Primary immunodeficiencies associated with eosinophilia.

Background: Eosinophilia is not an uncommon clinical finding. However, diagnosis of its cause can be a dilemma once common culprits, namely infection, allergy and reactive causes are excluded. Primary immunodeficiency disorders (PID) are among known differentials of eosinophilia.

[X-linked lymphoproliferative syndrome type 1 complicated with secondary hemophagocytic lymphohistiocytosis and ileal perforation: case report and literature review].

Objective: To analyze and summarize the clinical characteristics, laboratory tests and treatment of X-linked lymphoproliferative syndrome type 1 (XLP-1).

Method: A retrospective study was done in 2012 on an XLP-1 patient to collect the data on clinical manifestation, laboratory examination, gene and protein expression, complications and prognosis. Literatures were reviewed in Pubmed with the key word"X-linked lymphoproliferative syndrome".

Hematopoietic Stem Cell Transplant for Primary Immunodeficiency Diseases: A Single-Center Experience.

Objectives: The only curative treatment for many patients with primary immunodeficiency disease is hematopoietic stem cell transplant. In this study, we report the transplant outcomes of patients with primary immunodeficiency diseases.

Materials And Methods: Herein, we present the transplant outcomes of 20 patients with primary immunodeficiency disease seen at our center in Kayseri, Turkey, from 2010 to 2015.

Poor growth, thyroid dysfunction and vitamin D deficiency remain prevalent despite reduced intensity chemotherapy for hematopoietic stem cell transplantation in children and young adults.

Myeloablative conditioning regimens for hematopoietic stem cell transplant (HSCT) are known to affect endocrine function, but little is known regarding reduced intensity conditioning (RIC) regimens. We retrospectively reviewed 114 children and young adults after single RIC HSCT. The analysis was grouped by age (<2 and ⩾2 years) and diagnosis (hemophagocytic lymphohistiocystosis/X-linked lymphoproliferative syndrome (HLH/XLP), other immune disorders, metabolic/genetic disorders).

Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome.

Loss of CD40 ligand (CD40L) expression or function results in X-linked hyper-immunoglobulin (Ig)M syndrome (X-HIGM), characterized by recurrent infections due to impaired immunoglobulin class-switching and somatic hypermutation. Previous attempts using retroviral gene transfer to correct murine CD40L expression restored immune function; however, treated mice developed lymphoproliferative disease, likely due to viral-promoter-dependent constitutive CD40L expression. These observations highlight the importance of preserving endogenous gene regulation in order to safely correct this disorder.

Intact Regulatory T-Cell Function but Defective Generation of IL-17A-Producing CD4+ T Cells in XIAP Deficiency.

Objective: X-linked inhibitor of apoptosis (xIAP) deficiency is a primary immune deficiency disorder associated with hemophagocytic lymphohistiocytosis. About 17% of xIAP-deficient patients present with very early onset severe colitis with high mortality. We hypothesized that xIAP deficiency leads to defective generation and/or survival of T regulatory cells (Treg) through its involvement in transforming growth factor-β signaling.

The diagnostic challenge of very early-onset enterocolitis in an infant with XIAP deficiency.

Background: Aggressive course and resistance to treatments usually characterize very early onset inflammatory bowel disease (VEO-IBD). Some VEO-IBD cases are due to monogenic immune defects and can benefit from hematopoietic stem cell transplantation (HSCT).

Case Presentation: We describe a Caucasian male baby who presented in the first months of life macrophage activation syndrome, followed by intractable colitis, recurrent episodes of fever and mild splenomegaly.

A de novo whole gene deletion of XIAP detected by exome sequencing analysis in very early onset inflammatory bowel disease: a case report.

Background: Children with very early-onset inflammatory bowel disease (VEO-IBD), those diagnosed at less than 5 years of age, are a unique population. A subset of these patients present with a distinct phenotype and more severe disease than older children and adults. Host genetics is thought to play a more prominent role in this young population, and monogenic defects in genes related to primary immunodeficiencies are responsible for the disease in a small subset of patients with VEO-IBD.

BIRC4 Mutation: An Important Rare Cause of Uveitis.

We report a 6-year-old man with chronic severe recalcitrant bilateral anterior uveitis and a remote history of hemophagocytic lymphocytic histiocytosis secondary to Epstein-Barr virus infection. The patient was treated for idiopathic uveitis after an initial extensive evaluation failed to reveal a specific diagnosis. The patient failed to achieve sustained inactive disease with multiple monotherapies including topical glucocorticoid, methotrexate, infliximab, mycophenolate mofeti, and cyclosporine.

The autoimmune conundrum in common variable immunodeficiency disorders.

Purpose Of Review: Autoimmune and inflammatory manifestations are the biggest clinical challenge in the care of patients with common variable immunodeficiency (CVID). The increasing pathogenic knowledge and potential therapeutic implications require a new evaluation of the status quo. (Figure is included in full-text article.

Cerebral Vasculitis in X-linked Lymphoproliferative Disease Cured by Matched Unrelated Cord Blood Transplant.

Unlabelled: Vasculitis occurs rarely in association with X-linked lymphoproliferative disease (XLP). There are four published cases of non-EBV XLP-associated cerebral vasculitis reported, none of whom have survived without major cognitive impairment.

Case: A 9-year old boy initially presented aged 5 years with a restrictive joint disease.

Successful Allogeneic Hematopoietic Stem Cell Transplantation in XIAP Deficiency Using Reduced-Intensity Conditioning.

Hematopoietic stem cell transplantation (HSCT) is currently the only available curative therapy for X-linked inhibitor of apoptosis (XIAP) deficiency. Myeloablative conditioning regimens are associated with high mortality rates. Reduced-intensity conditioning (RIC) is recommended in order to decrease treatment-related toxicities, but RIC regimens increase the risk for mixed donor-recipient chimerism that may progress to graft loss.

