- Email: [email protected]
Autoimmune enteropathy in adults
THE LANCET 1
2
3
4
5
Brookes AJ, Howell WM, Woodburn K, Johnstone EC, Carothers A. Presenilin-I, presenilin-II, and VLDL-R associations in early onset Alzheimer’s disease. Lancet 1997; 350: 336–37. Wragg M, Hutton M, Talbot C, Alzheimer’s Disease Collaborative Group. Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer’s disease. Lancet 1996; 347: 509–12. Scott WK, Yamaoka LH, Locke PA, et al. No association or linkage between an intronic polymorphism of presenilin-1 and sporadic or late-onset familial Alzheimer’s disease. Genet Epidemiol 1997; 14: 307–15. Ezquerra M, Blesa R, Tolosa E, et al. The genotype of the presenilin-1 polymorphism is decreased in Spanish early-onset Alzheimer’s disease. Neurosci Lett 1997; 227: 201–04. Kehoe P, Williams J, Lovestone S, et al. Presenilin-1 polymorphism and Alzheimer’s disease. Lancet 1996; 347: 185.
SIR—Mutations that alter the protein structure in the recently discovered presenilin-1 gene (PS-1) might account for 50–70% cases of presenile (onset <65 years) familial Alzheimer’s disease.1 Missense mutations in the homologous presenilin-2 gene (PS-2) are very rare, but are associated with both presenile and senile (onset 65 years) familial Alzheimer’s disease.2 Wragg and colleagues3 reported a higher proportion of homozygosity for a common polymorphic allele (1) in a non-coding (intronic) region of PS-1 among sporadic and predominantly senile cases than among non-demented controls. Subsequent investigations of this association have yielded controversial results, including those of Anthony Brookes and colleagues (Aug 2, p 336)4, whose study of presenile Alzheimer’s disease showed a higher frequency of 2/2 homozygotes in those with the disease. PS-1 genotypes were not associated with Alzheimer’s in a much larger study, including familial sporadic, presenile, and senile cases.5 We developed a PCR assay for a common biallelic polymorphism (silent substitution: CAT or CAC corresponding to aminoacid position His872) in PS-2. The PCR assay uses standard amplification parameters for genomic DNA with primer oligonucleotides ps2-el (5'-CTGGAGGAAGAGCTAC-
CCTC) and ps2-e2 (5'GTAGAAGCGCACAGACTT-GAT), 30 cycles with denaturation at 94°C, annealing at 57°C, and extension at 72°C for 25 s. We detected the polymorphism by digestion of the PCR product with Eco72I enzyme and separation of the restriction fragments on an 8% polyacrylamide gel, visualised by ethydium bromide staining. We evaluated the allelic distributions for this polymorphism and the PS-1 marker3 in a sample of Russian patients and controls. All patients were randomly selected with respect to family history of dementia and were evaluated with criteria from the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association. The distributions of PS-1 and PS-2 alleles and genotypes did not differ between the total sample of cases and controls (table). To investigate the possibility of an interaction between genotypes for APOE, PS-1, and PS-2, age, and sex, we did a logistic regression analysis with indicator variables representing APOE, PS-1, and PS-2 genotypes. We found no association between PS-1 and PS-2 genotypes and risk of the disease in the total sample. It is noteworthy that the odds of developing Alzheimer’s disease was 5·8 times higher among APOE 4 allele carriers than among 3 homozygotes in this sample (unpublished). In those below age 65 years, the odds were 4·0 (1·0–17·0) times greater in PS-2 C/C than in T/T individuals after adjustment for age and sex. The C/C effect was significantly stronger (p<0·001) among APOE non-4 individuals (odds ratio 4·3) than among 4 (2·6), but these results should be interpreted cautiously because of small subgroup sizes. Thus, unlike others, we have not found an association between PS-1 homozygosity and Alzheimer’s disease. Our finding of an association between a common neutral polymorphism in the PS-2 coding sequence and presenile disease accords with data from Brookes and co-workers showing disequilibrium between presenile disease and
PS1 n
PS2 Allele
Genotype
n
1
2
1/1
1/2
2/2
122 110
62·7 60·4
37·3 39·6
33·6 33·6
58·2 53·6
8·2 12·7
Age <65* AD Controls
62 66
62·1 63·6
37·9 36·4
32·3 39·4
59·7 48·5
Age 65† AD Controls
60 44
63·3 55·7
36·7 44·3
35·0 25·0
56·7 61·4
Overall AD Controls
Allele
Genotype
C
T
C/C
C/T
T/T
130 107
46·2 38·8
53·8 61·2
16·2 10·3
60·0 57·0
23·8 32·7
8·1 12·1
66 64
47·0 36·7
53·0 63·3
18·2 7·8
57·6 57·8
24·2 34·4
8·3 13·6
64 43
45·3 41·9
54·7 58·1
14·1 14·0
62·5 55·8
23·4 30·2
AD=Alzheimer’s disease. *Mean age at onset for cases 57·5 (SD 5·7); mean age at exam for controls 52·5 (8·7). †Mean age at onset for cases 71·9 (5·1); mean age at exam for controls 73·4 (7·4).
