Study of patients with Hyper-IgM type IV phenotype who recovered spontaneously during late childhood and review of the literature

Hyper-IgM syndromes are characterized by normal or elevated serum IgM levels with the absence or reduced levels of other immunoglobulins. There are some patients with defective class-switch recombination (CSR) who do not have CD40L, CD40, AID, and UNG defects. The aim of this study is to determine the B-cell functions of patients with Hyper-IgM type 4 phenotype. Ten patients (seven males and three females) 84.2 ± 16.5 months of age with initial low serum IgG and IgA and high or normal IgM levels were included. Clinically, 50% had recurrent upper respiratory tract, 10% urinary tract, 10% lower respiratory tract infections, and 30% had mixed type infections. Lymphoid hyperplasia, overt autoimmune manifestations, or malignancy was not noted. Seven of 10 patients were studied twice; at the age of 34.2 ± 13.7 and at 86.6 ± 12.3 months. Absolute lymphocyte counts and lymphocyte subsets were normal in all cases. All of them had normal expression of CD40 on B cells and CD40L on activated T cells for males. At first examination, all patients had normal in vitro sCD40L+rIL-4-induced B cell proliferation response and somatic hypermutation but CSR towards IgE was absent. AID and UNG genes did not show any abnormalities. All showed improvement in both clinical findings and Ig levels during the follow-up period of 55.8 ± 14.8 months. Ages for normalization of IgG and IgA were 68.2 ± 8.7 and 70.2 ± 21.6 months, respectively. During the second evaluation: In vitro sCD40L+rIL-4-induced B-cell proliferation was normal in all cases, whereas CSR was still abnormal in five of eight patients. Two of the patients had an increase in in vitro CSR response but still low IgG2 subclass levels. Three patients with initially absent in vitro CSR response also normalized. Conclusion: Clinical manifestations and immunoglobulin levels of the patients with Hyper-IgM type 4 phenotype recovered in late childhood at about 6 years of age. There was a transient CSR defect which was not observed in cases with transient hypogammaglobulinemia of infancy. Detection of a non-AID or non-UNG associated CSR defect in infancy should be confirmed later on since spontaneous recovery may occur.     

Proinflammatory cytokines, prostaglandins and zinc in febrile convulsions

BACKGROUND: Some changes in the levels of proinflammatory cytokines, prostaglandins and zinc (Zn) in peripheral blood and cerebrospinal fluid (CSF) have been suggested to occur for the pathogenesis of febrile convulsions (FC). METHODS: In order to test this hypothesis, the levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha, IL-1 beta and prostaglandins (PGE(2), PGF(2 alpha), PGD(2)) in the CSF and plasma and the levels of Zn in serum and CSF were investigated in children during the acute and late phases of FC. Results were compared with control subjects with meningismus. RESULTS: During the acute phase of FC, children had significantly elevated plasma levels of IL-1 beta, CSF levels of TNF-alpha, plasma levels of PGE(2), PGF(2 alpha) and PGD(2) and CSF levels of PGD(2) (P<0.05). A positive correlation between the degree of fever and plasma IL-1 beta levels was observed in both patients and controls. Three months after the acute phase of FC, plasma levels of IL-1 beta had returned to levels seen in controls. Children with FC also had significantly decreased serum Zn levels during the acute phase (P<0.05). However, there was no significant difference between the groups with respect to CSF Zn levels (P>0.05). CONCLUSIONS: During the acute phase of FC, patients had significantly increased plasma IL-1 beta and prostaglandin levels and decreased serum Zn levels. These changes may be responsible for FC pathogenesis.     

Successful bone marrow transplantation in an 8-month-old patient with chronic granulomatous disease

An eight-month-old boy with chronic granulomatous disease (CGD) received HLA identical sibling bone marrow transplantation (BMT) following busulphan and cyclophosphamide conditioning. No graft-versus-host disease was demonstrated. Five years after transplantation, mixed chimerism was 60% in peripheral blood, and 85% of his neutrophils had normal oxidative burst activity. He is now six years old, in very good health and growing well. In this period, he experienced no severe infectious diseases. To our knowledge, this is the first case of CGD who had BMT in Turkey. His successful outcome illustrates that BMT in a patient with CGD in the first years of life should be considered early if an HLA-matched donor is already available, before development of any recurrent life-threatening infections or irreversible organ damage.     