Human Immunodeficiencies Related to Defective APC/T Cell Interaction.

The primary event for initiating adaptive immune responses is the encounter between T lymphocytes and antigen presenting cells (APCs) in the T cell area of secondary lymphoid organs and the formation of highly organized intercellular junctions referred to as immune synapses (IS). In vivo live-cell imaging of APC-T cell interactions combined to functional studies unveiled that T cell fate is dictated, in large part, by the stability of the initial contact. Immune cell interaction is equally important during delivery of T cell help to B cells and for the killing of target cells by cytotoxic T cells and NK cells.

Autoimmunity and Immune Dysregulation in Primary Immune Deficiency Disorders.

Primary immune deficiencies are often associated with autoimmune disease due to the dysregulation of the immune system as a whole. In many immune deficiencies, lymphocytes may be present but dysfunctional, allowing for the development of excessive autoreactivity and resultant autoimmune disease. Autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy, autoimmune lymphoproliferative syndrome, immunodyregulation polyendocrinopathy enteropathy X-linked, IL-10/IL-10 receptor deficiencies, and PLCG2-associated antibody deficiency and immune dysregulation are disorders in which autoimmunity is a hallmark of the clinical disease presentation.

Eosinophilia Associated with Disorders of Immune Deficiency or Immune Dysregulation.

Increased serum eosinophil levels have been associated with multiple disorders of immune deficiency or immune dysregulation. Although primary immunodeficiency diseases are rare, it is important to consider these in the differential diagnosis of patients with eosinophilia. In this review, the clinical features, laboratory findings, diagnosis, and genetic basis of disease of several disorders of immune deficiency or dysregulation are discussed.

Dysgammaglobulinemia Associated With Glu349del, a Hypomorphic XIAP Mutation.

Background: X-linked lymphoproliferative syndrome type 2 is a rare hereditary immunodeficiency caused by mutations in the XIAP gene. This immunodeficiency frequently results in hemophagocytic lymphohistiocytosis, although hypogammaglobulinemia and dysgammaglobulinemia are also common.

Objective: We identified 17 patients from 12 Japanese families with mutations in XIAP.

The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis.

Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis.

Symptomatic males and female carriers in a large Caucasian kindred with XIAP deficiency.

Purpose: X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was originally described in male patients with X-linked lymphoproliferative syndrome type 2 (XLP2). Recent observations have highlighted a critical role of XIAP for the regulation of NOD2 signaling and are probably the molecular basis for increasingly recognized further immune dysregulatory symptoms of XIAP deficient patients, such as inflammatory bowel disease (IBD). We describe a large Caucasian family in which IBD and erythema nodosum (EN) also manifested in female carriers of XIAP mutations.

X-linked inhibitor of apoptosis protein deficiency: more than an X-linked lymphoproliferative syndrome.

X-linked inhibitor of apoptosis (XIAP) deficiency (also known as X-linked lymphoproliferative syndrome type 2, XLP-2) is a rare primary immunodeficiency. Since the disease was first described in 2006, more than 70 patients suffering from XIAP-deficiency have been reported, thus extending the clinical presentations of the disease. The main clinical features of XLP-2 are (i) elevated susceptibility to hemophagocytic lymphohistiocytosis (HLH, frequently in response to infection with Epstein-Barr virus (EBV)), (ii) recurrent splenomegaly and (iii) inflammatory bowel disease (IBD) with the characteristics of Crohn's disease.

The immunology of Epstein-Barr virus-induced disease.

Epstein-Barr virus (EBV) is usually acquired silently early in life and carried thereafter as an asymptomatic infection of the B lymphoid system. However, many circumstances disturb the delicate EBV-host balance and cause the virus to display its pathogenic potential. Thus, primary infection in adolescence can manifest as infectious mononucleosis (IM), as a fatal illness that magnifies the immunopathology of IM in boys with the X-linked lymphoproliferative disease trait, and as a chronic active disease leading to life-threatening hemophagocytosis in rare cases of T or natural killer (NK) cell infection.

XIAP deficiency syndrome in humans.

The X-linked inhibitor of apoptosis (XIAP) deficiency, also known as the X-linked lymphoproliferative syndrome type 2 (XLP-2), is a rare primary immunodeficiency. XIAP deficiency is characterized by a key triad of clinical manisfestations, which consist of a high susceptibility to develop hemophagocytic lymphohistiocytosis (HLH) frequently triggered by Epstein-Barr virus (EBV) infection, recurrent splenomegaly and inflammatory bowel disease (IBD) with the features of a Crohn's disease. XIAP deficiency can be considered as one of the genetic causes for inherited IBD.

Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden.

Background: Primary hemophagocytic lymphohistiocytosis (HLH) represents a group of inherited hyperinflammatory immunodeficiencies, including familial HLH (FHL), Griscelli syndrome type 2 (GS2), and X-linked lymphoproliferative syndrome (XLP). We previously reported an annual incidence of suspected primary HLH in Sweden 1971-1986 of 0.12 per 100,000 children.

Successful treatment of idiopathic colitis related to XIAP deficiency with allo-HSCT using reduced-intensity conditioning.

Recently, it has been reported that Crohn's-like intractable colitis occurred in approximately 20% of the patients with XIAP deficiency, also known as X-linked lymphoproliferative disease type 2. Because treatment used for Crohn's disease is not always effective for Crohn's-like colitis related to XIAP deficiency, more effective treatment should be established. Although several studies reported allo-HSCT might be promising even for Crohn's-like colitis related to XIAP deficiency, the outcome of allo-HSCT using MAC for XIAP deficiency is extremely poor due to frequent TRM.