Lipopolysaccharide-responsive Beige-like Anchor Deficiency Research Articles

Diagnosis of primary immunodeficiency diseases by flow cytometry: Experience from Bangladesh

Abstract BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and immunologically diverse and require a wide array of clinical and laboratory modalities to make specific diagnosis. Serum immunoglobulin levels and T cell, B cell and NK (Natural killer) cell immunophenotyping are routine laboratory investigations advised to diagnose the PIDD cases in Bangladesh. Along with T-B-NK markers, use of Naïve (CD45RA+) and memory (CD45RO+) T cell, switched memory B cell (CD27+IgD-) markers, detection of intracellular BTK (Bruton’s tyrosine kinase), LRBA (Lipopolysaccharide-responsive beige-like anchor), DOCK8 (Dedicator of cytokinesis 8) protein expression and DHR123 (Dihydro-rhodamine 123) assay of neutrophil can increase the PIDD cases detection in Bangladesh. METHODS: The study was conducted in the Department of Microbiology and Immunology, Bangabandhu Sheikh Mujib Medical University (BSMMU) during the time period of March, 2021 to February, 2022. Seventy clinically suspected PIDD cases were enrolled in this study on the basis of clinical findings and peripheral venous blood was collected from all patients to perform immunophenotyping. Routine T-B-NK cell, naïve and memory T cell with switched memory B cell markers were detected by flow-cytometry. Serum immunoglobulins (IgG, IgM, IgA & IgE) were estimated by Nephelometry and by Chemiluminescence. Intracellular BTK, LRBA and DOCK8 protein expression was detected by flow-cytometry in suspected X-linked agammaglobulinemia (XLA), LRBA and DOCK8 deficiency patients respectively. DHR123 assay was performed in suspected Chronic granulomatous disease (CGD) patients. RESULTS: Among the 70 clinically suspected PIDD cases, 9 (12.9%) were diagnosed as patients of PIDDs on the basis of laboratory evidence. Five (55.55%) cases were diagnosed as predominantly antibody deficiencies (PADs), 3 (33.33%) were patients of combined immunodeficiency (CID) and 1 (11.11%) was CGD patient. Among the diagnosed PIDD cases, 2 (22.22%) were diagnosed by T-B-NK cell immunophenotyping with serum immunoglobulin levels and 7 (77.77%) cases were diagnosed by additional CD45RA+, CD45RO+, CD27+IgD- markers, BTK protein expression detection and DHR123 assay. LRBA and DOCK8 deficiency cases could not found in this study. CONCLUSION: The use of additional markers (CD45RA+, CD45RO+, CD27+IgD-) with BTK, LRBA, DOCK8 intracellular protein expression evaluation and DHR123 assay by flow-cytometry can increase rate of specific diagnosis of the PIDD cases in Bangladeshi paediatric population.

Therapeutic modalities and clinical outcomes in a large cohort with LRBA deficiency and CTLA4 insufficiency

LPS-responsive beige-like anchor (LRBA) deficiency (LRBA-/-) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) insufficiency (CTLA4+/-) are mechanistically overlapped diseases presenting with recurrent infections and autoimmunity. The effectiveness of different treatment regimens remains unknown. Our aim was to determine the comparative efficacy and long-term outcome of therapy with immunosuppressants, CTLA4-immunoglobulin (abatacept), and hematopoietic stem cell transplantation (HSCT) in a single-country multicenter cohort of 98 patients with a 5-year median follow-up. The 98 patients (63 LRBA-/- and 35 CTLA4+/-) were followed and evaluated at baseline and every 6 months for clinical manifestations and response to the respective therapies. The LRBA-/- patients exhibited a more severe disease course than did the CTLA4+/- patients, requiring more immunosuppressants, abatacept, and HSCT to control their symptoms. Among the 58 patients who received abatacept as either a primary or rescue therapy, sustained complete control was achieved in 46 (79.3%) without severe side effects. In contrast, most patients who received immunosuppressants as primary therapy (n= 61) showed either partial or no disease control (72.1%), necessitating additional immunosuppressants, abatacept, or transplantation. Patients with partial or no response to abatacept (n= 12) had longer disease activity before abatacept therapy, with higher organ involvement and poorer disease outcomes than those with a complete response. HSCT was performed in 14 LRBA-/- patients; 9 patients (64.2%) showed complete remission, and 3 (21.3%) continued to receive immunosuppressants after transplantation. HSCT and abatacept therapy gave rise to similar probabilities of survival. Abatacept is superior to immunosuppressants in controlling disease manifestations over the long term, especially when started early, and it may provide a safe and effective therapeutic alternative to transplantation.

