antibodies

2026-06-24 | Recurrent and unusual infections unmasking a rare inborn error of immunity: a case report RAS-associated Autoimmune Lymphoproliferative Disease (RALD).

RAS-associated Autoimmune Lymphoproliferative Disease (RALD) is a rare, non-malignant lymphoproliferative disorder caused by somatic mutations in RAS genes that impair lymphocyte apoptosis. Patients often present with features of lymphoproliferation, autoimmune manifestations, and an increased risk of malignant transformation. We report the case of a 3-year-old boy with splenic microabscesses and Burkholderia pseudomallei IgM serology positivity, who was treated as melioidosis. He had recurrent respiratory infections and chronic rhinorrhoea since the age of one year. Clinical examination revealed persistent lymphadenopathy and hepatosplenomegaly. Laboratory investigations demonstrated persistent absolute monocytosis and thrombocytopenia, while immunological evaluation showed elevated IgM levels and B-cell lymphocytosis. Whole exome sequencing identified a heterozygous pathogenic variant in NRAS, NM_002524.5:c.35G > C, NP_002515.1:p.Gly12Ala, establishing the diagnosis of RALD. The patient was subsequently started on antibiotic prophylaxis and immunoglobulin replacement therapy, and his family was counseled regarding the potential role of immunosuppressive therapy and hematopoietic stem cell transplantation (HSCT) in future management. This case highlights the coexistence of an unusual infection with a rare inborn error of immunity, expanding the recognized infectious spectrum of RALD. It underscores the importance of considering RALD in patients presenting with recurrent or atypical infections and persistent lymphoproliferative features. Early recognition and molecular genetic testing are essential for confirming the diagnosis and guiding individualized management.

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2025-12-22 | First Steps with Facilitated Subcutaneous Immunoglobulin (fSCIg) Therapy: A Single Center Experience

Introduction Several studies have shown that facilitated subcutaneous immunoglobulin (fSCIg) is as good as intravenous (IVIg) and conventional subcutaneous immunoglobulin (cSCIg) preventing infections in innate errors of immunity (IEIs). Presentation The objective is to describe the follow-up of 29 patients with fSCIg treatment in the last 3 years in a single center in Argentina (April 2022 – June 2025). 29 patients (p) were included who diagnosed with (15p) common variable immunodeficiency, (5p) specific antibody deficiency with normal Ig levels and normal B cells, (2p) hypogammaglobulinemia and specific antibody deficiency, (2p) primary hypogammaglobulinemia, (1p) x-linked agammaglobulinemia, (1p) specific antibody deficiency with IgA deficiency, (1p) specific antibody deficiency and familial Mediterranean fever, (1p) LRBA deficiency, and (1p) autoimmune lymphoproliferative syndrome and IgA deficiency. Mean time of follow-up with fSCIg was 20 months [1.1 – 38.6]. Mean dose was 560 mg/kg/month [345 – 1,360]. 76% received fSCIg every 4 weeks, the others more frequently. Mean serum IgG level was 1,274 mg/dl [range 615 – 3,014]. Annual rate of infection was 0.27 infections/year of follow-up. 8/29p suffered 13 cases of bacterial infections: 3 pneumonia, 3 bronchitis, 2 acute media otitis, 1 giardiasis, 1 adenitis, 1 bacterial parotitis, 1 pharyngitis, and 1 tracheitis. One patient with low adherence to treatment required two hospitalizations (pneumonia, adenitis). Tolerance 9p (31%) reported local symptoms: erythema (5p), swelling (4p), pain (2p), and pruritus (2p); most of them lasted less than 24 hours; only 3p reported erythema (1p) and swelling (2p) of 4-5 days of duration; none of the local symptoms required treatment. 4p reported systemic adverse reactions (headache and/or fever) during the first infusions. Discussion fSCIg therapy is safe and effective for replacement treatment in patients with IEIs. Further systemic clinical studies are needed to better define optimal dosage and application intervals.

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2025-04-25 | Correlation of IgG Levels and Frequency of Infections in Antibody-Deficiency Patients