Juvenile psoriatic arthritis carrying familial Mediterranean fever gene mutations in a 14-year-old Turkish girl

Juvenile psoriatic arthritis (JPsA) is characterized by asymmetric arthritis of big and small joints, enthesitis, dactylitis, psoriatic skin lesions and nail pitting. Investigators agree that JPsA is a relatively common chronic arthropathy of childhood that differs clinically, serologically, and genetically from both juvenile idiopathic arthritis and juvenile ankylosing spondylitis. Familial Mediterranean fever (FMF) is a multisystemic autosomal recessive disease occasionally accompanied by sacroiliitis. This is characterized by recurrent self-limited attacks of fever and accompanying abdominal, chest and arthricular pain. We present a 14-year-old Turkish girl with JPsA and carrying FMF gene mutations. In this patient, JPsA was diagnosed according to her physical, laboratory and skin biopsy findings and a treatment with methotrexate and sulfasalazine was started. As an inadequate clinical and laboratory response was obtained after the first month of therapy, the patient was investigated for FMF, and was diagnosed by molecular analyses of related gene (E148Q heterozygous/V726A homozygous mutation) besides clinical findings. After 2 weeks of the colchicine treatment, symptoms of the patient regressed and acute phase reactants decreased. To our knowledge, this is the first case presenting with psoriatic arthritis and FMF gene mutations together and responds to colchicine, methotrexate and sulfasalazine dramatically in clinical and laboratory findings. This case has been presented to remind that cases with psoriatic arthritis may also carry mutations in the MEFV gene.     

The influence of marginal zinc deficient diet on post-vaccination immune response against hepatitis B in rats.

AIM: To evaluate in vitro T lymphocyte proliferation and specific antibody response to hepatitis B vaccination in two groups of rats fed with normal and marginal zinc content. METHODS: Twenty-two Wistar-Albino rats were randomly assigned into two groups and were fed with constant diet. Zinc was suplemented 10mg/kg dry weight in group I (marginal zinc content) (n=14) and 30mg/kg dry weight in group II (n=8). Hepatitis B vaccine (Engerix B, 4mug) was administered intramuscularly after 8 weeks on feeding and a booster dose was applied 4 weeks after the first injection. Rats were killed 3 weeks after the second injection. Peripheral blood mononuclear cells were stimulated in vitro by PHA (2.5mug/ml) and hepatitis B surface antigen (2.5, 5, 10mug/ml). Proliferation was evaluated by ELISA (celltiter-96 aqueous one solution cell proliferation assay). Serum zinc, anti-HBs titer and zinc per dry liver weight were also measured. Two groups were compared with respect to antigen specific antibody and lymphocyte proliferation responses. Proliferation response to HbsAg were expressed as net percent increase (pci) in lymphocyte proliferation from the baseline activity. RESULTS: Rats' mean body weight and weight gain per month were similar. Median serum zinc was 39 (23-75) and 76(64-115)mug/dl of groups I and II rats, respectively (p<0.05), while there was no difference in liver zinc content between the two groups (37mug/g dry weight versus 32mug/g dry weight). Median anti-HBs levels of groups I and II were 741 (0-10,000)IU/l, 5791 (558-10,000)IU/l, respectively (p<0.05). In lymphocyte proliferation assays, mean net pci with HbsAg of 5 and 10mug/ml were 9.4% and 11.3% in group I rats; while they were 25.3% and 26.1% in group II rats (p<0.01 and p<0.01, respectively). CONCLUSION: In vitro cell-mediated immune response and in vivo specific antibody response to hepatitis B vaccine was decreased in rats fed a diet with marginal zinc content. These observations have shown that marginal Zn deficiency might influence the efficacy of hepatitis B vaccination in humans.     

Study of pro-inflammatory (TNF-α, IL-1α, IL-6) and T-cell-derived (IL-2, IL-4) cytokines in plasma and synovial fluid of patients with juvenile chronic arthritis: Correlations with clinical and laboratory parameters