Identification of novel compound heterozygous LRBA mutations associated with recurrent hemophagocytic lymphohistiocytosis and CNS manifestations

Background: Lipopolysaccharide-responsive beige-like anchor (LRBA) is an intracellular protein that regulates the recycling of cytotoxic T lymphocyte-associated protein 4 (CTLA4), an immune checkpoint molecule which prevents ongoing activation of T cells. Deficiency of LRBA results in increased trafficking and degradation of CTLA4, and consequently, uncontrolled T cell responses. The phenotypic spectrum of LRBA deficiency arising from biallelic loss-of-function typically includes recurrent infections, autoimmunity, lymphoproliferation, chronic diarrhea, hypogammaglobulinemia, and cytopenia. Aim: To report an atypical presentation of LRBA deficiency arising from a set of compound heterozygous LRBA variants, encompassing recurrent hemophagocytic lymphocytosis (HLH) and neurological manifestations. Methods: Clinical data was gathered through retrospective chart review. Expanded genetic analysis including whole exome sequencing was performed. Results: Our patient initially presented at age 15 months with fever, seizures, and encephalopathy. HLH-work-up showed bicytopenia, elevated ferritin and triglyceride, and low fibrinogen, however, he did not yet meet the diagnostic criteria for HLH. MRI brain and EEG at diagnosis was suggestive of acute necrotizing encephalopathy of childhood. He responded to pulsed IV methylprednisolone treatment with minimal residual neurological deficit on follow-up. At 36 months of age, he had a repeat presentation and rapidly deteriorated. He developed severe encephalopathy with fixed dilated pupils. Whole exome sequencing revealed a set of compound heterozygous missense variants in the LRBA gene, a novel c.2206A>T (p.R736W) and c.5989C>T (p.R1997C) variant. Conclusion: Compound heterozygous mutations in the LRBA gene caused an atypical presentation of recurrent HLH with central nervous system (CNS) manifestations in our patient. Statement of Novelty: We herein report a novel set of compound heterozygous mutations in LRBA with atypical presentation of recurrent HLH with CNS manifestations, thus expanding the known phenotypic spectrum of LRBA deficiency.

AN ATYPICAL PRESENTATION OF LIPOPOLYSACCHARIDE-RESPONSIVE BEIGE-LIKE ANCHOR PROTEIN DEFICIENCY

<h3>Introduction</h3> Lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency is associated with diarrhea, autoimmune disorders, organomegaly, recurrent infections, hypogammaglobulinemia, chronic lung manifestations, and growth retardation. However, LRBA mutations show a wide range of phenotypic variability. We present a case of a sixteen-year-old girl with a variant of uncertain significance (VUS) in the LRBA gene with atypical symptoms of LRBA deficiency. <h3>Case Description</h3> The patient is a sixteen-year-old female with type one diabetes mellitus, chronic urticaria, and idiopathic anaphylaxis requiring admission. Her complete blood count with differential, B and T cell phenotyping, and immunoglobulin levels were normal. She failed high dose antihistamines and omalizumab. Due to atypical symptoms, including soft tissue swelling, joint pains, recurrent abdominal pain, and elevated interleukin 10, interleukin 6, and S100 during an episode, we obtained an auto-inflammatory panel that showed a heterozygous VUS mutation in the LRBA gene. Parental LRBA testing showed the variants were trans-acting, increasing the likelihood that the variants contribute to her phenotype. She was started on abatacept with hydroxychloroquine, which improved her symptoms. <h3>Discussion</h3> This case highlights an atypical presentation of LRBA deficiency presenting with chronic urticaria and idiopathic anaphylaxis with a normal immune work up, symptoms of which are responsive to abatacept and hydroxychloroquine.