Introduction/Background Patients with antibody deficiency commonly receive immunoglobulin replacement therapy (IgRT), but markers for disease control vary. The normal range for IgG ranges from 600 to 1700 mg/dL, with providers commonly aiming for a lower threshold of at least 550 mg/dL in these patients. A case series of two patients suggested that levels >800 mg/dL could provide significantly increased protection against infection and advocated tailoring IgRT doses based on specific patient outcomes (1). Methods Data collection was completed for 75 antibody-deficiency patients receiving subcutaneous immunoglobulin (SCIG) or intravenous immunoglobulin (IVIG). Of 75 patients, 13 were adults and all had CVID. Among pediatric patients, 55 had primary immunodeficiencies (PID): 9 CVID, 29 hypogammaglobulinemia, 7 Bruton’s agammaglobulinemia, 3 STAT-1 gain-of-function (GOF) mutation, 3 autoimmune lymphoproliferative syndrome (ALPS), and 4 specific antibody deficiency (SAD) with normal immunoglobulins and B cells. Seven remaining pediatric patients had secondary immunodeficiencies (SID) caused by end-stage renal disease or lymphoma. Data were annualized and patients were divided into “well-controlled” and “uncontrolled” disease. Lack of disease control was defined as greater than three courses of oral antibiotics or steroids yearly and >1 ED/ICU admission annually. Data/Results On average, well-controlled patients had three to four infections per year, while uncontrolled patients had six despite consistent IgRT treatment. The upper limit of IgG levels for any patient in this study did not exceed 1,394 mg/dL. The calculated average steady state IgG levels across the key subgroups are as follows: Well-controlled CVID: 844 mg/dL Well-controlled hypogammaglobulinemia: 899 mg/dL Suboptimally-controlled CVID: 635 mg/dL Suboptimally-controlled hypogammaglobulinemia: 606 mg/dL Bruton’s patients had no fewer than 4 infections annually, and an average IgG level of 637 mg/dL. Patients with SAD and ALPS had better disease control with an average steady-state IgG of 1,012 mg/dL. Patients with STAT-1 GOF had the highest steady-state IgG levels (988 mg/dL). In SID, IgG levels were difficult to capture due to inconsistent therapy use. There was no statistically significant difference between the adult and pediatric cohorts. Conclusion These results indicate the optimal IgG level for treatment should change based on diagnosis, but likely begins at least 800 mg/dL.

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2024-11-28 | Nonspecific increase of αβTCR+ double-negative T cells in pediatric rheumatic diseases.

An increased number of double-negative T (DNT) cells expressing the αβ T cell receptor (αβ+DNT cells) is one of the diagnostic criteria for autoimmune lymphoproliferative syndrome (ALPS). Moreover, these cells are expanded in a widely used murine model for lupus. However, the homeostasis of αβ+DNT cells remains inadequately investigated in rheumatic disorders, especially in pediatric patients. In this cross-sectional, prospective, and observational study, children with rheumatic disorders and healthy controls were recruited to analyze the quantity and characteristics of circulating DNT cells using flow cytometry. Overall, the two study groups did not differ in their total DNT cell pool in the bloodstream. However, the number of αβ+DNT cells was significantly higher in rheumatic children than that in the controls, whereas the γδ+DNT cells remained similar. This expansion in the circulating pool of αβ+DNT cells was comparable across different rheumatic diseases, all showing significant differences from the controls in this regard. Moreover, no significant correlation was found between αβ+DNT cell numbers and disease activity. These preliminary results indicate that circulating αβ+DNT cells are significantly expanded in children with rheumatic disorders; however, this finding appears to be a nonspecific (disease-unrelated) marker of autoimmunity. Further and larger studies are necessary to better investigate and define the role of DNT cells in pediatric rheumatic diseases.

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2023-10-01 | S4091 FAScinating Facts of Autoimmune Enteropathy in Autoimmune Lymphoproliferative Syndrome

Introduction: Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited condition caused by defective lymphocyte apoptosis leading to abnormal lymphocyte survival. These defective lymphocytes result in autoimmune disease, non-infectious, nonmalignant lymphadenopathy, hepatosplenomegaly, autoimmune cytopenia’s and secondary malignancies particularly lymphomas. We present a rare case of short bowel syndrome(SBS ) with intestinal failure with ALPS which showed improvement after initiating vedolizumab. Case Description/Methods: A 24-year-old woman presented to us from childhood with infiltrative intestinal malabsorption. She had been on parenteral nutrition (PN) for almost 10 years. As the differential diagnosis was broad, we evaluated for various malabsorption diseases including langerhans cells histiocytosis, CVID, enteropathy from storage or metabolic disorders, celiac disease, and Crohn's disease. Work-up demonstrated steatorrhea and protein losing enteropathy (elevated stool alpha 1 antitrypsin (A1AT). Langerhans CD-1 cells were not identified on HandE by immunohistochemistry (IHC). The lamina propria (duodenum) showed abundant macrophages with PAS positive inclusions that were alpha -1 antitrypsin positive by IHC. Video capsule endoscopy revealed nodular mucosa throughout the small bowel along with several small bowel ulcers, while the colonoscopy showed congested, inflamed, scarred with pseudo-membranes from distal ileum to cecum. Pathology results showed active colitis and enteritis with abundance of macrophages extending into lamina propria with positive PAS globules. She had elevated IL-10 level, sIL-2R and vitamin b12 levels. She has hepatosplenomegaly, organ dysfunction and inflammation in the intestine, non-malignant, non-infectious lymphadenopathy, and positive flow-cytometry for double negative T cells. She meets the current clinical criteria for ALPS and genome sequencing for FAS Ligand FADD mutation were sent. We continued her PN and started vedolizumab which led to weight gain and discontinuation of 40% PN requirements. Repeat biopsies showed improvement in histology (Figure 1). Discussion: This case illustrates the importance of evaluating for ALPS in infiltrative short bowel syndrome. A focused combination therapy with vedolizumab and sirolimus is planned, as M-TOR inhibition promotes apoptosis. This therapy looks promising in the treatment of APLS.Figure 1.: Figure A: Pre-vedolizumab Treatment: Endoscopic view showing inflamed, congested mucosa. Figure B: Post-vedolizumab Treatment: Endoscopy Shows improved inflammation and congestion of intestinal mucosa.

