Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases.

The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. Mutations in AIRE cause a rare autosomal-recessive disease, autoimmune polyendocrine syndrome type 1 (APS-1), distinguished by multi-organ autoimmunity. We have identified multiple cases and families with mono-allelic mutations in the first plant homeodomain (PHD1) zinc finger of AIRE that followed dominant inheritance, typically characterized by later onset, milder phenotypes, and reduced penetrance compared to classical APS-1. These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner, unlike CARD or truncated AIRE mutants that lacked such dominant capacity. Exome array analysis revealed that the PHD1 dominant mutants were found with relatively high frequency (>0.0008) in mixed populations. Our results provide insight into the molecular action of AIRE and demonstrate that disease-causing mutations in the AIRE locus are more common than previously appreciated and cause more variable autoimmune phenotypes.

Administering intravenous immunoglobulin during infection is associated with infusion reactions in selected patients.

BACKGROUND: Guidelines vary regarding the safety of administering intravenous immunoglobulin (IVIG) during infections, although evidence for this advice is lacking and is based on expert opinion. AIMS: We retrospectively studied patients with common variable immunodeficiency who reacted during IVIG therapy as to whether routinely obtained markers of infection such as C-reactive protein (CRP) were elevated. METHODS: 19 patients on replacement IVIG therapy in a hospital-based infusion unit were studied. CRP levels obtained were normalized to baseline levels without reactions (defined as 100). RESULTS: 8 of 19 patients had 16 reactions over a total of 107 infusions. Normalized CRP levels during reactions were higher [mean (±SD) of 258 (±215)] than during infusions with no reaction [mean 100 (±54.9), p = 0.017], and higher than in patients who did not react [mean 100 (±79.7), p = 0.017]. CONCLUSIONS: Some patients with IVIG reactions had elevated CRP levels suggesting that concurrent infection may have caused the reaction. Pre-emptive antibiotic therapy and delaying infusion could prevent unnecessary morbidity.

Do ribosomopathies explain some cases of common variable immunodeficiency?

The considerable clinical heterogeneity of patients with common variable immunodeficiency disorders (CVID) shares some similarity with bone-marrow failure disorders such as Diamond-Blackfan anaemia (DBA) and Shwachman-Diamond syndrome (SDS), now recognized as defects in ribosome biogenesis or ribosomopathies. The recognition of a patient with DBA who subsequently developed CVID lends support to our previous finding of a heterozygous mutation in the SBDS gene of SBDS in another CVID patient, suggesting that ribosome biogenesis defects are responsible for a subset of CVID. Genetic defects in the ribosomal translational machinery responsible for various bone marrow failure syndromes are recognized readily when they manifest in children, but diagnosing these in adults presenting with complex phenotypes and hypogammaglobulinaemia can be a challenge. In this perspective paper, we discuss our clinical experience in CVID patients with ribosomopathies, and review the immunological abnormalities in other conditions associated with ribosomal dysfunction. With genetic testing available for various bone marrow failure syndromes, our hypothesis that ribosomal abnormalities may be present in patients with CVID could be proved in future studies by testing for mutations in specific ribosomal genes. New knowledge might then be translated into novel therapeutic strategies for patients in this group of immunodeficiency disorders.

Limited value of testing for intrinsic factor antibodies with negative gastric parietal cell antibodies in pernicious anaemia.

