Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF(V600E) mutation occurs frequently, ...but clinical significance remains to be determined.
BRAF(V600E) mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae.
Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAF(V600E) mutation. Patients with BRAF(V600E) manifested more severe disease than did those with wild-type BRAF. Patients with BRAF(V600E) comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAF(V600E) mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAF(V600E) more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001).
In children with LCH, BRAF(V600E) mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.
Loss of NBEAL2 function leads to grey platelet syndrome (GPS), a bleeding disorder characterized by macro-thrombocytopenia and α-granule-deficient platelets. A proportion of patients with GPS develop ...autoimmunity through an unknown mechanism, which might be related to the proteins NBEAL2 interacts with, specifically in immune cells. Here we show a comprehensive interactome of NBEAL2 in primary T cells, based on mass spectrometry identification of altogether 74 protein association partners. These include LRBA, a member of the same BEACH domain family as NBEAL2, recessive mutations of which cause autoimmunity and lymphocytic infiltration through defective CTLA-4 trafficking. Investigating the potential association between NBEAL2 and CTLA-4 signalling suggested by the mass spectrometry results, we confirm by co-immunoprecipitation that CTLA-4 and NBEAL2 interact with each other. Interestingly, NBEAL2 deficiency leads to low CTLA-4 expression in patient-derived effector T cells, while their regulatory T cells appear unaffected. Knocking-down NBEAL2 in healthy primary T cells recapitulates the low CTLA-4 expression observed in the T cells of GPS patients. Our results thus show that NBEAL2 is involved in the regulation of CTLA-4 expression in conventional T cells and provide a rationale for considering CTLA-4-immunoglobulin therapy in patients with GPS and autoimmune disease.
Neurodegenerative (ND) complications in Langerhans cell histiocytosis (LCH) are a late‐onset but dramatic sequelae for which incidence and risk factors are not well defined. Based on a national ...prospective registry of paediatric LCH patients, we determined the incidence rate of clinical ND LCH (cND‐LCH) and analysed risk factors, taking into account disease extent and molecular characteristics. Among 1897 LCH patients, 36 (1·9%) were diagnosed with a cND‐LCH. The 10‐year cumulative incidence of cND‐LCH was 4·1%. cND‐LCH typically affected patients previously treated for a multisystem, risk organ–negative LCH, represented in 69·4% of cND‐LCH cases. Pituitary gland, skin and base skull/orbit bone lesions were more frequent (P < 0·001) in cND‐LCH patients compared to those without cND‐LCH (respectively 86·1% vs. 12·2%, 75·0% vs. 34·2%, and 63·9% vs. 28·4%). The ‘cND susceptible patients’ (n = 671) i.e., children who had experienced LCH disease with pituitary or skull base or orbit bone involvement, had a 10‐year cND risk of 7·8% vs. 0% for patients who did not meet these criteria. Finally, BRAFV600E status added important information among these cND susceptible patients, with the 10‐year cND risk of 33·1% if a BRAFV600E mutation was present compared to 2·9% if it was absent (P = 0·002).
Background Inflammatory bowel disease (IBD) is one of the most common chronic gastrointestinal diseases, but the underlying molecular mechanisms remain largely unknown. Studies of monogenic diseases ...can provide insight into the pathogenesis of IBD. Objective We thought to determine the underlying molecular causes of IBD occurring in 2 unrelated families in association with an immune deficiency. Methods We performed genetic linkage analysis and candidate gene sequencing on 13 patients from a large consanguineous family affected by early-onset IBD, progressive immune deficiency, and, in some cases, autoimmunity and alopecia, a condition we named enteropathy-lymphocytopenia-alopecia. The candidate gene was also sequenced in an unrelated patient with a similar phenotype. We performed histologic analysis of patients' intestinal biopsy specimens and carried out functional assays on PBMCs. Gut organoids derived from a patient's biopsy specimen were analyzed. Results We identified biallelic missense mutations in tetratricopeptide repeat domain 7A (TTC7A) in all patients from both families. The resulting TTC7A depletion modified the proliferation, adhesion, and migratory capacities of lymphocytes through inappropriate activation of the RhoA signaling pathway. Normal function was restored by wild-type TTC7A expression or addition of a RhoA kinase inhibitor. The growth and polarity of gut epithelial organoids were also found to be dependent on the RhoA signaling pathway. Conclusions We show that TTC7A regulates the actin cytoskeleton dynamics in lymphocytes through the RhoA signaling pathway and is required in both lymphocytes and epithelial cells for maintaining equilibrium between cell proliferation, migration, polarization, and cell death. Our study highlights variability in the phenotypic expression resulting from TTC7A deficiency and outlines that impairment of both epithelial cells and lymphocytes cooperatively causes IBD.
