Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome

Journal of Clinical Immunology - Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the...     

Up-regulation of activating and inhibitory NKG2 receptors in allogeneic and autologous hematopoietic stem cell grafts

Background

Hematopoietic Stem Cell Transplantation (HSCT) is known to induce the inhibitory immune receptor NKG2A on NK cells of donor origin. This occurs in allogeneic recipients, in both the haploidentical and HLA-matched settings.

Methods

To gain further insight, not only NKG2A, but also the activating receptors NKG2C and NKG2D were assessed by flow cytometry. Immunophenotyping was carried out not only on CD56⁺ but also on CD8⁺ lymphocytes from leukemia and lymphoma patients, receiving both HLA-matched (n = 7) and autologous (n = 5) HSCT grafts. Moreover, cognate NKG2 ligands (HLA-E, MICA, ULBP-1, ULBP-2 and ULBP-3) were assessed by immunohistochemistry in diagnostic biopsies from three autotransplanted patients, and at relapse in one case.

Results

All the NKG2 receptors were simultaneously up-regulated in all the allotransplanted patients on CD8⁺ and/or CD56⁺ cells between 30 and 90 days post-transplant, coinciding with, or following, allogeneic engraftment. Up-regulation was of lesser entity and restricted to CD8⁺ cells in the autotransplantation setting. The phenotypic expression ratio between activating and inhibitory NKG2 receptors was remarkably similar in all the patients, except two outliers (a long survivor and a short survivor) who surprisingly displayed a similar NKG2 activation immunophenotype. Tumor expression of 2 to 3 out of the 5 tested NKG2 ligands was observed in 3/3 diagnostic biopsies, and 3 ligands were up-regulated post-transplant in a patient.

Conclusions

Altogether, these results are consistent with a dual (activation-inhibition) NK cell re-education mode, an innate-like T cell re-tuning, and a ligand:receptor interplay between the tumor and the immune system following HSCT including, most interestingly, the up-regulation of several activating NKG2 ligands. Turning the immune receptor balance toward activation on both T and NK cells of donor origin may complement ex vivo NK cell expansion/activation strategies in unmanipulated patients.

Electronic supplementary material

The online version of this article (doi:10.1186/s13046-015-0213-y) contains supplementary material, which is available to authorized users.     

Platelet Survival in Healthy Volunteers After Storage with N-(2-mercaptopropionyl)-glycine

The sulphhydryl group containing drug N-(2-mercaptopropionyl)-glycine (MPG) was tested as a cytoprotective substance for storage of human platelets for transfusion. Autologous platelets stored for 48 h at 21 ± 1°C in the absence (control-platelets) or in the presence (MPG-platelets) of MPG, respectively, were labelled with Indium-III oxine and retransfused into the healthy donors. Significantly higher survival and a higher spleen/liver-ratio were obtained using stored MPG-platelets compared to stored control-platelets. Additionally, a very strong correlation was found between the percentage of discocytes counted after incubation of stored platelets in fresh plasma in vitro and the survival of stored platelets after retransfusion in vivo.     

Peripheral neuroectodermal tumor of the chest (Askin tumor) as secondary neoplasm after Hodgkin's disease: A case report

Summary The authors present the case of a 20-yearold woman who developed a peripheral neuroectodermal neoplasm of the thoracopulmonary region (Askin tumor) 7 years after achieving complete remission of stage-IV Hodgkin's disease. The previous treatment had consisted of eight courses of alternating MOPP/ ABVD combined with involved-field 20-Gy radiotherapy. The second neoplasm appeared in a nonirradiated area of the chest wall, with erosion of the ribs as shown by sonography and computed tomography. The histological pattern was in accordance with a generic diagnosis of a malignant small cell tumor; the immunostaining positivity of the neoplastic cells for the neuron-specific enolase allowed us to make the diagnosis of a tumor with a neuroectodermal origin. Partial resection of the neoplasm and four courses of chemotherapy including adriamycin, cisplatin, and ifosfamide induced a complete remission, confirmed by surgical restaging. She is alive and well 10 months after the completion of therapy. The clinical, radiological, and microscopic features of this tumor occurring as a secondary neoplasm after Hodgkin's disease are described.     