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small molecules

2026-08-20 | A Pediatric Case Series of Autoimmune Lymphoproliferative Syndrome (ALPS): A Single-Center Experience

Introduction Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immune dysregulation. A defect in lymphocyte apoptosis leads to their accumulation and the survival of autoreactive B lymphocytes. Main characteristics of the disease are lymphoproliferation (lymphadenopathy and/or organomegaly) and autoimmunity (primarily autoimmune cytopenias). There are clinical criteria for the diagnosis, and in most cases, genetic diagnosis is also possible (mutations in FAS, FASLG, and CASP10 genes). Some patients meet clinical criteria for ALPS, but genetic defects are still undetermined (ALPS-U). Material and Methods This is a descriptive study with an observational case series from the Department of Pediatrics at the University Hospital Centre Zagreb, Croatia. We reviewed medical records from January 2012 until February 2026 of eight patients with ALPS and analyzed their demographic, clinical, laboratory, genetic, and treatment data. Results Eight children (four males, four females) with ALPS are being followed up in our center. Median age at diagnosis was 5 years (range 4 months–11 years). The most common clinical manifestation was splenomegaly (87.5%), followed by autoimmune cytopenias (62.5%) and lymphadenopathy (37.5%). All patients had elevated double-negative T cells and vitamin B12. One patient had hypogammaglobulinemia. Five patients have identical mutations in the FAS gene (four heterozygous, one homozygous), one patient has a mutation in the FASLG gene, one patient has ALPS-U (mutation not found), and for one patient, genetic analysis is pending. Sirolimus was used in three patients, improving their blood counts and leading to regression of lymphadenopathy and splenomegaly, and was well tolerated. Conclusion Due to the variable penetrance and heterogeneous clinical presentation, ALPS should be considered even in cases with atypical manifestations. Timely diagnosis is important, especially in the presence of immune cytopenias, to make tailored treatment decisions. Genetic testing of family members is necessary due to the increased risk of developing lymphoma in all carriers of the mutation.

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2026-06-23 | ALPS-like Disorder Linked with STAT3 Mutation: De Novo Variant with Bicytopenia and Literature Review.

Autoimmune lymphoproliferative syndrome-like (ALPS-like) disorders are inherited conditions caused by non-FAS pathway mutations that clinically mimic ALPS, presenting with lymphoproliferation, autoimmunity, and cytopenias. This study describes a patient with STAT3-related ALPS-like disease that was initially misdiagnosed as ALPS and compares his clinical, immunological, and molecular features with those of previously reported cases to highlight diagnostic distinctions from classical ALPS. Clinical data were obtained from direct examination and medical records. Whole-Exome Sequencing (WES) identified the causative mutation. A literature review using PubMed, Web of Science, and Scopus retrieved previously reported ALPS-like cases with STAT3 mutations for comparative analysis of clinical, immunological, and molecular findings. We report a 10-year-old boy with bicytopenia (thrombocytopenia and neutropenia), autoimmune thrombocytopenic purpura, refractory lymphadenopathy, splenomegaly, and recurrent infections, initially misdiagnosed as ALPS. Elevated double-negative T cells and vitamin B12 levels were detected. WES revealed a heterozygous de novo STAT3 mutation (p.L666V). A reduced frequency of Treg cells was observed in our case. The patient responded well to JAK inhibitor therapy. Review of reported STAT3-mutant ALPS-like cases (66 cases) showed that immune thrombocytopenia was the most common cytopenia, often accompanied by autoimmune hemolytic anemia, variable hypogammaglobulinemia, reduced Treg cells, and increased double-negative T cells. STAT3 gain-of-function-associated ALPS-like disease can closely mimic classical ALPS due to overlapping clinical and immunological features, including elevated double-negative T cells, which may lead to diagnostic challenges. This case highlights that STAT3 GOF ALPS-like disease can closely mimic classical ALPS, and that integrating genetic analysis with immunological assessment is essential for accurate diagnosis and guiding targeted therapy.

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2026-06-04 | Successful Sirolimus Therapy in Steroid-Refractory RAS-Associated Autoimmune Lymphoproliferative Disorder with Mosaic KRAS Mutation

Introduction Autoimmune lymphoproliferative syndrome (ALPS) is characterized by defective lymphocyte apoptosis caused by abnormalities in the FAS signaling pathway and presents with lymphadenopathy, splenomegaly, and autoimmune manifestations. RAS-associated autoimmune lymphoproliferative disorder (RALD) is classified as an ALPS-related disorder and is caused by somatic mutations in NRAS or KRAS, resulting in constitutive activation of the RAS signaling pathway. This leads to impaired apoptosis, abnormal lymphocyte proliferation, and autoimmune manifestations. Compared with classic ALPS, RALD may exhibit distinct clinical features such as mild monocytosis or juvenile myelomonocytic leukemia (JMML)-like findings, making accurate differential diagnosis essential. Although glucocorticoids are generally considered first-line therapy, optimal management strategies for glucocorticoid-refractory cases remain to be established. Case Presentation A two-year-old boy who had been diagnosed with autoimmune hemolytic anemia at eight months of age developed transient thrombocytopenia and nephrotic syndrome. His cytopenia was unresponsive to glucocorticoid therapy, and he became transfusion dependent. Genetic testing later identified a mosaic KRAS variant (p.Gly13Asp), leading to the diagnosis of RALD. Based on recent reports suggesting the possibility of efficacy for mTOR inhibitors in monogenic disorders characterized by immune dysregulation and lymphoproliferation, an investigator-initiated clinical trial using sirolimus was proposed and initiated after obtaining consent. After the introduction of sirolimus, the patient achieved transfusion independence. However, his clinical course was complicated by secondary hypogammaglobulinemia, which currently requires ongoing immunoglobulin replacement therapy. Discussion Sirolimus suppresses the activation and proliferation of T and B lymphocytes, thereby controlling pathological lymphoproliferation and autoimmune manifestations in RALD. This case highlights the clinical utility of sirolimus as a promising therapeutic option for glucocorticoid-refractory RALD.

