Guzide Aksu

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.

Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans.

Impaired immune functions leading to primary immunodeficiencies often correlate with paradoxical autoimmune complications; patients with hyper-IgM syndromes who are deficient in activation-induced cytidine deaminase (AID), which is required for class-switch recombination and somatic hypermutation, are prone to develop autoimmune diseases. To investigate the impact of AID-deficiency on early B-cell tolerance checkpoints in humans, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from AID-deficient patients. New emigrant/transitional and mature naive B cells from AID-deficient patients express an abnormal Ig repertoire and high frequencies of autoreactive antibodies, demonstrating that AID is required for the establishment of both central and peripheral B-cell tolerance. In addition, B-cell tolerance was further breached in AID-deficient patients as illustrated by the detection of anti-nuclear IgM antibodies in the serum of all patients. Thus, we identified a major and previously unsuspected role for AID in the removal of developing autoreactive B cells in humans.

Inherited and acquired immunodeficiencies underlying tuberculosis in childhood.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life‐threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single‐gene inborn errors of IFN‐γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.

MYCOBACTERIUM FORTUITUM-CHELONAE COMPLEX INFECTION IN A CHILD WITH COMPLETE INTERLEUKIN-12 RECEPTOR BETA 1 DEFICIENCY

A 10-year-old boy had chronic diarrhea, abdominal pain, severe weight loss and hepatomegaly; multiple enlarged para-aortic and mesenteric lymph nodes. Mycobacterium fortuitum-chelonae complex was identified in the culture of the lymph nodes. Interleukin-12 receptor beta 1 expression could not be observed in phytohemagglutinin-driven T cell blasts. A homozygous missense interleukin-12 receptor beta 1 mutation was found (R173P).

Evaluation of the immunomodulatory properties in mice and in vitro anti-inflammatory activity of cycloartane type saponins from Astragalus species.

ETHNOPHARMACOLOGICAL RELEVANCE Astragalus roots are used to treat leukemia and for their wound healing properties in Southeast Anatolia-Turkey. MATERIALS AND METHODS In vivo studies to investigate the effects of two Astragalus saponins were carried out on the immune response cytokines by using six to eight weeks old male Swiss albino mice. The production of IL-1β, TGF-1β, TNF-α, IL-2, IL-4 and IFN-γ cytokines was determined by ELISA. The spleen and lymph nodes, isolated from the mice subjects, were analyzed to realize induction of the surface antigen productions for IL-2Rα (CD25) and CD69. In addition, their effects on the targets of inflammation such as NF κB, iNOS and NAG-1 were investigated in cell-based assays. RESULTS The results suggested that AST VII and Mac B had positive effect on Th1 cytokine release (IL-2 and IFN-γ), and suppression on Th2 cytokine production (IL-4). The immunohistochemical results exhibited induction of both IL-Rα (CD25) and CD69 surface receptors justifying the Th1 cytokine release. The compounds did not affect NF-κB or NAG-1 activity but iNOS activity was inhibited by Mac B with an IC(50) of 156 μg/ml. CONCLUSIONS The results show that Ast VII and Mac B create powerful immunoregulatory effects without the stimulation of inflammatory cytokines in mice, and have no significant effect on the inflammatory cellular targets in vitro.

Increases in serum immunoglobulins to age‐related normal levels in children with IgA and/or IgG subclass deficiency

Immunoglobulins (Ig) A and G subclass deficiencies are common immune system disorders which cause morbidity especially between 2 and 6 yr of age. Prognosis of these defects and therapeutic approach is unclear. The aim of the present retrospective study was to review the clinical and laboratory records of 87 children with IgA and/or IgG subclass deficiency to determine whether these patients experience changes in serum Ig concentrations during follow‐up and to give more clinic and laboratory information to the families about the course of these diseases. Among 87 patients studied, the most frequent defect was partial IgA deficiency combined with IgG3 subclass deficiency (41%). The other groups were as follows; partial IgA deficiency (32%), selective IgA deficiency (8%), partial IgA combined with IgG2‐G4 subclass deficiency (6%), and IgG subclass deficiency (13%). The commonest clinical presentations were recurrent upper respiratory tract infections (76%), pneumonia (14%), acute gastroenteritis (3%), urinary tractus infection (3%), sinusitis (2%), and acute otitis media (2%). Atopy was widely represented in the patients studied (24%). The number of patients who were given prophylactic treatment with benzathine penicilline, prophylactic oral antibiotic, or oral bacterial extract to prevent infections was 68 (78%). Frequency of recurrent infections decreased from 7.9 ± 4.9 per year to 2.5 ± 2.3 in 68 patients receiving any prophylactic regimen; however, decrease in frequency of infections did not show any significant difference between different prophylactic groups. None of the patients in the selective IgA deficiency group had reached normal serum levels of IgA. At the age of 58.3 ± 21.4 months, 52% of patients in partial IgA deficiency group and 51% of patients in partial IgA + IgG subclass deficiency group, serum IgA increased to normal ranges. Serum IgG subclass levels increased to normal range for age in 67% of patients in partial IgA + IgG subclass deficiency group and in 30% of patients in isolated IgG subclass deficiency group. The mean age for reaching age‐related normal IgG subclass levels for these patients was 69.0 ± 14.5 months. In conclusion, findings of this study suggest that IgA and/or IgG subclass deficiency may be either progressive or reversible disorders and emphasize the value of monitoring Ig levels in affected individuals.

