X-Linked Lymphoproliferative Syndrome and Common Variable Immunodeficiency May Not Be Differentiated by SH2D1A and XIAP/BIRC4 Genes Sequence Analysis

The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency characterized by recurrent episodes of hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and/or lymphomas. Recently, X-linked inhibitor of apoptosis (XIAP/BIRC4) gene defects, in families with XLP but without SH2D1A gene defects, has been defined. The distinction from primary immunodeficiencies with a defined genetic cause is mandatory. A six-year-old male patient was admitted with the complaints of persistent general lymphadenopathy, for two years had fever, bilateral cervical multiple microlymphadenopathy, hepatic/splenic enlargement with laboratory findings as decreased serum immunoglobulins, negative EBV VCA IgM (viral capsid antigen) and anti-EBV EA (antibody to early D antigen), positive EBV VCA IgG (viral capsid antigen) and EBV EBNA (antibody to nuclear antigen). SH2D1A gene analysis was negative. XIAP/BIRC4 sequencing revealed two novel single nucleotide variants (exon 7, 1978G > A, and 1996T > A) in the 3′UTR of the gene in both patient and mother which were not disease causing. XIAP protein expression was found to be normal. The clinical and laboratory resemblance, no gene mutations, and normal XIAP protein expression led us to think that there may be another responsible gene for XLP. The patient will to be followed up as CVID until he presents new diagnostic signs or until the identification of a new gene

CD4(+)CD25(+)Foxp3(+) T regulatory cells, Th1 (CCR5, IL-2, IFN-gamma) and Th2 (CCR4, IL-4, IL-13) type chemokine receptors and intracellular cytokines in children with common variable immunodeficiency

WOS: 000375028200010PubMed ID: 26684629Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiencies characterized by decreased serum immunoglobulin G along with a decrease in serum IgA and/or IgM, defective specific antibody production, and recurrent bacterial infections. Abnormal lymphocyte trafficking, dysregulated cellular responses to chemokines, and uncontrolled T cell polarization may be involved in the pathogenesis and may help to understand the clinical complications. We evaluated T helper cell subsets (chemokine receptors CCR4, CCR5, and CCR7), expressions on T lymphocytes, intracellular cytokines - IL-2, IL-4, IL-13, IFN- gamma-on CD4(+) T cells, and expression of CD4(+)CD25(+)Foxp3(+) regulatory T cells of 20 CVID patients and 26 healthy controls. Autoimmune clinical findings and other complications were also determined. Percentages and absolute numbers of CD4(+)CD25(+) Foxp3(+) cells did not show any significant difference between CVID cases and healthy controls nor between severe and moderate disease patients. The only significant difference regarding Th1 and Th2 type intracellular cytokines was the decreased absolute numbers of CD3(+)CD4(+)IL4(+) cells in CVID cases. There were some findings about T helper cell type dominance in CVID patients such as positive correlation between hepatomegaly and high IL-2 and IFN-gamma in CD3(+)CD4(+) cells and very high expression of CCR5 (Th1) on CD3(+)CD4(+) cells in patients with granuloma. Th1 (CCR5) and Th2 (CCR4) type chemokine receptors did not show any dominance in CVID cases. However, frequencies of CCR7 expressing CD3(+) T cells, CD3(+)CD4(+) T helper cells and CD3(+)CD8(+) T cytotoxic cells were significantly lower in severe CVID patients. In addition, presence of autoimmune clinical findings was negatively correlated with CCR7(+) cells. As CCR7 is a key mediator balancing immunity and tolerance in the immune system, the abnormality of this mediator may contribute to the profound immune dysregulation seen in CVID. In addition, Th1 cells seem to be more involved in the disease pathogenesis than Th2 cells.TUBITAK (The Scientific and Technological Research Council of Turkey)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [112S022]; European Research Projects on Rare Diseases (E-RARE)This work was supported by a grant (no. 112S022) from TUBITAK (The Scientific and Technological Research Council of Turkey) in association with European Research Projects on Rare Diseases (E-RARE)

Does intravenous immunoglobulin therapy prolong immunodeficiency in transient hypogammaglobulinemia of infancy?

Transient hypogammaglobulinemia of infancy (THI) is characterized by recurrent infections and one or more reduced serum immunoglobulin levels. Typically, THI patients recover spontaneously, mostly within 30-40 months of age, but sometimes recovery may be delayed until 5-6 years of age. The use of intravenous immunoglobulin (IVIg) as an alternative to antibiotic prophylaxis remains contraversial also in symptomatic THI patients. In fact, some authors believe that IVIg therapy may cause a delay in the maturation of the humoral immune system because of the interference from passively transfered antibodies. The aim of this study was to investigate the effect of IVIg replacement on recovery from immunodeficiency in THI patients and determine new parameters in order to include these patients in IVIg therapy groups. In this retrospective study, 43 patients (65%) received IVIg replacement therapy while 23 patients (34.8%) showed spontaneous normalization without IVIg. The percentages of patients who had more than six times the number of febrile infections in a year decreased from 91% to 21% in the group receiving IVIg treatment. At admission, before being recruited to IVIg therapy, serum immunoglobulin G (IgG) levels and anti-hemophilus B (Hib) antibody titers were found to be significantly low in cases who were selected for IVIg replacement. The percentages of patients who did not have protective levels of anti-Hib, anti-rubella or anti-rubeola-IgG were also significantly high in IVIg cases. There was no statistically significant difference in the age at which IgG levels normalized between the IVIg and the non-IVIg group. Patients in the IVIg group and non-IVIg group reached normal IgG levels at the age of 42.9±22.0 and 40.7±19.8 months, respectively. In conclusion, IVIg infusions do not cause a delay in the maturation of the immune system in THI patients. Besides the well-established criteria, very low and non-protective specific antibody responses against previously applied vaccines are important factors to consider when selecting patients for IVIg therapy

Are Proteinase 3 and Cathepsin C Enzymes Related to Pathogenesis of Periodontitis?

WOS: 000336597800001PubMed ID: 24949444Aim. Cathepsin C is the activator of the polymorphonuclear leukocyte-derived proteinase 3, which contributes to inflammatory processes. The aim of the present study was to investigate gingival crevicular fluid (GCF) proteinase 3 and cathepsin C levels in periodontal diseases. Design. Eighteen patients with chronic periodontitis (CP), 20 patients with generalized aggressive periodontitis (G-AgP), 20 patients with gingivitis, and 18 healthy subjects were included in the study. Periodontal parameters including probing depth, clinical attachment level, papilla bleeding index, and plaque index were assessed in all study subjects. GCF proteinase 3 and cathepsin C levels were analyzed by ELISA. Results. GCF proteinase 3 total amount was significantly higher in diseased groups compared to control group, after adjusting age(P0.05). Periodontal parameters of sampling sites were positively correlated with GCF proteinase 3 total amounts (P0.05). Conclusions. Elevated levels of GCF proteinase 3 in CP, G-AgP, and gingivitis might suggest that proteinase 3 plays a role during inflammatory periodontal events in host response. However, cathepsin C in GCF does not seem to have an effect on the pathogenesis of periodontal diseases.Ege University Research FoundationEge UniversityThe authors greatly appreciate the statistical advice received from Professor Mehmet Orman, Department of Biostatistics and Medical Informatics, School of Medicine, Ege University. This study was supported by grant from Ege University Research Foundation