RARE DISEASE
Hyper-IgM syndrome type 3
Hyper-IgM syndrome type 3
Hyper-IgM syndrome type 3
Synonyms: HIGM3, Hyper-IgM syndrome due to CD40 deficiency
Synonyms: HIGM3, Hyper-IgM syndrome due to CD40 deficiency
Synonyms: HIGM3, Hyper-IgM syndrome due to CD40 deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Hyper-IgM syndrome type 3 (HIGM3) is a rare autosomal recessive primary immunodeficiency caused by mutations in the CD40 gene, impairing B-cell/T-cell interaction and class-switch recombination. Patients exhibit hypogammaglobulinemia (low IgG, IgA, IgE) with normal/elevated IgM, leading to recurrent bacterial infections, opportunistic pathogens (e.g., Pneumocystis jirovecii), and autoimmune manifestations [1][2][12]. Chronic neutropenia, gastrointestinal complications (e.g., Cryptosporidium-induced sclerosing cholangitis), and increased malignancy risk are common [6][11].
Burden
High morbidity from recurrent infections (91% report pulmonary/ENT infections), chronic diarrhea (50%), and autoimmune disorders (e.g., thrombocytopenia, arthritis) [5][7][11].
Life-threatening complications include liver cirrhosis (25–50% with Cryptosporidium exposure) and malignancies (e.g., hepatocellular carcinoma) [6][8].
Mortality risk persists without HSCT, with median survival improving to >20 years with early transplantation [7][13].
Therapies
Immunoglobulin replacement therapy (IVIG/SCIG) to prevent infections [3][8][13].
Prophylactic trimethoprim-sulfamethoxazole for Pneumocystis and granulocyte colony-stimulating factor (G-CSF) for neutropenia [3][6].
Curative allogeneic hematopoietic stem cell transplantation (HSCT), preferred for severe cases with CD40 deficiency [6][18].
Categories: rare genetic diseases, rare immunological diseases, rare transplant-related disorders
Research Papers
148 drug discovery papers about Hyper-IgM syndrome type 3, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
148 drug discovery papers about Hyper-IgM syndrome type 3, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-08-11 | Pulmonary alveolar proteinosis and Pneumocystis jirovecii infection in an infant with hyper-IgM syndrome caused by a novel CD40LG variant: a case report
Background Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease. While autoimmunity is the leading cause of PAP in adults, the majority of pediatric cases occur secondary to immunodeficiency and opportunistic infections. Secondary PAP associated with CD40 ligand (CD40L) deficiency is extremely rare, and the underlying pathophysiology remains poorly understood. Case presentation We report the case of a 4-month-old boy admitted due to failure to thrive and severe hypoxemic respiratory failure. Chest computed tomography demonstrated diffuse ground-glass opacities with interlobular septal thickening. Bronchoalveolar lavage yielded clear fluid containing Periodic acid-Schiff-positive material consistent with PAP, and polymerase chain reaction was positive for Pneumocystis jirovecii . An immunologic evaluation showed hypogammaglobulinemia (IgG and IgA), a normal IgM level for his age, an absence of class-switched memory B cells, and significantly reduced CD40L expression on activated T lymphocytes. Targeted genetic testing identified a previously unreported hemizygous CD40LG missense variant [c.137T>C, p.(Leu46Pro)]. Integration of the patient’s immunophenotype, an in silico variant evaluation, and segregation data permitted classification of this variant as likely pathogenic, confirming X-linked hyper-IgM syndrome. The patient improved with ventilatory support, high-dose trimethoprim-sulfamethoxazole, and immunoglobulin replacement therapy. Conclusions Early-onset PAP associated with P. jirovecii infection may reveal CD40L deficiency and should prompt evaluation for primary immunodeficiency. An integrated clinico-immunologic assessment coupled with genetic testing is essential to provide a molecular diagnosis, guide management, and prognostication, and to support timely consideration of curative hematopoietic stem cell transplantation.
2026-05-05 | Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in X-Linked Hyper IgM Syndrome: A Multicenter Chinese Cohort Study from CCBMT.
X-linked hyper-IgM syndrome (XHIGM) is a rare immunodeficiency for which allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option, yet large pediatric Chinese datasets are scarce. We retrospectively analyzed 71 boys with genetically confirmed CD40L deficiency who underwent allogeneic HSCT between 2009 and 2020 at eight centers in China. Median age at HSCT was 3 yr (range, 0.6 to 17), with 74.6% transplanted before age 5. Donors were mismatched unrelated (42.3%), matched unrelated (33.8%), matched sibling (18.3%), and haploidentical (5.6%). Peripheral blood was the predominant stem cell source (67.6%), followed by cord blood (31.0%). Myeloablative conditioning was used in 95.8%. Median times to neutrophil and platelet engraftment were 12 and 14 d, respectively. Primary graft failure occurred in 5.6%. Acute GVHD developed in 60.6% (grade III to IV, 11.3%), and chronic GVHD in 25.4% (none-severe). Cytomegalovirus and EBV-DNAemia occurred in 56.3% and 39.4%, respectively; post-transplant lymphoproliferative disorder developed in 4.2%. Other complications included sinusoidal obstruction syndrome and hemorrhagic cystitis (7.0% each). At last follow-up, 9 patients (12.1%) had died, mainly from infections (8.5%). At a median follow-up of 7.8 yr, the estimated 10-yr overall, disease-free, and GVHD-free survival rates were 85.91%, 64.79%, and 77.14%, respectively. Survival was superior in younger patients, those with lower body weight, and well-matched related or unrelated donors. Immune reconstitution showed early NK recovery with progressive T and B cell restoration over 1 yr. These data support HSCT as effective long-term therapy for XHIGM and highlight benefits of early timing and optimal HLA matching.
2023-12-25 | Clinical and Immunological Features, Genetic Variants, and Outcomes of Patients with CD40 Deficiency.
Inherited deficiencies of CD40 and CD40 ligand (CD40L) reflect the crucial immunological functions of CD40-CD40L interaction/signaling. Although numerous studies have provided a detailed description of CD40L deficiency, reports of CD40 deficiency are scarce. Herein, we describe the characteristics of all reported patients with CD40 deficiency. The PubMed, Embase and Web of Science databases were searched for relevant literature published till 7th August 2023. Study deduplication and identification of relevant reports was performed using the online PICO Portal. The data were extracted using a pre-designed data extraction form and the SPSS software was used for analysis. Systematic literature review revealed 40 unique patients with CD40 deficiency. Respiratory tract and gastrointestinal infections were the predominant clinical manifestations (observed in 93% and 57% patients, respectively). Sclerosing cholangitis has been reported in nearly one-third of patients. Cryptosporidium sp. (29%) and Pneumocystis jirovecii (21%) were the most common microbes identified. Very low to undetectable IgG levels and severely reduced/absent switch memory B cells were observed in all patients tested/reported. Elevated IgM levels were observed in 69% patients. Overall, splice-site and missense variants were the most common (36% and 32%, respectively) molecular defects identified. All patients were managed with immunoglobulin replacement therapy and antimicrobial prophylaxis was utilized in a subset. Hematopoietic stem cell transplantation (HSCT) has been performed in 45% patients (curative outcome observed in 73% of these patients). Overall, a fatal outcome was reported in 21% patients. We provide a comprehensive description of all important aspects of CD40 deficiency. HSCT is a promising curative treatment option for CD40 deficiency.
