X-linked hyper-IgM Syndrome Research Articles

Preimplantation diagnosis for immunodeficiencies

Preimplantation genetic diagnosis (PGD) has become an established procedure for the detection of single gene disorders, and has recently been performed together with human leukocyte antigen (HLA) typing for couples with children affected by genetic disorders that require HLA-identical stem cell transplantation therapy. For these couples, PGD can ensure the birth of an unaffected child, and because HLA-matched stem cell transplantation improves or completely restores the immune system, this child may also serve as a potential stem cell donor for affected siblings. This paper presents the first cumulative experience (18 cycles) of PGD for detection of the following immunodeficiencies: Wiscott–Aldrich syndrome, X-linked hyper-IgM syndrome (HIGM), X-linked hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID), ataxia telangiectasia and Omenn syndrome, resulting in the transfer of unaffected embryos in 13 cycles and the birth of seven unaffected children, with one healthy pregnancy ongoing. HLA-identical stem cells from some of these children have been used for transplantation therapy, resulting in the restoration of normal function in siblings with HIGM and HED-ID.

C-Rel plays a key role in deficient activation of B cells from a non–X-linked hyper-IgM patient

AbstractOur previous results demonstrated that B cells from a patient (pt1) with non–X-linked hyper-IgM syndrome (HIGM) possess an atypical CD23lo phenotype that is unaffected by CD40-mediated activation. To investigate the molecular mechanism underlying defective CD23 expression in pt1 B cells, we used lymphoblastoid cell lines that express LMP1 under the control of a tetracycline-inducible promoter (LCLtet). Our analysis revealed that the CD23lo phenotype in the pt1-LCLtet cells is a direct consequence of diminished CD23 transcription. We demonstrate a marked decrease in c-Rel–containing complexes that bind to the proximal CD23a/b promoters in pt1-LCLtet extracts, resulting from an overall lower expression of c-Rel in pt1-LCLtet cells. Analysis of c-Rel mRNA revealed relatively equal amounts in pt1-LCLtet and control LCLtet cells, indicating that diminished c-Rel protein expression is unrelated to decreased transcription. Finally, a critical role for c-Rel in CD23 regulation was demonstrated by effectively altering c-Rel expression that resulted in the direct modulation of CD23 surface expression. Collectively, these findings demonstrate that low levels of c-Rel are the underlying cause of aberrant CD23 expression in pt1 B cells and are likely to play a critical role in the pathophysiology of this form of HIGM.

Prévalence de la pneumopathie à Pneumocystis Jiroveci au cours des déficits immunitaires héréditaires observés en Tunisie

Pneumocystis Jiroveci pneumonia (PJP) is a rare opportunistic infection in immunodeficient patients in Tunisia, as well as in other Africain countries including those with a high prevalence of AIDS. In the literature, PJP has been reported in primary immunodeficiency diseases (PID) namely SCID T –B – or T –B + or X-linked hyper-IgM syndrome. Objective To evaluate the prevalence of PJP in the different PID observed in Tunisia. Patients and methods This retrospective study concerned 290 cases of PID confirmed by immunological investigation including the study of specific and/or non-pecific humoral and cellular immunity. The identification of P. Jiroveci in patients suspected of pneumocystosis was achieved by parasitological investigation in bronchoalveolar lavages. Results A PID associated to a parasitologically confirmed pneumocystic infection was found in 9 out of 290 patients (3%) among whom the majority (7 patients) had an HLA class II combined immunodeficiency. The latter is an autosomic recessive disease which has been reported mainly in North African families. Indeed, this population is characterized by a high rate of consanguinity. Interestingly, no PJP has been observed neither in SCID T –B – or T –B + nor in X-linked hyper-IgM syndrome. Discussion and conclusion PJP seems to be particularly frequent in HLA class II deficiency patients, since 7 out of 22 patients with this deficiency had a PJP (31%). Due to this defect, antigen presenting cells are unable to present the antigen to T lymphocytes demonstrating the critical role of CD4 + T lymphocytes responses in the immune response to this pathogen.