Wiskott-Aldrich syndrome is a rare primary immunodeficiency associated with severe microthrombocytopenia. Partially HLA antigen-matched allogeneic hematopoietic stem cell (HSC) transplantation is ...often curative but is associated with significant comorbidity.
To assess the outcomes and safety of autologous HSC gene therapy in Wiskott-Aldrich syndrome.
Gene-corrected autologous HSCs were infused in 7 consecutive patients with severe Wiskott-Aldrich syndrome lacking HLA antigen-matched related or unrelated HSC donors (age range, 0.8-15.5 years; mean, 7 years) following myeloablative conditioning. Patients were enrolled in France and England and treated between December 2010 and January 2014. Follow-up of patients in this intermediate analysis ranged from 9 to 42 months.
A single infusion of gene-modified CD34+ cells with an advanced lentiviral vector.
Primary outcomes were improvement at 24 months in eczema, frequency and severity of infections, bleeding tendency, and autoimmunity and reduction in disease-related days of hospitalization. Secondary outcomes were improvement in immunological and hematological characteristics and evidence of safety through vector integration analysis.
Six of the 7 patients were alive at the time of last follow-up (mean and median follow-up, 28 months and 27 months, respectively) and showed sustained clinical benefit. One patient died 7 months after treatment of preexisting drug-resistant herpes virus infection. Eczema and susceptibility to infections resolved in all 6 patients. Autoimmunity improved in 5 of 5 patients. No severe bleeding episodes were recorded after treatment, and at last follow-up, all 6 surviving patients were free of blood product support and thrombopoietic agonists. Hospitalization days were reduced from a median of 25 days during the 2 years before treatment to a median of 0 days during the 2 years after treatment. All 6 surviving patients exhibited high-level, stable engraftment of functionally corrected lymphoid cells. The degree of myeloid cell engraftment and of platelet reconstitution correlated with the dose of gene-corrected cells administered. No evidence of vector-related toxicity was observed clinically or by molecular analysis.
This study demonstrated the feasibility of the use of gene therapy in patients with Wiskott-Aldrich syndrome. Controlled trials with larger numbers of patients are necessary to assess long-term outcomes and safety.
Aims
The aim was to test the expression of PU.1 on different types of histiocytoses and to test the utility of PU.1 in confirming or excluding a histiocytic origin in tumour samples with suspicion of ...histiocytosis.
Methods and Results
We analysed 66 biopsies of nonmalignant histiocytoses represented by Langerhans‐cell histiocytosis (n = 13), Erdheim–Chester disease (ECD) (n = 19), Rosai–Dorfman disease (RDD) (n = 14), mixed ECD‐RDD (n = 3), ALK‐positive histiocytosis (n = 6), and juvenile xanthogranuloma (n = 11). All cases were positive for PU.1 in reactive and neoplastic histiocytes. In addition, 39 cases of tumours with high‐grade cytological atypia were referred to our center as suspicion of malignant histiocytosis/histiocytic sarcoma and only 18 were confirmed. Indeed, more than half of these tumours (21/39) were either undifferentiated malignant tumours with a stroma rich in histiocytes, diffuse large B‐cell lymphoma, or high‐grade dedifferentiated liposarcoma. PU.1 was useful to distinguish between the negativity of large atypical nuclei and the positivity of stromal reactive histiocytes.
Conclusion
PU.1 is expressed by all types of histiocytosis. It distinguishes histiocytosis from histiocyte‐rich tumours with an easy interpretation due to its sharp nuclear staining. Its negativity in lesional/tumour cells in histiocyte‐like lesions is useful to eliminate a histiocytosis.
