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1.
Artigo em Inglês | MEDLINE | ID: mdl-33895260

RESUMO

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Whilst increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations. OBJECTIVE: To analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts. METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies (ESID) registry. Patients with autoinflammatory diseases were excluded due to the limited number registered. RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed due to family history only and 0.8% presented with malignancy. Two thirds of IEI patients presented before the age of 6 years, but a quarter of patients only developed initial symptoms as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between 6 and 25 years of age with male predominance until age 10, shifting to female predominance after age 40. Infections were most prevalent as a first manifestation in patients presenting after age 30. CONCLUSION: An exclusive focus on infection-centered warning signs would have missed around 25% of IEI patients that initially present with other manifestations. CLINICAL IMPLICATIONS: We provide a data-based rationale to add immune dysregulation and syndromic features to the IEI warning signs, which may significantly improve early IEI diagnosis.

5.
J Exp Med ; 218(2)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33170215

RESUMO

The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαß+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET- expression pattern. These unconventional T cells are present in healthy individuals, are generated before birth, are enriched in lymphoid tissue, and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative, noncytotoxic T cells with an IL-10 cytokine bias. Mechanistically, regulation of this physiological population is mediated by FAS and CTLA4 signaling, and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease.

6.
Front Immunol ; 11: 612977, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362801

RESUMO

Griscelli syndrome type 2 (GS-2) is an inborn error of immunity characterized by partial albinism and episodes of hemophagocytic lymphohistiocytosis (HLH). It is caused by RAB27A mutations that encode RAB27A, a member of the Rab GTPase family. RAB27A is expressed in many tissues and regulates vesicular transport and organelle dynamics. Occasionally, GS-2 patients with RAB27A mutation display normal pigmentation. The study of such variants provides the opportunity to map distinct binding sites for tissue-specific effectors on RAB27A. Here we present a new case of GS-2 without albinism (GS-2 sine albinism) caused by a novel missense mutation (Val143Ala) in the RAB27A and characterize its functional cellular consequences. Using pertinent animal cell lines, the Val143Ala mutation impairs both the RAB27A-SLP2-A interaction and RAB27A-MUNC13-4 interaction, but it does not affect the RAB27A-melanophilin (MLPH)/SLAC2-A interaction that is crucial for skin and hair pigmentation. We conclude that disruption of the RAB27A-MUNC13-4 interaction in cytotoxic lymphocytes leads to the HLH predisposition of the GS-2 patient with the Val143Ala mutation. Finally, we include a review of GS-2 sine albinism cases reported in the literature, summarizing their genetic and clinical characteristics.

7.
Front Pediatr ; 8: 556155, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194891

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disease, which can be mistaken for sepsis easily. Among the infectious causes that may trigger secondary HLH, tuberculosis (TBC), a rather rare pathogen nowadays, is typical. To our knowledge, this is the first case report of an infant suffering from TBC-associated HLH-induced acute respiratory failure who was treated successfully using extracorporeal membrane oxygenation. An 8-month-old boy with fever (over the last 8 wk) and pancytopenia was transferred to our institution with acute respiratory failure and for extracorporeal membrane oxygenation therapy. Bone marrow biopsy revealed hemophagocytosis. Immunological work-up for familial HLH was negative. In a desperate search for the cause of secondary HLH, an interferon-gamma release assay for TBC returned positive. However, microscopy for acid-fast bacteria as well as polymerase chain reaction for TBC were initially negative. Despite this, the child was treated with tuberculostatic therapy. TBC was finally confirmed. The child remained on extracorporeal membrane oxygenation for 28 d. Further work-up showed typical lesions of disseminated TBC. The mother was identified as the source of TBC. The boy presents with mild sequelae (fine motor skills). In infants with suspected septicemia, TBC should be considered as differential diagnosis even if the results are initially negative.