High-Grade Neuroendocrine Tumor in a 21 Year Old Man with X-Linked Hyper IgM Syndrome

High-Grade Neuroendocrine Tumor in a 21 Year Old Man with X-Linked Hyper IgM Syndrome

Use of intravenous immunoglobulin in human disease: A review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology

Human immunoglobulin prepared for intravenous administration (IGIV) has a number of important uses in the treatment of disease. Some of these are in diseases for which acceptable treatment alternatives do not exist. In this review we have evaluated the evidence underlying a wide variety of IGIV uses and make specific recommendations on the basis of these data. Given the potential risks and inherent scarcity of IGIV, careful consideration of the indications for and administration of IGIV is warranted.

Penicillosis in Patients with X-linked Hyperimmunoglobulin M Syndrome (XHIGM), Case Reports from Thailand

Penicillosis in Patients with X-linked Hyperimmunoglobulin M Syndrome (XHIGM), Case Reports from Thailand

Natural Evolution of a Human Virus-Specific Antibody Gene Repertoire by Somatic Hypermutation Requires Both Hotspot-Directed and Randomly-Directed Processes

Somatic hypermutation of antibody genes is mediated by activation-induced cytidine deaminase and targets primarily hotspot motifs. We tested the hypothesis that the antibody variable genes of virus-specific B cells from infants exhibit a decreased frequency of somatic mutations compared with adults. We also sought to determine whether virus-specific B cells exhibit predominantly hotspot or randomly directed processes. We analyzed somatic mutations in rotavirus (RV)-specific B cells from otherwise healthy but recently RV-infected infants or adults in comparison with B cells from healthy volunteers not recently infected. We compared these antibody variable gene sequences with those derived from RV-specific B cells from an adult patient with X-linked hyper-IgM syndrome (XHIM). We found that the overall mutational frequency within the antibody variable region was lowest in RV-specific B cells from RV-infected infants, followed by randomly selected B cells, followed by RV-specific B cells from the patient with XHIM. RV-specific memory B cells from healthy adults exhibited the highest frequency of mutations. Approximately half of mutations in random or RV-specific B cells from adults or infants occurred at the DGYW/WRCH or WA/TW hotspot motifs. These findings suggest that virus-specific antibodies require both hotspot and randomly-directed processes.

Autoimmune Retinopathy with RPE Hypersensitivity and ‘Negative ERG’ in X-Linked Hyper-IgM Syndrome

Purpose: To report the clinical, electrophysiological, and immunological features of a patient with X-linked hyper-IgM immunodeficiency syndrome type 1 (HIGM1) accompanied by a novel type of autoimmune retinopathy, including retinal pigment epithelium (RPE) hypersensitivity. Methods: Comprehensive ophthalmological examinations, electrophysiological function testing, and inquiries into the immunological status of a 13-year-old presenting with subacute loss of vision in association with a molecularly confirmed diagnosis of HIGM1 were performed. The patient was genotyped by a PCR-based sequence tag content mapping strategy to define the genetic defect within the causative X-HIM gene TNFSF5. Since conventional allogenic bone marrow transplantation has been reported to cure HIGM1, a peripheral blood stem-cell transplantation was performed. Results: (1) The patient's reduced visual acuity included prolonged dark adaptation and visual field constriction. Electrophysiology revealed a ‘negative ERG’ indicating post-receptoral dysfunction. (2) Initial immunological examination of the patient's serum identified abnormal antibody activity with components of the photoreceptors and the inner nuclear layer. The patient later developed indications of RPE hypersensitivity. A massively reduced light-peak to dark-trough ratio of the EOG slow oscillations (L/D ratio) corresponded to impaired RPE-photoreceptor complex function. (3) Molecular genetic analyses revealed the patient to be nullizygous for the tumor necrosis factor ligand member 5 gene (TNFSF5; CD40LG). A large chromosomal deletion of ∼27.6–32.3 kb in size was identified in Xq26. (4) The transplant with its associated immunomodulation appeared to worsen rather than improve the patient's condition. Conclusions: The fundus appearance and electrophysiological function testing revealed indications of atypical retinal degeneration. However, the clinical course and the serological findings were consistent with those of ocular autoimmunity involving both antiretinal activity and RPE hypersensitivity. In this case, peripheral stem-cell transfusion with its associated chemotherapy failed to benefit the patient's vision; indications of autoimmunity appeared to increase following this treatment.