BACKGROUND: The appropriate testing strategy for diagnosing pernicious anaemia using gastric parietal cell (GPC) and/or intrinsic factor antibodies (IFA) is controversial. Intrinsic factor antibodies are found in only about 70% of cases. Indirect immunofluorescence screening for gastric parietal cell antibodies is more sensitive, labour intensive, and less specific. METHODS: The frequency of antibody positivity (IFA and/or GPC) was retrospectively examined in patients tested for both autoantibodies over a three-year period. It was investigated whether B12 levels were related to antibody status. These findings were validated in a prospective study of IFA in 91 GPC negative patients with low B12 levels. RESULTS: Of 847 samples identified in the retrospective study, 4 (0.47%) were positive for only intrinsic factor antibodies, 731 (86.3%) positive for GPC alone, and 112 (13.2%) for both. Student t test on log-transformed data showed B12 levels had no bearing on autoantibody status. 91 consecutive patients with low B12 levels were tested for both autoantibodies; all were negative for gastric parietal cell antibodies. Only one sample was positive for intrinsic factor antibody using the porcine intrinsic factor assay, but was negative by a human recombinant intrinsic factor-based ELISA. CONCLUSIONS: This study provides evidence that testing for gastric parietal cell antibodies is an appropriate screening test for pernicious anaemia, with intrinsic factor antibodies reserved for confirmatory testing or in patients with other autoantibodies that mask the GPC pattern; B12 levels are not related to autoantibody status.

Antibody deficiency.

Antibody deficiencies may arise as primary disorders or secondary to a variety of diseases, drugs and other environmental/iatrogenic factors. Significant primary antibody deficiencies are relatively rare but, collectively, account for the majority of primary immunodeficiency syndromes encountered in clinical practice. The genetic basis of a number of primary deficiencies has been clarified, although there is considerable genotype/phenotype heterogeneity and the role of gene/environment interactions has yet to be fully elucidated. Primary antibody deficiency can present at any age. The hallmark clinical presentation is recurrent bacterial infection, but these disorders are also associated with a wide variety of other infectious and non-infectious complications and with a high incidence of chronic, structural tissue damage, particularly in the respiratory tract. Clinical recognition of primary antibody deficiency is frequently delayed with consequent increased morbidity, diminished quality of life and early mortality. Clinical laboratories can contribute to improved and timely detection through awareness of routine test results which may be overtly or indirectly suggestive of antibody deficiency. Secondary deficiency is associated with increased awareness, better recognition and earlier diagnosis than in primary disorders. Early liaison and referral of patients with suspected antibody deficiency for specialist opinion and prompt, appropriate therapy is central to the achievement of good clinical outcomes.

Clinical immunology review series: an approach to the use of the immunology laboratory in the diagnosis of clinical allergy.

In the last 10 years UK immunology laboratories have seen a dramatic increase in the number and range of allergy tests performed. The reasons for this have been an increase in the incidence of immunoglobulin E (IgE)-mediated allergic disease set against a background of greater public awareness and more referrals for assessment. Laboratory testing forms an integral part of a comprehensive allergy service and physicians treating patients with allergic disease need to have an up-to-date knowledge of the range of tests available, their performance parameters and interpretation as well as the accreditation status of the laboratory to which tests are being sent. The aim of this review is to describe the role of the immunology laboratory in the assessment of patients with IgE-mediated allergic disease and provide an up-to-date summary of the tests currently available, their sensitivity, specificity, interpretation and areas of future development.

The clinical significance of antinucleolar antibodies.

BACKGROUND: The importance of antinucleolar antibodies seen by indirect immunofluorescence on HEp-2 cells, although associated with systemic sclerosis (SSc), in unselected patients is unknown. AIMS: To determine the true clinical significance of antinucleolar antibodies in an unselected patient population. METHODS: Antinucleolar antibody (ANoA) positive samples were identified in the immunology laboratory during routine autoimmune screening tests; case notes were reviewed using a standard proforma. RESULTS: 104 patients with ANoA were identified and ANoA+ samples were subclassified into homogeneous, clumpy and speckled antinucleolar types. SSc was evident in only two (1.8%) patients. Other connective tissue diseases were identified in 33 patients (32%); 22 patients (21%) had evidence of various malignancies. Both disordered liver function and anaemia were seen in 22 patients and were the commonest laboratory abnormalities. CONCLUSIONS: Neither the presence nor subtype of ANoA is specific for systemic sclerosis. Laboratory comments appended to results should reflect this fact.