2023-10-26 | Case Report: The impact of severe cryptosporidiosis on the gut microbiota of a pediatric patient with CD40L immunodeficiency
Cryptosporidium parvum is a protozoan parasite and one of the leading causes of gastroenteritis in the world, primarily affecting very young children and immunocompromised patients. While infection is usually self-limiting, it can become chronic and even lethal in these vulnerable populations, in whom Cryptosporidium treatments are generally ineffective, due to their acting in concert with a functioning immune system. Here, we describe a case of chronic cryptosporidiosis in a European child with severe CD40L immunodeficiency infected with Cryptosporidium parvum of the IIa20G1 subgenotype, a lineage which has thus far only ever been described in the Middle East. After years of on-off treatment with conventional and non-conventional anti-parasitic drugs failed to clear parasitosis, we performed targeted metagenomics to observe the bacterial composition of the patient’s gut microbiota (GM), and to evaluate fecal microbiota transplantation (FMT) as a potential treatment option. We found that C. parvum infection led to significant shifts in GM bacterial composition in our patient, with consequent shifts in predicted intestinal functional signatures consistent with a state of persistent inflammation. This, combined with the patient’s poor prognosis and increasing parasitic burden despite many rounds of anti-parasitic drug treatments, made the patient a potential candidate for an experimental FMT procedure. Unfortunately, given the many comorbidities that were precipitated by the patient’s immunodeficiency and chronic C. parvum infection, FMT was postponed in favor of more urgently necessary liver and bone marrow transplants. Tragically, after the first liver transplant failed, the patient lost his life before undergoing FMT and a second liver transplant. With this case report, we present the first description of how cryptosporidiosis can shape the gut microbiota of a pediatric patient with severe immunodeficiency. Finally, we discuss how both our results and the current scientific literature suggest that GM modulations, either by probiotics or FMT, can become novel treatment options for chronic Cryptosporidium infection and its consequent complications, especially in those patients who do not respond to the currently available anti-parasitic therapies.
2023-05-13 | CD40LG-associated X-linked Hyper-IgM Syndrome (XHIGM) with pulmonary alveolar proteinosis: a case report
Abstract Background D40LG -associated X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis has rarely been reported, and its genotype-phenotypic correlation remains elusive. Case presentation We describe a five-month-old boy with CD40LG mutation (c.516T > A, p.Tyr172Ter) X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis as the first manifestation. The patient completely recovered after immunotherapy and allogeneic hematopoietic stem cell transplantation. In addition, four previously reported patients with CD40LG mutation with pulmonary alveolar proteinosis were also analyzed. All of these patients presented with early onset of pulmonary infections and a good response to immunotherapy. The structural model of CD40LG indicated that all mutations caused the X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis to be located within the tumor necrosis factor homology domain. Conclusions A case was presented, and the characteristics of four cases of CD40LG -associated X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis were summarized. The variant locations may explain the phenotypic heterogeneity of patients with the CD40LG mutation.
proteins
2026-07-14 | Relevance of a Computational Deep-Dive to Characterize the Molecular Biology of a Novel Cd40l Variant
CD40L deficiency is a well-described inborn error of immunity (IEI). The disease is characterized immunologically by impaired class-switching and T cell costimulation. A male infant presented at 8 months of age with recurrent cellulitis. At 11 months, he was admitted for prolonged fever and leukopenia with vomiting and watery diarrhea, periorbital edema, back abscess, increased sIL2R at 50,598 pg/mL (<14,491), and normal CXCL9 at 22 pg/mL with mild to modest increases in IL-18 at 694 pg/mL (<185.4), IL-6 at 226.4 pg/mL (<10), serum amyloid A (SAA) at 1,413 mcg/mL (<373.8), IL-8 at 196 (<10), and IL-10 at 101pg/mL (<10). His IgG and IgA were low at <30 and <10 mg/dL, respectively. He developed Pseudomonas sepsis, palatal ulceration, jejunal perforation requiring repair, Candida peritonitis, persistent neutropenia, CMV, and Parechovirus viremia. Along with the hypogammaglobulinemia, class-switched memory B cells were decreased for age. Flow cytometry was performed for CD40L expression on activated CD4+ T cells along with functional evaluation of ligand binding to a soluble form of the receptor (CD40), using CD40-muIg. There was significantly diminished CD40L expression with essentially absent binding to the receptor. Genetic testing confirmed a diagnosis of CD40L deficiency due to a hemizygous variant in CD40LG, c.674T>C; p.Leu225Ser (NM_000074.2). We had previously evaluated a 4-year-old male with intermittent, non-bloody diarrhea, pneumonia, hypogammaglobulinemia, and significant neutropenia, and identified this novel variant, now also observed in this infant. We utilized advanced computational tools to evaluate the molecular impact of this variant on the structure and function of CD40L. The Leu225Ser variant is located within the trimerization interface of CD40L. Molecular modeling, mutagenesis alanine scanning, and molecular dynamic simulations revealed that the variant causes loss of critical intramolecular time-dependent interactions between hydrophobic molecules that would typically facilitate trimerization of wild-type CD40L for optimal interaction with the CD40 receptor. This analysis of the Leu225Ser variant revealed the molecular basis of the decreased CD40L protein expression (loss of contact to form trimers) and impaired CD40 binding (loss of intramolecular bonds affecting folding and impaired interaction at the trimerization interface). The patient also had immune paralysis due to decreased MHC class II (HLA-DR) expression on CD14+ monocytes, a result of a compensatory anti-inflammatory response syndrome (CARS). Assessment of neutrophil activation and granule markers (CD66b, lactoferrin, myeloperoxidase [MPO], and elastase) revealed low-normal CD66b and lactoferrin with slightly increased MPO and elastase, suggesting a complex and dysfunctional neutrophil response rather than simple activation or deactivation. This phenotype is consistent with the known pathology of CD40L deficiency, in which neutrophils are defective in their ability to respond effectively to infection, leading to chronic inflammation and tissue damage despite persistent signs of granule release. Treatment with rIFNg has been shown to reverse neutrophil dysfunction in X-linked hyper-IgM syndrome (XHIGM) but also restore HLA-DR expression on monocytes and reverse immune paralysis. He is currently being evaluated for hematopoietic cell transplantation (HCT). This case exemplifies the relevance of utilizing a variety of strategies to evaluate novel variants in IEI genes. Further, molecular and computational studies permitted an improved understanding of the impact of the Leu225Ser variant on CD40L protein expression and function.