PS1 and PS2 allele and genotype frequencies (%) in AD cases and controls by age at onset
Vol 350 • September 27, 1997
homozygosity of an allele for a different marker in the 3 untranslated region of the PS-2 gene. Although it is unlikely that these DNA markers are risk factors for sporadic disease, results from these two studies favour the hypothesis that another biologically meaningful and recessively acting polymorphism in the PS-2 gene or adjacent regulatory region accounts for some of the genetic susceptibility to Alzheimer’s. This work was supported by grants from the HHMI (75195-546801), INTAS-RFBR (95-0871), RFBR (95-5-4a), RHG Program, and the NIH (AG09029).
Galina I Korovaitseva, Anna Bukina, Lindsay A Farrer, *Evgeny I Rogaev *Laboratory of Molecular Brain Genetics, Mental Health Research Center, Center of Medical Genetics, Academy of Medical Science, 113152 Moscow, Russia; and Departments of Neurology, Epidemiology, and Biostatistics, Boston University School of Public Health, Boston, USA
1
2
3
4
5
Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995; 375: 754–60. Rogaev EI, Sherrington R, Rogaeva AE, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s type 3 gene. Nature 1995; 376: 775–78. Wragg M, Hutton M, Talbot C, Alzheimer’s Disease Collaborative Group. Genetic association between intronic polymorphism in presenilin 1 gene and late-onset Alzheimer’s disease. Lancet 1996; 347: 509–12. Brookes AJ, Howell WM, Woodburn K, Johnstone EC, Carothers A. Presenilin-1, presenilin-II, and VLDL-R associations in early onset Alzheimer’s disease. Lancet 1997; 350: 336–37. Scott WK, Yamaoka LH, Locke PA, et al. No association or linkage between an intronic polymorphism of presenilin-1 and sporadic or late-onset familial Alzheimer disease. Genet Epidemiol 1997; 14: 307–15.
Autoimmune enteropathy in adults S IR —Gino Corazza and colleagues (July 12, p 106)1 found enterocyte autoantibodies in two adults with gluten-resistant enteropathy. Their description of a possible autoimmune form of enteropathy in adults could open a new field in gastroenterology. We would be interested to know whether the similarities between the adult and the paediatric forms of enteropathy extend beyond the detection of circulating enterocyte autoantibodies. In particular, whether immunoglobulin and immune complex depositions were detected in the smallbowel biopsies of patients who were enterocyte-autoantibody positive, as reported by Mirakian and co-workers2 in children with the same specificity. Detection of these depositions would substantiate the preliminary indication
959
THE LANCET
that an autoimmune process also underlies the clinical condition in adults. Furthermore, because enterocyte antibodies were found in only two patients, Corazza and colleagues might know whether colitis was present in the patients with upper-intestinal disorder. Although the inflammatory process can be mild in the colon, most of the affected children with autoimmune enteropathy we have investigated presented with a generalised gut disorder of differing severity.3 Differences between the adult and the paediatric variant of autoimmune enteropathy might have already started to emerge. In fact, hyperplastic crypts and increased intraepithelial lymphocyte (IEL) counts were observed in the small-intestinal biopsies of the two reported adult cases, whereas in the paediatric samples hypoplastic crypts were found in the two original cases, and IEL counts were mainly decreased when a cohort of children was investigated.5 Finally, since enterocyte autoantibodies are routinely tested in human blood group O duodenum for diagnostic purposes, it would be of interest to know whether the same autoantibodies detected in the adult patients on monkey substrate also react with the human duodenum. Standard protocols should be undertaken and exchanges of serum samples among centres is needed to validate the detection of the enterocyte autoantibodies. *R Mirakian, P Collins, G F Bottazzo *Department of Immunology, St Bartholomews and Royal London School of Medicine and Dentistry, London E1 2AD, UK
1
2
3
4
5
Corazza GR, Biagi F, Volta U, Andreani ML, De Franceschi L, Gasbarrini G. Autoantimmune enteropathy and villous atrophy in adults. Lancet 1997; 350: 106–09. Mirakian R, Richardson A, Milla PJ, et al. Protracted diarrhoea of infancy: evidence in support of an autoimmune variant. BMJ 1986; 293: 1132–36. Hill SM, Milla PJ, Bottazzo GF, Mirakian R. Autoimmune enteropathy and colitis: is there a generalised disorder? Gut 1991; 32: 36–42. Savage MO, Mirakian R, Wozniak ER, et al. Specific autoantibodies to gut epithelium in two infants with severe protracted diarrhoea. J Pediatr Gastroenterol Nutr 1985; 4: 187–95. Mirakian R, Hill S, Richardson A, Milla PJ, Walker-Smith JA, Bottazzo GF. HLA product expression and lymphocyte subpopulations in jejunum biopsies of children with idiopathic protracted diarrhoea and enterocyte autoantibodies. J Autoimmun 1988; 1: 263–77.