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2026-05-01 | Clinical and Genetic Spectrum of Autoimmune Lymphoproliferative Syndrome (ALPS) and ALPS-Like Disorders in Brazil: Insights from the First Year of the CNE3i National Cohort

The recognition of disorders of immune dysregulation, particularly those presenting with lymphoproliferation and systemic autoimmunity (International Union of Immunological Societies [IUIS] Group 4.6), has markedly increased in recent years. Initially, many of these conditions were collectively classified as Autoimmune Lymphoproliferative Syndrome (ALPS); however, the advent and dissemination of next-generation sequencing enabled the identification of patients with distinct genetic etiologies despite sharing overlapping clinical and immunological features. Through a national collaborative effort, the Centro nacional de Erros Inatos da Imunidade e Imunodesregulação (CNE3i) has systematically collected data on ALPS and ALPS-related disorders across Brazil since 2024. Here, we report the first year of CNE3i’s dataset on ALPS and ALPS-like diseases, highlighting their genetic diversity, clinical presentations, and immunological signatures within the Brazilian population. A total of 33 individuals were identified, 33.3% female (n = 11), from all 5 major regions of Brazil, with a mean age of 17 years (range 6–56 years) and a mean diagnostic delay of 5 years. Lymphadenopathy was the most common clinical finding (94%, n =31), followed by diffuse splenomegaly (72.7%, n = 24), hepatomegaly (54.6%, n = 18), and cytopenia (48.5%, n = 16), all present in a substantial proportion of patients. An elevated double-negative T cell (DNTs) was found in 14 individuals (42%), and diverse monogenic etiologies were identified (n = 15) (supplemental table). Despite extensive investigation, around 50% of the time, a causative gene could not be found. Most patients received corticosteroids as first-line therapy, followed by an mTOR inhibitor (41%) and mycophenolate mofetil (44%). The CNE3i Brazilian ALPS cohort reflects the complex phenotypic overlap between ALPS and ALPS-like disorders, underscoring the central role of autoimmune cytopenias and lymphoproliferation. The identification of canonical FAS mutations and ALPS-like defects (e.g., LRBA, TNFAIP3, and CTLA4) reinforces the importance of broad genetic screening in cases of immune dysregulation. These findings contribute to a more refined understanding of the genetic and clinical heterogeneity of IEIs and support optimized therapeutic strategies, particularly involving mTOR inhibition and a selective PI3Kδ inhibitor. FINEP funding: 0956/24; FAPESP funding: 2023/09965-0; Instituto de Investigação em Imunologia funding CNPQ/MCTI: 408685/2024-7 Tabular data are included as downloadable supplement files.

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2026-04-18 | 1995-2025: A long journey in the ALPS.

The discovery of heterozygous germline mutations in FAS 30 years ago led to an understanding of the pathophysiology associated with familial forms of autoimmune lymphoproliferative syndrome (ALPS). Ten years later, the identification of somatic mutations in FAS was the first description of an acquired mutation in a non-cancerous disease. It was subsequently observed that haploinsufficient germline mutations are accompanied by a somatic mutation in the second FAS allele or by somatic loss of heterozygosity. More recently, germline and combined mutations in FADD have also been described in ALPS. In contrast, mutations in other proteins of the signaling pathway, such as caspases 8 and 10, do not appear to be associated with ALPS. Finally, biallelic mutations in the FAS ligand (FASLG) can also lead to an ALPS phenotype. In all these genetic forms of ALPS, hyperactivation of the mTOR pathway, observed in animal models and subsequently in humans, has demonstrated the efficacy of mTOR inhibitors as a standard treatment for ALPS. Since the discovery of FAS in ALPS, mutations in numerous other genes (CTLA4, LRBA, STAT3) have been described in patients presenting with ALPS symptoms combined with signs of immunodeficiency. It has been proposed to distinguish these monogenic ALPID disorders to avoid confusing them with ALPS, which is specifically associated with a defect in the FASLG/FAS pathway.