2025-11-20 | Coexistence of familial hemophagocytic lymphohistiocytosis type 3 and X-linked hyper IgM syndrome in a child
Background: Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening hyperinflammatory syndrome characterized by excessive activation of the immune system, leading to symptoms such as fever, multilineage cytopenia, coagulopathy, and multi-organ failure, with a high risk of mortality. Its non-specific clinical presentation often poses a diagnostic challenge, especially when the line between primary and secondary HLH is blurred, as secondary triggers, such as infections, can unmask an underlying genetic condition. The incidence of HLH is elevated in patients with inborn errors of immunity (IEI). Case report: We report the case of a 9-month-old male infant with classic HLH, including prolonged fever, hepatosplenomegaly, thrombocytopenia, elevated ferritin, and hemophagocytosis in the bone marrow aspirate. Notably, the patient also had an opportunistic Aspergillus infection, which is a hallmark of severe immunodeficiency. Genetic analysis revealed a rare co-occurrence of two pathogenic variants: a compound heterozygous c.859-3C>T mutation in UNC13D (causing familial hemophagocytic lymphohistiocytosis type 3) and a recessive c.158_161del mutation in CD40LG (causing hyper-IgM syndrome). The infant was diagnosed with HLH on the background of hyper-IgM syndrome based on HLH-2004 criteria and responded well to a combined treatment of chemotherapy and immunoglobulin replacement therapy. Conclusions: This case highlights the crucial role of comprehensive IEI screening in patients with HLH, particularly those with a history of recurrent or opportunistic infections, to facilitate accurate diagnosis and optimize treatment strategies.
2020-04-23 | Blood-Borne ST6GAL1 Regulates Immunoglobulin Production in B Cells
Humoral immunity is an effective but metabolically expensive defense mechanism. It is unclear whether systemic cues exist to communicate the dynamic need for antigen presentation and immunoglobulin production. Here, we report a novel role for the liver-produced, acute phase reactant ST6GAL1 in IgG production. B cell expression of ST6GAL1, a sialyltransferase mediating the attachment of a2,6-linked sialic acids on N-glycans, is classically implicated in the dysregulated B cell development and immunoglobulin levels of St6gal1-deficient mice. However, the blood-borne pool of ST6GAL1, upregulated during systemic inflammation, can also extrinsically modify leukocyte cell surfaces. We show that B cell independent, extracellular ST6GAL1 enhances B cell IgG production and increases blood IgG titers. B cells of mice lacking the hepatocyte specific St6gal1 promoter have reduced sialylation of cell surface CD22 and CD45 and produce less IgG upon stimulation. Sialylation of B cells by extracellular ST6GAL1 boosts expression of IgM, IgD, and CD86, proliferation, and IgG production in vitro. In vivo, elevation of blood ST6GAL1 enhances B cell development and systemic IgG in a CD22- dependent manner. Our data point to a function of an extracellular glycosyltransferase in promoting humoral immunity. Manipulation of systemic ST6GAL1 may represent an effective therapeutic approach for humoral insufficiency
2019-09-17 | CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ.
Patients with X-linked hyper-IgM syndrome caused by CD40 ligand (CD40L) deficiency often present with episodic, cyclic, or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L-CD40 interaction. However, even when not neutropenic and despite immunoglobulin replacement therapy, CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired phagocyte function and the need for novel therapeutic approaches. We sought to analyze whether peripheral neutrophils from CD40L-deficient patients display functional defects and to explore the in vitro effects of recombinant human IFN-γ (rhIFN-γ) on neutrophil function. We investigated the microbicidal activity, respiratory burst, and transcriptome profile of neutrophils from CD40L-deficient patients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function. Neutrophils from CD40L-deficient patients exhibited defective respiratory burst and microbicidal activity, which were improved in vitro by rhIFN-γ but not soluble CD40L. Moreover, neutrophils from patients showed reduced CD16 protein expression and a dysregulated transcriptome suggestive of impaired differentiation. Similar to CD40L-deficient patients, CD40L knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that soluble CD40L induces the promyelocytic cell line HL-60 to proliferate and mature by regulating the expression of genes of the same Gene Ontology categories (eg, cell differentiation) when compared with those dysregulated in peripheral blood neutrophils from CD40L-deficient patients. Our data suggest a nonredundant role of CD40L-CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN-γ, indicating a potential novel therapeutic application for this cytokine.
2018-12-06 | A tetrameric form of CD40 ligand with potent biological activities in both mouse and human primary B cells
CD40 ligand (CD40 L) expressed by activated T cells interacts with CD40 on B cells and triggers B cell survival, proliferation and differentiation. Deficiency in CD40 L or CD40 in humans causes hyper IgM syndrome due to a defect in T-B interaction that is essential for Ig gene class switch recombination (CSR). CD40 L belongs to the tumor necrosis factor family and normally forms a homotrimer on the cell surface, which is important for its biological activity. To generate a multimeric CD40 L that can be used to stimulate both mouse and human B cells, we fused the extracellular domain of mouse CD40 L, which is known to also bind human CD40, with streptavidin (SA) that forms a stable tetramer under physiological conditions. As expected, 293 T cells transiently transfected with an SA-CD40 L expression vector secreted tetrameric SA-CD40 L in the culture supernatant. The secreted SA-CD40 L exhibited > 25-fold stronger activities in inducing the survival, activation and proliferation of both mouse and human primary B cells than did an agonistic anti-mouse or anti-human CD40 antibody. In the presence of IL-4, SA-CD40 L also induced efficient CSR and plasma cell differentiation in both mouse and human B cells. Moreover, administration of SA-CD40 L in mice induced activation and proliferation of spleen B cells in vivo. These results demonstrate that the SA-CD40 L fusion protein generated in the present study recapitulates the function of membrane-bound trimeric CD40 L and has potent biological activities in both mouse and human primary B cells.