Authors’ reply SIR—We have reviewed the notes of our two adult patients with auto-
960
immune enteropathy. Colonoscopy had been done and multiple biopsies were taken. In both patients the large intestine was normal on endoscopy but the colonic biopsies showed an increase in intraepithelial lymphocytes (26% in patient 1; 49% in patient 2), some epithelial flattening, and absence of subepithelial collagen layer. Thus, according to Lazenby and colleagues 1 our patients also had lymphocytic colitis. We agree that these two cases lend further support to the hypothesis of a generalised gut disorder in patients who have autoimmune enteropathy . 2 Interestingly, adult patients with lymphocytic colitis, refractory coeliac disease, and associated autoimmune disease have been reported.3,4 Perhaps even those patients might have autoimmune enteropathy. As R Mirakian and colleagues point out, the study of the adult form of autoimmune enteropathy has just begun. More data will need to be collected before the adult variant can be compared with the paediatric one. Direct immunofluorescence of small-bowel biopsies and counting of intraepithalial / T-cells are among the first studies that should be carried out. As far as detection of enterocyte autoantibodies in human blood group O duodenum is concerned, the fact that they have been found even on rat intestine5 leads us to think that multiple species specificity for the enterocyte autoantibodies should be tested before any conclusion about optimum conditions. We agree with Mirakian and coworkers that this could be done by validation of enterocyte autoantibody detection through exchange of serum samples between centres. F Biagi, *G R Corazza Department of Internal Medicine, University of L’Aquila, 67100 L’Aquila, Italy
1
2
3
4
5
Lazenby AJ, Yardley JH, Giardiello FM, Jessurun J, Bayless TM. Lymphocytic (“microscopic”) colitis: a comparative histopathologic study with particular reference to collagenous colitis. Hum Pathol 1989; 20: 18–28. Hill SM, Milla PJ, Bottazzo GF, Mirakian R. Autoimmune enteropathy and colitis: is there a generalised autoimmune gut disorder? Gut 1991; 32: 36–42. Giardiello FM, Lazenby AJ, Bayless TM, et al. Lymphocytic (microscopic) colitis: clinicopathologic study of 18 patients and comparison to collagenous colitis. Dig Dis Sci 1989; 34: 1730–38. DuBois RN, Lazenby AJ, Yardley JH, et al. Lymphocytic enterocolitis in patients with “refractory sprue”. JAMA 1989; 262: 935–37. Walker-Smith JA, Unsworth DJ, Hutchins P, Phillips AD, Holborow EJ. Autoantibodies against gut epithelium in child with small-intestinal enteropathy. Lancet 1982; i: 566–67.
