Glynis Frans

Brief Report: IFIH1 Mutation Causes Systemic Lupus Erythematosus With Selective IgA Deficiency

To identify the underlying genetic defect in a 16‐year‐old girl with severe early‐onset and refractory systemic lupus erythematosus (SLE), IgA deficiency, and mild lower limb spasticity without neuroradiologic manifestations.

Addressing diagnostic challenges in primary immunodeficiencies: laboratory evaluation of Toll-like receptor- and NF-κB-mediated immune responses.

Abstract Toll-like receptors (TLRs) play an important role in immunity and mediate their actions via multiple signaling pathways, in particular, the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) pathway. Rare inherited defects of TLR- and NF-κB-dependent responses have recently been recognized. These primary immunodeficiencies predispose children to life-threatening infections and often remain undiagnosed. Establishing a sensitive, specific, cost-effective and simple method for diagnosis is therefore important. In this article, we review the known defects of TLR- and NF-κB-mediated pathways and the assays that can be used to screen for such defects.

Fifth Percentile Cutoff Values for Antipneumococcal Polysaccharide and Anti-Salmonella typhi Vi IgG Describe a Normal Polysaccharide Response

Background Serotype-specific antibody responses to unconjugated pneumococcal polysaccharide vaccine (PPV) evaluated by a World Health Organization (WHO)-standardized enzyme-linked immunosorbent assay (ELISA) are the gold standard for diagnosis of specific polysaccharide antibody deficiency (SAD). The American Academy of Allergy, Asthma and Immunology (AAAAI) has proposed guidelines to interpret the PPV response measured by ELISA, but these are based on limited evidence. Additionally, ELISA is costly and labor-intensive. Measurement of antibody response to Salmonella typhi (S. typhi) Vi vaccine and serum allohemagglutinins (AHA) have been suggested as alternatives. However, there are no large cohort studies and cutoff values are lacking. Objective To establish cutoff values for antipneumococcal polysaccharide antibody response, anti-S. typhi Vi antibody, and AHA. Methods One hundred healthy subjects (10–55 years) were vaccinated with PPV and S. typhi Vi vaccine. Blood samples were obtained prior to and 3–4 weeks after vaccination. Polysaccharide responses to 3 serotypes were measured by WHO ELISA and to 12 serotypes by an in-house bead-based multiplex assay. Anti-S. typhi Vi IgG were measured with a commercial ELISA kit. AHA were measured by agglutination method. Results Applying AAAAI criteria, 30% of healthy subjects had a SAD. Using serotype-specific fifth percentile (p5) cutoff values for postvaccination IgG and fold increase pre- over postvaccination, only 4% of subjects had SAD. One-sided 95% prediction intervals for anti-S. typhi Vi postvaccination IgG (≥11.2 U/ml) and fold increase (≥2) were established. Eight percent had a response to S. typhi Vi vaccine below these cutoffs. AHA titer p5 cutoffs were ½ for anti-B and ¼ for anti-A. Conclusion We establish reference cutoff values for interpretation of PPV response measured by bead-based assay, cutoff values for S. typhi Vi vaccine responses, and normal values for AHA. For the first time, the intraindividual consistency of all three methods is studied in a large cohort.

PID in Disguise: Molecular Diagnosis of IRAK-4 Deficiency in an Adult Previously Misdiagnosed With Autosomal Dominant Hyper IgE Syndrome

Autosomal recessive IL-1R-associated kinase 4 (IRAK-4) deficiency is a rare cause of recurrent pyogenic infections with limited inflammatory responses. We describe an adult female patient with severe lung disease who was phenotypically diagnosed as suffering from autosomal dominant Hyper IgE syndrome (AD HIES) because of recurrent skin infections with Staphylococcus aureus, recurrent pneumonia and elevated serum IgE levels. In contrast to findings in AD HIES patients, no abnormalities were found in the Th17 and circulating follicular helper T cell subsets. A panel-based sequencing approach led to the identification of a homozygous IRAK4 stop mutation (c.877C > T, p.Gln293*).

Novel Mutation of ZAP-70-related Combined Immunodeficiency: First Case from the National Iranian Registry and Review of the Literature

ABSTRACT ZAP-70 deficiency is a rare autosomal recessive form of combined immunodeficiency (CID) characterized by selective absence of circulating CD8 T cells with low, normal, or increased CD4 T cells in peripheral blood. Up to now, 14 unique mutations in the ZAP70 gene have been identified in patients with ZAP-70-related CID. We present a 3-year-old boy with a history of recurrent bacterial infections and autoimmunity. Initial laboratory findings showed a normal total lymphocyte count, but low levels of CD8 and CD4 T cells and an abnormal lymphocyte proliferation response. Immunoglobulin levels were normal, but the specific antibody response was impaired. Whole exome sequencing revealed a mutation within the kinase domain of ZAP-70. ZAP-70 deficiency should be considered in infants and young children with recurrent bacterial infections, in spite of having palpable lymph nodes, a notable thymus shadow, and a normal total lymphocyte count.