CD40-CD40L interactions in platelet activation

C D40L (CD154) is a type II transmembrane protein and a member of the tumor necrosis factor (TNF) family. It exists as a trimer in membranes, held together through interactions within the extracellular domains of the protein. During an immune response, the TNF homology domains of the protein on T cells bind CD40 on antigen-presenting cells, an activity required for isotype switching from immunoglobulin M to immunoglobulin G. Accordingly, a defective CD40L gene is responsible for the X-linked hyper-IgM syndrome, a rare immunodeficiency disease characterized by the absence of circulating IgE or IgA, and germinal centers. Since its initial description on lymphocytes, a large body of evidence has been accumulating, demonstrating that CD40L is present on other vascular cells, where it plays a pivotal role in inflammation and thrombosis in various clinical conditions, such as atherothrombosis, immuno- inflammatory disease or cancer. . . .

Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation

Hypomorphic mutations in the zinc finger domain of NF-κB essential modulator (NEMO) cause X-linked hyper-IgM syndrome with ectodermal dysplasia (XHM-ED). Here we report that patient B cells are characterized by an absence of Ig somatic hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction of activation-induced cytidine deaminase (AID) and Iε-Cε transcripts. This indicates that AID expression alone is insufficient to support neutralizing antibody responses. Furthermore, we show that patient B cells stimulated with CD40 ligand are impaired in both p65 and c-Rel activation, and whereas addition of IL-4 can enhance p65 activity, c-Rel activity remains deficient. This suggests that these NF-κB components have different activation requirements and that IL-4 can augment some but not all NEMO-dependent NF-κB signaling. Finally, using microarray analysis of patient B cells we identified downstream effects of impaired NF-κB activation and candidate factors that may be necessary for CSR and SHM in B cells.

Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation

Hypomorphic mutations in the zinc finger domain of NF-kappaB essential modulator (NEMO) cause X-linked hyper-IgM syndrome with ectodermal dysplasia (XHM-ED). Here we report that patient B cells are characterized by an absence of Ig somatic hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction of activation-induced cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts. This indicates that AID expression alone is insufficient to support neutralizing antibody responses. Furthermore, we show that patient B cells stimulated with CD40 ligand are impaired in both p65 and c-Rel activation, and whereas addition of IL-4 can enhance p65 activity, c-Rel activity remains deficient. This suggests that these NF-kappaB components have different activation requirements and that IL-4 can augment some but not all NEMO-dependent NF-kappaB signaling. Finally, using microarray analysis of patient B cells we identified downstream effects of impaired NF-kappaB activation and candidate factors that may be necessary for CSR and SHM in B cells.

5. IgE, mast cells, basophils, and eosinophils

IgE, mast cells, basophils, and eosinophils constitute essential elements in allergic inflammation. Allergen-specific IgE, synthesized in response to allergens in the environment, becomes fixed to FcepsilonRI on the membranes of mast cells and basophils. Aggregation of receptor-bound IgE molecules on re-exposure to specific allergen results in the production of mediators that produce the allergic response. Principal among the cells drawn to sites of mediator release is the eosinophil.

