Off-Label Use of Sirolimus and Everolimus in a Pediatric Center: A Case Series and Review of the Literature.

Background: It has been 15 years since sirolimus, an mTOR inhibitor, received Food and Drug Administration approval to prevent acute rejection in kidney transplantation, and 8 years since its analog everolimus acquired the same status. Since then, these drugs have become more and more utilized and their immunosuppressive and antiproliferative properties have been tested in a great variety of clinical conditions, often achieving excellent results. Despite such positive evidence, the on-label indications for these rapalogs are still very restrictive, especially in children.

Disturbances in NK Cells in Various Types of Hemophagocytic Lymphohistiocytosis in a Population of Polish Children.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease associated with immune system hyperactivation and the appearance of serious systemic disturbances. The purpose of this study was an assessment of natural killer (NK) cell disturbances in a group of children with clinical signs of HLH. A total of 43 children with HLH and 17 healthy children were enrolled in the study.

X-Linked Lymphoproliferative Syndrome Presenting as Adult-Onset Multi-Infarct Dementia.

Pathogenic hemizygous variants in the SH2D1A gene cause X-linked lymphoproliferative (XLP) syndrome, a rare primary immunodeficiency usually associated with fatal Epstein-Barr virus infection. Disease onset is typically in early childhood, and the average life expectancy of affected males is ∼11 years. We describe clinical, radiographic, neuropathologic, and genetic features of a 49-year-old man presenting with central nervous system vasculitis that was reminiscent of adult primary angiitis but which was unresponsive to treatment.

Epstein-Barr Virus-Associated γδ T-Cell Lymphoproliferative Disorder Associated With Hypomorphic Mutation.

Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is an EBV-associated lymphoproliferative disease characterized by repeated or sustainable infectious mononucleosis (IM)-like symptoms. EBV is usually detected in B cells in patients who have IM or Burkitt's lymphoma and even in patients with X-linked lymphoproliferative syndrome, which is confirmed to have vulnerability to EBV infection. In contrast, EBV infects T cells (CD4 T, CD8 T, and γδT) or NK cells mono- or oligoclonally in CAEBV patients.

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case-based review.

An array of monogenic immune defects marked by autoimmunity, lymphoproliferation, and hyperinflammation rather than infections have been described. Primary immune regulatory disorders pose a challenge to pediatric hematologists and oncologists. This paper focuses on primary immune regulatory disorders including autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like syndromes, immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-like disorders, common variable immunodeficiency (CVID), CVID-like, and late-onset combined immunodeficiency (CID) disorders.

An 18-Year-Old Male With X-linked Lymphoproliferative Syndrome Type 1 Who Developed Primary Central Nervous System Lymphoma 6 Months After Primary Epstein-Barr Virus Infection.

X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare congenital immunodeficiency disease. We report the case of an 18-year-old male who developed hemophagocytic lymphohistiocytosis (HLH) with neurologic complications after primary Epstein-Barr virus (EBV) infection and subsequently developed EBV-related central nervous system lymphoma (CNSL). Given the vulnerability to EBV, he was finally diagnosed with XLP1 and treated with whole-brain irradiation along with chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation from a SH2D1A wild-type sibling donor.

XIAP deficiency in hematopoietic recipient cells drives donor T-cell activation and GvHD in mice.

Patients with X-linked lymphoproliferative syndrome type 2 (XLP-2) (BIRC4 deficiency) suffer from hyperinflammation often observed during the conditioning regimen prior to allogeneic bone marrow transplant. This article shows that in mice hematopoietic recipient cells contribute to graft-versus-host disease by the secretion of elevated levels of proinflammatory cytokines during engraftment when BIRC4 is absent.

Management of XLP-1 and ITK deficiency: The challenges posed by PID with an unpredictable spectrum of disease manifestations.

The incorporation of next generation sequencing into routine immunological practice has enabled the identification of novel inborn errors of disease, helped define new categories of immune deficiency and extended the clinical spectrum associated with many long-recognised diseases. The family of EBV (Epstein Barr Virus)-sensitive primary immune deficiencies is one such group and in this paper we describe three families: two with X-linked lymphoproliferative disease type-1 (XLP-1) and one with deficiency of Interleukin-2 Inducible T-cell Kinase (ITK). Both diseases have a wide range of clinical manifestations and are united by an exquisite predisposition to EBV, dysgammaglobulinemia, hemophagocytic lymphohistiocytosis, and lymphoma.

Hemophagocytic Lymphohistiocytosis: Clinical Presentations and Diagnosis.

Hemophagocytic lymphohistiocytosis (HLH) is an overwhelming clinical syndrome associated with extreme immune activation. Familial HLH is caused by autosomal-recessive inheritance of gene mutations that cripple lymphocyte cytotoxicity. X-linked lymphoproliferative diseases and mutations in Nod-like receptor caspase activation and recruitment domain containing protein 4 (NLRC4) also feature HLH as a predominant manifestation.