Hodgkin's disease of the nasopharynx: diagnostic and therapeutic approach with a review of the literature

The lymphoid tissues of Waldeyer's ring, including the nasopharynx, are rarely involved in Hodgkin's disease (HD). Between March 1977 and July 2001, about 2150 patients affected by HD were observed in our institute; 7 of them (0.32%), all male patients, had HD of the nasopharynx. They had no symptoms and blood tests were normal. All patients were treated with chemotherapy and/or radiotherapy and achieved complete remission. At a median follow-up of 72 months, they are alive and in continuous complete remission. We conclude that Hodgkin's disease of the nasopharynx is a rare and predominantly male disease with a particularly favorable prognosis. Bone marrow biopsy could be avoided. We believe that two to four cycles of a chemotherapeutic regimen and involved field radiotherapy at an intermediate-high dosage (25-30 Gy) could be the first line treatment for these patients.     

Mediastinal large B-cell lymphoma: clinical and immunohistological findings in 18 patients treated with different third-generation regimens

We report on the immunophenotype, clinical findings and response to aggressive chemotherapy of 18 patients with mediastinal large B-cell lymphoma (MLCL). Cases were collected from a series of 286 high-grade non-Hodgkin's lymphomas (HG-NHL) which, in the period September 1988 to August 1991, were enrolled in a prospective multicentre trial designed to compare the MACOP-B and F-MACHOP regimens. Immunostaining on frozen sections revealed a previously unrecognized phenotype, i.e. co-expression of B-cell (CD19, CD20, CD22, Ig-associated dimer) and activation-associated antigens (CD30 and CDw70) in about 60% of MLCL cases; in contrast, the activation-associated antigens CD25 and Ki-27 (unclustered) were consistently negative. This peculiar phenotype may reflect a derivation of the tumour from a subset of thymic activated B cells. Clinically, the patients (median age 31 years; F/M ratio 2.6) presented with bulky mediastinal mass (72%) associated with mediastinal syndrome in >50% cases; disease was stage IIA in most cases. All 18 patients received aggressive chemotherapy (F-MACHOP 11; MACOP-B 7). Complete response (CR) was achieved in 57.1% of cases treated with MACOP-B. In contrast, the response of the 11 MLCL treated with F-MACHOP was poor (CR 18.2%) as compared to that of the 135 HG-NHL treated with the same regimen during the trial (CR 69.6%). This difference was still statistically significant after adjusting for negative prognostic factors (mediastinal mass > 10 cm plus increased LDH) and suggests that F-MACHOP might not be the most appropriate regimen for this kind of lymphoma.     

Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases.

A retrospective analysis on chronic lymphocytic leukemia (CLL) patients 55 years of age) were observed. At diagnosis, younger and older patients displayed a similar distribution of clinical features, except for a significantly higher male/female ratio in younger patients (2.85 v 1. 29; P <.0001). Both groups showed an elevated rate of second primary cancers (8.3% v 10.7%), whereas the occurrence of Richter's syndrome was significantly higher in younger patients (5.9% v 1.2%; P <. 00001). Younger and older patients showed a similar overall median survival probability (10 years) but were characterized by a different distribution of causes of deaths: CLL unrelated deaths and second primary malignancies predominated in the older age group, whereas the direct effects of leukemia were prevalent in the younger age group. Although younger and older patients displayed a similar survival, the evaluation of the relative survival rates showed that the disease had a greater adverse effect on the expected survival probability of the younger population. Multivariate analysis showed that for young CLL patients only dynamic parameters, such as lymphocyte doubling time and other signs of active disease, were the independent factors that significantly influenced survival probability (P =.00001). A prolonged clinico-hematologic follow-up allowed us to identify two subsets of young CLL patients with a different prognostic outcome: a group of patients (40%) with long-lasting stable disease without treatment and an actuarial survival probability of 94% at 12 years from diagnosis and another group (60%) with progressive disease and a median survival probability of 5 years after therapy. For the latter patients, the therapeutic effect of innovative therapies with curative intents needs to be investigated in prospective, comparative clinical trials.     