Smarter rather than stronger treatment of haematological malignancies and non-malignant indications for stem-cell transplantation

In today's Lancet, David Jacobsohn and colleagues summarise their experience with reduced-intensity conditioning or non-myeloablative stem-cell transplantation for the treatment of various non-malignant diseases in children, including sickle-cell anaemia, X-linked hyper-IgM syndrome, Sandhoff's disease, and immune dysfunction syndromes. The use of non-myeloablative stem-cell transplantation, with fludarabine and busulfan and later busulfex, for more reliable bioavailability, especially in children and to reduce possible liver toxicity from first pass of the absorbed compound, was pioneered in Jerusalem in adults and subsequently in children. 1 Slavin S Nagler A Naparstek E et al. Non–myeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and non malignant hematologic diseases. Blood. 1998; 91: 756-763 PubMed Google Scholar Reduced intensity haemopoietic stem-cell transplantation for treatment of non-malignant diseases in childrenThis reduced intensity regimen followed by HSCT provides a good alternative to myeloablative HSCT for children with non-malignant disorders, except for haemoglobinopathies, in which engraftment is poor. Even patients with unrelated donor haemopoietic stem-cell transplants had adequate engraftment with acceptable toxicities. Full-Text PDF

Allogeneic hematopoietic stem cell transplantation for seven children with X-linked hyper-IgM syndrome: a single center experience.

X-linked hyper-IgM syndrome (XHIM), or hyper-IgM syndrome type 1 (HIGM1), is a rare primary immunodeficiency disorder susceptible to recurrent bacterial infection and opportunistic infection such as Pneumocystis carinii and Cryptosporidium parvum. The long-term outcome is quite poor, and allogeneic hematopoietic stem cell transplantation (HSCT) offers the only cure. Seven patients with XHIM, from age 3 to 19 years (mean 11.3 years), underwent allogeneic HSCT in our institution. Details of pre- and post-transplantation data and transplantation procedure were analyzed retrospectively. The donors were HLA-identical siblings for three patients and HLA-identical unrelated donors for four patients. All but one received conventional conditioning regimen consisting of busulfan and cyclophosphamide and prophylaxis for graft-versus-host disease (GVHD) consisting of cyclosporine and methotrexate. Five out of seven patients are alive and well with normal CD40L expression, and four of these five are free of intravenous immunoglobulin supplementation. The two patients who died had prolonged episodes of severe and recurrent infections and organ damage. We conclude that conventional allogeneic HSCT from HLA matched related or unrelated donors is curative and feasible for XHIM patients, if performed before significant infections and organ damage occur. For the high-risk patients, an alternative approach including nonmyeloablative HSCT may be more feasible.

Asymptomatic cryptosporidiosis with atypical cholangitis and eosinophilic hepatitis in X-linked hyper-IgM syndrome (XHIM)

Rationale XHIM is a rare form of immunodeficiency due to abnormally low expression of CD40 Ligand on CD4+ T-cells. XHIM patients present with variably diminished IgG, IgA, IgE and normal to high IgM levels. XHIM patients are predisposed to infections with fungi, encapsulated organisms and opportunistic organisms such as Cryptosporidium (Cry.). Cry. infection is usually associated with gastrointestinal symptoms but may also cause cholangitis in immune deficient patients. Methods 8 year old asymptomatic Hispanic male with XHIM and elevated liver enzymes was diagnosed with Cry. infection on fecal exam for oocytes and antigen. After failing metronidazole therapy, Cry. cleared from his stools after fourteen months of paromomycin therapy. Persistently elevated liver enzymes prompted an abdominal ultrasound (AUS), endoscopic retrograde cholangiopancreatography (ERCP) and liver biopsies. Results AUS showed mild dilatation throughout the biliary tract. ERCP revealed marked beading of the intrahepatic biliary tree suggesting cholangitis. Liver biopsy specimens obtained at three months and twelve months from the onset of elevated liver enzymes revealed eosinophilic inflammation with little fibrosis and no demonstrable organisms. Conclusions XHIM patients with Cry. infection and asymptomatic elevation of hepatic enzymes are at an increased risk for developing cholangitis and hepatic inflammation despite effective clearing of infection from the gastrointestinal tract. XHIM patients should be monitored closely for these complications.