Joint Involvement in Patients with LPS-Responsive and Beige-Like Anchor Protein (LRBA) Deficiency: A Case Report and Literature Review

Background: Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is an inborn error of immunity characterized by a heterogeneous spectrum of manifestations, including enteropathy, immune dysregulation, and autoimmune disorder. Joint involvement has been less frequently reported, and limited data regarding its clinical presentation in LRBA deficiency has been published.&#x0D; Case presentation and review results: We reported an Iranian girl who was initially presented with recurrent respiratory tract infections and otitis media, later complicated by arthritis, growth failure, and organomegaly. The diagnosis of LRBA deficiency was confirmed by the identification of a novel homozygous missense variant in the LRBA gene (c.7742T&gt;A, p.M2581K). Along with this report, a literature review focused on joint involvement, on 26 patients with LRBA deficiency was performed.&#x0D; Conclusion: Non-infectious manifestations such as joint involvement have a broad spectrum in LRBA deficiency. For the timely diagnosis and appropriate clinical management, LRBA deficiency should always be kept in mind as a differential diagnosis in patients with joint involvement and clinically typical immune dysregulation.

Comprehensive comparison between 222 CTLA-4 haploinsufficiency and 212 LRBA deficiency patients: a systematic review

Cytotoxic T lymphocyte antigen 4 (CTLA-4) haploinsufficiency (CHAI) and lipopolysaccharide-responsivebeige-like anchor (LRBA) deficiency (LATAIE) are newly identified inborn errors of immunity with shared molecular pathomechanisms and clinical manifestations. In this review, we aimed to provide differential comparisons regarding demographic, clinical, immunological and molecular characteristics between these two similar conditions. A literature search was conducted in PubMed, Web of Science and Scopus databases and included studies were systematically evaluated. Overall, 434 (222 CHAI and 212 LATAIE) patients were found in 101 eligible studies. The CHAI patients were mainly reported from North America and western Europe, while LATAIE patients were predominantly from Asian countries. In CHAI, positive familial history (P<0·001) and in LATAIE, consanguineous parents (P<0·001) were more common. In CHAI patients the rates of granulomas (P<0·001), malignancies (P=0·001), atopy (P=0·001), cutaneous disorders (P<0·001) and neurological (P=0·002) disorders were higher, while LATAIE patients were more commonly complicated with life-threatening infections (P=0·002), pneumonia (P=0·006), ear, nose and throat disorders (P<0·001), organomegaly (P=0·023), autoimmune enteropathy (P=0·038) and growth failure (P<0·001). Normal lymphocyte subsets and immunoglobulins except low serum levels of CD9+ B cells (14·0 versus 38·4%, P<0·001), natural killer (NK) cells (21 versus 41·1%, P<0·001), immunoglobulin (Ig)G (46·9 versus 41·1%, P=0·291) and IgA (54·5 versus 44·7%, P=0·076) were found in the majority of CHAI and LATAIE patients, respectively. The most frequent biological immunosuppressive agents prescribed for CHAI and LATAIE patients were rituximab and abatacept, respectively. Further investigations into the best conditioning and treatment regimens pre- and post-transplantation are required to improve the survival rate of transplanted CHAI and LATAIE patients.

Unusual Late-onset Enteropathy in a Patient With Lipopolysaccharide-responsive Beige-like Anchor Protein Deficiency

In recent years, monogenic causes of immune dysregulation syndromes, with variable phenotypes, have been documented. Mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) protein are associated with common variable immunodeficiency, autoimmunity, chronic enteropathy, and immune dysregulation disorders. The LRBA protein prevents degradation of cytotoxic T-lymphocyte antigen 4 (CTLA4) protein, thus inhibiting immune responses. Both LRBA and CTLA4 deficiencies usually present with immune dysregulation, mostly characterized by autoimmunity and lymphoproliferation. In this report, we describe a patient with an atypical clinical onset of LRBA deficiency and the patient's response to abatacept, a fusion protein-drug that mimics the action of CTLA4.

A Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects.

Autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management. Fifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES). The median age on admission and age of diagnosis were 7years (0.3-16.5) and 11years (5-44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαβ+CD4-CD8-) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2years (1-3). In total, one patient died from sepsis during adulthood before HSCT. Patients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell's important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.

Recessively Inherited LRBA Mutations Cause Autoimmunity Presenting as Neonatal Diabetes

Biallelic mutations in the human lipopolysaccharide responsive beige-like anchor (LRBA) gene lead to a primary immunodeficiency known as LRBA deficiency, characterized early-onset hypogammaglobulinemia, severe autoimmune manifestations, enteropathy, lymphoproliferation, and recurrent respiratory tract infections. Neonatal diabetes mellitus (NDM) has not been previously described in patients with LRBA mutations. In this study, the proband was diagnosed at 7 weeks of age with diabetes and additional autoimmunity and 3 other patients presented before 6 months of age. The other patients had diabetes onset between 6 and 12 months. Only 1 patient was positive for GAD antibody of those that were tested. However these patients had other autoimmune conditions including hematological manifestations, autoimmune enteropathy, and hypothyroidism. Identifying the underlying genetic etiology is clinically important for these patients as understanding the disease mechanism may allow the use of personalized therapy.

