Deficiency of Adenosine Deaminase 2 Causes Antibody Deficiency.

PURPOSE: Determining the monogenic cause of antibody deficiency and immune dysregulation in a non-consanguineous family with healthy parents, two affected children, and one unaffected child. METHODS: Whole Exome Sequencing (WES) was performed in the index family. WES results were confirmed by Sanger Sequencing. Dried plasma spots of the male patient and his mother were analyzed for ADA2 enzymatic activity. RESULTS: Following data analysis of WES, we found a compound heterozygous mutation in CECR1 (encoding adenosine deaminase 2, ADA2) that segregated in the two affected children. Enzyme activity measurement confirmed a severely diminished ADA2 activity in our patient. The 32 year old index patient was suffering from recurrent respiratory infections and was previously diagnosed with common variable immunodeficiency (CVID), showing no signs of vasculitis. His sister had a systemic lupus erythematosus (SLE)-like phenotype and died at age 17. CONCLUSIONS: Deficiency of ADA2 (DADA2) has been reported to cause vasculopathy and early-onset stroke. Our case suggests that it should also be considered when evaluating patients with antibody deficiencies and immune dysregulation syndromes.

SYK expression endows human ZAP70-deficient CD8 T cells with residual TCR signaling.

Autosomal recessive human ZAP70 deficiency is a rare cause of combined immunodeficiency (CID) characterized by defective CD4 T cells and profound CD8 T cell lymphopenia. Herein, we report two novel patients that extend the molecular genetics, the clinical and functional phenotypes associated with the ZAP70 deficiency. The patients presented as infant-onset CID with severe infections caused by varicella zoster virus and live vaccines. Retrospective TCR excision circle newborn screening was normal in both patients. One patient carried a novel non-sense mutation (p.A495fsX75); the other a previously described misense mutation (p.A507V). In contrast to CD4 T cells, the majority of the few CD8 T cells showed expression of the ZAP70-related tyrosine kinase SYK that correlated with residual TCR signaling including calcium flux and degranulation. Our findings highlight the differential requirements of ZAP70 and SYK during thymic development, peripheral homeostasis as well as effector functions of CD4 and CD8 T cells.

Surface expression and genotypes of Toll-like receptors 2 and 4 in patients with juvenile idiopathic arthritis and systemic lupus erythematosus.

BACKGROUND: Chronic arthritis is a common feature of juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE). It was subsequently discovered that Toll-like receptors (TLRs) are able to upregulate cytokine production in response to endogenous ligands released after tissue damage, suggesting that TLRs can maintain an inflammatory response even in absence of pathogen. Thus, TLRs may contribute to increased inflammation in JIA and SLE patients. The aim of this study was to investigate the role of TLRs in JIA and SLE. We examined the in vivo expression and polymorphisms of TLR2 and TLR4 in peripheral monocytes of patients with JIA and SLE during active and inactive disease phases. METHODS: This single center cohort study consisted of JIA and SLE affected children and control subjects. TLR2 and TLR4 protein expression on CD14+ monocytes was examined by flow cytometry. TLR2 and TLR4 genotypes were determined using the polymerase chain reaction-restriction fragment length polymorphism method (RFLP-PCR). RESULTS: A significant reduction in the level of TLR4 expression (p ≤ 0.001) was observed on monocytes of patients with JIA and SLE compared with that of healthy control subjects. There was no correlation between the TLR2 or TLR4 genotypes and the observed differential TLR protein expression on monocytes. CONCLUSIONS: To conclude, our observations suggest involvement of investigated TLRs in the pathogenesis of JIA and SLE. It still remains to be elucidated whether reduced TLR4 expression is cause of chronic arthritis or a result of some feedback loop.

Immunogenicity and safety of a tetravalent measles-mumps-rubella-varicella vaccine co-administered with a booster dose of a combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine in healthy children aged 12-23 months.

This study was undertaken to assess the co-administration of an experimental measles-mumps-rubella-varicella vaccine (MMRV, GlaxoSmithKline Biologicals) with a combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b conjugate (DTPa-HBV-IPV/Hib) vaccine in healthy children. Healthy children aged 12-23 months (N = 451) were randomised to one of three parallel groups to receive one dose of MMRV vaccine co-administered with a booster dose of DTPa-HBV-IPV/Hib vaccine (co-administration group), or one dose of MMRV vaccine alone (MMRV group), or a booster dose of DTPa-HBV-IPV/Hib vaccine alone (DTPa-HBV-IPV/Hib group). No differences in seroconversion rates for measles (>95%), mumps (>80%), rubella (>99%) and varicella (>98%) were seen between the co-administration group and the MMRV group. No differences in geometric mean titres (GMTs) were observed between the two groups with the exception of anti-measles titres, which were observed to be higher in the MMRV group than in the co-administration group (4,419.2 vs. 3,441.8 mIU/ml respectively). Immune response to the booster dose of DTPa-HBV-IPV/Hib vaccine was observed to be similar in the co-administration group and the DTPa-HBV-IPV/Hib group. Co-administration of the MMRV vaccine with a booster dose of DTPa-HBV-IPV/Hib vaccine was well-tolerated and did not exacerbate the reactogenicity profile of either vaccine. In summary, GlaxoSmithKline Biologicals' experimental MMRV vaccine was immunogenic and well-tolerated when administered with a booster dose of DTPa-HBV-IPV/Hib vaccine during the second year of life. The ability to co-administer the MMRV vaccine at the same time as other routine childhood immunisation vaccines could increase compliance with varicella vaccination in countries where this vaccine is already recommended and may facilitate implementation of varicella vaccination elsewhere.

Safety of reduced-antigen-content tetanus-diphtheria-acellular pertussis vaccine in adolescents as a sixth consecutive dose of acellular pertussis-containing vaccine.

OBJECTIVE: The safety of a booster dose of a reduced-antigen-content tetanus-diphtheria-acellular pertussis (Tdap) vaccine was evaluated in adolescents previously vaccinated with five doses of acellular pertussis-containing vaccine. STUDY DESIGN: Adolescents (n = 319) previously vaccinated with either 5 doses of diphtheria-tetanus-acellular pertussis (DTaP) (n = 193) or 4 doses of DTaP plus another acellular pertussis-containing vaccine received one dose each of Tdap and hepatitis A vaccine in a double-blinded, randomized, crossover trial. Rates of adverse events (AEs) after vaccination with Tdap versus hepatitis A and rates of local AEs among adolescents vaccinated with Tdap (sixth acellular pertussis-containing vaccine dose) versus rates in these same individuals after vaccination with their fifth DTaP dose were assessed. RESULTS: After Tdap, pain (63.6%), redness (51.7%), and swelling (41.4%) were the most frequently reported AEs. Large injection site swelling (swelling > 100 mm, arm circumference increase > 50 mm or diffuse swelling interfering with daily activities) occurred in three adolescents and resolved without sequelae. After the sixth dose of acellular pertussis-containing vaccine, adolescents reported more pain and less redness and swelling compared with incidences of these AEs reported when these same individuals received their fifth DTaP dose. CONCLUSIONS: These results suggest that Tdap is well tolerated as a sixth consecutive dose of acellular pertussis-containing vaccine.