gene therapies
2026-05-01 | A First-in-Human Base Edit Gene Therapy for CD40L Deficiency X-Linked Hyper IgM (XHIGM) Syndrome
CD40L-deficient X-linked hyper IgM (XHIGM) syndrome is characterized by defective B cell class switching, deficiency of immunoglobulins G, A, and E, plus other immune abnormalities due to disrupted CD40L–CD40 interaction. Allogeneic hematopoietic stem cell (HSC) transplant can cure XHIGM but requires myeloablative conditioning and risks graft versus host disease (GVHD), posing a high mortality risk. We developed ex vivo base editing (BE) of autologous HSC and T cells to treat a 37-year-old man (P1) diagnosed late in life with a CD40LG c.C>T p.Q220X mutation in a single-patient Investigational New Drug application targeting his mutation (IND32000; NIH protocol 002385). Preclinical studies achieved >90% gene correction of P1 HSC and T cells with base editor ABE8e SpWT/A5 guide, devoid of significant unintended off-target edits. BE-HSC was intended as a definitive transplant to achieve long-term hematopoietic and immune reconstitution, whereas the BE-T cells were designed to serve as a transient bridge therapy of functional T cells during the period preceding differentiation of T cells from the BE-HSC graft. P1 presented pre-gene therapy with sclerosing cholangitis, cryptosporidium infection, nodular regenerative hyperplasia, portal hypertension, bronchiectasis, and lacked HLA-matched donors. Autologous BE-HSC transplant was given after low-dose busulfan conditioning together with prophylactic defibrotide to mitigate chemo-related veno-occlusive disease. The original treatment schema was alemtuzumab (days −21, −20, −19), busulfan 6mg/kg total (days −3, −2) with prophylactic defibrotide, BE-HSC (day 0), and BE-T on day +14 and as indicated for lymphopenia and/or infection. Following alemtuzumab, P1’s baseline abnormal liver function tests (LFTs) worsened (transaminases approximately doubled, bilirubin increased ∼18-fold) with persistent detection of previously undetectable cryptosporidium. We paused busulfan and BE-HSC and administered BE-T products, which corrected LFTs sufficiently to allow uneventful busulfan conditioning and BE-HSC product infusion. Post-treatment at months 1 and 2, blood studies confirmed robust engraftment with normal wild-type alleles in myeloid cells (>90%) and increasing levels in natural killer (>60%), B (>40%), and T (27%) cells and with first-time detection of class-switched IgG+ B cells. This innovative, dual-product strategy provides immediate, on-demand immune protection through infusion of functional BE-T cells, effectively bridging patients through the critical pre-engraftment period and until BE-HSC achieves durable, multilineage reconstitution.
2021-05-06 | Complex preimplantation genetic tests for Robertsonian translocation, HLA, and X-linked hyper IgM syndrome caused by a novel mutation of CD40LG gene.
To perform complex preimplantation genetic tests (PGT) for aneuploidy screening, Robertsonian translocation, HLA-matching, and X-linked hyper IgM syndrome (XHIGM) caused by a novel mutation c.156 G>T of CD40LG gene. Reverse transcription PCR (RT-PCR) and Sanger sequencing were carried out to confirm the causative variant of CD40LG gene in the proband and parents. Day 5 and D6 blastocysts, obtained by in vitro fertilization (IVF) with intracytoplasmic sperm injection, underwent trophectoderm (TE) biopsy and whole genomic amplification (WGA) and next generation sequencing (NGS)-based PGT to detect the presence of a maternal CD40LG mutation, aneuploidy, Robertsonian translocation carrier, and human leukocyte antigen (HLA) haplotype. Sanger sequencing data of the genomic DNA showed that the proband has a hemizygous variant of c. 156 G>T in the CD40LG gene, while his mother has a heterozygous variant at the same position. Complementary DNA (cDNA) of CD40LG amplification and sequencing displayed that no cDNA of CD40LG was found in proband, while only wild-type cDNA of CD40LG was amplified in the mother. PGT results showed that only one of the six tested embryos is free of the variant c.156 G>T and aneuploidy and having the consistent HLA type as the proband. Meanwhile, the embryo is a Robertsonian translocation carrier. The embryo was transplanted into the mother's uterus. Amniotic fluid testing results are consistent with that of PGT. A healthy baby girl was delivered, and the peripheral blood testing data was also consistent with the testing results of transplanted embryo. The novel mutation of c. 156 G>T in CD40LG gene probably leads to XHIGM by nonsense-meditated mRNA decay (NMD), and complex PGT of preimplantation genetic testing for monogenic disease (PGT-M), aneuploidy (PGT-A), structural rearrangement (PGT-SR), and HLA-matching (PGT-HLA) can be performed in pedigree with both X-linked hyper IgM syndrome and Robertsonian translocation.
2020-06-11 | CD40 ligand deficiency: treatment strategies and novel therapeutic perspectives.
CD40 ligand (CD40L) deficiency or X-linked Hyper-IgM syndrome is a severe primary immunodeficiency caused by mutations in the CD40L gene. Despite currently available treatments, CD40L-deficient patients remain susceptible to life-threatening infections and have poor long term survival. Areas covered: Here, we discuss clinical and immunological characteristics of CD40L deficiency as well as current therapeutic strategies used for patient management. This review highlights that beyond B cell defects, patients' susceptibility to opportunistic pathogens might be due to impaired T cell and innate immune responses. In this context, we discuss how better knowledge of CD40L function and regulation may result in the development of new treatments. Expert opinion: Despite the introduction of hematopoietic stem-cell transplantation, immunoglobulin replacement, granulocyte colony-stimulating factor (G-CSF) administration, and prophylactic antibiotic therapies, life-threatening infections still cause high morbidity and mortality among CD40L-deficient patients. The reasons for this inadequate response to current therapies remains poorly understood, but recent reports suggest the involvement of CD40L-CD40 interaction in early stages of the innate immune system ontogeny. The development of novel gene therapeutic approaches and the use of redirected immunotherapies represent alternative treatment methods that could offer reduced morbidity and mortality rates for patients with CD40L deficiency.
2018-05-01 | Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome
X-linked hyper-immunoglobulin M (hyper-IgM) syndrome (XHIM) is a primary immunodeficiency due to mutations in CD40 ligand that affect immunoglobulin class-switch recombination and somatic hypermutation. The disease is amenable to gene therapy using retroviral vectors, but dysregulated gene expression results in abnormal lymphoproliferation in mouse models, highlighting the need for alternative strategies. Here, we demonstrate the ability of both the transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) platforms to efficiently drive integration of a normal copy of the CD40L cDNA delivered by Adeno-Associated Virus. Site-specific insertion of the donor sequence downstream of the endogenous CD40L promoter maintained physiologic expression of CD40L while overriding all reported downstream mutations. High levels of gene modification were achieved in primary human hematopoietic stem cells (HSCs), as well as in cell lines and XHIM-patient-derived T cells. Notably, gene-corrected HSCs engrafted in immunodeficient mice at clinically relevant frequencies. These studies provide the foundation for a permanent curative therapy in XHIM.