Some cases of common variable immunodeficiency may be due to a mutation in the SBDS gene of Shwachman-Diamond syndrome.

Known genetic defects currently account for only a small proportion of patients meeting criteria for 'probable' or 'possible' common variable immunodeficiency (CVID). A 59-year-old male with a 12-year history of CVID on intravenous immunoglobulin (IVIG) is presented who developed bronchiectasis, cytopenias and malabsorption that are recognized complications of CVID. Work-up for his malabsorption suggested the possibility of Shwachman-Diamond syndrome, confirmed by mutation testing. With the identification of the molecular defect in Shwachman-Diamond syndrome (SDS), it is becoming clear that not all SDS patients have the prominent features of neutropenia or pancreatic malabsorption. A meta-analysis of published immunological defects in SDS suggests that four of 14 hypogammaglobulinaemic SDS patients meet criteria for 'possible' CVID. Mutations in the SBDS gene may therefore be the fifth identified molecular defect in CVID.

Abnormal O-glycosylation of CD43 may account for some features of Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder characterized by eczema, recurrent infections, thrombocytopenia and small platelets. There is an increased incidence of autoimmune phenomena particularly autoimmune haemolytic anaemias and vasculitic disorders. Mutations in the WASP gene encoding the cytoskeleton regulatory protein WASp (Wiskott-Aldrich syndrome protein) result in abnormal protein activity with defective cytoplasmic signaling and actin polymerization. This accounts for abnormal T cell responses to proliferation and susceptibility to infections, but does not fully explain the autoimmune phenomena nor the progressive lymphopenia seen in these patients. Wiskott Aldrich patients also demonstrate abnormal O-glycosylation of a highly conserved transmembrane glycoprotein CD43 that is expressed on most haemopoeitic cells. The altered glycosylation pattern on WAS lymphocytes is due to increased beta1-->6 GlcNACtransferase activity which leads to branched core 2 glycans or lower molecular forms of CD43 glycoprotein. The clinical hypothesis put forward is that abnormal O-glycosylation of CD43 may underlie the development of the autoimmune disorders and the progressive lymphopenia observed in WAS patients. Regulation of glycosylation of CD43 is important in the selection process of T cells within the thymus and abnormalities of glycosylation may cause many immune perturbations, such as the escape of self-reactive T cells into the periphery and subsequent development of autoimmune disease in these patients.

Secondary systemic lupus erythematosus: an analysis of 4 cases of uncontrolled hereditary angioedema.

The association of systemic lupus erythematosus and hereditary angioedema (HAE) has formed the basis of numerous case reports and is hypothesised to result from consumption of complement C4 with consequent impaired clearance of apoptotic cells. We describe the development of frank lupus or lupus-like syndrome in four HAE patients with uncontrolled angioedema and low levels of serum C4. Measures that limit hypocomplementaemia in HAE may reduce the incidence of secondary SLE.

Early indicators of immunodeficiency in adults and children: protocols for screening for primary immunological defects.

Early recognition of primary immunodeficiency is essential to reduce morbidity and mortality, and yet failure to recognize these conditions is still a major problem for clinicians around the world. The problem is that general practitioners, physicians and paediatricians lack familiarity with these rare disorders, and lack guidance regarding the appropriate use of immunological investigations. A working party from the European Society for Immunodeficiencies (ESID) has published screening protocols for these rare disorders, which aim to help select which tests should be done in which patients. The success of these proposals will depend on all immunologists disseminating this information in a format that is suitable for the busy generalist, who may not be familiar with these immunological tests and concepts. Laboratories should expect increasing requests for these screening investigations, and should make themselves familiar with these protocols so that appropriate second-line investigations can be arranged in a timely fashion. Speedy and effective communication between the laboratory and clinician is essential, and clinically interpreted reports are mandatory. Although these protocols are part of a screening process, their effectiveness in practice remains to be established, and further refinement will be required over time. The early involvement of the clinical immunologist in cases of suspected immunodeficiency is key.