cells rapidly clear an infectious challenge with C albicans more effectively than recirculating T cells, although both populations participate. We found that in normal human skin IL-17-producing CD4+ TRM cells that responded to C albicans in an MHC class II-restricted fashion could be identified readily. CONCLUSIONS: These studies demonstrate that C albicans infection of skin preferentially generates CD4+ IL-17-producing TRM cells, which mediate durable protective immunity.

Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity.

Protective T-cell memory has long been thought to reside in blood and lymph nodes, but recently the concept of immune memory in peripheral tissues mediated by resident memory T (T(RM)) cells has been proposed. Here we show in mice that localized vaccinia virus (VACV) skin infection generates long-lived non-recirculating CD8(+) skin T(RM) cells that reside within the entire skin. These skin T(RM) cells are potent effector cells, and are superior to circulating central memory T (T(CM)) cells at providing rapid long-term protection against cutaneous re-infection. We find that CD8(+) T cells are rapidly recruited to skin after acute VACV infection. CD8(+) T-cell recruitment to skin is independent of CD4(+) T cells and interferon-γ, but requires the expression of E- and P-selectin ligands by CD8(+) T cells. Using parabiotic mice, we further show that circulating CD8(+) T(CM) and CD8(+) skin T(RM) cells are both generated after skin infection; however, CD8(+) T(CM) cells recirculate between blood and lymph nodes whereas T(RM) cells remain in the skin. Cutaneous CD8(+) T(RM) cells produce effector cytokines and persist for at least 6 months after infection. Mice with CD8(+) skin T(RM) cells rapidly cleared a subsequent re-infection with VACV whereas mice with circulating T(CM) but no skin T(RM) cells showed greatly impaired viral clearance, indicating that T(RM) cells provide superior protection. Finally, we show that T(RM) cells generated as a result of localized VACV skin infection reside not only in the site of infection, but also populate the entire skin surface and remain present for many months. Repeated re-infections lead to progressive accumulation of highly protective T(RM) cells in non-involved skin. These findings have important implications for our understanding of protective immune memory at epithelial interfaces with the environment, and suggest novel strategies for vaccines that protect against tissue tropic organisms.

CCR7 plays no appreciable role in trafficking of central memory CD4 T cells to lymph nodes.

CCR7⁻/⁻ mice exhibit profound anomalies in lymph node and spleen architecture, which complicates the study of CCR7-mediated T cell trafficking in vivo. To circumvent this problem, we established in vivo models in which wild-type and CCR7⁻/⁻ populations coexist within mice possessing normal lymphoid organs and must compete for developmental niches within the tissues of these mice. Under the conditions we have created in vivo, we find the entry of memory CD4 T cells into lymph nodes from the blood to be independent of CCR7. Thus, the central memory CD4 T cells that traffic though lymph nodes, which are often defined by their expression of CCR7, do not appear to gain any competitive homing advantage by expressing this receptor. Furthermore, in contrast to cutaneous dendritic cell populations, we found that CCR7 deficiency had no appreciable effect on the exit of CD4 T cells from inflamed skin. Finally, we found that wild-type and CCR7⁻/⁻ precursors were equally represented within the major thymic subpopulations, despite previous findings that CCR7 plays a role in seeding the thymus from bone marrow-derived T cell precursors.

Ly6G ligation blocks recruitment of neutrophils via a ß2-integrin-dependent mechanism.

Ly6G is a glycosylphosphatidylinositol (GPI)-anchored protein of unknown function that is commonly targeted to induce experimental neutrophil depletion in mice. In the present study, we found that doses of anti-Ly6G Abs too low to produce sustained neutropenia remained capable of inhibiting experimental arthritis, leaving joint tissues free of infiltrating neutrophils. Thioglycollate-stimulated peritonitis was also attenuated. No alteration in neutrophil apoptosis was observed, implicating impaired recruitment. Indeed, Ly6G ligation abrogated neutrophil migration toward LTB(4) and other chemoattractants in a transwell system. Exploring the basis for this blockade, we identified colocalization of Ly6G and ß2-integrins by confocal microscopy and confirmed close association by both coimmunoprecipitation and fluorescence lifetime imaging microscopy. Anti-Ly6G Ab impaired surface expression of ß2-integrins in LTB(4)-stimulated neutrophils and mimicked CD11a blockade in inhibiting both ICAM-1 binding and firm adhesion to activated endothelium under flow conditions. Correspondingly, migration of ß2-integrin-deficient neutrophils was no longer inhibited by anti-Ly6G. These results demonstrate that experimental targeting of Ly6G has functional effects on the neutrophil population and identify a previously unappreciated role for Ly6G as a modulator of neutrophil migration to sites of inflammation via a ß2-integrin-dependent mechanism.

Identification of cells initiating human melanomas.

Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies and solid cancers. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5- bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ subpopulations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5- progeny, whereas ABCB5- tumour populations give rise, at lower rates, exclusively to ABCB5- cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy.

Joint-specific memory, resident memory T cells and the rolling window of opportunity in arthritis.

In rheumatoid arthritis, juvenile idiopathic arthritis and other forms of inflammatory arthritis, the immune system targets certain joints but not others. The pattern of joints affected varies by disease and by individual, with flares most commonly involving joints that were previously inflamed. This phenomenon, termed joint-specific memory, is difficult to explain by systemic immunity alone. Mechanisms of joint-specific memory include the involvement of synovial resident memory T cells that remain in the joint during remission and initiate localized disease recurrence. In addition, arthritis-induced durable changes in synovial fibroblasts and macrophages can amplify inflammation in a site-specific manner. Together with ongoing systemic processes that promote extension of arthritis to new joints, these local factors set the stage for a stepwise progression in disease severity, a paradigm for arthritis chronicity that we term the joint accumulation model. Although durable drug-free remission through early treatment remains elusive for most forms of arthritis, the joint accumulation paradigm defines new therapeutic targets, emphasizes the importance of sustained treatment to prevent disease extension to new joints, and identifies a rolling window of opportunity for altering the natural history of arthritis that extends well beyond the initiation phase of disease.

Capturing the Range of Disease Involvement in Localized Scleroderma: The Localized Scleroderma Total Severity Scale.

OBJECTIVE: Juvenile localized scleroderma (jLS) is a chronic autoimmune disease commonly associated with poor outcomes, including contractures, hemiatrophy, uveitis, and seizures. Despite improvements in treatment, >25% of patients with jLS have functional impairment. To improve patient evaluation, our workgroup developed the Localized scleroderma Total Severity Scale (LoTSS), an overall disease severity measure. METHODS: LoTSS was developed as a weighted measure by a consensus process involving literature review, surveys, case vignettes, and multicriteria decision analysis. Feasibility was assessed in larger Childhood Arthritis and Rheumatology Research Alliance groups. Construct validity with physician assessment and inter-rater reliability was assessed using case vignettes. Additional evaluation was performed in a prospective patient cohort initiating treatment. RESULTS: LoTSS severity items were organized into modules that reflect jLS disease patterns, with modules for skin, extracutaneous, and craniofacial manifestations. Construct validity of LoTSS was supported by a strong positive correlation with the Physician Global Assessment (PGA) of severity and damage and weak positive correlation with PGA-Activity, as expected. LoTSS was responsive, with a small effect size identified. Moderate-to-excellent inter-rater reliability was demonstrated. LoTSS was able to discriminate between patient subsets, with higher scores identified in those with greater disease burden and functional limitation. CONCLUSION: We developed a new LS measure for assessing cutaneous and extracutaneous severity and have shown it to be reliable, valid, and responsive. LoTSS is the first measure that assesses and scores all the major extracutaneous manifestations in LS. Our findings suggest LoTSS could aid assessment and management of patients and facilitate outcome evaluation in treatment studies.

Analysis of glycoprotein E-selectin ligands on human and mouse marrow cells enriched for hematopoietic stem/progenitor cells.

Although well recognized that expression of E-selectin on marrow microvessels mediates osteotropism of hematopoietic stem/progenitor cells (HSPCs), our knowledge regarding the cognate E-selectin ligand(s) on HSPCs is incomplete. Flow cytometry using E-selectin-Ig chimera (E-Ig) shows that human marrow cells enriched for HSPCs (CD34(+) cells) display greater E-selectin binding than those obtained from mouse (lin(-)/Sca-1(+)/c-kit(+) [LSK] cells). To define the relevant glycoprotein E-selectin ligands, lysates from human CD34(+) and KG1a cells and from mouse LSK cells were immunoprecipitated using E-Ig and resolved by Western blot using E-Ig. In both human and mouse cells, E-selectin ligand reactivity was observed at ~ 120- to 130-kDa region, which contained two E-selectin ligands, the P-selectin glycoprotein ligand-1 glycoform "CLA," and CD43. Human, but not mouse, cells displayed a prominent ~ 100-kDa band, exclusively comprising the CD44 glycoform "HCELL." E-Ig reactivity was most prominent on CLA in mouse cells and on HCELL in human cells. To further assess HCELL's contribution to E-selectin adherence, complementary studies were performed to silence (via CD44 siRNA) or enforce its expression (via exoglycosylation). Under physiologic shear conditions, CD44/HCELL-silenced human cells showed striking decreases (> 50%) in E-selectin binding. Conversely, enforced HCELL expression of LSK cells profoundly increased E-selectin adherence, yielding > 3-fold more marrow homing in vivo. These data define the key glycoprotein E-selectin ligands of human and mouse HSPCs, unveiling critical species-intrinsic differences in both the identity and activity of these structures.