Administration of glutathione in patients with type 2 diabetes mellitus increases the platelet constitutive nitric oxide synthase activity and reduces PAI-1

Several studies suggest that nitric oxide (NO) production is impaired in diabetes mellitus. Reduced levels of NO could contribute to cardiovascular mortality. Furthermore, NO synthesis is impaired in glutathione (GSH)-depleted human umbilical vein endothelial cells and GSH is reduced in patients with type 2 diabetes mellitus (T2DM). We tested the hypothesis that treatment with GSH may improve platelet constitutive NO sinthase (cNOS) activity in patients with T2DM. Fifteen patients with T2DM underwent a treatment with GSH 600 mg/day i.m. for 10 days. With respect to the basal values on the 10th day of treatment, the red blood cell GSH concentration and platelets cNOS increased (1.4+/-0.1 vs 1.9+/-0.1 micromol/10(10) RBC, p<0.001 and 0.7+/-0.1 vs 2.9+/-0.2 fmol x min(-1) x 10(-9) PLTs, p<0.001, respectively) and the plasma PAI-1 levels diminished (81.4+/-3.7 vs 68.7+/-4.0 ng/ml, p<0.002). A negative correlation between the cNOS and the PAI-1 was found on the basal values. After a wash-out of 30 days the values of red blood cell GSH concentration, platelet cNOS activity and PAI-1 Ag returned to the basal levels. These data suggest that the administration of GSH, in patients with T2DM, is able to improve platelet cNOS activity together with a reduction of PAI-1.     

Treatment of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): report of a case and literature review

Sinus histiocytosis with massive lymphadenopathy (SHML) is a rare disorder of unknown etiology, usually associated with lymph node enlargement in various superficial or deep sites. It usually shows a prolonged clinical course with occasional exacerbation and remission phases. We describe the long-term follow-up of a case of SHML that showed typical clinical features and in which various therapeutic strategies were attempted. Chemotherapy and alpha-interferon (IFN) were ineffective; surgery was ultimately required with satisfactory results. From an extensive literature review we found different treatment strategies in SHML in the 80 cases published between 1969 and 2000. Spontaneous resolution of adenopathies is frequently observed: 32 out of 40 cases which did not receive chemotherapy, radiotherapy, or surgery were healthy at the time of publication. Radiotherapy alone showed conflicting results: 3 complete remissions (CR) were obtained in the 9 patients treated. Surgical debulking when required was effective--8/9 CR--while chemotherapy showed generally negative results. IFN has been previously employed in only one case. In conclusion, clinical observation without treatment is advisable when possible. In the presence of vital organ compression and/or extranodal localization with important clinical signs, surgical debulking may be necessary. Radiotherapy has shown limited efficacy, while chemotherapy is in general ineffective. More experience is needed to evaluate the role of IFN.     

Primary cutaneous B‐cell lymphoma is associated with somatically hypermutated immunoglobulin variable genes and frequent use of VH1‐69 and VH4‐59 segments

Background Accurate assessment of the somatic mutational status of clonal immunoglobulin variable region (IgV) genes is relevant in elucidating tumour cell origin in B‐cell lymphoma; virgin B cells bear unmutated IgV genes, while germinal centre and postfollicular B cells carry mutated IgV genes. Furthermore, biases in the IgV repertoire and distribution pattern of somatic mutations indicate a possible antigen role in the pathogenesis of B‐cell malignancies. Objectives This work investigates the cellular origin and antigenic selection in primary cutaneous B‐cell lymphoma (PCBCL). Methods We analysed the nucleotide sequence of clonal IgV heavy‐chain gene (IgVH) rearrangements in 51 cases of PCBCL (25 follicle centre, 19 marginal zone and seven diffuse large B‐cell lymphoma, leg‐type) and compared IgVH sequences with their closest germline segment in the GenBank database. Molecular data were then correlated with histopathological features. Results We showed that all but one of the 51 IgVH sequences analysed exhibited extensive somatic hypermutations. The detected mutation rate ranged from 1·6% to 21%, with a median rate of 9·8% and was independent of PCBCL histotype. Calculation of antigen‐selection pressure showed that 39% of the mutated IgVH genes displayed a number of replacement mutations and silent mutations in a pattern consistent with antigenic selection. Furthermore, two segments, VH1‐69 (12%) and VH4‐59 (14%), were preferentially used in our case series. Conclusions Data indicate that neoplastic B cells of PBCBL have experienced germinal centre reaction and also suggest that the involvement of IgVH genes is not entirely random in PCBCL and that common antigen epitopes could be pathologically relevant in cutaneous lymphomagenesis.