2017-11-13 | Prospects for modulating the CD40/CD40L pathway in the therapy of the hyper-IgM syndrome
The critical role of the CD40/CD40L pathway in B-cell proliferation, immunoglobulin (Ig) isotype switching and germinal center formation has been studied and described extensively in previous literature. Interruption of the CD40/CD40L signal causes hyper-IgM (HIGM) syndrome, which has been classified and recognized as a group of rare inherited immune deficiency disorders. Defects in CD40 and CD40L interactions or in downstream signaling molecules, including activation-induced cytidine deaminase, uracyl-DNA-glycosylase, NF-κB and DNA repair enzymes, result in an increased level of serum IgM and a significantly decreased or absent level of IgA, IgG and IgE that is accompanied by severe recurrent infections and autoimmune diseases. Many genetic defects in HIGM have been identified and, as a result, it is possible for patients to be definitively diagnosed by gene sequencing and to delineate the immunological features of the patients. Modifying the CD40/CD40L signaling pathway may offer the possibility of restoring the normal serum Ab production and curing the immunodeficiency. Hematopoietic stem cell transplantation has achieved a high rate of success using a sibling donor. In addition, successful examples of treating other immunodeficiencies using gene therapy indicated that there was a possibility of eradicating HIGM with this approach. In this review, we summarize the current drugs and a variety of therapeutic approaches for the treatment of the HIGM syndrome by interfering with the defective CD40/CD40L pathway.
cell therapies
2026-08-11 | Pulmonary alveolar proteinosis and Pneumocystis jirovecii infection in an infant with hyper-IgM syndrome caused by a novel CD40LG variant: a case report
Background Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease. While autoimmunity is the leading cause of PAP in adults, the majority of pediatric cases occur secondary to immunodeficiency and opportunistic infections. Secondary PAP associated with CD40 ligand (CD40L) deficiency is extremely rare, and the underlying pathophysiology remains poorly understood. Case presentation We report the case of a 4-month-old boy admitted due to failure to thrive and severe hypoxemic respiratory failure. Chest computed tomography demonstrated diffuse ground-glass opacities with interlobular septal thickening. Bronchoalveolar lavage yielded clear fluid containing Periodic acid-Schiff-positive material consistent with PAP, and polymerase chain reaction was positive for Pneumocystis jirovecii . An immunologic evaluation showed hypogammaglobulinemia (IgG and IgA), a normal IgM level for his age, an absence of class-switched memory B cells, and significantly reduced CD40L expression on activated T lymphocytes. Targeted genetic testing identified a previously unreported hemizygous CD40LG missense variant [c.137T>C, p.(Leu46Pro)]. Integration of the patient’s immunophenotype, an in silico variant evaluation, and segregation data permitted classification of this variant as likely pathogenic, confirming X-linked hyper-IgM syndrome. The patient improved with ventilatory support, high-dose trimethoprim-sulfamethoxazole, and immunoglobulin replacement therapy. Conclusions Early-onset PAP associated with P. jirovecii infection may reveal CD40L deficiency and should prompt evaluation for primary immunodeficiency. An integrated clinico-immunologic assessment coupled with genetic testing is essential to provide a molecular diagnosis, guide management, and prognostication, and to support timely consideration of curative hematopoietic stem cell transplantation.
2026-05-05 | Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in X-Linked Hyper IgM Syndrome: A Multicenter Chinese Cohort Study from CCBMT.
X-linked hyper-IgM syndrome (XHIGM) is a rare immunodeficiency for which allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option, yet large pediatric Chinese datasets are scarce. We retrospectively analyzed 71 boys with genetically confirmed CD40L deficiency who underwent allogeneic HSCT between 2009 and 2020 at eight centers in China. Median age at HSCT was 3 yr (range, 0.6 to 17), with 74.6% transplanted before age 5. Donors were mismatched unrelated (42.3%), matched unrelated (33.8%), matched sibling (18.3%), and haploidentical (5.6%). Peripheral blood was the predominant stem cell source (67.6%), followed by cord blood (31.0%). Myeloablative conditioning was used in 95.8%. Median times to neutrophil and platelet engraftment were 12 and 14 d, respectively. Primary graft failure occurred in 5.6%. Acute GVHD developed in 60.6% (grade III to IV, 11.3%), and chronic GVHD in 25.4% (none-severe). Cytomegalovirus and EBV-DNAemia occurred in 56.3% and 39.4%, respectively; post-transplant lymphoproliferative disorder developed in 4.2%. Other complications included sinusoidal obstruction syndrome and hemorrhagic cystitis (7.0% each). At last follow-up, 9 patients (12.1%) had died, mainly from infections (8.5%). At a median follow-up of 7.8 yr, the estimated 10-yr overall, disease-free, and GVHD-free survival rates were 85.91%, 64.79%, and 77.14%, respectively. Survival was superior in younger patients, those with lower body weight, and well-matched related or unrelated donors. Immune reconstitution showed early NK recovery with progressive T and B cell restoration over 1 yr. These data support HSCT as effective long-term therapy for XHIGM and highlight benefits of early timing and optimal HLA matching.
2023-12-25 | Clinical and Immunological Features, Genetic Variants, and Outcomes of Patients with CD40 Deficiency.
Inherited deficiencies of CD40 and CD40 ligand (CD40L) reflect the crucial immunological functions of CD40-CD40L interaction/signaling. Although numerous studies have provided a detailed description of CD40L deficiency, reports of CD40 deficiency are scarce. Herein, we describe the characteristics of all reported patients with CD40 deficiency. The PubMed, Embase and Web of Science databases were searched for relevant literature published till 7th August 2023. Study deduplication and identification of relevant reports was performed using the online PICO Portal. The data were extracted using a pre-designed data extraction form and the SPSS software was used for analysis. Systematic literature review revealed 40 unique patients with CD40 deficiency. Respiratory tract and gastrointestinal infections were the predominant clinical manifestations (observed in 93% and 57% patients, respectively). Sclerosing cholangitis has been reported in nearly one-third of patients. Cryptosporidium sp. (29%) and Pneumocystis jirovecii (21%) were the most common microbes identified. Very low to undetectable IgG levels and severely reduced/absent switch memory B cells were observed in all patients tested/reported. Elevated IgM levels were observed in 69% patients. Overall, splice-site and missense variants were the most common (36% and 32%, respectively) molecular defects identified. All patients were managed with immunoglobulin replacement therapy and antimicrobial prophylaxis was utilized in a subset. Hematopoietic stem cell transplantation (HSCT) has been performed in 45% patients (curative outcome observed in 73% of these patients). Overall, a fatal outcome was reported in 21% patients. We provide a comprehensive description of all important aspects of CD40 deficiency. HSCT is a promising curative treatment option for CD40 deficiency.
2023-10-26 | Case Report: The impact of severe cryptosporidiosis on the gut microbiota of a pediatric patient with CD40L immunodeficiency
Cryptosporidium parvum is a protozoan parasite and one of the leading causes of gastroenteritis in the world, primarily affecting very young children and immunocompromised patients. While infection is usually self-limiting, it can become chronic and even lethal in these vulnerable populations, in whom Cryptosporidium treatments are generally ineffective, due to their acting in concert with a functioning immune system. Here, we describe a case of chronic cryptosporidiosis in a European child with severe CD40L immunodeficiency infected with Cryptosporidium parvum of the IIa20G1 subgenotype, a lineage which has thus far only ever been described in the Middle East. After years of on-off treatment with conventional and non-conventional anti-parasitic drugs failed to clear parasitosis, we performed targeted metagenomics to observe the bacterial composition of the patient’s gut microbiota (GM), and to evaluate fecal microbiota transplantation (FMT) as a potential treatment option. We found that C. parvum infection led to significant shifts in GM bacterial composition in our patient, with consequent shifts in predicted intestinal functional signatures consistent with a state of persistent inflammation. This, combined with the patient’s poor prognosis and increasing parasitic burden despite many rounds of anti-parasitic drug treatments, made the patient a potential candidate for an experimental FMT procedure. Unfortunately, given the many comorbidities that were precipitated by the patient’s immunodeficiency and chronic C. parvum infection, FMT was postponed in favor of more urgently necessary liver and bone marrow transplants. Tragically, after the first liver transplant failed, the patient lost his life before undergoing FMT and a second liver transplant. With this case report, we present the first description of how cryptosporidiosis can shape the gut microbiota of a pediatric patient with severe immunodeficiency. Finally, we discuss how both our results and the current scientific literature suggest that GM modulations, either by probiotics or FMT, can become novel treatment options for chronic Cryptosporidium infection and its consequent complications, especially in those patients who do not respond to the currently available anti-parasitic therapies.
2023-05-13 | CD40LG-associated X-linked Hyper-IgM Syndrome (XHIGM) with pulmonary alveolar proteinosis: a case report
Abstract Background D40LG -associated X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis has rarely been reported, and its genotype-phenotypic correlation remains elusive. Case presentation We describe a five-month-old boy with CD40LG mutation (c.516T > A, p.Tyr172Ter) X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis as the first manifestation. The patient completely recovered after immunotherapy and allogeneic hematopoietic stem cell transplantation. In addition, four previously reported patients with CD40LG mutation with pulmonary alveolar proteinosis were also analyzed. All of these patients presented with early onset of pulmonary infections and a good response to immunotherapy. The structural model of CD40LG indicated that all mutations caused the X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis to be located within the tumor necrosis factor homology domain. Conclusions A case was presented, and the characteristics of four cases of CD40LG -associated X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis were summarized. The variant locations may explain the phenotypic heterogeneity of patients with the CD40LG mutation.
proteins
2026-07-14 | Relevance of a Computational Deep-Dive to Characterize the Molecular Biology of a Novel Cd40l Variant
CD40L deficiency is a well-described inborn error of immunity (IEI). The disease is characterized immunologically by impaired class-switching and T cell costimulation. A male infant presented at 8 months of age with recurrent cellulitis. At 11 months, he was admitted for prolonged fever and leukopenia with vomiting and watery diarrhea, periorbital edema, back abscess, increased sIL2R at 50,598 pg/mL (<14,491), and normal CXCL9 at 22 pg/mL with mild to modest increases in IL-18 at 694 pg/mL (<185.4), IL-6 at 226.4 pg/mL (<10), serum amyloid A (SAA) at 1,413 mcg/mL (<373.8), IL-8 at 196 (<10), and IL-10 at 101pg/mL (<10). His IgG and IgA were low at <30 and <10 mg/dL, respectively. He developed Pseudomonas sepsis, palatal ulceration, jejunal perforation requiring repair, Candida peritonitis, persistent neutropenia, CMV, and Parechovirus viremia. Along with the hypogammaglobulinemia, class-switched memory B cells were decreased for age. Flow cytometry was performed for CD40L expression on activated CD4+ T cells along with functional evaluation of ligand binding to a soluble form of the receptor (CD40), using CD40-muIg. There was significantly diminished CD40L expression with essentially absent binding to the receptor. Genetic testing confirmed a diagnosis of CD40L deficiency due to a hemizygous variant in CD40LG, c.674T>C; p.Leu225Ser (NM_000074.2). We had previously evaluated a 4-year-old male with intermittent, non-bloody diarrhea, pneumonia, hypogammaglobulinemia, and significant neutropenia, and identified this novel variant, now also observed in this infant. We utilized advanced computational tools to evaluate the molecular impact of this variant on the structure and function of CD40L. The Leu225Ser variant is located within the trimerization interface of CD40L. Molecular modeling, mutagenesis alanine scanning, and molecular dynamic simulations revealed that the variant causes loss of critical intramolecular time-dependent interactions between hydrophobic molecules that would typically facilitate trimerization of wild-type CD40L for optimal interaction with the CD40 receptor. This analysis of the Leu225Ser variant revealed the molecular basis of the decreased CD40L protein expression (loss of contact to form trimers) and impaired CD40 binding (loss of intramolecular bonds affecting folding and impaired interaction at the trimerization interface). The patient also had immune paralysis due to decreased MHC class II (HLA-DR) expression on CD14+ monocytes, a result of a compensatory anti-inflammatory response syndrome (CARS). Assessment of neutrophil activation and granule markers (CD66b, lactoferrin, myeloperoxidase [MPO], and elastase) revealed low-normal CD66b and lactoferrin with slightly increased MPO and elastase, suggesting a complex and dysfunctional neutrophil response rather than simple activation or deactivation. This phenotype is consistent with the known pathology of CD40L deficiency, in which neutrophils are defective in their ability to respond effectively to infection, leading to chronic inflammation and tissue damage despite persistent signs of granule release. Treatment with rIFNg has been shown to reverse neutrophil dysfunction in X-linked hyper-IgM syndrome (XHIGM) but also restore HLA-DR expression on monocytes and reverse immune paralysis. He is currently being evaluated for hematopoietic cell transplantation (HCT). This case exemplifies the relevance of utilizing a variety of strategies to evaluate novel variants in IEI genes. Further, molecular and computational studies permitted an improved understanding of the impact of the Leu225Ser variant on CD40L protein expression and function.