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cell therapies

2026-07-31 | Beyond Infections: Clinical and Genetic Spectrum of Pediatric Immune Dysregulation Disorders

Aim: Primary immune regulatory disorders represent a rapidly expanding subgroup of inborn errors of immunity.Unlike classical infectionpredominant immunodeficiencies, these disorders may initially present with autoimmunity, lymphoproliferation, cytopenias, dermatologic disease, allergy, enteropathy, hemophagocytic lymphohistiocytosis, or malignancy. Materials and Methods:We conducted a retrospective single-center observational cohort study of children with genetically confirmed diseases of immune dysregulation who had been followed at a tertiary pediatric immunology center between 2005 and 2025.Patients were included if their molecular diagnosis was classified under the International Union of Immunological Societies (IUIS) category of diseases of immune dysregulation.Demographic, clinical, genetic, therapeutic, transplant-related, and outcome data were extracted from the medical records and analyzed descriptively.Results: Twenty-one children were included.Parental consanguinity was frequent (71.4%), and more than half of the cohort had a family history of primary immunodeficiency (57.1%).A substantial diagnostic delay was observed, with a median delay of 28 months (interquartile range, 8-105.5).The most common IUIS subcategory was regulatory T-cell defects (52.4%), followed by familial hemophagocytic lymphohistiocytosis syndromes with hypopigmentation (19.0%), autoimmune lymphoproliferative syndrome (14.3%), susceptibility to Epstein-Barr virus and lymphoproliferative conditions (9.5%), and immune dysregulation with colitis (4.8%).The main clinical features were lymphoproliferation (76.2%), hematologic abnormalities (66.7%) and autoimmunity (52.4%).Notably, malignancy was documented in 2 patients (9.5%).Antimicrobial prophylaxis was administered in 90.5% of the patients, immunoglobulin replacement in 66.7%, conventional immunosuppressive therapy in 38.1%, and biological or targeted therapy in 33.3%.Hematopoietic stem cell transplantation (HSCT) was performed in 8 patients (38.1%); immune reconstitution was achieved in all of the surviving transplant patients.Conclusion: Pediatric diseases of immune dysregulation frequently present with non-infectious manifestations, particularly lymphoproliferation, cytopenias, autoimmunity, and dermatologic findings.Recognition beyond infection-centered warning signs, the integration of genetic testing, and the individualized use of targeted therapies or HSCT may improve care for this heterogeneous group of disorders.

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2026-02-04 | αβT/CD19-depleted Allogeneic Stem Cell Transplantation in Adults with Inborn Errors of Immunity.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is successful in pediatric patients with inborn errors of immunity (IEI), but its use in adults is complicated by pre-existing organ damage and increased risk of treatment-related mortality. Ex vivo graft engineering using αβTCR/CD19 depletion has shown promising safety profiles in pediatric IEI, yet evidence in adults is limited. We assessed the feasibility and outcomes of αβTCR/CD19-depleted allo-HSCT in adults with IEI, focusing on engraftment, immune reconstitution, and clinical outcomes. We included 9 adults with IEI and 1 with VEXAS (age 21-51). IEIs included CTLA4HI, APDS, DOCK8, ALPS, DADA2, CVID2, and HA20, with Immune Deficiency and Dysregulation Activity (IDDA) scores of 17-92. αβTCR/CD19-depleted allografts from related, unrelated or haplo-identical donors were used after antithymocyte globulin (ATG) and myeloablative conditioning (thiotepa, melphalan, and fludarabine). Post-transplant immunoprophylaxis included mycophenolate mofetil; 4/10 patients received additional transplant-associated immunosuppression. All patients achieved primary engraftment. One patient with secondary rejection successfully underwent a second allo-HSCT. 5 patients developed grade 2-4 acute GvHD; no chronic GvHD was observed. One patient with GvHD died from COVID-19. All remaining 9 patients were successfully tapered off immunosuppression and showed improved IDDA scores. At 6 months NK, γδT, B and CD8 + T cells normalized; CD4 + numbers reached 149 cells/µl at 1 year. Most patients were successfully vaccinated and could stop immunoglobulin substitution. In conclusion, ex vivo graft engineering using αβTCR/CD19 depletion was feasible in adults with IEI. Clinical outcomes are encouraging, but need to be confirmed in larger studies.

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2025-09-05 | Case Report: FAS spontaneous mutation in a familial hemophagocytic lymphohistiocytosis patient with a complex heterozygous mutation in PRF1.

Familial hemophagocytic lymphohistiocytosis type 2 (FHL2), caused by perforin 1 (PRF 1), is a rare and fatal autosomal recessive disorder characterized by a hyperinflammatory syndrome and the accumulation of activated T lymphocytes and histiocytes in the reticuloendothelial system. Autoimmune lymphoproliferative syndrome (ALPS) is an autoimmune disease that typically presents in children with lymphadenopathy, splenomegaly, and cytopenias or lymphomas. We report a case of a 9-year-old boy who was newly diagnosed with FHL, carrying a new type of compound heterozygous mutations (c.305G>T and c.139G>T) in PRF1 and a spontaneous heterozygous mutation in the FAS gene (c.776T>C). He met six of the eight hemophagocytic lymphohistiocytosis (HLH) diagnostic criteria: fever, splenomegaly, cytopenia, hypofibrinogenemia, hemophagocytosis in the bone marrow, and elevated sCD25. He also had a high proportion of CD3+CD4-CD8- T lymphocytes and a spontaneous mutation of FAS, which are features of ALPS. Chemotherapy failed to control the disease, and the child died within 3 months. FAS and PRF1 comutation may have contributed to the adverse outcome in this patient. Notably, hematopoietic stem cell transplantation (HSCT) should be performed early in these patients.

