The role of a mutation of the CXCR4 gene in WHIM syndrome

We investigated the role of a mutation of the CXCR4 gene in 11-year-old twin sisters with WHIM syndrome. The mutated gene may result in production of the mutant CXCR4 protein causing abnormal apoptosis and migratory function, which are thought to be related to the cause of chronic neutropenia in WHIM syndrome.     

Intravenous immunoglobulin (IVIG) efficiency in women with common variable immunodeficiency (CVID) decreases significantly during pregnancy

Immunoglobulin replacement therapy, including intravenous immunoglobulin (IVIG), is essential for pregnant women with common variable immunodeficiency (CVID) since it prevents infection and improves the health of the newborn. There are no established IVIG treatment protocols for pregnant women with CVID, and the relationship between IVIG treatment and maternal serum IgG changes during pregnancy remains unclear. Therefore, we reviewed the medical charts of four CVID patients, including one receiving subcutaneous immunoglobulin (SCIG), for IVIG dose and frequency, maternal serum IgG changes, obstetrical findings, and perinatal outcomes. There were no serious infections but one abortion and all patients continued therapy without IVIG-related adverse events. All eight children born to the patients were healthy at one month. However, the IVIG efficiency in those with CVID significantly decreased with progression of the gestational period, suggesting that IVIG dose and frequency may be changed during pregnancy to maintain stable serum IgG trough levels in women with CVID.     

Novel Igalpha (CD79a) gene mutation in a Turkish patient with B cell-deficient agammaglobulinemia

Mutations that impair early B cell development result in profound antibody deficiency, which is characterized by a paucity of mature B cells and the early onset of recurrent pyogenic infections. Among these inherited early B cell defects, X-linked agammaglobulinemia (XLA) with mutations in Bruton's tyrosine kinase (BTK) gene is mostly identified. Recent studies have shown that mutations in the gene for mu heavy chain (IGHM) and for other components of the pre-B cell receptor complex, including lambda5/14.1 (IGLL1) or Igalpha (CD79a), can cause a disorder that is clinically similar to XLA. In a genetic survey of XLA in Turkey, we examined possible mutations in the IGHM, IGLL1, and Igalpha genes in some male patients with presumed XLA who did not have identifiable BTK mutations. We found an eight-year-old boy with a novel homozygous mutation in the Igalpha gene (IVS2+1G>A) causing B cell defect. This is the second case of agammaglobulinemia due to an Igalpha (CD79a) deficiency in the world.     

Developmental changes of FOXP3-expressing CD4+CD25+ regulatory T cells and their impairment in patients with FOXP3 gene mutations

FOXP3 is required for the generation and function of CD4(+)CD25(+) regulatory T (Treg) cells. To elucidate the biological role of Treg cells, we used a monoclonal anti-FOXP3 antibody to examine the frequencies of Treg cells during child development. The percentages of CD4(+)CD25(+)FOXP3(+) T cells were constant shortly from after birth through adulthood. CD4(+)CD25(+)FOXP3(+) T cells in cord blood showed the naive CD45RA(+)CD45RO(-) phenotype, whereas adult CD4(+)CD25(+)FOXP3(+) T cells expressed mostly the memory CD45RA(-)CD45RO(+) phenotype. The age-dependent dominance of memory CD4(+)CD25(+)FOXP3(+) T cells implies functional differences between naive and memory Treg cells. Notably, four patients with FOXP3 gene mutations revealed a paucity of CD4(+)CD25(+)FOXP3(+) T cells. Importantly, one patient with a frame shift mutation, who showed typical symptoms of IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked), exhibited marked T cell activation, whereas others with missense mutations, who were clinically milder, did not. This observation suggests a possible genotype-phenotype correlation in IPEX.     

MxA-based recognition of viral illness in febrile children by a whole blood assay

Febrile children are often given antibiotics empirically and unnecessarily. MxA is a protein induced in peripheral lymphoid cells by type 1 interferons during active viral infection. The ability of a whole blood ELISA assay for MxA to identify children with viral illness was studied in 122 children who presented with acute onset fever and 52 age-matched healthy controls. The febrile children were divided into three groups according to their final diagnoses: etiologically diagnosed viral infection, clinically diagnosed viral infection, and bacterial infection. MxA levels in the bacterial infection group and controls were similar and low (90.9 +/- 69.7 and 76.9 +/- 63.2 ng/mL, respectively). In contrast, mean MxA levels in the two viral infection groups were higher than in both the bacterial and control groups (719.2 +/- 386.4 and 827.0 +/- 651.1, respectively). A receiver operating characteristic analysis showed that the area under the curve of the MxA level was greater than under the curves of both the white blood cell count and the C-reactive protein concentration. Whole blood assay of MxA is a clinically useful tool for diagnosing viral illness in febrile children and should help reduce use of unnecessary antibiotics.     