Respiratory manifestations in LPS-responsive beige-like anchor (LRBA) protein-deficient patients.

Pulmonary manifestations are common in LRBA deficiency. Respiratory characteristics in LRBA-deficient patients should be investigated, monitored, and treated from the time of diagnosis. What is Known: • Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is a syndrome of primary immune deficiency and immune dysregulation. • Studies concerning the pulmonary characteristics of LRBA-deficient patients are lacking. What is New: • Respiratory manifestations include infections, bronchiectasis, interstitial lung disease, thoracic lymphadenopathy, and clubbing. • Awareness to pulmonary morbidity in LRBA-deficient patients and involvement of a pulmonologist in the workup and clinical decision-making is important. • Respiratory characteristics in LRBA-deficient patients should be investigated, monitored, and treated from a young age.

Rapid Flow Cytometry-Based Test for the Diagnosis of Lipopolysaccharide Responsive Beige-Like Anchor (LRBA) Deficiency.

The diagnosis of lipopolysaccharide-responsive beige-like-anchor-protein (LRBA) deficiency currently relies on gene sequencing approaches that do not support a timely diagnosis and clinical management. We developed a rapid and sensitive test for clinical implementation based on the detection of LRBA protein by flow cytometry in peripheral blood cells after stimulation. LRBA protein was assessed in a prospective cohort of 54 healthy donors and 57 patients suspected of LRBA deficiency. Receiver operating characteristics analysis suggested an LRBA:MFI ratio cutoff point of 2.6 to identify LRBA-deficient patients by FACS with 94% sensitivity and 80% specificity and to discriminate them from patients with a similar clinical picture but other disease-causing mutations. This easy flow cytometry-based assay allows a fast screening of patients with suspicion of LRBA deficiency reducing therefore the number of patients requiring LRBA sequencing and accelerating the treatment implementation. Detection of biallelic mutations in LRBA is however required for a definitive diagnosis.

Precision medicine in the treatment of primary immunodeficiency diseases.

Since the 1990s with the advances in molecular biology, a number of genetic defects have been described. The International Union of Immunological Sciences has recently updated the classification of genetic defects associated with primary immune deficiencies that now number 354. With the ever-expanding list of new monogenic disorders and a better understanding of the immunobiology and function of these defective genes, new therapies have emerged particularly aimed at the autoimmune and inflammatory conditions that plague these patients. Immune deficiencies associated with gain-of-function (GOF) mutations are a potential category for targeted therapies to control the GOF activities of the mutated gene. In addition to the increased susceptibility to infections these patients have autoimmune and inflammatory diseases that are difficult to control with conventional therapies. The dysregulated immune functions of the activated phospholipase-3-kinase δ syndrome, cytotoxic T lymphocyte-associated antigen-4 haploinsufficiency, lipopolysaccharide-responsive beige-like anchor deficiency, the GOF mutations of signal transducer and activator of transcription 1 and 3 immune deficiencies will be reviewed. The targeted therapies for each of these immune deficiencies using small molecule kinase inhibitors and fusion protein biologic modifiers will be described. In this review, we explore the recent advances in precision medicine treatment of several primary immunodeficiency syndromes in which immune dysregulation is a key feature. Understanding the immunobiology associated with these GOF mutations has led to the use of biologic therapies to better control the associated autoimmune and inflammatory manifestations.

LRBA Eksikliği Tanısında Akan Hücre Ölçerde Protein İfadesi

Objective: Lipopolysaccharide-responsive beige-like anchor (LRBA) plays a role in cell surface expression of inhibitory cytotoxic T lymphocyte-associated protein-4 (CTLA-4) protein. Recently identified LRBA deficiency leads to immune deficiency and autoimmunity and is diagnosed by mutation analyses and protein expression. Herein, we quantified stimulated and unstimulated intracellular LRBA protein expression by flow cytometry in LRBA deficiency patients.Materials and Methods: Five LRBA deficient patients and seven healthy controls were evaluated. The LRBA expressions were assessed in peripheral-blood-mononuclear-cells in the presence or absence of phorbol-miristat-acetate and ionomycin stimulation. The difference in mean-fluorescence-intensity (ΔMFI) was calculated.Results: The differences in mean-fluorescence-intensity values of LRBA by flow cytometry were 24±9 for the healthy controls and 4.8±2.8 for the patients. ΔMFIs were 20.8 for P3, 19 for P4 and 49.6 for healthy controls with stimulants and 4.8, 4.6 and 20.1 respectively without stimulants.Conclusion: As a rapid and widely available assay, flow cytometric assessment of intracellular LRBA expression has been found to be an effective and reliable method in the identification of LRBA deficiency.