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2024-06-24 | Unveiling the Uncommon: A Unique Case of ALPS-like Syndrome Complicated by Plasma Cell Disorder.

Multiple myeloma is a rare disease in pediatrics, where about 30 cases are described under 15 years old. It is even rarer when atypical multiple myeloma occurs in the context of autoimmunity. This case describes a 9-year-old female with autoimmune lymphoproliferative-like disease and combined immune deficiency that developed acute kidney failure with monoclonal peak associated with RAC2 and TNFRSF9 variants. An adapted protocol from the backbone adult multiple myeloma standard of care with the addition of an allogeneic hematopoietic stem cell transplant was used. The patient, now nearly a year posttransplant, shows 100% chimerism with no sign of relapse.

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2021-10-15 | Immune cytopenias as a continuum in inborn errors of immunity: An in-depth clinical and immunological exploration.

Immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia (AIN) are disorders characterized by immune-mediated destruction of hematopoietic cell lineages. A link between pediatric immune cytopenias and inborn errors of immunity (IEI) was established in particular in the combined and chronic forms. Aim of this study is to provide clinical-immunological parameters to hematologists useful for a prompt identification of children with immune cytopenias deserving a deeper immunological and genetic evaluation. We retrospectively collected 47 pediatric patients with at least one hematological disorder among which persistent/chronic ITP, AIHA, and AIN, aged 0-18 years at onset of immune cytopenias and/or immune-dysregulation. The cohort was divided into two groups (IEI+ and IEI-), based on the presence/absence of underlying IEI diagnosis. IEI+ group, formed by 19/47 individuals, included: common variable immune deficiency (CVID; 9/19), autoimmune lymphoproliferative syndrome (ALPS; 4/19), DiGeorge syndrome (1/19), and unclassified IEI (5/19). IEI prevalence among patients with ITP, AIHA, AIN, and Evans Syndrome was respectively of 42%, 64%, 36%, and 62%. In IEI+ group the extended immunophenotyping identified the presence of statistically significant (p < .05) specific characteristics, namely T/B lymphopenia, decrease in naїve T-cells%, switched memory B-cells%, plasmablasts%, and/or immunoglobulins, increase in effector/central memory T-cells% and CD21low B-cells%. Except for DiGeorge and three ALPS patients, only 2/9 CVID patients had a molecular diagnosis for IEI: one carrying the pathogenic variant CR2:c.826delT, the likely pathogenic variant PRF1:c.272C> and the compound heterozygous TNFRSF13B variants p.Ser144Ter (pathogenic) and p.Cys193Arg (variant of uncertain significance), the other one carrying the likely pathogenic monoallelic variant TNFRSF13B:p.Ile87Asn. The synergy between hematologists and immunologists can improve and fasten diagnosis and management of patients with immune cytopenias through a wide focused clinical/immunophenotypical characterization, which identifies children worthy of IEI-related molecular analysis, favouring a genetic IEI diagnosis and potentially unveiling new targeted-gene variants responsible for IEI phenotype.

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gene therapies

2026-02-12 | Lipid Nanoparticle Fas Gene Therapy Suppresses Autoimmune Lymphoproliferative Syndrome in Mice.

Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disease of deregulated leukocyte homeostasis caused by FAS gene mutation or loss of Fas function. Despite three decades having passed since its discovery, except for bone marrow stem transplantation, there is currently no effective treatment for ALPS. The recent breakthrough of COVID-19 mRNA vaccine demonstrated the effectiveness of nucleic acid-based therapy for a human disease. We determined that Fas mediates caspase activation-dependent apoptosis of human hematopoietic cells in vitro. In the ALPS mice, loss of Fas function leads to decreased hematopoietic cell spontaneous apoptosis and mass accumulation of lymphocytes. To restore Fas expression and function, we generated lipid nanoparticle-encapsulated Fas-encoding plasmid (LNP-mFas). LNP-mFas therapy decreased the accumulation of CD4-CD8- lymphocytes and increased CD4+ and CD8+ mature T cells in mice, resulting in suppression of ALPS in mice. We therefore determine that LNP-mFas is potentially an effective therapy for ALPS.

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2024-10-29 | Functional role of UNC13D in immune diseases and its therapeutic applications.

UNC13 family (also known as Munc13) proteins are evolutionarily conserved proteins involved in the rapid and regulated secretion of vesicles, including synaptic vesicles and cytotoxic granules. Fast and regulated secretion at the neuronal and immunological synapses requires multiple steps, from the biogenesis of vesicles to membrane fusion, and a complex array of proteins for each step. Defects at these steps can lead to various genetic disorders. Recent studies have shown multiple roles of UNC13D in the secretion of cytotoxic granules by immune cells. Here, the molecular structure and detailed roles of UNC13D in the biogenesis, tethering, and priming of cytotoxic vesicles and in endoplasmic reticulum are summarized. Moreover, its association with immune diseases, including familial hemophagocytic lymphohistiocytosis type 3, macrophage activation syndrome, juvenile idiopathic arthritis, and autoimmune lymphoproliferative syndrome, is reviewed. Finally, the therapeutic application of CRISPR/Cas9-based gene therapy for genetic diseases is introduced.

