Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-03-05
2003-11-25
Housel, James (Department: 1645)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007920, C530S350000, C530S387100
Reexamination Certificate
active
06653085
ABSTRACT:
BACKGROUND OF THE INVENTION
Several known antigens are known and are presently being used for identifying celiac disease in both adults and children. Some of these antigens and the screening procedures are outlined in the articles “Precipitins to antigens of wheat and cow's milk in celiac disease” by Heiner D C, Lahey M E, Wilson J F, et al., published in 1962 in
J. Pediatr.
61,814; “A reliable screening test for childhood celiac disease: fluorescent immunosorbent test for gliadin antibodies. A prospective multicenter study,” published in 1983 in
J. Pediatr.
102:655-60; “Gliadin antibodies in celiac disease” published in 1983 in
J. Pediatr.
102:711-2. There are also several other papers and publications concerned primarily with tests for detecting celiac disease. While some tests have been found to be somewhat effective and at least sometimes accurate, there is a need for a more reliable antigen and uniform interpretation of screening assays for celiac patients.
Childhood Celiac Disease (CD) is a condition characterized by malabsorption and growth disturbances in association with a specific histological lesion of the small intestine. Patients with malabsorptive symptoms have been found to date to the second century AD. In 1950's Dicke, a pediatrician found the relationship between grain consumption and severe malabsorption condition. He noticed that during WWII children in Holland with malabsorptive symptoms improved when wheat and rye flour were unobtainable and that the condition reappeared after wheat flour was again made available. He and his associates were also credited with identifying gluten, the water-insoluble protein fraction in wheat, as the toxic dietary substance responsible for the syndrome, noting that symptoms subside in response to gluten elimination.
Recently, the European Society for Pediatric Gastroenterology and Nitrition (ESPGAN) revised the criteria for the diagnosis of gluten sensitive enteropathy (GSE), celiac disease. The previous criteria set forth in 1969 required at least three small intestinal biopsies. The salient histological features of CD were required at the initial suspicion of the enteropathy. The histological findings were expected to resolve following a period of gluten elimination and be reinduced during a gluten challenge phase of establishing the diagnosis. Since then, the success of newer diagnostic a markers—antigliadin, antireticulin and antiendomysial antibodies—in serving as indicators of active disease has prompted a revision of the criteria. Current requirements include a characteristic histologic appearance of the mucosa at the time of presentation with resolution of symptoms following gluten elimination. The presence of the previously mentioned circulating antibodies at time of diagnosis and disappearance following gluten withdrawal adds weight to the diagnosis especially in those who are asymptomatic.
Few controversies in the discipline of Pediatric Gastroenterology are viewed with less emotion that the selection of the best serologic screening test for celiac disease. The discovery of circulating antibodies to gliadin (AGA), reticulin (ARA) and the endomysium (EMA) have brought us closer to the discovery of a simple non-invasive screening test for establishing the diagnosis; but none are universally accepted as being pathognomonic indicators of the condition. Although none can be considered, as yet, pathognomonic, the serologic antibodies can still be used for screening and aid in diagnosis if one realizes their limitations and interprets their presence or absence in light of the clinical situation faced. We are approaching a better understanding of their roles and interrelationships.
The above mentioned present day serological markers are circulating antibodies which serve as one piece of evidence for the immunological nature of the disease. Circulating antigliadin antibodies (AGA) represent antibodies to the cereal protein, which presumably is absorbed intact across the intestinal mucosa. AGA have been extensively investigated since initial descriptions appeared in the late 1950's and early 1960's. Techniques for detection have evolved over the years varying from precipitating antibodies to cereal proteins, microimmunodiffusion, radioimmunoassay, binding serum antibodies to wheat grains and detection by fluorescent horse antihuman IgG. The first ELISA method appeared in 1977 and is defined and described in detail in Hekkens W T, Van Twist M: Physiological role of antigliadin antibodies and their appearance in celiac disease; Chorzelski T P Beutner E H, Kuman V, Zalewski T K, eds. Serologic Diagnosis of Celiac Disease. Cleveland:CRC Press, 1990: 2A: 21058 and Hekkens W T, VanLems-Kan P H, Rosekrans PCM: Bepaling van gliadin antistoffen met de ELISA-Techniek. Ned Tijdschr Geneesk 121, 1908, 1977. The differences in techniques for detection led to problems with standardization and therefore reproducibility between studies. Several authors have attempted to improve the sensitivity of the method of detection by using a diffusion to gel ELISA as described in Lindberg T, Nilsson L. Borulf S, et al.: Serum IgA and IgG gliadin antibodies and small intestinal mucosal damage in children. J. Pediatr Gastroenterol Nut 4, 917, 1985. It is understandable that even similar techniques such as ELISA may yield difference results because gliadins are a complex mixture of proteins that contain at least 40 different components for a single variety of wheat. Several authors have attempted to improve the sensitivity of detection method by using gliadin fractions or peptides as antigens. In one study, different gliadin peptides were found to have differing reactivity to serum antibodies of untreated celiac patients. However, other authors report that there are no demonstrable differences in ELISA values using different gliadin fractions as antigens. Discordant results, therefore, have been reported despite the use of similar methodologies such as ELISA.
Further controversy exists regarding the value of the specific class of AGA antibodies in the diagnosis of celiac disease. Some investigators advocate IgG class AGA whereas the IGA-AGA are favored by others. In studies using purified gliadin peptides as antigens in RIA or ELISA, IGA antibodies seem to have greater specificity to celiac disease and IgG antibodies seem to be more sensitive. The usefulness of gliadin antibodies for diagnosis, however, is open for criticism because their sensitivity and specificity varies so much from study to study. Figures for specificity range between 65-100% for IgA antibodies and 50-100% for IgG antibodies. Sensitivity reports for IGA antibodies range between 52-99.9% and for IgG between 82-100%. Unfortunately, IgG antibodies can be found in normal controls as well as other disease controls such as Chrohn's disease, liver disease and other G.I. disorders. IgA antibodies, on the other hand, although being specific for celiac disease, are not found in all celiacs. Additionally, IgG are found to increase with age in normal controls making them unsuitable for diagnosis in older age groups. The combined use of the two classes of antibodies, therefore, has been proposed by some authors as improving the sensitivity and specificity of the AGA for diagnosis. At least one recent report did not find advantage in combining each. The merit of using the IgG AGA seems to be in its ability to discriminate those 3% of celiac patients who are also IgA deficient and therefore would not be identified by screening for IgA AGA.
Gluten challenge is followed by an increase in titres of both IgA and IgG-class antibodies and titres fall with gluten exclusion. IgG antibodies take longer to decline than IgA antibodies. They may take more than six months to decline whereas IgA antibodies decline by 2-6 months. Their appearance is stated to occur before symptoms become overt. IgA AGA antibodies are therefore suitable to monitor dietary compliance and also response to gluten provocation.
Antireticulin antibodies (ARA), on the other hand, have been investigated s
Cookfair, Pat. Agent Arthur S.
Housel James
Ralabate Esq. James J.
Xybernaut Corporation
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