Atypical patterns of STAT3 phosphorylation in subpopulations B cells in patients with common variable immunodeficiency.

BACKGROUND: Common Variable Immunodeficiency (CVID) is a heterogeneous disorder characterized by defective B cell differentiation and antibody production. Interleukin (IL)-21 activates STAT3, a potent regulator of B cell differentiation into plasma cells. We have studied the phosphorylation of STAT3 in CVID patients and its contribution to B cells subsets. METHODS: We studied 23 CVID patients and 14 healthy donors (HD), determining pSTAT3 in naïve and memory B cells, stimulated with IL-21 at 15 and 60 min. RESULTS: pSTAT3 was increased in total (p = 0.044), naïve (p = 0.023), and memory (p = 0.001) B cells at 60 min in CVID patients compared with HD. We classified patients by the percentage of isotype-switched memory B cells. We observed an increase in pSTAT3 at 60 min in memory B cells in both CVID groups of patients (p = 0.026, p = 0.007, respectively). Interestingly, the analysis of each group individually; demonstrated that patients with decreased memory B cells exhibited an increase in pSTAT3 at 60 min (p = 0.023), while HD had an expected decrease in pSTAT3 (p = 0.045). CONCLUSION: CVID patients showed an increased atypical of pSTAT3, which could affect the differentiation of B cells. Further studies in the IL-21 pathway are necessary to understand how this alteration could promote differentiation defects in patient B cells.

Bronchiolitis Obliterans With Anti-Epiplakin Antibodies in a Boy With Paraneoplastic Pemphigus.

Paraneoplastic pemphigus is a rare and severe autoimmune blistering disease characterized by a recalcitrant and severe mucositis, and polymorphic cutaneous lesions, associated with benign and malignant neoplasms. Paraneoplastic pemphigus is caused by production of autoantibodies against various epidermal proteins involved in cell adhesion. Bronchiolitis obliterans (BO) is one of the leading causes of mortality in these patients. Recent advances have associated the presence of anti-epiplakin antibodies with the development of BO in adult patients. Here we describe the first pediatric patient in whom the association of anti-epiplakin antibodies and BO have been reported so far.

Diagnostic and therapeutic caveats in Griscelli syndrome.

Griscelli syndrome (GS) is a rare autosomal recessive disease with characteristic pigment distribution, and there are currently 3 types according to the underlying genetic defect and clinical features. We present the case of a girl born from consanguineous parents who presented with predominant neurologic symptoms, silvery hair and granulomatous skin lesions. Cerebral magnetic resonance revealed diffuse white matter lesions, and central nervous system (CNS) lymphocytic infiltration was suspected. The patient underwent haematopoietic stem cell transplantation with graft failure and autologous reconstitution. She developed elevated liver enzyme with a cholestatic pattern. Multiple liver biopsies revealed centrilobular cholestasis and unspecific portal inflammation that improved with immunomodulatory treatment. She was revealed to have an impaired cytotoxicity in NK cells and a decreased expression of RAB27A. However, no variants were found in the gene. All types of GS present with pigment dilution and irregular pigment clumps that can be seen through light microscopy in hair and skin biopsy. Dermic granulomas and immunodeficiency with infectious and HLH predisposition have been described in GS type 2 (GS2). Neurologic alterations might be seen in GS type 1 (GS1) and GS type 2 (GS2), due to different mechanisms. GS1 presents with neurologic impairment secondary to myosin Va role in neuronal development and synapsis. Meanwhile, GS2 can present with neurologic impairment secondary to SNC HLH. Clinical features and cytotoxicity might aid in differentiating GS1 and GS2, especially since treatment differs.

Use of Infliximab in the Treatment of Macrophage Activation Syndrome Complicating Kawasaki Disease.

Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology. KD can be complicated with macrophage activation syndrome. The optimal treatment for this KD complication has not been established, and a variety of treatments have been used. Infliximab, a chimeric monoclonal antibody that binds tumor necrosis factor, has proved to be efficacious in IV gammaglobulin resistant KD. We present 2 cases of KD complicated with macrophage activation syndrome, including 1 patient with DiGeorge syndrome successfully treated with a combined treatment of IV gammaglobulin, corticosteroids, cyclosporine, and infliximab.

Failing to Make Ends Meet: The Broad Clinical Spectrum of DNA Ligase IV Deficiency. Case Series and Review of the Literature.

DNA repair defects are inborn errors of immunity that result in increased apoptosis and oncogenesis. DNA Ligase 4-deficient patients suffer from a wide range of clinical manifestations since early in life, including: microcephaly, dysmorphic facial features, growth failure, developmental delay, mental retardation; hip dysplasia, and other skeletal malformations; as well as a severe combined immunodeficiency, radiosensitivity, and progressive bone marrow failure; or, they may present later in life with hematological neoplasias that respond catastrophically to chemo- and radiotherapy; or, they could be asymptomatic. We describe the clinical, laboratory, and genetic features of five Mexican patients with LIG4 deficiency, together with a review of 36 other patients available in PubMed Medline. Four out of five of our patients are dead from lymphoma or bone marrow failure, with severe infection and massive bleeding; the fifth patient is asymptomatic despite a persistent CD4+ lymphopenia. Most patients reported in the literature are microcephalic females with growth failure, sinopulmonary infections, hypogammaglobulinemia, very low B-cells, and radiosensitivity; while bone marrow failure and malignancy may develop at a later age. Dysmorphic facial features, congenital hip dysplasia, chronic liver disease, gradual pancytopenia, lymphoma or leukemia, thrombocytopenia, and gastrointestinal bleeding have been reported as well. Most mutations are compound heterozygous, and all of them are hypomorphic, with two common truncating mutations accounting for the majority of patients. Stem-cell transplantation after reduced intensity conditioning regimes may be curative.