Role of transforming growth factor-beta in breast milk for initiation of IgA production in newborn infants

BACKGROUND: Transforming growth factor (TGF)-beta has a crucial effect on IgA production, which is the major humoral effector of mucosal immunity. Breast milk contains the abundant amount of TGF-beta in the early period of lactation. AIM-STUDY DESIGN: To verify the notion that TGF-beta in breast milk might contribute to the development of IgA production in newborns, we investigated the association of TGF-beta in maternal colostrum with an increase of serum IgA in newborns during the first month of life. SUBJECTS AND METHODS: The concentrations of TGF-beta1 and TGF-beta2, including IL-6 and IL-10, in colostrum samples from 55 healthy mothers were determined by ELISA. The levels of IgA and IgM in serum samples collected from corresponding newborn babies at birth and at 1 month of age were measured by ELISA. RESULTS: TGF-beta1 and TGF-beta2 were detected in substantial quantities in all colostrum samples, but IL-6 and IL-10 were present only in a proportion of samples. An increase of serum IgA in newborn during the first month of life was significantly higher than that of serum IgM (p<0.001). Notably, an increase of serum IgA in newborns during 1 month of life was well correlated with levels of both TGF-beta1 (r=0.38, p=0.005) and TGF-beta2 (r=0.45, p=0.0005) in colostrum, while that of IgM was marginally correlated with colostral TGF-beta2 (r=0.28, p=0.04). The association of increase of serum IgA in newborns with IL-6 and IL-10 in colostrum was not evident. CONCLUSION: Our findings suggest that TGF-beta in colostrum might serve as the starter of IgA production in newborn infants.     

Genetic analysis of contiguous X-chromosome deletion syndrome encompassing the BTK and TIMM8A genes

Patients with X-linked agammaglobulinemia (XLA) can present with sensorineural deafness. This can result from a gross deletion that not only involved the Bruton's tyrosine kinase (BTK) gene, but also TIMM8A, mutations in which underlie the Mohr-Tranebj?rg syndrome (MTS). We analyzed the genomic break points observed in three XLA-MTS patients and compared these with deletions break points from XLA patients. Patient 1 had a 63-kb deletion with break points in intron 15 of BTK and 4?kb upstream of TAF7L. Patients 2 and 3 had 149.7 and 196?kb deletions comprising BTK, TIMM8A, TAF7L and DRP2. The break points in patients 1 and 3 were located in Alu and endogenous retrovirus (ERV) repeats, whereas the break points in patient 2 did not show involvement of transposable elements. Comparison of gross deletion sizes and involvement of transposable elements in XLA and XLA-MTS patients from the literature showed preferential involvement of Alu elements in smaller deletions (<10?kb). These results show further insights into the molecular mechanisms underlying gross deletions in patients with primary immunodeficiency.     

Identification of FOXP3-negative regulatory T-like (CD4(+)CD25(+)CD127(low)) cells in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune disorder caused by mutations in the FOXP3 gene, which plays a key role in the generation of CD4⁺CD25⁺regulatory T (Treg) cells. We selected CD127 as the surface marker of Treg cells to illustrate the development and function of Treg cells in IPEX syndrome. CD4⁺CD25⁺FOXP3⁺ T cells, the putative Treg cells, were almost completely absent in all patients. Importantly, a substantial number of CD4⁺CD25⁺CD127^low T cells were observed in 3 IPEX patients with hypomorphic mutations in the FOXP3 gene. We demonstrated that CD4⁺CD25⁺CD127^low T cells isolated from these 3 patients exhibited an appreciable suppressive activity on effector T cell proliferation, although less than that displayed by Treg cells from healthy controls. These results suggest that genetically altered FOXP3 can drive the generation of functionally immature Treg cells, but that intact FOXP3 is necessary for the complete function of Treg cells.     

Disseminated BCG Infection Mimicking Metastatic Nasopharyngeal Carcinoma in an Immunodeficient Child with a Novel Hypomorphic NEMO Mutation

Background

Nuclear factor-??B essential modulator (NEMO) deficiency is a developmental and immunological disorder. The genetic and phenotypic correlation has been described.

Methods

We report a unique clinical presentation and the identification of a novel missense mutation in the NEMO gene in a 3-year-old boy with bacillus Calmette-Guerin (BCG) infection.

Results

The patient presented with fever, cervical lymphadenopathy, and abnormal anti-Epstein?CBarr virus (EBV) antibody titers, suggestive of EBV-related diseases including chronic active EBV infection, X-linked lymphoproliferative syndrome, or nasopharyngeal carcinoma. Although the biopsy specimen from a nasopharyngeal lesion was initially diagnosed as squamous cell carcinoma, this was changed to disseminated BCG infection involving the nasopharynx, multiple systemic lymph nodes, and brain. A novel mutation (designated D311E) in the NEMO gene, located in the NEMO ubiquitin-binding (NUB) domain, was identified as the underlying cause of the immunodeficiency. Impaired immune responses which are characteristic of patients with NEMO deficiency were demonstrated. The patient underwent successful unrelated bone marrow transplantation at 4.9 years of age.

Conclusion

This study suggests the importance of the NUB domain in host defense against mycobacteria. The unique presenting features in our patient indicate that a hypomorphic NEMO mutation can be associated with atypical pathological findings of the epithelial tissues in patients with BCG infection.