2025-11-20 | Coexistence of familial hemophagocytic lymphohistiocytosis type 3 and X-linked hyper IgM syndrome in a child
Background: Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening hyperinflammatory syndrome characterized by excessive activation of the immune system, leading to symptoms such as fever, multilineage cytopenia, coagulopathy, and multi-organ failure, with a high risk of mortality. Its non-specific clinical presentation often poses a diagnostic challenge, especially when the line between primary and secondary HLH is blurred, as secondary triggers, such as infections, can unmask an underlying genetic condition. The incidence of HLH is elevated in patients with inborn errors of immunity (IEI). Case report: We report the case of a 9-month-old male infant with classic HLH, including prolonged fever, hepatosplenomegaly, thrombocytopenia, elevated ferritin, and hemophagocytosis in the bone marrow aspirate. Notably, the patient also had an opportunistic Aspergillus infection, which is a hallmark of severe immunodeficiency. Genetic analysis revealed a rare co-occurrence of two pathogenic variants: a compound heterozygous c.859-3C>T mutation in UNC13D (causing familial hemophagocytic lymphohistiocytosis type 3) and a recessive c.158_161del mutation in CD40LG (causing hyper-IgM syndrome). The infant was diagnosed with HLH on the background of hyper-IgM syndrome based on HLH-2004 criteria and responded well to a combined treatment of chemotherapy and immunoglobulin replacement therapy. Conclusions: This case highlights the crucial role of comprehensive IEI screening in patients with HLH, particularly those with a history of recurrent or opportunistic infections, to facilitate accurate diagnosis and optimize treatment strategies.
2020-04-23 | Blood-Borne ST6GAL1 Regulates Immunoglobulin Production in B Cells
Humoral immunity is an effective but metabolically expensive defense mechanism. It is unclear whether systemic cues exist to communicate the dynamic need for antigen presentation and immunoglobulin production. Here, we report a novel role for the liver-produced, acute phase reactant ST6GAL1 in IgG production. B cell expression of ST6GAL1, a sialyltransferase mediating the attachment of a2,6-linked sialic acids on N-glycans, is classically implicated in the dysregulated B cell development and immunoglobulin levels of St6gal1-deficient mice. However, the blood-borne pool of ST6GAL1, upregulated during systemic inflammation, can also extrinsically modify leukocyte cell surfaces. We show that B cell independent, extracellular ST6GAL1 enhances B cell IgG production and increases blood IgG titers. B cells of mice lacking the hepatocyte specific St6gal1 promoter have reduced sialylation of cell surface CD22 and CD45 and produce less IgG upon stimulation. Sialylation of B cells by extracellular ST6GAL1 boosts expression of IgM, IgD, and CD86, proliferation, and IgG production in vitro. In vivo, elevation of blood ST6GAL1 enhances B cell development and systemic IgG in a CD22- dependent manner. Our data point to a function of an extracellular glycosyltransferase in promoting humoral immunity. Manipulation of systemic ST6GAL1 may represent an effective therapeutic approach for humoral insufficiency
2019-09-17 | CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ.
Patients with X-linked hyper-IgM syndrome caused by CD40 ligand (CD40L) deficiency often present with episodic, cyclic, or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L-CD40 interaction. However, even when not neutropenic and despite immunoglobulin replacement therapy, CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired phagocyte function and the need for novel therapeutic approaches. We sought to analyze whether peripheral neutrophils from CD40L-deficient patients display functional defects and to explore the in vitro effects of recombinant human IFN-γ (rhIFN-γ) on neutrophil function. We investigated the microbicidal activity, respiratory burst, and transcriptome profile of neutrophils from CD40L-deficient patients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function. Neutrophils from CD40L-deficient patients exhibited defective respiratory burst and microbicidal activity, which were improved in vitro by rhIFN-γ but not soluble CD40L. Moreover, neutrophils from patients showed reduced CD16 protein expression and a dysregulated transcriptome suggestive of impaired differentiation. Similar to CD40L-deficient patients, CD40L knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that soluble CD40L induces the promyelocytic cell line HL-60 to proliferate and mature by regulating the expression of genes of the same Gene Ontology categories (eg, cell differentiation) when compared with those dysregulated in peripheral blood neutrophils from CD40L-deficient patients. Our data suggest a nonredundant role of CD40L-CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN-γ, indicating a potential novel therapeutic application for this cytokine.
2018-12-06 | A tetrameric form of CD40 ligand with potent biological activities in both mouse and human primary B cells
CD40 ligand (CD40 L) expressed by activated T cells interacts with CD40 on B cells and triggers B cell survival, proliferation and differentiation. Deficiency in CD40 L or CD40 in humans causes hyper IgM syndrome due to a defect in T-B interaction that is essential for Ig gene class switch recombination (CSR). CD40 L belongs to the tumor necrosis factor family and normally forms a homotrimer on the cell surface, which is important for its biological activity. To generate a multimeric CD40 L that can be used to stimulate both mouse and human B cells, we fused the extracellular domain of mouse CD40 L, which is known to also bind human CD40, with streptavidin (SA) that forms a stable tetramer under physiological conditions. As expected, 293 T cells transiently transfected with an SA-CD40 L expression vector secreted tetrameric SA-CD40 L in the culture supernatant. The secreted SA-CD40 L exhibited > 25-fold stronger activities in inducing the survival, activation and proliferation of both mouse and human primary B cells than did an agonistic anti-mouse or anti-human CD40 antibody. In the presence of IL-4, SA-CD40 L also induced efficient CSR and plasma cell differentiation in both mouse and human B cells. Moreover, administration of SA-CD40 L in mice induced activation and proliferation of spleen B cells in vivo. These results demonstrate that the SA-CD40 L fusion protein generated in the present study recapitulates the function of membrane-bound trimeric CD40 L and has potent biological activities in both mouse and human primary B cells.
gene therapies
2026-05-01 | A First-in-Human Base Edit Gene Therapy for CD40L Deficiency X-Linked Hyper IgM (XHIGM) Syndrome
CD40L-deficient X-linked hyper IgM (XHIGM) syndrome is characterized by defective B cell class switching, deficiency of immunoglobulins G, A, and E, plus other immune abnormalities due to disrupted CD40L–CD40 interaction. Allogeneic hematopoietic stem cell (HSC) transplant can cure XHIGM but requires myeloablative conditioning and risks graft versus host disease (GVHD), posing a high mortality risk. We developed ex vivo base editing (BE) of autologous HSC and T cells to treat a 37-year-old man (P1) diagnosed late in life with a CD40LG c.C>T p.Q220X mutation in a single-patient Investigational New Drug application targeting his mutation (IND32000; NIH protocol 002385). Preclinical studies achieved >90% gene correction of P1 HSC and T cells with base editor ABE8e SpWT/A5 guide, devoid of significant unintended off-target edits. BE-HSC was intended as a definitive transplant to achieve long-term hematopoietic and immune reconstitution, whereas the BE-T cells were designed to serve as a transient bridge therapy of functional T cells during the period preceding differentiation of T cells from the BE-HSC graft. P1 presented pre-gene therapy with sclerosing cholangitis, cryptosporidium infection, nodular regenerative hyperplasia, portal hypertension, bronchiectasis, and lacked HLA-matched donors. Autologous BE-HSC transplant was given after low-dose busulfan conditioning together with prophylactic defibrotide to mitigate chemo-related veno-occlusive disease. The original treatment schema was alemtuzumab (days −21, −20, −19), busulfan 6mg/kg total (days −3, −2) with prophylactic defibrotide, BE-HSC (day 0), and BE-T on day +14 and as indicated for lymphopenia and/or infection. Following alemtuzumab, P1’s baseline abnormal liver function tests (LFTs) worsened (transaminases approximately doubled, bilirubin increased ∼18-fold) with persistent detection of previously undetectable cryptosporidium. We paused busulfan and BE-HSC and administered BE-T products, which corrected LFTs sufficiently to allow uneventful busulfan conditioning and BE-HSC product infusion. Post-treatment at months 1 and 2, blood studies confirmed robust engraftment with normal wild-type alleles in myeloid cells (>90%) and increasing levels in natural killer (>60%), B (>40%), and T (27%) cells and with first-time detection of class-switched IgG+ B cells. This innovative, dual-product strategy provides immediate, on-demand immune protection through infusion of functional BE-T cells, effectively bridging patients through the critical pre-engraftment period and until BE-HSC achieves durable, multilineage reconstitution.