8.
JMIR Med Inform ; 8(10): e17420, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33026355

RESUMO

BACKGROUND: The German Network on Primary Immunodeficiency Diseases (PID-NET) utilizes the European Society for Immunodeficiencies (ESID) registry as a platform for collecting data. In the context of PID-NET data, we show how registries based on custom software can be made interoperable for better collaborative access to precollected data. The Open Source Registry System for Rare Diseases (Open-Source-Registersystem für Seltene Erkrankungen [OSSE], in German) provides patient organizations, physicians, scientists, and other parties with open source software for the creation of patient registries. In addition, the necessary interoperability between different registries based on the OSSE, as well as existing registries, is supported, which allows those registries to be confederated at both the national and international levels. OBJECTIVE: Data from the PID-NET registry should be made available in an interoperable manner without losing data sovereignty by extending the existing custom software of the registry using the OSSE registry framework. METHODS: This paper describes the following: (1) the installation and configuration of the OSSE bridgehead, (2) an approach using a free toolchain to set up the required interfaces to connect a registry with the OSSE bridgehead, and (3) the decentralized search, which allows the formulation of inquiries that are sent to a selected set of registries of interest. RESULTS: PID-NET uses the established and highly customized ESID registry software. By setting up a so-called OSSE bridgehead, PID-NET data are made interoperable according to a federated approach, and centrally formulated inquiries for data can be received. As the first registry to use the OSSE bridgehead, the authors introduce an approach using a free toolchain to efficiently implement and maintain the required interfaces. Finally, to test and demonstrate the system, two inquiries are realized using the graphical query builder. By establishing and interconnecting an OSSE bridgehead with the underlying ESID registry, confederated queries for data can be received and, if desired, the inquirer can be contacted to further discuss any requirements for cooperation. CONCLUSIONS: The OSSE offers an infrastructure that provides the possibility of more collaborative and transparent research. The decentralized search functionality includes registries into one search application while still maintaining data sovereignty. The OSSE bridgehead enables any registry software to be integrated into the OSSE network. The proposed toolchain to set up the required interfaces consists of freely available software components that are well documented. The use of the decentralized search is uncomplicated to use and offers a well-structured, yet still improvable, graphical user interface to formulate queries.

9.
J Immunol ; 205(11): 2979-2987, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33115853

RESUMO

Mutations in two genes can result in activated PI3Kδ syndrome (APDS), a rare immunodeficiency disease with limited therapeutic options. Seletalisib, a potent, selective PI3Kδ inhibitor, was evaluated in patients with APDS1 and APDS2. In the phase 1b study (European Clinical Trials Database 2015-002900-10) patients with genetic and clinical confirmation of APDS1 or APDS2 received 15-25 mg/d seletalisib for 12 wk. Patients could enter an extension study (European Clinical Trials Database 2015-005541). Primary endpoints were safety and tolerability, with exploratory efficacy and immunology endpoints. Seven patients (median age 15 years; APDS1 n = 3; APDS2 n = 4) received seletalisib; five completed the phase 1b study. For the extension study, four patients entered, one withdrew consent (week 24), three completed ≥84 wk of treatment. In the phase 1b study, patients had improved peripheral lymphadenopathy (n = 2), lung function (n = 1), thrombocyte counts (n = 1), and chronic enteropathy (n = 1). Overall, effects were maintained in the extension. In the phase 1b study, percentages of transitional B cells decreased, naive B cells increased, and senescent CD8 T cells decreased (human cells); effects were generally maintained in the extension. Seletalisib-related adverse events occurred in four of seven patients (phase 1b study: hepatic enzyme increased, dizziness, aphthous ulcer, arthralgia, arthritis, increased appetite, increased weight, restlessness, tendon disorder, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (aphthous ulcer). Serious adverse events occurred in three of seven patients (phase 1b study: hospitalization, colitis, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (stomatitis). Patients with APDS receiving seletalisib had improvements in variable clinical and immunological features, and a favorable risk-benefit profile was maintained for ≤96 wk.

10.
Nat Commun ; 11(1): 5341, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087723

RESUMO

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.


Assuntos
Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Autoimunidade/genética , Proteína 1 Supressora da Sinalização de Citocina/deficiência , Proteína 1 Supressora da Sinalização de Citocina/genética , Adolescente , Adulto , Idade de Início , Doenças Autoimunes/metabolismo , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Haploinsuficiência , Humanos , Masculino , Modelos Moleculares , Mutação , Linhagem , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina/química , Linfócitos T/imunologia
11.
J Exp Med ; 217(12)2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-32766723

RESUMO

The Nck-associated protein 1-like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage-specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4+ and CD8+ cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients' T cells displayed impaired early activation, immune synapse morphology, and leading edge formation. Moreover, knockdown of nckap1l in zebrafish led to defects in neutrophil migration. Hence, NCKAP1L mutations lead to broad immune dysregulation in humans, which could be classified within actinopathies.

12.
J Exp Med ; 217(11)2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-32812031

RESUMO

Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.