Multiple juvenile idiopathic arthritis subtypes demonstrate proinflammatory IgG glycosylation.

OBJECTIVE: Rheumatoid arthritis is associated with an excess of agalactosylated (G0) IgG that is considered relatively proinflammatory. Assessment of this association in juvenile idiopathic arthritis (JIA) is complicated by age-dependent IgG glycan variation. The aim of this study was to conduct the first large-scale survey of IgG glycans in healthy children and patients with JIA, with a focus on early childhood, the time of peak JIA incidence. METHODS: IgG glycans from healthy children and disease-modifying antirheumatic drug-naive patients with JIA were characterized using high-performance liquid chromatography. Agalactosylated glycans were quantitated with reference to monogalactosylated (G1) species. Associations were sought between the G0:G1 ratio and disease characteristics. RESULTS: Among healthy children ages 9 months to 16 years (n = 165), the G0:G1 ratio was highly age dependent, with the ratio peaking to 1.19 in children younger than age 3 years and declining to a nadir of 0.83 after age 10 years (Spearman's ρ = 0.60, P < 0.0001). In patients with JIA (n = 141), the G0:G1 ratio was elevated compared with that in control subjects (1.32 versus 1.02; P < 0.0001). The G0:G1 ratio corrected for age was abnormally high in all JIA subtypes (enthesitis-related arthritis was not assessed), most strikingly in systemic JIA. Glycosylation aberrancy was comparable in patients with and those without antinuclear antibodies and in both early- and late-onset disease and exhibited at most a weak correlation with markers of inflammation. CONCLUSION: IgG glycosylation is skewed toward proinflammatory G0 variants in healthy children, in particular during the first few years of life. This deviation is exaggerated in patients with JIA. The role for IgG glycan variation in immune function in children, including the predilection of JIA for early childhood, remains to be defined.

Why so low? An unusual case of myositis in a child.

BACKGROUND: Sarcoidosis is characterized by non-caseating epithelioid granulomas in various tissues throughout the body, most commonly the lung. Non-caseating granulomas may be seen in skeletal muscle, though typically asymptomatic and under-recognized. While rare in children, there is a need to better characterize the disease and its management. Here we present a 12-year-old female with bilateral calf pain who was ultimately found to have sarcoid myositis. CASE PRESENTATION: A 12-year-old female presented to rheumatology with significantly elevated inflammatory markers and isolated lower leg pain. MRI of the distal lower extremities demonstrated extensive bilateral myositis with active inflammation, atrophy, and to a lesser extent fasciitis. This distribution of myositis in a child garnered a broad differential requiring a systematic evaluation. Ultimately, muscle biopsy revealed non-caseating granulomatous myositis with perivascular inflammation, extensive muscle fibrosis, and fatty replacement of the muscle with a CD4+ T cell predominant, lymphohistiocytic infiltrate consistent with sarcoidosis. Review of histopathology from age 6 of an extraconal mass resected from her right superior rectus muscle further confirmed the diagnosis. She had no other clinical symptoms or findings of sarcoidosis. The patient improved significantly with methotrexate and prednisone, though flared again after self-discontinuation of medications and was subsequently lost to follow-up. CONCLUSION: This is the second reported case of granulomatous myositis associated with sarcoidosis in a pediatric patient, and the first to present with a chief complaint of leg pain. Increased knowledge of pediatric sarcoid myositis within the medical community will enhance recognition of the disease, improve the evaluation of lower leg myositis, and advance outcomes for this vulnerable population.

Cognitive dysfunction in pediatric systemic lupus erythematosus: current knowledge and future directions.

Cognitive dysfunction (CD) is a neurologic complication of pediatric systemic lupus erythematosus (SLE) that remains poorly understood and understudied, despite the potential negative effects of CD on long-term socioeconomic status and quality of life. Data regarding the prevalence and risk factors for CD in pediatric SLE as well as the optimal screening, treatment, and long-term outcomes for CD are lacking. In this review, we present current knowledge on CD in pediatric SLE with a focus on the application to clinical practice. We discuss the challenges in diagnosis, clinical screening methods, potential impacts, and interventions for this complication. Finally, we discuss the remaining gaps in our knowledge of CD in pediatric SLE, and avenues for future research efforts.

The Association Between Age at Diagnosis and Disease Characteristics and Damage in Patients With ANCA-Associated Vasculitis.