Murine LRBA deficiency causes CTLA-4 deficiency in Tregs without progression to immune dysregulation.

Inherited mutations in lipopolysaccharide-responsive beige-like anchor (LRBA) cause a recessive human immune dysregulation syndrome with memory B-cell and antibody deficiency (common variable immunodeficiency), inflammatory bowel disease, enlarged spleen and lymph nodes, accumulation of activated T cells and multiple autoimmune diseases. To understand the pathogenesis of the syndrome, C57BL/6 mice carrying a homozygous truncating mutation in Lrba were produced using CRISPR/Cas9-mediated gene targeting. These mice revealed that LRBA has a critical, cell-autonomous role in promoting cytotoxic T-lymphocyte antigen-4 (CTLA-4) accumulation within CD4 effector T cells and FOXP3+ T-regulatory cells (Tregs). In young mice, or in chimeric mice where only half of the T cells are LRBA deficient, low CTLA-4 was the only detectable abnormality in Tregs, whereas in old mice FOXP3 was also decreased. Low CTLA-4 did not translate into increased CD86 on B cells unless the LRBA-deficient mice were immunised, and neither immunisation nor chronic lymphocytic choriomeningitis virus infection precipitated immune dysregulation. LRBA deficiency did not alter antigen-specific B-cell activation, germinal centre (GC) formation, isotype switching or affinity maturation. Paradoxically, CD86 was decreased on GC B cells in LRBA-deficient mice, pointing to compensatory mechanisms for controlling CD86 in the face of low CTLA-4. These results add to the experimental rationale for treating LRBA deficiency with the CTLA4-Ig fusion protein, Abatacept, and pose questions about the limitations of laboratory experiments in mice to reproduce human disease in natura.

Immunological phenotype of the murine Lrba knockout.

Biallelic mutations in the human lipopolysaccharide responsive beige-like anchor (LRBA) gene lead to a primary immunodeficiency known as LRBA deficiency, characterized by a broad range of clinical manifestations including autoimmunity, organomegaly, hypogammaglobulinemia and recurrent infections. Considering the phenotypic heterogeneity in patients and the severity of the disease, our aim was to assess the role of LRBA in immune cells and to understand the underlying pathomechanisms through the study of a Lrba knockout (Lrba-/-) mouse model. LRBA-deficient mice did not show severe clinical or immunological signs of disease, either at steady state under specific-pathogen-free conditions, after vaccination with T-dependent and T-independent antigens, or in the context of acute infections with lymphocytic choriomeningitis virus (LCMV) or Salmonella Typhimurium. Although Lrba-/- mice were able to produce normal serum immunoglobulin M (IgM) and IgG and to mount a specific immune response after immunization, they showed elevated serum and secretory basal IgA levels. LRBA was dispensable for B- and T-cell development, as well as for in vitro B-cell proliferation, survival, isotype switching and plasmablast differentiation. Interestingly, Lrba-/- mice displayed decreased cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) expression by regulatory T cells and activated conventional CD4+ and CD8+ T lymphocytes, reduced frequency of peritoneal B-1a cells along with diminished interleukin-10 production and increased percentages of T follicular helper cells in Peyer's patches, but without developing overt signs of autoimmunity. Our findings expand the role of LRBA in immune regulatory mechanisms previously reported in patients, and suggest a novel role in IgA production that is crucial for the protection of mucosal surfaces and gut-associated immune tolerance.

Treatment of Infantile Inflammatory Bowel Disease and Autoimmunity by Allogeneic Stem Cell Transplantation in LPS-Responsive Beige-Like Anchor Deficiency.