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.

Griscelli syndrome without hemophagocytosis in an eleven‐year‐old girl: Expanding the phenotypic spectrum of Rab27A mutations in humans

We present an eleven‐year‐old female patient who was referred to us with silvery hair, hepatosplenomegaly, neutropenia‐thrombocytopenia, hypogammaglobulinemia and degenerative white matter disease, with a family history of a female sibling dying at the age of five and two living male cousins, ages 10 and 11. She had been followed up for her cytopenia the last three years and had totally recovered from a hemiplegic episode before admission. The family was of Arabic origin, and a second‐degree consanguinity was reported between the parents. Microscopic analysis of her hair shafts revealed irregularly distributed small and large clumps of melanin, and skin biopsy findings were consistent with partial albinism. Bone marrow aspiration and biopsy did not detect any evidence of hemophagocytosis. Genetic analysis identified a homozygous two‐base‐pair deletion (51 del CT leading to S18X) in the Rab27A gene of the patient. She suffered from febrile neutropenic episodes. Her persistent cytopenia could not be corrected with immunoglobulin, thrombocyte infusions, or a short course of growth factor treatment. Splenectomy was planned due to her progressive splenic enlargement. She was also considered for bone marrow transplantation. She unfortunately died from an intracranial hemorrhage. Her clinical presentation was remarkable, mostly resembling partial albinism immunodeficiency/Elejalde syndrome due to her older age and absence of hemophagocytosis, but with molecular findings confirming Griscelli syndrome.

Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases

BACKGROUND Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. OBJECTIVE Our objective was to assess the effect of mycobacterial disease in patients with CGD. METHODS We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. RESULTS Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. CONCLUSION Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.

Association between anti-endomysial antibody and total intestinal villous atrophy in children with coeliac disease

BACKGROUND There is growing evidence to suggest that detection of anti-gliadin antibody (AGA) and anti-endomysial antibody (EmA) can serve as sensitive markers of the degree of histological abnormalities in patients with coeliac disease. AIM To evaluate the association between the presence of AGA and EmA and villous atrophy in intestinal biopsies of children with suspected coeliac disease. SETTINGS AND DESIGN Intestinal samples of 46 children with failure to thrive, chronic diarrhoea, malabsorption and short stature with either AGA and/or EmA positivity were evaluated, retrospectively. The diagnosis of coeliac disease was based on ESPGHAN criteria. METHODS AND MATERIAL Patients with total villous atrophy who fulfilled the ESPGHAN criteria for the diagnosis of coeliac disease were diagnosed to have coeliac disease. Nine patients without villous atrophy were taken as negative controls for this study. AGA-IgA was measured both by immunoflourescence (IF) and ELISA and EmA-IgA by IF while patients were on normal diet. Relationship between autoantibody positivity and intestinal total villous atrophy was evaluated. RESULTS Overall positivity for AGA IgA was 85% (39/46) by IF+ELISA and EmA positivity was 85% (39/46) by IF within the study group. Histological examination revealed total villous atrophy with lymphocyte infiltration and crypt hyperplasia in 37 (80%) patients. AGA IgA was positive in 14 (38%) and 31 (84%) of these children by ELISA and IF, respectively. EmA positivity was detected in 35/37 (95%) cases with atrophy and 4/9 (44%) without atrophy (p=0.002). Thirty out of 37 (81%) patients with villous atrophy had both AGA IgA (IF) and EmA positivity (p=0.186). All of the sixteen patients that had both positive AGA IgA (ELISA+IF) and EmA had total villous atrophy (p=0.037). CONCLUSION A significant association between total villous atrophy and EmA positivity has been documented in this study.