OBJECTIVE: This study examined the relationship between age at diagnosis and disease characteristics and damage in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Analysis of a prospective longitudinal cohort of patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA) in the Vasculitis Clinical Research Consortium (2013-2021). Disease cohorts were divided by age at diagnosis (years): children (<18), young adults (18-40), middle-aged adults (41-65), and older adults (>65). Data included demographics, ANCA type, clinical characteristics, Vasculitis Damage Index (VDI) scores, ANCA Vasculitis Index of Damage (AVID) scores, and novel disease-specific and non-disease-specific damage scores built from VDI and AVID items. RESULTS: Analysis included data from 1020 patients with GPA/MPA and 357 with EGPA. Female predominance in GPA/MPA decreased with age at diagnosis. AAV in childhood was more often GPA and proteinase 3-ANCA positive. Children with GPA/MPA experienced more subglottic stenosis and alveolar hemorrhage; children and young adults with EGPA experienced more alveolar hemorrhage, need for intubation, and gastrointestinal involvement. Older adults (GPA/MPA) had more neurologic manifestations. After adjusting for disease duration, medications, tobacco, and ANCA, all damage scores increased with age at diagnosis for GPA/MPA (P < 0.001) except the disease-specific damage score, which did not differ (P = 0.44). For EGPA, VDI scores increased with age at diagnosis (P < 0.009), whereas all other scores were not significantly different. CONCLUSION: Age at diagnosis is associated with clinical characteristics in AAV. Although VDI and AVID scores increase with age at diagnosis, this is driven by non-disease-specific damage items.

Children With Enthesitis-Related Arthritis and Possible Benefits From Treatments for Adults With Spondyloarthritis.

This review will summarize clinical, genetic, and pathophysiologic characteristics that are shared between children with enthesitis-related arthritis (ERA) with axial involvement and adults with nonradiographic (and in some cases radiographic) axial spondyloarthritis (SpA), as well as between children with ERA and primarily peripheral disease manifestations and adults with peripheral SpA. Due to the differences in classification criteria for children with ERA and adults with axial and peripheral SpA, the US Food and Drug Administration (FDA) granted automatic full waivers of studies in children for new medications for "axial spondyloarthropathies including ankylosing spondylitis" up until July 2020. Thus, although current juvenile idiopathic arthritis treatment guidelines recommend the use of biologic disease-modifying antirheumatic drugs as part of the early treatment for patients with ERA, none of the FDA-approved therapies for peripheral SpA or nonradiographic axial SpA (certolizumab pegol, ixekizumab, and secukinumab) have been studied or are labeled for use in children with ERA. Considering the similarities between adult SpA and ERA in terms of etiology, genetics, pathogenesis, and clinical manifestations summarized in this review, medications approved for axial SpA or peripheral SpA should also be studied in children with active ERA involving axial or peripheral joints, respectively, with the intent to achieve labeling for use in children. Considering the current lack of effective FDA-approved therapies for ERA, the FDA should also consider requiring pediatric studies for medications that have already been approved for the treatment of adults with SpA.

The immune system, the skin, and childhood rheumatic disease.

As the body's largest organ and first line of defense against the environment, the skin plays a vital role in host immune defense. In addition to its function as a physical barrier, the skin contains an active immune surveillance network and can mount highly specific responses to eliminate invading organisms. In this review, we discuss the functions of adhesion molecules in regulating the recruitment of distinct cell populations to skin in both healthy and disease states, and the interaction between innate and adaptive immune mechanisms active in the skin. We also review how these systems underlie the pathogenesis of skin manifestations of pediatric rheumatologic diseases.

Maintenance of peripheral tolerance through controlled tissue homing of antigen-specific T cells in K14-mOVA mice.

Immunological tolerance is crucial to avoid autoimmune and inflammatory diseases; however, the mechanisms involved are incompletely understood. To study peripheral tolerance to skin-associated Ags, we generated new transgenic mice expressing a membrane-bound form of OVA in skin under the human keratin 14 (K14) promoter (K14-mOVA mice). In contrast to other transgenic mice expressing similar self-Ags in skin, adoptive transfer of Ag-specific T cells does not induce inflammatory skin disease in our K14-mOVA mice. OVA-specific T cells transferred into K14-mOVA mice are activated in lymphoid tissues, undergo clonal expansion, and eventually acquire effector function. Importantly, these Ag-specific T cells selectively up-regulate expression of E-selectin ligand in cutaneous lymph nodes but not in mesenteric lymph nodes and spleen, demonstrating that expression of endogenous self-Ags in skin dictates imprinting of skin tissue homing in vivo. However, an additional inflammatory signal, here induced by tape stripping, is required in K14-mOVA mice to induce T cell migration to skin and development of inflammatory skin disease. Depletion of regulatory CD4(+)CD25(+) T cells did not provoke homing of transferred T cells to skin under steady-state conditions, indicating that these cells are not the key regulators for inhibiting T cell homing in K14-mOVA mice. Both skin-derived and lymph node-resident CD8alpha(+) dendritic cells are responsible for Ag presentation in vivo and induce tolerance to skin Ags, as we show by selective depletion of langerin(+) and CD11c(+) dendritic cells. Taken together, controlled skin homing of T cells is critical for the maintenance of peripheral immune tolerance to epidermal self-Ags.