Successful hematopoietic stem cell transplantation for myelofibrosis in an adult with warts-hypogammaglobulinemia-immunodeficiency-myelokathexis syndrome

Please cite this article as: Moens L, Frans G, Bosch B, Bossuyt X, Verbinnen B, Poppe W, Boeckx N, Slatter M, Brusselmans C, Diaz G, Tousseyn T, Flipts H, Corveleyn A, Dierickx D, Meyts I, Successful hematopoietic stem cell transplantation for myelofibrosis in an adult with WartsHypogammaglobulinemia-Immunodeficiency-Myelokathexis syndrome, Journal of Allergy and Clinical Immunology (2016), doi: 10.1016/j.jaci.2016.04.057.

Effect of previous vaccination with pneumococcal conjugate vaccine on pneumococcal polysaccharide vaccine antibody responses

During the past 10 years, pneumococcal conjugate vaccine (PCV) has become part of the standard childhood vaccination programme. This may impact upon the diagnosis of polysaccharide antibody deficiency by measurement of anti‐polysaccharide immunoglobulin (Ig)G after immunization with unconjugated pneumococcal polysaccharide vaccine (PPV). Indeed, contrary to PPV, PCV induces a T‐dependent, more pronounced memory response. The antibody response to PPV was studied retrospectively in patients referred for suspected humoral immunodeficiency. The study population was divided into four subgroups based on age (2–5 years versus ≥ 10 years) and time tested (1998–2005 versus 2010–12). Only 2–5‐year‐old children tested in 2010–12 had been vaccinated with PCV prior to PPV. The PCV primed group showed higher antibody responses for PCV–PPV shared serotypes 4 and 18C than the unprimed groups. To a lesser extent, this was also found for non‐PCV serotype 9N, but not for non‐PCV serotypes 19A and 8. Furthermore, PCV‐priming elicited a higher IgG2 response. In conclusion, previous PCV vaccination affects antibody response to PPV for shared serotypes, but can also influence antibody response to some non‐PCV serotypes (9N). With increasing number of serotypes included in PCV, the diagnostic assessment for polysaccharide antibody deficiency requires careful selection of serotypes that are not influenced by prior PCV (e.g. serotype 8). Further research is needed to identify more serotypes that are not influenced.

Value of allohaemagglutinins in the diagnosis of a polysaccharide antibody deficiency

Polysaccharide antibody deficiency is characterized by a poor or absent antibody response after vaccination with an unconjugated pneumococcal polysaccharide vaccine. Allohaemagglutinins (AHA) are antibodies to A or B polysaccharide antigens on the red blood cells, and are often used as an additional or alternative measure to assess the polysaccharide antibody response. However, few studies have been conducted to establish the clinical significance of AHA. To investigate the value of AHA to diagnose a polysaccharide antibody deficiency, pneumococcal polysaccharide antibody titres and AHA were studied retrospectively in 180 subjects in whom both tests had been performed. Receiver operating characteristic curves for AHA versus the pneumococcal vaccine response as a marker for the anti‐polysaccharide immune response revealed an area under the curve between 0·5 and 0·573. Sensitivity and specificity of AHA to detect a polysaccharide antibody deficiency, as diagnosed by vaccination response, were low (calculated for cut‐off 1/4–1/32). In subjects with only low pneumococcal antibody response, the prevalence of bronchiectasis was significantly higher than in subjects with only low AHA (45·5 and 1·3%, respectively) or normal pneumococcal antibody response and AHA (2·4%). A logistic regression model showed that low pneumococcal antibody response but not AHA was associated with bronchiectasis (odds ratio 46·2). The results of this study do not support the routine use of AHA to assess the polysaccharide antibody response in patients with suspected immunodeficiency, but more studies are warranted to clarify the subject further.

Clinical characteristics of patients with low functional IL-6 production upon TLR/IL-1R stimulation.

Please cite this article as: Frans G, Van der Werff Ten Bosch J, Moens L, Wuyts G, Schaballie H, Tuerlinckx D, De Bie M, Vermeulen F, Schrijvers R, Meert W, Hestand MS, Delanghe J, Vermeesch Ir JR, Meyts I, Bossuyt X, Clinical characteristics of patients with low functional IL-6 production upon TLR/ IL-1R stimulation, Journal of Allergy and Clinical Immunology (2017), doi: 10.1016/j.jaci.2017.04.017.

Mild humoral immunodeficiency in a patient with X-linked Kabuki syndrome

Mild Humoral Immunodeficiency in a Patient with X-Linked Kabuki Syndrome Glynis Frans, Isabelle Meyts, Koen Devriendt, Adrian Liston, FranS cois Vermeulen, and Xavier Bossuyt* Department of Microbiology and Immunology, Experimental Laboratory Immunology, KU Leuven, Leuven, Belgium Department of Microbiology and Immunology, Childhood Immunology, KU Leuven, Leuven, Belgium Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium Department of Microbiology and Immunology, Autoimmune Genetics, KU Leuven and VIB, Leuven, Belgium Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium