ObjectivesTo characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype.MethodsWe studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients’ primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM).ResultsWe identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients’ fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth.ConclusionsMutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.

Natural antibodies provide an early defense mechanism against pathogens, show a frequent self-reactivity, and are present throughout life. Two questions concern the physiological control of self-reactivity and the pathogenetic link to autoimmune disease. Here we propose a concept of conditional autoimmunity involving natural antibodies against the alpha chain of the high-affinity receptor for IgE (Fc(epsilon)RIalpha ). Like other natural antibodies, anti-Fc(epsilon)RIalpha antibodies are found in sera of healthy donors. We now report the first human recombinant anti-Fc(epsilon)RIalpha autoantibodies isolated by repertoire cloning from a human tonsillar IgM library. These high-affinity antibodies recognize Fc(epsilon)RIalpha on cells and trigger histamine release from freshly isolated blood basophils. However, the latter effect requires IgE removal from the Fc(epsilon)RI. The same conditional histamine release is seen when using sera from individual normal donors and affinity-purified anti-Fc(epsilon)RIalpha antibodies isolated from multidonor therapeutic IgG preparations. We propose that such anti-Fc(epsilon)RIalpha antibodies can become pathogenic and that this is dependent on the state of occupancy of the Fc(epsilon)RIalpha by its natural ligand IgE. We suggest that an imbalance between Fc(epsilon)RIalpha occupancy and natural anti-Fc(epsilon)RIalpha antibodies may be implicated in the pathogenesis of autoimmune urticaria.

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Angiotensin receptor blockers are potent antihypertensive drugs with very few side effects [1,2]. No association has been documented between use of angiotensin receptor blockers during the first trimester of gestation and congenital defects. However, there are several reports of malformations and physiologic disturbances, mostly with lethal outcome, in infants exposed to these drugs during the second and third trimesters, as recently reviewed [3,4]. We report the adverse long-term sequelae noted in an infant following maternal treatment with an angiotensin receptor blocker.A 39-year old woman on treatment with candesartan cilexetil 16 mg once a day [5] for mild essential hypertension became pregnant but the drug was not discontinued. At 31 weeks a male boy weighing 1.65 kg was delivered by cesarian section. The physical examination disclosed climb contractures, skull hypoplasia with microcephaly (head circumference 0.265 m) and moderately underdeveloped calvarial bones. The child developed immediate respiratory distress (treated with oxygen, exogenous surfactant and mechanical respiratory support), arterial hypotension (treated with dopamine and epinephrine), and moderate oliguria (creatinine up to 281 μmol/l, urea up to 15.6 mmol/l and a pathologically increased urinary protein to creatinine ratio of 739 mg/mmol; upper reference 50). His conditions improved during the second week of postnatal life. However, a tendency towards arterial hypertension (mean blood pressure 75-80 mm Hg; upper reference 68) was noted, requiring treatment with the calcium channel blocker amlodipine once a day during 6 weeks. Routine chromosome analysis revealed a normal male karyotype.The boy is currently 34 months of age. Body weight is 11.1 kg (−2.8 SDS), length 0.901 m (−1.5 SDS), head circumference 0.481 m (−2 SDS) and blood pressure slightly elevated (approximately 110/70 mm Hg; upper reference 106/66) and the calvarial bones normally developed. His cognitive and especially his linguistic development are moderately retarded. The physical examination is otherwise normal. Plasma creatinine (36 μmol/l) and urea (6.0 mmol/l) are normal. The urinary protein to creatinine ratio is slightly increased (29 mg/mmol, upper reference 20). Renal ultrasound study demonstrates rather small hyperechogenic kidneys and loss of corticomedullary differentiation.In conclusion during pregnancy the use of drugs that block the renin-angiotensin-aldosterone system, namely angiotensin receptor blockers [3,4] and converting enzyme inhibitors [4,6], is strongly cautioned against. Infants surviving the exposition to these agents during the second and third trimesters tend to a chronic kidney disease and a developmental delay. A corresponding long-term follow up is warranted. Giacomo D. Simonetti is currently supported by a scholarship of the Ettore e Valeria Rossi Foundation.

Chronic urticaria may be characterized by conditional autoantibodies against the alpha-chain of the high-affinity receptor for IgE (FcepsilonRI). These autoantibodies are termed conditional as they only recognize unoccupied FcepsilonRI. The same conditional reactivity pattern has also been found in sera of atopic and normal healthy donors. Any condition resulting in accessibility of FcepsilonRI will render these autoantibodies anaphylactogenic. This finding offers a unifying hypothesis for the manifestation of different forms of urticaria. Non-immunologic triggers may thereby influence directly or indirectly the number of accessible FcepsilonRI allowing the conditional autoantibodies to induce urticaria symptoms.

It is well established that heat–denatured IgE is no longer capable of binding to FcεRI. We have found an antibody that interacts with heat–denatured IgE. Interestingly, this antibody can also be used to detect some serum IgE, but not IgE synthesized de novo in vitro. However, native IgE can be transformed into an IgE that is recognized by this antibody, if antigen is added. Our data indicate that physiological mechanisms exist that biologically inactivate IgE which might still be mistaken for 'functional' IgE by assays based on polyclonal antibodies.

A 12-month-old boy developed a mild hemolytic uremic syndrome with no acute diarrheal prodrome. The typical clinical, hematological, and serological features of infectious mononucleosis were also noted. The clinical course of both hemolytic uremic syndrome and infectious mononucleosis was uneventful. A review of the literature disclosed that hemolytic uremic syndrome has been noted in two adolescents with infectious mononucleosis.