SUMMARY Primary antibody deficiencies are the most common primary immunodeficiency diseases. They are a heterogeneous group of disorders with various degrees of dysfunctional antibody production resulting from a disruption of B-cell differentiation at different stages. While there has been tremendous recent progress in the understanding of some of these disorders, the etiology remains unknown for the majority of patients. As there is a large spectrum of underlying defects, the age at presentation varies widely, and the clinical manifestations range from an almost complete absence of B cells and serum immunoglobulins to selectively impaired antibody responses to specific antigens with normal total serum immunoglobulin concentrations. However, all of these disorders share an increased susceptibility to infections, affecting predominantly the respiratory tract. A delay of appropriate treatment for some diseases can result in serious complications related to infections, while timely diagnosis and adequate therapy can significantly decrease morbidity and increase life expectancy and quality of life.

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Background Congenital pancytopenia is a rare and often lethal condition. Current knowledge of lymphoid and hematopoietic development in mice, as well as understanding regulators of human hematopoiesis, have led to the recent discovery of genetic causes of bone marrow failure disorders. However, in the absence of mutations of specific genes or a distinct clinical phenotype, many cases of aplastic anemia are labeled as idiopathic, while congenital immune deficiencies are described as combined immune deficiency. Procedure We describe the case of a 33-week gestation age male with severe polyhydramnios, hydrops, and ascites who was noted to be pancytopenic at birth. Bone marrow examination revealed a hypocellular marrow with absent myelopoiesis. An immune workup demonstrated profound B lymphopenia, near absent NK cells, and normal T cell number. Due to the similarity of the patient's phenotype with the IKAROS knockout mouse, studies were performed on bone marrow and peripheral blood to assess a potential pathogenic role of Ikaros. Results DNA studies revealed a point mutation in one allele of the IKAROS gene, resulting in an amino acid substitution in the DNA-binding zinc finger domain. Functional studies demonstrated that the observed mutation decreased Ikaros DNA-binding affinity, and immunofluorescence microscopy revealed aberrant Ikaros pericentromeric localization. Conclusions Our report describes a novel case of congenital pancytopenia associated with mutation of the IKAROS gene. Furthermore, these data suggest a critical role of IKAROS in human hematopoiesis and immune development.

Some, but not all, TACI mutations found in CVID impair TACI function and may potentially contribute to B cell dysfunction in heterozygotes via haploinsufficiency. Keywords TACI; common variable immunodeficiency; APRIL; BAFF; BLyS To the EditorMutations in TNFRSF13B, the gene encoding for the transmembrane activator, calciummodulator and cyclophilin ligand interactor (TACI), have been identified in 5-10% of patients with CVID 1, 2 . The most common TACI variants in CVID are C104R, in the ligand binding cysteine-rich domain 2 (CRD2), and A181E, in the transmembrane (TM) domain of TACI. Each is found in the heterozygous state in 2-5% of CVID patients, but also in 0.5-1% of healthy individuals [1][2][3] . Both destroy the capacity of TACI ligation to activate NFκB. We have examined the function of TACI coding variants that have been described in CVID patients and their relatives, but so far not in healthy individuals [3][4][5] . Figure 1A shows the location of the missense mutations examined in the TACI protein. The CRD1 mutants W40R and D41H, the CRD2 mutant I87N, the TM domain mutants C172Yand A181E, and the IC domain mutants K188M and V246F were expressed on the surface of 293T cell transfectants at levels comparable to WT TACI ( Figure 1B). Surface expression of the CRD2 mutants Y79C and C104R was modestly decreased to ~ half of WT, while that of the L171R mutant was reduced ~8 fold. Protein expression of the L171R mutant in whole cell lysates was similarly reduced, but its mRNA expression was comparable to that of WT (data not shown), suggesting that the mutant protein was unstable. Both of the CRD1 domain mutants, W40R and D41H, showed normal binding of BAFF (Fig. 1C). There was total loss of BAFF binding by the Y79C and C104R mutants. The I87N mutant had residual BAFF binding, which increased with increasing concentrations of ligand (Fig. S1). The poorly expressed L171R mutant had negligible ligand binding. The TM domain mutants, C172Y and A181E and the IC domain mutants K188M and V246F had intact BAFF binding.Address correspondence and reprint requests to: Raif S. Geha, Karp 10, Division of Immunology, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA. Phone: (617) 919 2482, Fax: (617) 730 0528, raif.geha@childrens.harvard.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. TACI signaling was examined by measuring NFκB and NF-AT activation using a dual luciferase reporter system 6 . Mutant or WT TACI were transfected into 293T cells with either NFκB luciferase or NF-AT luciferase reporter plasmids together with Renilla luciferase, and the cap...

RASGRP1 is a guanine-nucleotide-exchange factor essential for MAP-kinase mediated signaling in lymphocytes. We report the second case of RASGRP1 deficiency in a patient with a homozygous nonsense mutation in the catalytic domain of the protein. The patient had epidermodysplasia verruciformis, suggesting a clinically important intrinsic T cell function defect. Like the previously described patient, our proband also presented with CD4+ T cell lymphopenia, impaired T cell proliferation to mitogens and antigens, reduced NK cell function, and EBV-associated lymphoma. The severity of the disease and the development of EBV lymphoma in both patients suggest that hematopoietic stem cell transplantation should be performed rapidly in patients with RASGRP1 deficiency.

Mastocytosis arises from clonal mast cell expansion and the resultant accumulation of mast cells in cutaneous and sometimes extracutaneous tissues. Recent studies have demonstrated that c-kit mutations seem to be more prevalent in pediatric mastocytosis than previously assumed, but what determines disease evolution and severity in the individual patient remains elusive. For the large majority of children, mastocytosis is a self-limited cutaneous disease that spontaneously regresses before they reach adult age. Rarely, children develop systemic disease progression that is the hallmark of adult-onset disease. Therefore, invasive diagnostic testing, including performing a bone marrow biopsy, is not routinely recommended and usually reserved for children that present with signs of systemic involvement and persistently elevated serum tryptase levels. Despite its often-transient nature and limited skin involvement, some children experience challenging disease-associated symptoms due to spontaneous or trigger-induced mast cell degranulation. Anticipation of and preparation for potential complications can in many instances avoid symptomatic exacerbations. Proper symptomatic treatment and supportive care can often improve the child's quality of life. Cytoreductive therapy is usually not indicated given the natural history of spontaneous disease resolution.

Antibody concentration and avidity correlate with patient clinical characteristics and distinguish patients from controls. Measurement of antibody avidity may provide another dimension for the clinical assessment of pneumococcal polysaccharide antibody response.