The general characteristics of our patients with primer immunodeficiency

In this study, we aimed to identify the general characteristics of the patients who came to our department with primer immunodeficiency (PII) between 1993-200. We analyzed the medical files of the patients with PII followed up between 1993-2003 retrospectively. A total of 53 patients had PII. There were 31 males (58.5%), and 22 females (41.5%). The average age for the onset of symptoms was 5.8 months and the average age of the time of referral was 15.8 months. Of these patients, 32 (60.4%)had humoral immunodeficiency, 18 had (33.1%) T-cell immunodeficiency, and 3 had (5.6%) had phagocytic system dysfunction. The types of humoral immunodeficiencies were as follow; 11 patients had IgG subclass deficiency, 7 sIgA deficiency, 4 transient hypogammaglobulinemia of infancy, 4 X-linked agammaglobulinemia, 4 common variable immunodeficiency, and 2 autosomal hyper-IgM syndrome. Of the patients with T-cell deficiency, 7 had ataxia-telangiectasia, 5 SCID, 3 X-linked hyper-IgM syndrome, 2 Wiskott-Aldrich syndrome, and 1 DiGeorge. In phagocyte deficiency, 2 patients had Chediac-Higashi syndrome and 1 had LAD. Infection diseases of the patients according to their frequency were as follows; recurrent upper airway infections, lower recurrent lower airway infections, gastroenteritis, skin infections, deep layer apse, candidiasis, meningitis and septic arthritis. In conclusion, we found the humoral immunodeficiencies as the most common primary immunodeficiency disease, which is consistent with results in the literature. However, we believe that our results may not reflect the actual frequency and types of immunodeficiencies as most patients die without diagnosis or wrong diagnosis.

Functional defects of dendritic cells in patients with CD40 deficiency

AbstractWe have recently identified 2 patients with a rare autosomal recessive form of hyper IgM disease, known as HIGM3, caused by mutations in theCD40 gene. These patients had opportunistic infections observed on X-linked hyper IgM syndrome (HIGM), suggesting that the CD40-CD40 ligand interaction is important for promoting T-cell-mediated immunity. To evaluate whether innate immunity signals may substitute CD154 for inducing the maturation of dendritic cells (DCs), we analyzed monocyte-derived DCs in these patients. Monocyte-derived DCs of HIGM3 subjects on ex vivo stimulation with tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS) combined with interferon-γ (IFN-γ) normally express all the markers of mature DCs, such as CD83 and DC-LAMP. However, cell surface levels of HLA-DR in mature DCs are reduced, as is costimulatory activity of these cells for allogeneic naive T cells. In addition, CD40-deficient DCs secrete lower amounts of interleukin-12 (IL-12) but larger quantities of IL-10 than control subjects. Finally, analysis of circulating plasmacytoid DCs demonstrates a normal percentage of this subset in CD40-deficient cells, but IFN-α secretion in response to herpes simplex virus 1 (HSV-1) infection is severely reduced in patients. These observations suggest that the severe impairment of DC maturation may contribute to the defect of T-cell-mediated immunity observed in HIGM3 patients. (Blood. 2003;102:

X-linked Hyper IgM (HIGM1) in an African kindred: the first report from South Africa

BackgroundThe objective of this study was to describe the clinical and molecular features of the first South African family with X-linked hyper-IgM syndrome (HIGM1).MethodsDiagnoses were based on immunoglobulin results and the absence of CD40 ligand (CD40L) expression on activated T-cells. Complete molecular characterisation involved CD40L cDNA sequencing, and genomic DNA analysis by polymerase chain reaction amplification, restriction enzyme digestion and sequencing. A PCR-based diagnostic assay was established for carrier detection and prenatal diagnosis in this family.ResultsThere were originally six children, three males and three females. The eldest boy died after being diagnosed with hypogammaglobulinaemia, before HIGM1 was considered. This disorder was diagnosed in the second eldest boy at the age of 5 years, after failing to detect CD40L expression on his activated T-cells. A deficiency of CD40L was also confirmed in the youngest male at the age of 5 years. Both younger brothers have since died of infections relating to HIGM1. Molecular investigation showed that exon 3 was deleted from the CD40L mRNA of the affected males. Genomic DNA analysis identified a 1.5 kilobase deletion, spanning exon 3 and including extended flanking intronic sequence. Carrier status in the mother was confirmed by RT-PCR of her CD40L mRNA. Genetic analysis of the three female children was deferred because they were below the legal consenting age of 18 years. A PCR-based assay for genomic DNA was established for easy identification of female carriers and affected males in the future.ConclusionsThis study confirmed the diagnosis of HIGM1 in the first South African family to be investigated and identified a novel mutation in the CD40L gene.