Kawasaki Disease Complicated With Macrophage Activation Syndrome: A Systematic Review.

Macrophage activation syndrome (MAS), also known as secondary hemophagocytic lymphohistiocytosis, is a rare and potentially fatal complication of Kawasaki disease (KD). We report 2 cases, performed a literature search, and analyze the characteristics of MAS associated with KD. A total of 69 patients were evaluated, 34 reported the date of the diagnosis of MAS and KD, 6% had a diagnosis of MAS before KD, 21% had a simultaneous presentation, and 73% had the diagnosis of MAS after KD. Different treatment approaches were observed with corticosteroids administered in 87%, cyclosporine in 49%, etoposide (VP-16) in 39%, and monoclonal anti-TNF in 6% of cases. Coronary abnormalities were especially high in this group of patients (46%) and 9 patients died (13%). The persistence of fever with splenomegaly, hyperferritinemia, thrombocytopenia, and elevated aspartate aminotransferase (AST) should prompt the consideration of MAS complicating KD.

Clinical Features, Non-Infectious Manifestations and Survival Analysis of 161 Children with Primary Immunodeficiency in Mexico: A Single Center Experience Over two Decades.

PURPOSE: The hallmark of Primary immunodeficiencies (PID) is unusual infection, although other immunological non-infectious manifestations such as autoimmunity, allergy and cancer are often present. Most published reports focus on one disease or defect groups, so that a global prevalence of non-infectious manifestations of PID is hard to find. We aimed to describe the clinical features of our pediatric patients with PID, as well as the frequency and evolution of allergy, cancer and autoimmunity. METHODS: We reviewed all the available charts of patients being followed for PID from 1991 to the spring of 2012 at the National Institute of Pediatrics, Mexico City, to describe their demographic, clinical and laboratory features. Their diagnoses were established by pediatric immunologists in accordance to ESID criteria, including routine immunological workup and specialized diagnostic assays. We divided patients by decade of diagnosis to analyze their survival curves. RESULTS: There were 168 charts available, from which we excluded one duplicate and six equivocal diagnoses. We studied the charts of 161 PID patients (68% male, 86% alive), mostly from the center of the country, with a positive family history in 27% and known consanguinity in 11%. Eighty percent of the patients were diagnosed during the last decade. Current median age was 124 months; median age at onset of infections, 12 months; median age at diagnosis, 52 months; median age at death, 67.5 months. Severe infection and bleeding were the cause of 22 deaths. Eighty-six percent of all patients had at least one infection, while non-infectious manifestations had a global prevalence of 36%, namely: autoimmunity 19%, allergies 17%, and cancer 2.4%. Survival curves were not significantly different when compared by decade of diagnosis. CONCLUSIONS: Compared to other registry reports, we found a lower prevalence of antibody defects, and of associated allergy and cancer. We could only locate two isolated IgA deficiencies and four cases of cancer among our PID patients. Although antibody defects are the most prevalent group (30%), the distribution we found is similar to that reported in Iran, Kuwait, Egypt and Taiwan, with a close 27% share for phagocyte defects, and 26% for the formerly called "well-defined" syndromes. Of note, autoimmune and inflammatory complications are high among our patients with chronic granulomatous disease, as has been reported in both the United States and Japan, but not in Europe.

Intravenous immunoglobulin treatment for macrophage activation syndrome complicating chronic granulomatous disease.

OBJECTIVES: Chronic granulomatous disease is a rare phagocyte disorder characterized by an increased susceptibility to infections and inflammatory complications. We describe two patients with chronic granulomatous disease (CGD) complicated by macrophage activation syndrome (MAS) (secondary hemophagocytic lymphohistiocytosis) treated with intravenous immunoglobulin (IVIG). METHODS: A report of two cases of CGD complicated by MAS who were successfully treated with IVIG was made, and a comparison was made with ten other cases reported in the literature. RESULTS: MAS is a severe potentially fatal complication of CGD. Most cases are associated with Burkholderia cepacia and leishmaniasis infection. The treatment of these patients varies between centers, and one example is the use of the HLH-2004 protocol. IVIG could be an effective first line option for this complication in CGD patients. CONCLUSIONS: The exaggerated inflammatory response characteristic of CGD patients could play a role in the development of this complication. IVIG appears to be a safe and effective first line treatment in these patients.

Corticosteroid therapy for refractory infections in chronic granulomatous disease: case reports and review of the literature.

BACKGROUND: Chronic granulomatous disease (CGD) is a primary phagocyte immunodeficiency. It is often accompanied by an exuberant and aberrant inflammatory response, with granulomata and obstruction of the gastrointestinal and genitourinary tracts and inflammatory bowel disease. Although corticosteroids are successful in managing the obstructive and inflammatory disorders of CGD, they are not ordinarily used for the management of infection because of the possibility of further compromising the patient's immune system. OBJECTIVES: To discuss the pros and cons of the use of corticosteroids for the treatment of infections in CGD. METHODS: We describe 2 patients with CGD and refractory infections who were successfully treated with systemic corticosteroids in addition to antimicrobial agents. We also review the medical literature in which corticosteroids have been used for CGD infection. RESULTS: Our cases add to 3 other reports in which antibiotics and corticosteroids were used successfully in patients with CGD. However, in the presence of a potential pathogen, notably, aspergilla, corticosteroids may mask or favor dissemination of the fungus, especially in adults. CONCLUSIONS: Corticosteroids may play an important adjunctive role in CGD refractory infections.