13.
EBioMedicine ; 59: 102961, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32841837

RESUMO

BACKGOUND: The potential of a single progenitor cell to establish and maintain long-term protective T-cell immunity in humans is unknown. For genetic disorders disabling T-cell immunity, somatic reversion was shown to support limited T-cell development attenuating the clinical phenotype. However, the cases reported so far deteriorated over time leaving unanswered the important question of long-term activity of revertant precursors and the robustness of the resulting T-cell system. METHODS: We applied TCRß-CDR3 sequencing and mass cytometry on serial samples of a now 18 year-old SCIDX1 patient with somatic reversion to analyse the longitudinal diversification and stability of a T-cell system emerging from somatic gene rescue. FINDINGS: We detected close to 105 individual CDR3ß sequences in the patient. Blood samples of equal size contained about 10-fold fewer unique CDR3ß sequences compared to healthy donors, indicating a surprisingly broad repertoire. Despite dramatic expansions and contractions of individual clonotypes representing up to 30% of the repertoire, stable diversity indices revealed that these transient clonal distortions did not cause long-term repertoire imbalance. Phenotypically, the T-cell system did not show evidence for progressive exhaustion. Combined with immunoglobulin substitution, the limited T-cell system in this patient supported an unremarkable clinical course over 18 years. INTERPRETATION: Genetic correction in the appropriate cell type, in our patient most likely in a T-cell biased self-renewing hematopoietic progenitor, can yield a diverse T-cell system that provides long-term repertoire stability, does not show evidence for progressive exhaustion and is capable of providing protective and regulated T-cell immunity for at least two decades. FUNDING: DFG EH 145/9-1, DFG SCHW 432/4-1 and the German Research Foundation under Germany's Excellence Strategy-EXC-2189-Project ID: 390939984.

14.
J Clin Immunol ; 40(6): 901-916, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32638196

RESUMO

Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.

15.
Pediatr Blood Cancer ; 67(9): e28523, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32618429

RESUMO

BACKGROUND: Reduced toxicity conditioning for hematopoietic stem cell transplantation of patients with hemophagocyticlymphohistiocytosis (HLH) results in favorable survival, however at the expense of relevant rates of mixed chimerism. Factors predisposing to mixed chimerism remain to be determined. PROCEDURE: Patients with primary HLH transplanted 2009-2016 after treosulfan- or melphalan-based conditioning regimens were analyzed in a retrospective multicenter study for survival, engraftment, chimerism, and adverse events. Mixed chimerism was considered substantial if < 25% donor chimerism occurred and/or if secondary cell therapy was administered. Donor type, graft source, type of alkylating agent, type of serotherapy, and remission status were analyzed as potential risk factors in a multivariable logistic regression model. RESULTS: Among 60 patients, engraftment was achieved in 95%, and the five-year estimated overall survival rate was 75%. Prevalence of any recipient chimerism was 48%. Substantial recipient chimerism was recorded in 32% of patients. Secondary post-HSCT cell therapy was administered in 30% of patients. A human leukocyte antigen (HLA)-mismatched donor (< 10/10) was the only significant risk factor for the occurrence of substantial recipient chimerism (P = 0.01; odds ratio, 5.8; CI 95%, 1.5-26.3). CONCLUSION: The use of an HLA-matched donor is the most important factor to avoid substantial recipient chimerism following treosulfan -or melphalan-based conditioning in primary HLH.

16.
Blood ; 136(9): 1055-1066, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32518946

RESUMO

Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.

17.
Blood Adv ; 4(9): 1998-2010, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32384542

RESUMO

Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic lymphohistiocytosis (HLH). Unstable donor chimerism (DC) and relapses are clinical challenges . We examined the effect of a reduced-intensity conditioning regimen based on targeted busulfan to enhance myeloid DC in HLH. The European Society for Bone and Marrow Transplantation-approved reduced-intensity conditioning protocol comprised targeted submyeloablative IV busulfan, IV fludarabine, and serotherapy comprising IV alemtuzumab (0.5-0.8 mg/kg) for unrelated-donor and IV rabbit anti-T-cell globulin for related-donor transplants. We assessed toxicity, engraftment, graft-versus-host disease (GHVD), DC in blood cell subtypes, and overall survival/event-free survival. Twenty-five patients from 7 centers were treated (median age, 0.68 year). The median total dose and cumulative area under the curve of busulfan was 13.1 mg/kg (6.4-26.4) and 63.1 mg/L × h (48-77), respectively. Bone marrow, peripheral blood stem cell, or cord blood transplants from HLA-matched related (n = 7) or unrelated (n = 18) donors were administered. Donor cells engrafted in all patients (median: neutrophils d+20/platelets d+28). At last follow-up (median, 36 months; range, 8-111 months), the median DC of CD15+ neutrophils, CD3+ T cells, and CD16+56+ natural killer cells was 99.5% (10-100), 97% (30-100), and 97.5% (30-100), respectively. Eight patients (32%) developed sinusoidal obstruction syndrome, resolving after defibrotide treatment. The 3-year overall survival and event-free survival rates were both 100%. None of the patients developed acute grade III to IV GHVD. Limited chronic GVHD was encountered in 4%. This regimen achieves excellent results with stable DC in patients with HLH.