The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.

The X-linked hyper-IgM (XHIGM) syndrome is an uncommon primary immunodeficiency disease caused by mutations in the gene for CD40 ligand and characterized by normal or elevated serum IgM, reduced levels of IgG and IgA, and defective T-cell function. Because of its rarity, it has been difficult for any single investigator or institution to develop a comprehensive clinical picture of this disorder. Accordingly, a national registry was developed in the United States to provide demographic, genetic, immunologic, and clinical information on a relatively large number of patients with the XHIGM syndrome.A total of 79 patients from 60 unrelated families were registered between January 1997 and July 2002. The estimated minimal incidence was approximately 1/1,030,000 live births. All of the patients had significant IgG deficiency and most had IgA deficiency, but only one-half had elevated IgM levels. Most patients presented initially with a history of an increased susceptibility to infection including Pneumocystis carinii pneumonia. The average age of diagnosis was significantly earlier in patients born into a family with a previously affected individual. However, only one-third of the patients born into a family with a previously affected individual were diagnosed exclusively because of the presence of the positive family history before any clinical symptoms developed. Over half the patients developed symptoms of immunodeficiency and were diagnosed by 1 year of age, and over 90% by 4 years of age. The most prominent clinical infections were pneumonia (81% of patients), upper respiratory infections (49%) including sinusitis (43%) and recurrent otitis (43%), recurrent/protracted diarrhea (34%), central nervous system infections (14%), sepsis (13%), cellulitis (13%), hepatitis (9%), and osteomyelitis (1%). In addition to infections caused by encapsulated bacteria, opportunistic infections were relatively common and were caused by P. carinii, members of the herpes virus family (including cytomegalovirus), Cryptosporidium, Cryptococcus, Candida, Histoplasma, and Bartonella. Sclerosing cholangitis occurred in 5 patients and in 4 of these was associated with Cryptosporidium infection. Eight patients had died at the time of their entry into the Registry; 2 of pneumonia (1 P. carinii and 1 cytomegalovirus), 2 of encephalitis (1 ECHO virus and 1 cytomegalovirus), 2 of malignancy (both hepatocellular carcinoma), 1 of sclerosing cholangitis caused by Cryptosporidium, and 1 of hemolytic uremic syndrome.

Three novel mutations reflect the variety of defects causing phenotypically diverse X-linked hyper-IgM syndrome.

X-linked hyper-IgM syndrome (HIGM1) (MIM musical sharp 308230), is a severe primary immunodeficiency caused by mutations in the gene coding for CD40 ligand (CD40L or CD154), a member of the tumour necrosis factor (TNF) superfamily. The interaction of this protein with its ligand, CD40, mediates crucial processes in the immune response. The variety of defects that have been described in HIGM1 patients range from a complete lack of CD40L protein expression to missense mutations that interfere with its interaction with CD40L. In this study we describe three families - a total of seven HIGM1 patients and carriers, presenting a spectrum of severity in clinical evolution. In two of these families, patient DNA samples were available for genetic studies. In the third, carrier detection was performed on female family members. The results of immunological studies - the different patterns of CD40L expression and binding capacity as measured by flow cytometry - and molecular diagnosis are presented. Three novel mutations were identified: an intron mutation that partially interferes with the splicing process (intron 3, position + 5 G/T); a missense mutation (Ser222 Phe) located in the molecular region which interacts with the receptor and which abrogates binding capacity; and a 14 base pair deletion leading to a frameshift and a premature truncated mutation (del I 171 X 195). An attempt to correlate protein expression and function of the CD40L mutants with clinical disease evolution is described.