Inflammatory bowel disease (IBD) in young children can be a clinical manifestation of various primary immunodeficiency syndromes. Poor clinical outcome is associated with poor quality of life and high morbidity from the complications of prolonged immunosuppressive treatment and malabsorption. In 2012, mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene were identified as the cause of an autoimmunity and immunodeficiency syndrome. Since then, several LRBA-deficient patients have been reported with a broad spectrum of clinical manifestations without reliable predictive prognostic markers. Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been performed in a few severely affected patients with complete or partial response. Herein, we present a detailed course of the disease and the transplantation procedure used in a LRBA-deficient patient suffering primarily from infantile IBD with immune enteropathy since the age of 6 weeks, and progressive autoimmunity with major complications following long-term immunosuppressive treatment. At 12 years of age, alloHSCT using bone marrow of a fully matched sibling donor—a healthy heterozygous LRBA mutant carrier—was performed after conditioning with a reduced-intensity regimen. During the 6-year follow-up, we observed a complete remission of enteropathy, autoimmunity, and skin vitiligo, with complete donor chimerism. The genetic diagnosis of LRBA deficiency was made post-alloHSCT by detection of two compound heterozygous mutations, using targeted sequencing of DNA samples extracted from peripheral blood before the transplantation.

Infancy-Onset T1DM, Short Stature, and Severe Immunodysregulation in Two Siblings With a Homozygous LRBA Mutation.

Type 1 diabetes mellitus (T1DM) is caused by autoimmunity against pancreatic β-cells. Although a significant number of T1DM patients have or will develop further autoimmune disorders during their lifetime, coexisting severe immunodysregulation is rare. Presuming autosomal-recessive inheritance in a complex immunodysregulation disorder including T1DM and short stature in two siblings, we performed whole-exome sequencing. Two Libyan siblings born to consanguineous parents were presented to our diabetology department at ages 12 and 5 years, respectively. Apart from T1DM diagnosed at age 2 years, patient 1 suffered from chronic restrictive lung disease, mild enteropathy, hypogammaglobulinemia, and GH deficiency. Fluorescence-activated cell sorting analysis revealed B-cell deficiency. In addition, CD4(+)/CD25(+) and CD25(high)/FoxP3(+) cells were diminished, whereas an unusual CD25(-)/FoxP3(+) population was detectable. The younger brother, patient 2, also developed T1DM during infancy. Although his enteropathy was more severe and electrolyte derangements repeatedly led to hospitalization, he did not have significant pulmonary problems. IgG levels and B-lymphocytes were within normal ranges. By whole-exome sequencing we identified a homozygous truncating mutation (c.2445_2447del(C)3ins(C)2, p.P816Lfs*4) in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene in both siblings. The diagnosis of LRBA deficiency was confirmed by a fluorescence-activated cell sorting-based immunoassay showing the absence of LRBA protein in phytohemagglutinin-stimulated peripheral blood mononuclear cells. We identified a novel truncating LRBA mutation in two siblings with T1DM, short stature, and severe immunodysregulation. LRBA mutations have previously been reported to cause multiorgan autoimmunity and immunodysfunction. In light of the variable phenotypes reported so far in LRBA-mutant individuals, LRBA deficiency should be considered in all patients presenting with T1DM and signs of severe immunodysregulation.

Lipopolysaccharide-Responsive Beige-like Anchor Is Required for Both Activation and Deactivation of NFkB

The molecular mechanisms why mutations of the lipopolysaccharide-responsive beige-like anchor (LRBA) paradoxically cause both autoimmunity and common variable immunodeficiency (CVID) are unknown. LRBA regulates vesicle trafficking and signal transduction required for the regulation and function of many immune molecules. It is hypothesized that LRBA deficiency attenuates both activation and deactivation of nuclear factor kappa beta (NFkB) resulting in immunodeficiency and autoimmunity.

Common variable immunodeficiency (CVID): new genetic insight and unanswered questions.

Common variable immunodeficiency (CVID): new genetic insight and unanswered questions.

LRBA Causes Immunodeficiency and Autoimmunity By Deregulating NFkB-Mediated Multiple Immune Effectors Critical For B Cell Activation

The absence of lipopolysaccharide-responsive beige-like anchor (LRBA) gene causes common variable immunodeficiency (CVID), autoimmunity and chronic inflammation. It is the only CVID gene that regulates vesicle trafficking and signal transduction, required for the regulation and function of many immune molecules. It is hypothesized that LRBA deficiency causes these medical conditions by deregulating NFkB-mediated multiple immune effectors critical for B cell activation.