Hypersensitivity reactions to ß-lactams: relevance of hapten-protein conjugates

B-Lactams (BL) are the drugs most frequently involved in allergic reactions. They are classified according to their chemical structure as penicillins, cephalosporins, monobactams, carbapenems, and clavams. All BL antibiotics have a BL ring that is fused to a 5-member or 6-member ring (except in monobactams) and has 1, 2 or 3 side chains (except in clavams). Differences in chemical structure mean that a wide range of BLs are recognized by the immune system, and patients may experience clinical reactions to one BL while tolerating others. Diagnosis is based on skin and in vitro testing, although both display low sensitivity, possibly because they are based on drugs or drug conjugates that are not optimally recognized by the immune system. BLs are haptens that need to bind to proteins covalently to elicit an immune response. These drugs have a high capacity to form covalent adducts with proteins through nucleophilic attack of amino groups in proteins on the BL ring. Allergenic determinants have been described for all BLs, although benzylpenicillin is the most widely studied. Moreover, formation of BL-protein adducts is selective, as we recently demonstrated for amoxicillin, which mainly modifies albumin, transferrin, and immunoglobulin heavy and light chains in human serum. Given the complexity of BL allergy, understanding the immunological mechanisms involved and optimization of diagnostic methods require multidisciplinary approaches that take into account the chemical structures of the drugs and the carrier molecules, as well as the patient immune response (AU)

Las betalactamas (BL) son los fármacos implicados más frecuentemente en reacciones alérgicas. Se clasifican según su estructura química en penicilinas, cefalosporinas, monobactamas, carbapenems y clavamas. Poseen un anillo betalactámico que, excepto en las monobactamas, está fusionado a un anillo de cinco o seis miembros y, excluyendo las clavamas, tienen 1, 2 o 3 cadenas laterales. Las diferencias en las estructuras químicas resultan en un amplio rango de BLs, que puede ser discriminado por el sistema inmune, con inducción de reacciones clínicas a una BL y tolerancia a otras. El diagnóstico está basado en pruebas cutáneas e in vitro, aunque ambas presentan una baja sensibilidad. Esto podría deberse a que los fármacos o conjugados de fármacos empleados en estos tests que no se reconocen de manera óptima por el sistema inmune. Las BLs son haptenos que necesitan de su unión covalente a proteínas para inducir una respuesta inmunológica. Estos fármacos presentan una elevada capacidad para formar aductos covalentes con proteínas mediante el ataque nucleofílico de grupos aminos de proteínas al anillo BL. Aunque la bencilpenicilina ha sido la mejor estudiada, también se han descrito determinantes alergénicos del resto de BLs. Además, la formación de los aductos BLs-proteína muestra selectividad, así se ha demostrado recientemente para la amoxicilina, que principalmente modifica la albúmina en suero (HSA), la transferrina y las cadenas ligeras y pesadas en suero humano. Dada la complejidad de la alergia a BL, el conocimiento de los mecanismos inmunológicos implicados y la optimización de los métodos diagnósticos requieren de abordajes multidisciplinares teniendo en cuenta tanto la estructura química de los fármacos y de las moléculas portadoras, como las respuestas de los pacientes (AU)

Infantile hepatic dysfunction improved by elimination of cows' milk formulas.

We present three infants who showed hypertransaminasemia without extrahepatic symptoms, which improved by eliminating cows' milk formulas. The levels of milk protein-specific lymphocyte proliferation were elevated in all three patients. These cases indicate the importance of food allergy in the diagnosis of infantile hepatic dysfunction.

[Tissue anti-transglutaminase antibodies: a better test to detect minor dietary transgressions in celiac patients?]. / Anticuerpos anti-transglutaminasa tisular: una mejor prueba para detectar transgresiones menores de la dieta en pacientes celíacos?

BACKGROUND: Endomysium antibodies (EMA) do not detect minor dietary transgressions in patients with celiac disease. AIM: To compare the sensitivity and specificity of tissue transglutaminase antibodies (tTGA) and endomysium antibodies (EMA) in biopsy proven celiac patients at the time of diagnosis and during gluten free diet (GFD). PATIENTS AND METHODS: One hundred fifty three subjects were studied: a) 30 healthy controls; b) 9 cases with cow's milk allergy; c) 24 celiac patients at time of diagnosis; d) 25 celiac patients adhering to the GFD; e) 65 celiac patients with poor/no adhesion to GFD. EMA and tTGA IgA were measured by immunofluorescence and ELISA, respectively. RESULTS: Sensitivity and specificity were 100% and 97.4% for tTGA, respectively. All patients with cow's milk allergy were EMA (-) and 8 of 9 (88.9%) were tTGA (-). In celiac patients not adhering to the GFD, EMA and tTGA positivity were similar (80% and 81.5%, respectively); 95.4% of the subjects tested positive for at least one of them. All patients adhering to GFD were EMA (-) but tTGA were (+) in 28% of them. CONCLUSIONS: EMA and tTGA have similar sensitivity and specificity at the time of diagnosis of celiac disease. Positive tTGA in 28% of patients that adhered strictly to the GFD and whose EMA were negative suggest that tTGA may be helpful in detecting minor dietary transgressions and should be further evaluated.

Mucosal enterokinase activity in cow's milk protein sensitive enteropathy.

Enterokinase has a critical role in initiating proteolytic digestion by hydrolysing the conversion of pancreatic trypsinogen into trypsin. The enzyme is synthesised by enterocytes of the proximal small intestine and initially incorporated into the brush border from where it is released into the intestinal lumen by the action of pancreatic secretions. The aim of the study was to analyse enterokinase activity in the duodenal mucosa of infants with diarrhoeal disease including cow's milk protein-sensitive enteropathy. Our observations show that the mean depletion of enterokinase was only 17% compared to 60-80% for other brush border enzymes like disaccharidases, peptidases and alkaline phosphatases in infants with diarrhoea. This suggests that enterokinase activity in the small bowel enteropathies may be dependent not only on the degree of mucosal damage specifically but also on the extent of damage to the goblet cell population where the enzyme is synthesised. Thus the enterokinase activity was reduced in acute and chronic diarrhoea with marked mucosal damage where significant reduction of goblet cell population was evident but the enzyme was relatively little affected when the mucosa was damaged mildly.

Mucosal and serum alkaline phosphatase activities in milk allergy.

The effect of cow's milk protein (CMP) challenge on the levels of alkaline phosphatase (ALP) in the upper jejunal mucosa and the serum were studied in 25 infants clinically suspected to have cow's milk allergy. Following CMP provocation 3 groups were identified. Group 1 consisted of 10 infants who had clinical and histological reaction to CMP challenge. All 10 infants had significant depletion in the levels of tissue and serum ALP. Group 2 consisted of 5 infants who had histological reaction but no clinical reaction. Tissue ALP was depressed in 3 but not in 2 following CMP challenge. Serum ALP were essentially unaltered in all 5. Group 3 consisted of 10 infants who clinically and histologically tolerated CMP challenge. Tissue and serum ALP were not depressed in any. Estimation of sucrase levels in the mucosa and xylose absorption before and after CMP challenge were also performed for comparison with changes of tissue and serum ALP levels. The clinical significance of the changes in serum ALP level is discussed.