18.
Eur J Immunol ; 50(11): 1770-1782, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32419134

RESUMO

Familial hemophagocytic lymphohistiocytosis (FHL) is a hyperinflammatory syndrome affecting patients with genetic cytotoxicity defects. Perforin-deficient (PKO) mice recapitulate the full clinical picture of FHL after infection with lymphocytic choriomeningitis virus (LCMV). Hyperactivated CD8+ T cells and IFN-γ have been identified as the key drivers of FHL and represent targets for therapeutic interventions. However, the response of patients is variable. This could be due to trigger-dependent differences in pathogenesis, which is difficult to address in FHL patients, since the trigger frequently escapes detection. We established an alternative FHL model using intravenous infection of PKO mice with murine CMV (MCMV)Smith . PKO mice developed acute FHL after both infections and fulfilled HLH diagnostic criteria accompanied by excessive IFN-γ production by disease-inducing T cells, that enrich in the BM. However, direct comparison of the two infection models disclosed trigger-dependence of FHL progression and revealed a higher contribution of CD4 T cells and NK cells to IFN-γ production after MCMV infection. Importantly, therapeutic intervention by IFN-γ neutralization or CD8+ T-cell depletion had less benefit in MCMV-triggered FHL compared to LCMV-triggered FHL, likely due to MCMV-induced cytopathology. Thus, the context of the specific triggering viral infection can impact the success of targeted immunotherapeutic HLH control.

19.
Front Immunol ; 11: 808, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32457750

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous hyperinflammatory syndrome with different pathways of pathogenesis resulting in similar clinical presentations. It is best defined and understood if presenting in the context of genetic immunodeficiencies associated with defects of lymphocyte cytotoxicity. In these "primary" forms of HLH, cellular and soluble immune effectors are relatively well characterized. While etoposide-based broad cell-directed therapies remain standard of care, more specific therapies targeting these effectors individually are increasingly available. Anti-CD52 as a cell-directed therapy and anti-IFN-gamma, IL-18BP, and JAK-inhibition as cytokine-directed therapies are expected to broaden the therapeutic options, but the precise role of these drugs in first-line and rescue treatment indications remains to be defined. A number of additional inborn errors of immunity are associated with episodes of immune activation fulfilling the clinical criteria of HLH. Impaired pathogen control is a key driver of hyperinflammation in some conditions, while others are characterized by a strong autoinflammatory component. This heterogeneity of disease-driving factors and the variable severity in disease progression in these conditions do not allow a simple adaptation of protocols established for "primary" HLH to HLH in the context of other inborn errors of immunity. Cytokine-directed therapies hold significant promise in these increasingly recognized disorders.

20.
Pediatr Blood Cancer ; 67(6): e28302, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32285995

RESUMO

This report offers novel clinical and diagnostic aspects of the association between germline mutations in HAVCR2 and subcutaneous panniculitis-like T-cell lymphoma (SPTCL). The patient presented with panniculitis-like T-cell lymphoma involving mesenteric fatty tissue associated with hemophagocytic lymphohistiocytosis (HLH). Five years later, he developed a clonally unrelated SPTCL and underwent hematopoietic stem cell transplantation. Retrospectively, he was found to carry germline mutations in HAVCR2 associated with reduced T-cell immunoglobulin mucin-3 (TIM-3) expression. We show that mesenteric fatty tissue localization of SPTCL can be the presenting manifestation of TIM-3 deficiency, that this condition predisposes to recurrent lymphoma, and that flow cytometry is a possible screening tool.


Assuntos
Mutação em Linhagem Germinativa , Receptor Celular 2 do Vírus da Hepatite A/deficiência , Receptor Celular 2 do Vírus da Hepatite A/genética , Linfo-Histiocitose Hemofagocítica/patologia , Linfoma de Células T/patologia , Mesentério/patologia , Paniculite/patologia , Adolescente , Humanos , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/metabolismo , Linfoma de Células T/complicações , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Masculino , Mesentério/metabolismo , Paniculite/complicações , Paniculite/genética , Paniculite/metabolismo , Prognóstico
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