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2024-02-05 | Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study.

Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification. In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing. We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5-13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses. The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful to focus diagnostic and therapeutic efforts by triggering extended genetic analysis and consideration of targeted therapies, including in some children currently classified as having common variable immunodeficiency or Evans syndrome. Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy. For the German translation of the abstract see Supplementary Materials section.

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2023-10-09 | Guardians of Immunity: Advances in Primary Immunodeficiency Disorders and Management.

Primary immunodeficiency disorders (PIDs) are a heterogeneous group of genetic conditions profoundly impacting immune function. The investigation spans various PID categories, offering insights into their distinct pathogenic mechanisms and clinical manifestations. Within the adaptive immune system, B-cell, T-cell, and combined immunodeficiencies are dissected, emphasizing their critical roles in orchestrating effective immune responses. In the realm of the innate immune system, focus is directed toward phagocytes and complement deficiencies, underscoring the pivotal roles of these components in initial defense against infections. Furthermore, the review delves into disorders of immune dysregulation, encompassing hemophagocytic lymphohistiocytosis (HLH), autoimmune lymphoproliferative syndrome (ALPS), immune dysregulation, polyendocrinopathy, enteropathy, and X-linked(IPEX), and autoimmunity polyendocrinopathy candidiasis-ectodermal dystrophy(APECED), elucidating the intricate interplay between immune tolerance and autoimmunity prevention. Diagnostic strategies for PIDs are explored, highlighting advancements in genetic and molecular techniques that enable precise identification of underlying genetic mutations and alterations in immune function. We have also outlined treatment modalities for PIDs, which often entail a multidisciplinary approach involving immunoglobulin replacement, antimicrobial prophylaxis, and, in select cases, hematopoietic stem cell transplantation. Emerging therapies, including gene therapy, hold promise for targeted interventions. In essence, this review encapsulates the complexity of PIDs, emphasizing the critical importance of early diagnosis and tailored therapeutic interventions. As research advances, a clearer understanding of these disorders emerges, fostering optimism for enhanced patient care and management in the future.

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2017-10-23 | What's up in the ALPS

The autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant and non-infectious uncontrolled proliferation of lymphocytes accompanied by autoimmune cytopenia. This clinical entity was recognized in the mid 60s and its genetic etiology was described in 1995 by the discovery of the FAS gene mutations. This was the first description of a monogenic cause of autoimmunity but its non-Mendelian expression remained elusive until the description of somatic and germline mutations in ALPS patients. The related apoptosis defect accounts for the accumulation of autoreactive lymphocytes as well as for specific clinical and biological features that distinguish the ALPS-FAS from other monogenic causes of ALPS such as somatic mutations of RAS or the recently described CTLA-4 insufficiency. The recognition of these genetic diseases brought new information on the regulation of the adaptive immune responses and uncovered new therapeutical targets. Finally, the deciphering the role of somatic mutations may pave the way to the understanding of more common autoimmune diseases.

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2025-11-01 | Lipid Nanoparticle-mediated Fas Gene Immunotherapy Suppresses Autoimmune Lymphoproliferative Syndrome 3173

Abstract Description Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunodeficient disease caused by FAS,mutation. ALPS patients are predisposed to both hematopoietic and solid malignancies. There is still no standard therapy or cure currently for ALPS. The recent breakthrough of COVID-19 mRNA vaccine opens a new avenue for nucleic acid-based therapy for a human disease. Based on this concept, we have created FAS codon usage-optimized cDNA-encoding nanoplasmid (NTC9385R-FAS). We have formulated NTC9385R-FAS with cationic lipid nanoparticle DOTAP-Cholesterol to generate a first-in-class FAS cDNA cationic lipid nanoparticle (termed FASCO01). The Fas-deficient (MRL/MpJ-Faslpr/J) exhibits systemic autoimmunity, massive lymphadenopathy associated with proliferation of aberrant T cells, arthritis, and immune complex glomerulonephrosis and is therefore an ALPS mouse model. We determined that Faslpr mice exhibit decreased lymphocyte apoptosis in vivo. To translate this FASCO01 to human ALPS therapy, we tested human lymphoma cell lines and determined that Fas expression is correlated with FasL-induced apoptosis in vitro. FasL induces caspase 3 activation and PARP cleavage. Furthermore, the Fas- lymphoblast K562 cells do not respond to FasL to activate caspase 3 and are resistant to FasL-induced apoptosis in vitro. The Fas- K562 xenograft is therefore a human ALPS model and is being tested in humanized NSG mice for hFASCO01 therapy efficacy in suppressing human ALPS in vivo. Funding Sources NIH: R01CA278852 Veterans Affairs: 101cx001364 Genprix Inc. GPEX00001 Topic Categories Basic Autoimmunity (BA)

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2023-09-30 | Role of RNA Alternative Splicing in T Cell Function and Disease

Alternative RNA splicing, a ubiquitous mechanism of gene regulation in eukaryotes, expands genome coding capacity and proteomic diversity. It has essential roles in all aspects of human physiology, including immunity. This review highlights the importance of RNA alternative splicing in regulating immune T cell function. We discuss how mutations that affect the alternative splicing of T cell factors can contribute to abnormal T cell function and ultimately lead to autoimmune diseases. We also explore the potential applications of strategies that target the alternative splicing changes of T cell factors. These strategies could help design therapeutic approaches to treat autoimmune disorders and improve immunotherapy.

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2019-04-24 | IL1R8 Deficiency Drives Autoimmunity-Associated Lymphoma Development

Abstract Chronic inflammation, including that driven by autoimmunity, is associated with the development of B-cell lymphomas. IL1R8 is a regulatory receptor belonging to the IL1R family, which negatively regulates NF-κB activation following stimulation of IL1R or Toll-like receptor family members. IL1R8 deficiency is associated with the development of severe autoimmune lupus-like disease in lpr mice. We herein investigated whether concomitant exacerbated inflammation and autoimmunity caused by the deficiency of IL1R8 could recapitulate autoimmunity-associated lymphomagenesis. We thus monitored B-cell lymphoma development during the aging of IL1R8-deficient lpr mice, observing an increased lymphoid cell expansion that evolved to diffuse large B-cell lymphoma (DLBCL). Molecular and gene-expression analyses showed that the NF-κB pathway was constitutively activated in Il1r8−/−/lpr B splenocytes. In human DLBCL, IL1R8 had reduced expression compared with normal B cells, and higher IL1R8 expression was associated with a better outcome. Thus, IL1R8 silencing is associated with increased lymphoproliferation and transformation in the pathogenesis of B-cell lymphomas associated with autoimmunity.

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2017-03-28 | TCF1 deficiency ameliorates autoimmune lymphoproliferative syndrome (ALPS)-like phenotypes oflpr/lprmice

Abstract Autoimmune lymphoproliferative syndrome ( ALPS ) is an incurable disease, which is characterized by non‐malignant autoimmune lymphoproliferation. TCF 1 is a key effector in the canonical Wnt/ β ‐catenin pathway, regulating the development, activation and function of T cells. In this study, we aimed to explore the potential role of TCF 1 in the development of ALPS ‐like phenotypes of lpr/lpr mice. We acquired TCF 1 −/− lpr/lpr double mutant mice by crossing TCF 1 deficiency mice with lpr/lpr mice. Splenocyte compositions, serum cytokines levels, antids DNA antibody production and kidney pathology were examined in the TCF 1 −/− lpr/lpr mice. With these examinations, we revealed that TCF 1 deficiency relieved most manifestations of ALPS ‐like phenotype, which were caused by Fas mutation in TCF 1 −/− lpr/lpr mice. Splenocyte total numbers and compositions were downregulated to the similar levels with wildtype mice. T E and T EM cells were decreased in TCF 1 −/− lpr/lpr compared with lpr/lpr mice. The levels of autoantibodies and proinflammatory factors in serum, and the histopathology changes and the relative mRNA levels of proinflammatory factors in kidney all displayed parallel tendency in TCF 1 −/− lpr/lpr mice. Our study demonstrated that TCF 1 deficiency ameliorated the ALPS ‐like phenotypes of TCF 1 −/− lpr/lpr mice, which might indicate a potential therapeutic direction for ALPS .

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2016-11-10 | Abnormal thymic maturation and lymphoproliferation in MRL-Fas lpr/lpr mice can be partially reversed by synthetic oligonucleotides: implications for systemic lupus erythematosus and autoimmune lymphoproliferative syndrome.

MRL-Fas lpr/lpr mice represent an excellent animal model for studying non-malignant lymphoproliferation, regeneration and systemic autoimmunity. Retro-transposon insertion into the second intron of the pro-apoptotic Fas gene appears to be responsible for both lymphoproliferation and autoimmunity, while other genes are more likely to contribute to the regenerative healing characteristic of this mouse strain. Previous studies have shown that neonatal thymectomy can halt the development of abnormal lymphoproliferation. Whereas at four weeks of age primary and secondary lymphoid organs appear to be grossly intact, vigorous lymphoproliferation and autoantibody production subsequently ensues. This is first noticeable at six weeks of age, at which time lymph nodes, spleens and thymuses, but not the bone marrow, become infiltrated with abnormal B220+CD3+CD4-CD8- T cells. Around the same time, thymuses show a significant drop in CD4+CD8+double-positive T cells generating an abnormal ratio between double-positive and single-positive thymocytes. The objective of current study was to evaluate the effect of synthetic oligonucleotides-toll-like receptor antagonists on early lymphoid development in this strain of mice. Herein, we demonstrate the ability of synthetic oligonucleotides made with the nuclease-resistant phosphorothioate backbone to partially reverse abnormal lymphoproliferation and thymic involution in pre-diseased MRL-Fas lpr/lpr mice when administered intraperitoneally starting from week four of age. This curative effect of oligonucleotides was primary sequence/secondary oligonucleotide structure-independent, suggesting an effect through the toll-like receptor 7. A similar approach may potentially benefit patients with autoimmune lymphoproliferative syndrome who, like MRL-Fas lpr/lpr mice, carry a mutation in the Fas gene.

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