2021-05-06 | Complex preimplantation genetic tests for Robertsonian translocation, HLA, and X-linked hyper IgM syndrome caused by a novel mutation of CD40LG gene.
To perform complex preimplantation genetic tests (PGT) for aneuploidy screening, Robertsonian translocation, HLA-matching, and X-linked hyper IgM syndrome (XHIGM) caused by a novel mutation c.156 G>T of CD40LG gene. Reverse transcription PCR (RT-PCR) and Sanger sequencing were carried out to confirm the causative variant of CD40LG gene in the proband and parents. Day 5 and D6 blastocysts, obtained by in vitro fertilization (IVF) with intracytoplasmic sperm injection, underwent trophectoderm (TE) biopsy and whole genomic amplification (WGA) and next generation sequencing (NGS)-based PGT to detect the presence of a maternal CD40LG mutation, aneuploidy, Robertsonian translocation carrier, and human leukocyte antigen (HLA) haplotype. Sanger sequencing data of the genomic DNA showed that the proband has a hemizygous variant of c. 156 G>T in the CD40LG gene, while his mother has a heterozygous variant at the same position. Complementary DNA (cDNA) of CD40LG amplification and sequencing displayed that no cDNA of CD40LG was found in proband, while only wild-type cDNA of CD40LG was amplified in the mother. PGT results showed that only one of the six tested embryos is free of the variant c.156 G>T and aneuploidy and having the consistent HLA type as the proband. Meanwhile, the embryo is a Robertsonian translocation carrier. The embryo was transplanted into the mother's uterus. Amniotic fluid testing results are consistent with that of PGT. A healthy baby girl was delivered, and the peripheral blood testing data was also consistent with the testing results of transplanted embryo. The novel mutation of c. 156 G>T in CD40LG gene probably leads to XHIGM by nonsense-meditated mRNA decay (NMD), and complex PGT of preimplantation genetic testing for monogenic disease (PGT-M), aneuploidy (PGT-A), structural rearrangement (PGT-SR), and HLA-matching (PGT-HLA) can be performed in pedigree with both X-linked hyper IgM syndrome and Robertsonian translocation.
2020-06-11 | CD40 ligand deficiency: treatment strategies and novel therapeutic perspectives.
CD40 ligand (CD40L) deficiency or X-linked Hyper-IgM syndrome is a severe primary immunodeficiency caused by mutations in the CD40L gene. Despite currently available treatments, CD40L-deficient patients remain susceptible to life-threatening infections and have poor long term survival. Areas covered: Here, we discuss clinical and immunological characteristics of CD40L deficiency as well as current therapeutic strategies used for patient management. This review highlights that beyond B cell defects, patients' susceptibility to opportunistic pathogens might be due to impaired T cell and innate immune responses. In this context, we discuss how better knowledge of CD40L function and regulation may result in the development of new treatments. Expert opinion: Despite the introduction of hematopoietic stem-cell transplantation, immunoglobulin replacement, granulocyte colony-stimulating factor (G-CSF) administration, and prophylactic antibiotic therapies, life-threatening infections still cause high morbidity and mortality among CD40L-deficient patients. The reasons for this inadequate response to current therapies remains poorly understood, but recent reports suggest the involvement of CD40L-CD40 interaction in early stages of the innate immune system ontogeny. The development of novel gene therapeutic approaches and the use of redirected immunotherapies represent alternative treatment methods that could offer reduced morbidity and mortality rates for patients with CD40L deficiency.
2018-05-01 | Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome
X-linked hyper-immunoglobulin M (hyper-IgM) syndrome (XHIM) is a primary immunodeficiency due to mutations in CD40 ligand that affect immunoglobulin class-switch recombination and somatic hypermutation. The disease is amenable to gene therapy using retroviral vectors, but dysregulated gene expression results in abnormal lymphoproliferation in mouse models, highlighting the need for alternative strategies. Here, we demonstrate the ability of both the transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) platforms to efficiently drive integration of a normal copy of the CD40L cDNA delivered by Adeno-Associated Virus. Site-specific insertion of the donor sequence downstream of the endogenous CD40L promoter maintained physiologic expression of CD40L while overriding all reported downstream mutations. High levels of gene modification were achieved in primary human hematopoietic stem cells (HSCs), as well as in cell lines and XHIM-patient-derived T cells. Notably, gene-corrected HSCs engrafted in immunodeficient mice at clinically relevant frequencies. These studies provide the foundation for a permanent curative therapy in XHIM.
2017-11-13 | Prospects for modulating the CD40/CD40L pathway in the therapy of the hyper-IgM syndrome
The critical role of the CD40/CD40L pathway in B-cell proliferation, immunoglobulin (Ig) isotype switching and germinal center formation has been studied and described extensively in previous literature. Interruption of the CD40/CD40L signal causes hyper-IgM (HIGM) syndrome, which has been classified and recognized as a group of rare inherited immune deficiency disorders. Defects in CD40 and CD40L interactions or in downstream signaling molecules, including activation-induced cytidine deaminase, uracyl-DNA-glycosylase, NF-κB and DNA repair enzymes, result in an increased level of serum IgM and a significantly decreased or absent level of IgA, IgG and IgE that is accompanied by severe recurrent infections and autoimmune diseases. Many genetic defects in HIGM have been identified and, as a result, it is possible for patients to be definitively diagnosed by gene sequencing and to delineate the immunological features of the patients. Modifying the CD40/CD40L signaling pathway may offer the possibility of restoring the normal serum Ab production and curing the immunodeficiency. Hematopoietic stem cell transplantation has achieved a high rate of success using a sibling donor. In addition, successful examples of treating other immunodeficiencies using gene therapy indicated that there was a possibility of eradicating HIGM with this approach. In this review, we summarize the current drugs and a variety of therapeutic approaches for the treatment of the HIGM syndrome by interfering with the defective CD40/CD40L pathway.
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