Hematopoietic cell transplantation for asymptomatic X-linked lymphoproliferative syndrome type 1.

Background: X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immune deficiency, which is caused by gene mutations. XLP1 is commonly associated with Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and/or lymphoma. The only curative treatment for XLP1 is allogeneic hematopoietic cell transplantation.

2B4 dysfunction in XLP1 NK cells: More than inability to control EBV infection.

X-linked lymphoproliferative disease 1 (XLP1) is a monogenic disorder caused by mutations in SH2D1A, resulting in the absence/dysfunction of the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). Consequently, SLAM receptors as 2B4 (CD244) and NTB-A (SLAMF6), upon ligand engagement, exert inhibitory instead of activating function. This causes an immune dysfunction that is worsened by the selective inability of NK and T cells to kill EBV-infected B cells with dramatic clinical sequelae (e.

Langerhans cell histiocytosis complicated with hemophagocytic lymphohistiocytosis in a boy with a novel XIAP mutation: A case report.

Rationale: X-linked lymphoproliferative syndromes (XLPs) are rare, yet often fatal primary immunodeficiency diseases, which rarely manifest as Langerhans cell histiocytosis (LCH) complicated with hemophagocytic lymphohistiocytosis (HLH). Clinical data of a case of XLP-2 manifesting as LCH complicated with HLH was retrospectively analyzed to determine the etiology and causal gene.

Patient Concerns And Diagnosis: The diagnosis of multisystem LCH was confirmed by skin biopsy and other examinations in a 13-month boy with recurrent ear discharge, fever and hemorrhagic papules for 3 months.

Targeted next-generation sequencing for genetic diagnosis of 160 patients with primary immunodeficiency in south China.

Background: Primary immunodeficiency disorders (PID) is a group of heterogeneous diseases mainly characterized by severe and recurrent infections and an increased susceptibility to lymphoproliferative, atopic, and autoimmune conditions. The clinical diagnosis should preferably be complemented by a genetic diagnosis. To date, PID-related reports from China seldom attempt to make a genetic test for their patients.

Fatal Central Nervous System Lymphocytic Vasculitis after Treatment for Burkitt Lymphoma in a Patient with a SH2D1A Mutation.

Very rarely, patients with X-linked lymphoproliferative syndrome type 1 present central nervous system vasculitis. We report a patient carrying a SH2D1A mutation that, after treatment for lymphoma developed fatal central nervous system vasculitis. He lacked signs of ongoing Epstein-Barr virus infection.

Unique BIR domain sets determine inhibitor of apoptosis protein-driven cell death and NOD2 complex signal specificity.

The mammalian IAPs, X-linked inhibitor of apoptosis protein (XIAP) and cellular inhibitor of apoptosis protein 1 and 2 (cIAP1 and cIAP2), play pivotal roles in innate immune signaling and inflammatory homeostasis, often working in parallel or in conjunction at a signaling complex. IAPs direct both nucleotide-binding oligomerization domain-containing 2 (NOD2) signaling complexes and cell death mechanisms to appropriately regulate inflammation. Although it is known that XIAP is critical for NOD2 signaling and that the loss of cIAP1 and cIAP2 blunts NOD2 activity, it is unclear whether these three highly related proteins can compensate for one another in NOD2 signaling or in mechanisms governing apoptosis or necroptosis.

The Treatment of Inflammatory Bowel Disease in Patients with Selected Primary Immunodeficiencies.

The gastrointestinal tract is heavily populated with innate and adaptive immune cells that have an active role in preservation of mucosal homeostasis and prevention of inflammation. Inflammatory bowel diseases are thought to result from dysregulated immune function that is influenced by genetic background, environmental triggers, and microbiome changes. While most inflammatory bowel disease patients present in adolescent years or adulthood, in a minority of cases, the disease develops early in life, and in some of these young patients, a monogenic disease causing intestinal inflammation can be identified.

Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults.

Background: Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy.

[Rheumatological manifestations in primary immunodeficiency diseases].

Primary immune deficiencies (PIDs) are characterized by quantitative and/or functional abnormalities of the immune system elements. Bone and joint abnormalities are not rare in patients with immunodeficiencies. Joint manifestations, of which arthritis is the most common, occur mainly in humoral PIDs (X-linked agammaglobulinemia, common variable immunodeficiency, and IgA deficiency) and occasionally in defects of the phagocyte system (chronic granulomatous disease, glicogen storage diseases).

Comprehensive molecular diagnosis of Epstein-Barr virus-associated lymphoproliferative diseases using next-generation sequencing.

Epstein-Barr virus (EBV) is associated with several life-threatening diseases, such as lymphoproliferative disease (LPD), particularly in immunocompromised hosts. Some categories of primary immunodeficiency diseases (PIDs) including X-linked lymphoproliferative syndrome (XLP), are characterized by susceptibility and vulnerability to EBV infection. The number of genetically defined PIDs is rapidly increasing, and clinical genetic testing plays an important role in establishing a definitive diagnosis.