Langerhans cell histiocytosis (LCH) is defined by the association of a clinical and radiological involvement and a biopsy of a pathological tissue. Extension: it can affect any organ or system of the ...body but most commonly the bone (80% of cases), the skin (33%) and the pituitary (25%). Other organs are concerned such as liver, spleen, hematopoietic system and the lungs (15% each), lymph nodes (5-10%) and central nervous system (CNS) excluding the pituitary (2-4%). Natural history: the natural history of the disease is very heterogeneous, ranging from auto-regressive lesions to a disease affecting multiple organs with fatal consequences, while some lesions may be responsible for permanent sequels. A multidisciplinary approach: the perception of disease from physicians varies greatly depending on their speciality and experience, as well as the presentation of the disease or the short-term treatment outcomes. But whatever the initial view of the treating physician, a multidisciplinary approach to the LCH is recommended as well as the coordination of the necessary care of this systemic disease and its associated morbidity.
current treatment protocols, adapted to the situation of each patient, provide a survival of 98% in children. The sequels, such as diabetes insipidus, hormonal deficits, deafness and even more rarely respiratory failure and sclerosing cholangitis are seen in up to 30% of children.
Abstract
Background
Lung involvement in childhood Langerhans cell histiocytosis (LCH) is infrequent and rarely life threatening, but occasionally, severe presentations are observed.
Methods
Among ...1482 children (< 15 years) registered in the French LCH registry (1994–2018), 111 (7.4%) had lung involvement. This retrospective study included data for 17 (1.1%) patients that required one or more intensive care unit (ICU) admissions for respiratory failure.
Results
The median age was 1.3 years at the first ICU hospitalization. Of the 17 patients, 14 presented with lung involvement at the LCH diagnosis, and 7 patients (41%) had concomitant involvement of risk-organ (hematologic, spleen, or liver). Thirty-five ICU hospitalizations were analysed. Among these, 22 (63%) were secondary to a pneumothorax, 5 (14%) were associated with important cystic lesions without pneumothorax, and 8 (23%) included a diffuse micronodular lung infiltration in the context of multisystem disease.
First-line vinblastine–corticosteroid combination therapy was administered to 16 patients; 12 patients required a second-line therapy (cladribine:
n
= 7; etoposide-aracytine:
n
= 3; targeted therapy
n
= 2). A total of 6 children (35%) died (repeated pneumothorax:
n
= 3; diffuse micronodular lung infiltration in the context of multisystem disease:
n
= 2; following lung transplantation:
n
= 1). For survivors, the median follow-up after ICU was 11.2 years. Among these, 9 patients remain asymptomatic despite abnormal chest imaging.
Conclusions
Severe lung involvement is unusual in childhood LCH, but it is associated with high mortality. Treatment guidelines should be improved for this group of patients: viral infection prophylaxis and early administration of a new LCH therapy, such as targeted therapy.
...this risk is lower in patients with T-cell-repleted graft versus patients receiving T-cell-depleted transplant.2 During the posttransplant period, several prophylactic or preemptive antiviral ...treatments may be partially effective by inhibiting viral replication and thus stabilizing the viral load.3,4 However, antiviral drugs can also induce drug resistance and be responsible for organ toxicity.5 Because the transfer of donor memory T lymphocytes directed specifically against immunodominant viral antigens has been shown to control ongoing viral infections, we designed a French multicenter pilot trial (Clinicaltrials.gov: NCT01325636) with the aim of treating pediatric or adult recipients of allogeneic HSCT (regardless of the underlying disease).6-8 Inclusion criteria were as follow: (1) donor chimerism 10% or more at inclusion; (2) biological signs of infection with CMV with resistance or intolerance to conventional antiviral treatments, or CMV or ADV disease with documented organ damage; (3) graft versus host activity (<=II) controlled by corticoids (<1 mg/kg) at the time of inclusion; and (4) donor with positive CMV and/or ADV serology. Patient SAE Delay between SAE and specific T-cell infusion P1 Multivisceral failure due to disseminated CMV infectionDeath Day+7Day+31 P2 None NA P3 None NA P4 Sepsis Day+1 P5 Worsening respiratory symptoms 5 mo P6 Alveolar hemorrhage and death Day+3 P7 Gram-negative sepsis Day+12 P8 Pulmonary hypertension and intraalveolar hemorrhageDeath Day+36Day+96 P9 Multivisceral failureDeath Day+10Day+14 P10 Stage III GvHDDeath from ADV pneumonitis Day+5Day+97 P11 Intraalveolar hemorrhage, hematemesisDeath Day+14Day+25 P12 None NA P13 SepsisPneumopathy Day+23Day+48 P14 Respiratory distressDeath from PTLD Day+20Day+33 P15 Acute respiratory distress syndrome due to CMV and ADV and death Day+3 Table E3 Serious adverse event observed in treated patients GvHD, Graft versus host disease; NA, not applicable; P, patient; PTLD, posttransplant lymphoproliferative disease.
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