Acute phase proteins, synovial fluid (SF) cellular infiltrates, pro-inflammatory (TNF-, IL-1, IL-6) and Th1 (IL-2) and Th2 (IL-4) derived cytokine levels both in plasma and SF were examined in pauciarticular and polyarticular juvenile chronic arthritis (JCA) patients during the active (n=22) and inactive (n=14) period in order to determine pathogenic mechanisms and correlations between cytokines and laboratory parameters showing disease activity. The erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) and IgG concentrations were found to be significantly elevated in the active period of JCA. In pauciarticular JCA patients, when compared with their peripheral blood lymphocyte subpopulations, SF CD3+ cells (73.1%) and HLA-DR+ active T cells (22.5%) were found to be significantly increased. In the active period of JCA, plasma TNF- and IL-6 concentrations were significantly elevated. Plasma IL-2 and IL-4 levels were not elevated and were found to be similar to those in the inactive phase and in healthy controls. SF IL-6, TNF- and IL-1 levels were extremely high in all the patients. SF IL-4 and IL-2 levels were all undetectable. There was a significant correlation between ESR values and plasma IL-6 levels and between serum CRP levels and plasma IL-6 and TNF- concentrations. In conclusion, increased local production of pro-inflammatory cytokines appears to account for the articular manifestations of JCA. The impaired production of anti-inflammatory Th2-derived cytokines (IL-4) seems to cause increased production of inflammatory cytokines acting on the balance between them. The deficit in IL-2 production was not suggested to be primarily involved in the pathogenesis. In addition, not only CRP and ESR values, but also plasma IL-6 and TNF- concentrations may be used as markers of disease activity.     

Dental findings and treatment in consanguinity associated congenital chronic familial neutropenia

The purpose of this report is to describe dental findings and treatment of an 11-year old male patient and a 5-year old female patient, children of first cousins, suffering from severe benign congenital chronic familial neutropenia. This case report emphazises the importance of differential diagnosis of immunodeficiencies including congenital chronic familial neutropenia in the background of severe periodontal diseases and/or diffuse carious lesions in children.     

Evaluation of the relationship between caries indices and salivary secretory IgA, salivary pH, buffering capacity and flow rate in children with Down's syndrome

The aim of this study was to compare the caries prevalence and salivary secretory IgA (sIgA), salivary pH, buffering capacity and flow rate between Down's syndrome (DS) and control subjects. Seventy-three institutionalised children with DS and 70 normal children aged 7-12 years old were included in this study. Tooth-brushing habits and daily dietary sugar exposures of the children, family income and education levels of the parents were recorded. DMFS and dfs scores were assessed according to the World Health Organisation's criteria and stimulated whole saliva samples were collected. Salivary sIgA levels were determined by radial immunodiffusion technique, the average salivary flow rate was measured from the total volume, and salivary pH and buffering capacity were determined using a pH micro-electrode. All data were analysed using SPSS version 11.0. The DMFS and dfs scores were significantly lower in the DS group than the control group (P < 0.05). Otherwise, the difference in plaque scores between the DS and control groups was not statistically significant (P > 0.05). There were no significant differences in tooth-brushing habits and daily dietary sugar exposures of the children, family income and education levels of the parents between the two groups (P > 0.05). Salivary sIgA levels were significantly higher in the DS group (P < 0.05). Salivary pH, buffering capacity and flow rate were quite similar in both the DS and control groups (P > 0.05). In conclusion, the patients with DS had a significantly lower prevalence of caries and significantly higher levels of salivary sIgA in this study. This finding tends to support the hypothesis that higher levels of salivary sIgA may protect against dental caries.     

Hypercoagulability: interaction between inflammation and coagulation in familial Mediterranean fever

Familial Mediterranean fever (FMF) patients in clinical remission are reported to have increased baseline inflammation. Normal function of the natural anticoagulant pathways is particularly needed in diminishing inflammatory responses. In the presence of subclinical inflammation, natural anticoagulant response may be exaggerated. We aimed to observe the anticoagulant–procoagulant status in attack-free FMF patients. Twenty-seven FMF patients diagnosed in accordance with Tel-Hashomer criteria, and 26 healthy controls were included. All patients were attack-free under regular colchicine treatment. Amyloidosis, autoimmunity, accompanying liver and renal disease, and vasculitis were excluded. Predisposing factors for thrombosis were not present. Acute phase reactants (APRs), anticardiolipin antibody positivity, prothrombin time (PT), activated prothrombin time, thrombin time (TT) and d-dimer, protein C activity, activated protein C resistance, free protein S, antithrombin, lupus anticoagulant, human prothrombin fragment F 1 + 2, and human thrombin/antithrombin III complex were analyzed for all subjects. APRs were comparable with controls. Autoimmune markers were negative in all. Anti-streptolysin titers were significantly different than the control group. PT, TT, protein C activity, and F 1 + 2 levels were significantly different from those of healthy controls. Shortened PT and TT, decreased protein C activity vs increased levels of F 1 + 2 suggested a hypercoagulable state in our patients. The hypercoagulable state detected in FMF patients suggests that screening with abnormal coagulation tests may be beneficial for tracing the future consequences of subclinical inflammation in these patients. Studies covering larger groups of patients are needed to verify the currently observed hypercoagulable status in FMF.