Profound Reversible Hypogammaglobulinemia Caused by Celiac Disease in the Absence of Protein Losing Enteropathy.

When patients with hypogammaglobulinemia are encountered, a vigorous search should be undertaken for secondary treatable causes. Here we describe the first case of a patient with severe asymptomatic hypogammaglobulinemia where the underlying cause was undiagnosed celiac disease. A strict gluten free diet resulted in resolution of her mild long-standing abdominal symptoms and correction of her hypogammaglobulinemia. There was corresponding improvement in her duodenal histology and normalisation of her celiac serology. Protein losing enteropathy was unlikely to have been the mechanism of her profound hypogammaglobulinemia, as her albumin was within the normal range and she had a normal fecal alpha 1 antitrypsin level. Application of the Ameratunga et al. (2013) diagnostic criteria was helpful in confirming this patient did not have Common Variable Immunodeficiency Disorder (CVID). Celiac disease must now be considered in the differential diagnosis of severe hypogammaglobulinemia. There should be a low threshold for undertaking celiac serology in patients with hypogammaglobulinemia, even if they have minimal symptoms attributable to gut disease.

Identification of germinal centres in the lymph node of a patient with hyperimmunoglobulin M syndrome associated with congenital rubella.

BACKGROUND: The hyper immunoglobulin M syndrome (HIM) associated with congenital rubella infection (rHIM) is an extremely rare disorder, where patients have elevated serum IgM in association with reduced IgG and IgA. We have previously shown that in contrast to X-linked HIM (XHIM), a patient with well-characterised rHIM is able to express functional CD40 ligand, undergo immunoglobulin isotype switching and to generate memory B cells. Here we describe the ultrastructural features of an excised lymph node from this patient. METHODS: An inguinal lymph node was surgically removed and examined histologically as well as by immunohistochemistry. It was then stained with multiple fluorescent dyes to visualize the cellular interactions within the node. Flow cytometry was undertaken on a cellular suspension from the node. FINDINGS: Our patient has normal lymph node architecture by light microscopy. Immunohistochemistry studies showed the presence of scattered germinal centres. Polychromatic immunofluorescence staining showed disruption of the architecture with mostly abnormal germinal centres. A small number of relatively intact germinal centres were identified. Both IgM and IgG bearing cells were identified in germinal centres. INTERPRETATION: In contrast to XHIM where germinal centres are absent, the presence of small numbers of relatively normal germinal centres explain our previous identification of isotype switched memory B cells in rHIM.

Clinical variability of family members with the C104R mutation in transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI).

PURPOSE: Common Variable Immunodeficiency Disorder (CVID) is a complex disorder that predisposes patients to recurrent and severe infections. The C104R mutation in the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) is the most frequent mutation identified in patients with CVID. We carried out a detailed immunological and molecular study in a family with a C104R mutation. METHODS: We have undertaken segregation analysis of a kindred with C104R mutations of the TACI gene. Detailed immunological and molecular investigations were carried out for this kindred and the clinical phenotype was compared to the genotype. RESULTS: Segregation analysis of our kindred showed that inheriting single or double copy of the C104R mutation does not consign an individual to CVID. All heterozygotes in the family were phenotypically different, ranging from asymptomatic to ill-health. A family member with a wild type TACI variant had CVID-related phenotype including IgA deficiency and type 1 diabetes. Interestingly, a family member with the homozygous C104R/C104R variant did not meet the criteria for CVID because he had excellent, albeit unsustained, vaccine responses to T cell dependent and T cell independent vaccine antigens despite profound hypogammaglobulinemia. CONCLUSION: The C104R mutation does not correlate with the clinical phenotypes in this family.

Cellular and molecular characterisation of the hyper immunoglobulin M syndrome associated with congenital rubella infection.

INTRODUCTION: The hyper-immunoglobulin M syndrome (HIM) is a rare group of immune deficiency disorders characterised by normal or increased serum IgM with normal or reduced IgG, IgA and IgE. MATERIALS AND METHODS: We have undertaken detailed cellular and molecular studies in a 53-year-old man with HIM as a result of congenital rubella. RESULTS: No mutations were detected in the CD40 ligand, activation-induced cytidine deaminase and uracil DNA glycosylase. His T-cell responses to lectins and antigens were normal. Flow cytometry confirmed the presence of CD40 ligand on activated T cells. Most CD40-dependent functions that were tested, including B-cell proliferation, isotype switching and production of memory B cells, were normal. CD40/IL4 dependent rescue from anti-IgM-induced apoptosis was impaired. CONCLUSION: The detection of cell-surface IgG but lack of serum IgG indicated that he may have an antibody secretion defect.

Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus.

Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non-consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in TNFRSF13B/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID. The proband is heterozygous for the TNFRSF13B/TACI C104R mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a de novo nonsense mutation (T168fsX191) in the Transcription Factor 3 (TCF3) gene encoding the E2A transcription factors, present only in the proband and her son. We demonstrate mutations of TNFRSF13B/TACI impair immunoglobulin isotype switching and antibody production predominantly via T-cell-independent signalling, while mutations of TCF3 impair both T-cell-dependent and -independent pathways of B-cell activation and differentiation. We conclude that epistatic interactions between mutations of the TNFRSF13B/TACI and TCF3 signalling networks lead to the severe CVID-like disorder and SLE in the proband.

Application of diagnostic and treatment criteria for common variable immunodeficiency disorder.

Common variable immunodeficiency disorder (CVID) is the most frequent symptomatic primary immune deficiency disorder in adults. It probably comprises a spectrum of polygenic disorders, with hypogammaglobulinemia being the overarching feature. While the majority of patients with CVID can be identified with relative ease, a significant proportion can present with minimal symptoms in spite of profound laboratory abnormalities. Here we discuss three patients who were presented to the Auckland Hospital immunoglobulin treatment committee to determine if they qualified for immunoglobulin replacement. Two were asymptomatic with profound laboratory abnormalities while the third patient was severely ill with extensive bronchiectasis. The third patient had less severe laboratory abnormalities compared with the two asymptomatic patients. We have applied four sets of published diagnostic and treatment criteria to these patients to compare their clinical utility. We have chosen these patients from the broad phenotypic spectrum of CVID, as this often illustrates differences in diagnostic and treatment criteria.

New diagnostic criteria for CVID.

RESPONSE TO: Kumar R, Bhatia A. Common variable immunodeficiency in adults: current diagnostic protocol and laboratory measures. Expert Rev. Clin. Immunol. 10(2), 000-000 (2014).

Comparison of diagnostic criteria for common variable immunodeficiency disorder.

Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immune deficiency condition in adults. The genetic basis for the condition is not known and no single clinical feature or laboratory test can establish the diagnosis; it has been a diagnosis of exclusion. In areas of uncertainty, diagnostic criteria can provide valuable clinical information. Here, we compare the revised European society of immune deficiencies (ESID) registry (2014) criteria with the diagnostic criteria of Ameratunga et al. (2013) and the original ESID/pan American group for immune deficiency (ESID/PAGID 1999) criteria. The ESID/PAGID (1999) criteria either require absent isohemagglutinins or impaired vaccine responses to establish the diagnosis in patients with primary hypogammaglobulinemia. Although commonly encountered, infective and autoimmune sequelae of CVID were not part of the original ESID/PAGID (1999) criteria. Also excluded were a series of characteristic laboratory and histological abnormalities, which are useful when making the diagnosis. The diagnostic criteria of Ameratunga et al. (2013) for CVID are based on these markers. The revised ESID registry (2014) criteria for CVID require the presence of symptoms as well as laboratory abnormalities to establish the diagnosis. Once validated, criteria for CVID will improve diagnostic precision and will result in more equitable and judicious use of intravenous or subcutaneous immunoglobulin therapy.

Primary immune deficiency disorders in the South Pacific: the clinical utility of a customized genetic testing program in New Zealand.

Primary immune deficiency disorders (PIDs) are a group of diseases associated with a genetic susceptibility to recurrent infections, malignancy, autoimmunity, and allergy. The molecular basis of many of these disorders has been identified in the last two decades. Most are inherited as single gene defects. As discussed in this paper, identifying the underlying genetic defect plays a critical role in many areas-including patient management, diagnosis, identifying atypical presentations, family studies, providing prognostic information, prenatal diagnosis, and defining new diseases. New Zealand is a geographically isolated, developed country in the South Pacific. We have introduced a dedicated customized genetic testing service for PID patients in New Zealand. This accredited diagnostic program offers rapid turnaround times for genetic tests and minimizes the risk of laboratory errors. Here we review the clinical indications for genetic testing for PIDs based on cases referred to the molecular immunology diagnostic service at Auckland City Hospital.