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

Granulomatous pyoderma preceding chronic recurrent multifocal osteomyelitis triggered by vaccinations in a two-year-old boy: a case report

<p>Abstract</p> <p>Introduction</p> <p>Chronic recurrent multifocal osteomyelitis is a rare, systemic, aseptic, inflammatory disorder that involves different sites. Pathogenesis of chronic recurrent multifocal osteomyelitis is currently unknown.</p> <p>Case presentation</p> <p>A two-year-old Caucasian boy, diagnosed with chronic recurrent multifocal osteomyelitis with granulomatous pyoderma following routine vaccinations is presented for the first time in the literature.</p> <p>Conclusion</p> <p>We conclude that antigen exposures might have provoked this inflammatory condition for our case. Skin and/or bone lesions following vaccinations should raise suspicion of an inflammatory response such as chronic recurrent multifocal osteomyelitis only after thorough evaluation for chronic infection, autoimmune, immunodeficiency or vasculitic diseases.</p

Low Penetrance, Broad Resistance, and Favorable Outcome of Interleukin 12 Receptor β1 Deficiency: Medical and Immunological Implications

The clinical phenotype of interleukin 12 receptor β1 chain (IL-12Rβ1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rβ1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rβ1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most

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)

Clinical and Laboratory Evaluation of Periodically Monitored Turkish Children with IgG Subclass Deficiencies

WOS: 000266996300006PubMed ID: 19548629IgG subclass deficiencies are common immune system disorders during childhood. The aim of this retrospective study was to review clinical findings and laboratory results of patients with IgG subclass deficiencies in order to determine the changes in serum IgG subclass levels during follow-up, the percentage and time span until normalization of the IgG subclass levels to age-corresponding normal levels, the type of infections incurred and the benefits of prophylaxis. Among the 59 pediatric patients reviewed, the most frequent defect was an IgG3 subclass deficiency (77%). Nine percent of the patients had an isolated IgG2 deficiency and 14% had an IgG2+G3 deficiency. The most common clinical presentations were recurrent upper respiratory tract infections, followed by pneumonia, acute gastroenteritis and urinary tract infections. Atopy was present in 15% of the patients. Ninety percent of the patients were given a prophylactic treatment (benzathine penicillin, oral antibiotics, oral bacterial lysate or intravenous immunoglobulin). The frequency of recurrent infections decreased from 13.4 +/- 7.4 per year to 5.7 +/- 3.9 in patients receiving a prophylactic regimen. Serum IgG subclass levels reached normal ranges in 30% of the patients in the IgG3 deficiency group and in 35.7% of the patients in the IgG2+G3 deficiency group. Patients with an isolated IgG2 deficiency did not reach age-related normal levels during the study period. Our study shows that IgG subclass levels may normalize in 30 to 40% of patients at about 6 years of age. We emphasize the need of monitoring IgG levels together with the clinical symptomatology in affected individuals and initiate preventive measures when appropriate