Regression of mucosa-associated lymphoid-tissue lymphoma after eradication of Helicobacter pylori SIR—Takayuki Matsumoto and colleagues (July 12, p 115)1 report a case of mucosa-associated lymphoid tissue (MALT) lymphoma of the rectum that regressed after treatment of Helicobacter pylori with omeprazole, amoxycillin, and clarithromycin. They note previous reports of regression of a salivery gland and small-intestinal MALT lymphomas in response to antihelicobacter therapy. Wotherspoon and co-workers2 originally showed that eradication of H pylori was followed by regression of gastric MALT lymphomas. In-vitro studies suggested that the proliferation of low-grade MALT lymphoma cells is driven by Tcells responding to specific H pylori derived antigens, and other investigators3 have shown that this is due to CD40-mediated signalling and Th2-type cytokines.3 Since H pylori colonises only gastrictype mucosa, how can treatment of this organism lead to regression of lymphomas at other sites? The case reported by Fischbach et al4 showed gastric metaplasia with H pylori infection in the duodenal biopsy and might, therefore, be expected to respond to therapy. It is possible that the other patients originally developed gastric MALT lymphomas that subsequently disseminated to non-gastric sites. At these sites, the lymphoma might receive the necessary drive either from H pylori antigens in the blood, or within the intestinal lumen, or from circulating T-cells that have been activated by H pylori antigens in the stomach. Dissemination of gastric MALT lymphoma to the intestine has been demonstrated,5 and is in keeping with the behaviour of lymphoid cells of the mucosal immune system. However, this explanation would imply that the primary gastric lymphoma in these patients was subclinical or had regressed before the patient was investigated. These reports do not, however, necessarily imply an association between H pylori and extra-gastric MALT lymphomas. The antibiotics used to eliminate H pylori are active against other organisms and conceivably might eliminate as yet unidentified agents responsible for the induction and growth of MALT lymphomas outside the stomach. D H Wright Southampton General Hospital, Southampton, Hampshire SO16 6YD, UK
1
Matsumoto T, Iida M, Shimizu M. Regression of mucosa-associated lymphoid-
Vol 350 • September 27, 1997
2
3
4
5
Brookes AJ, Howell WM, Woodburn K, Johnstone EC, Carothers A. Presenilin-I, presenilin-II, and VLDL-R associations in early onset Alzheimer’s disease. Lancet 1997; 350: 336–37. Wragg M, Hutton M, Talbot C, Alzheimer’s Disease Collaborative Group. Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer’s disease. Lancet 1996; 347: 509–12. Scott WK, Yamaoka LH, Locke PA, et al. No association or linkage between an intronic polymorphism of presenilin-1 and sporadic or late-onset familial Alzheimer’s disease. Genet Epidemiol 1997; 14: 307–15. Ezquerra M, Blesa R, Tolosa E, et al. The genotype of the presenilin-1 polymorphism is decreased in Spanish early-onset Alzheimer’s disease. Neurosci Lett 1997; 227: 201–04. Kehoe P, Williams J, Lovestone S, et al. Presenilin-1 polymorphism and Alzheimer’s disease. Lancet 1996; 347: 185.
SIR—Mutations that alter the protein structure in the recently discovered presenilin-1 gene (PS-1) might account for 50–70% cases of presenile (onset <65 years) familial Alzheimer’s disease.1 Missense mutations in the homologous presenilin-2 gene (PS-2) are very rare, but are associated with both presenile and senile (onset 65 years) familial Alzheimer’s disease.2 Wragg and colleagues3 reported a higher proportion of homozygosity for a common polymorphic allele (1) in a non-coding (intronic) region of PS-1 among sporadic and predominantly senile cases than among non-demented controls. Subsequent investigations of this association have yielded controversial results, including those of Anthony Brookes and colleagues (Aug 2, p 336)4, whose study of presenile Alzheimer’s disease showed a higher frequency of 2/2 homozygotes in those with the disease. PS-1 genotypes were not associated with Alzheimer’s in a much larger study, including familial sporadic, presenile, and senile cases.5 We developed a PCR assay for a common biallelic polymorphism (silent substitution: CAT or CAC corresponding to aminoacid position His872) in PS-2. The PCR assay uses standard amplification parameters for genomic DNA with primer oligonucleotides ps2-el (5'-CTGGAGGAAGAGCTAC-
CCTC) and ps2-e2 (5'GTAGAAGCGCACAGACTT-GAT), 30 cycles with denaturation at 94°C, annealing at 57°C, and extension at 72°C for 25 s. We detected the polymorphism by digestion of the PCR product with Eco72I enzyme and separation of the restriction fragments on an 8% polyacrylamide gel, visualised by ethydium bromide staining. We evaluated the allelic distributions for this polymorphism and the PS-1 marker3 in a sample of Russian patients and controls. All patients were randomly selected with respect to family history of dementia and were evaluated with criteria from the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association. The distributions of PS-1 and PS-2 alleles and genotypes did not differ between the total sample of cases and controls (table). To investigate the possibility of an interaction between genotypes for APOE, PS-1, and PS-2, age, and sex, we did a logistic regression analysis with indicator variables representing APOE, PS-1, and PS-2 genotypes. We found no association between PS-1 and PS-2 genotypes and risk of the disease in the total sample. It is noteworthy that the odds of developing Alzheimer’s disease was 5·8 times higher among APOE 4 allele carriers than among 3 homozygotes in this sample (unpublished). In those below age 65 years, the odds were 4·0 (1·0–17·0) times greater in PS-2 C/C than in T/T individuals after adjustment for age and sex. The C/C effect was significantly stronger (p<0·001) among APOE non-4 individuals (odds ratio 4·3) than among 4 (2·6), but these results should be interpreted cautiously because of small subgroup sizes. Thus, unlike others, we have not found an association between PS-1 homozygosity and Alzheimer’s disease. Our finding of an association between a common neutral polymorphism in the PS-2 coding sequence and presenile disease accords with data from Brookes and co-workers showing disequilibrium between presenile disease and
PS1 n
PS2 Allele
Genotype
n
1
2
1/1
1/2
2/2
122 110
62·7 60·4
37·3 39·6
33·6 33·6
58·2 53·6
8·2 12·7
Age <65* AD Controls
62 66
62·1 63·6
37·9 36·4
32·3 39·4
59·7 48·5
Age 65† AD Controls
60 44
63·3 55·7
36·7 44·3
35·0 25·0
56·7 61·4
Overall AD Controls
Allele
Genotype
C
T
C/C
C/T
T/T
130 107
46·2 38·8
53·8 61·2
16·2 10·3
60·0 57·0
23·8 32·7
8·1 12·1
66 64
47·0 36·7
53·0 63·3
18·2 7·8
57·6 57·8
24·2 34·4
8·3 13·6
64 43
45·3 41·9
54·7 58·1
14·1 14·0
62·5 55·8
23·4 30·2
AD=Alzheimer’s disease. *Mean age at onset for cases 57·5 (SD 5·7); mean age at exam for controls 52·5 (8·7). †Mean age at onset for cases 71·9 (5·1); mean age at exam for controls 73·4 (7·4).
PS1 and PS2 allele and genotype frequencies (%) in AD cases and controls by age at onset
Vol 350 • September 27, 1997
homozygosity of an allele for a different marker in the 3 untranslated region of the PS-2 gene. Although it is unlikely that these DNA markers are risk factors for sporadic disease, results from these two studies favour the hypothesis that another biologically meaningful and recessively acting polymorphism in the PS-2 gene or adjacent regulatory region accounts for some of the genetic susceptibility to Alzheimer’s. This work was supported by grants from the HHMI (75195-546801), INTAS-RFBR (95-0871), RFBR (95-5-4a), RHG Program, and the NIH (AG09029).
Galina I Korovaitseva, Anna Bukina, Lindsay A Farrer, *Evgeny I Rogaev *Laboratory of Molecular Brain Genetics, Mental Health Research Center, Center of Medical Genetics, Academy of Medical Science, 113152 Moscow, Russia; and Departments of Neurology, Epidemiology, and Biostatistics, Boston University School of Public Health, Boston, USA
1
2
3
4
5
Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995; 375: 754–60. Rogaev EI, Sherrington R, Rogaeva AE, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s type 3 gene. Nature 1995; 376: 775–78. Wragg M, Hutton M, Talbot C, Alzheimer’s Disease Collaborative Group. Genetic association between intronic polymorphism in presenilin 1 gene and late-onset Alzheimer’s disease. Lancet 1996; 347: 509–12. Brookes AJ, Howell WM, Woodburn K, Johnstone EC, Carothers A. Presenilin-1, presenilin-II, and VLDL-R associations in early onset Alzheimer’s disease. Lancet 1997; 350: 336–37. Scott WK, Yamaoka LH, Locke PA, et al. No association or linkage between an intronic polymorphism of presenilin-1 and sporadic or late-onset familial Alzheimer disease. Genet Epidemiol 1997; 14: 307–15.
Autoimmune enteropathy in adults S IR —Gino Corazza and colleagues (July 12, p 106)1 found enterocyte autoantibodies in two adults with gluten-resistant enteropathy. Their description of a possible autoimmune form of enteropathy in adults could open a new field in gastroenterology. We would be interested to know whether the similarities between the adult and the paediatric forms of enteropathy extend beyond the detection of circulating enterocyte autoantibodies. In particular, whether immunoglobulin and immune complex depositions were detected in the smallbowel biopsies of patients who were enterocyte-autoantibody positive, as reported by Mirakian and co-workers2 in children with the same specificity. Detection of these depositions would substantiate the preliminary indication
959
THE LANCET
that an autoimmune process also underlies the clinical condition in adults. Furthermore, because enterocyte antibodies were found in only two patients, Corazza and colleagues might know whether colitis was present in the patients with upper-intestinal disorder. Although the inflammatory process can be mild in the colon, most of the affected children with autoimmune enteropathy we have investigated presented with a generalised gut disorder of differing severity.3 Differences between the adult and the paediatric variant of autoimmune enteropathy might have already started to emerge. In fact, hyperplastic crypts and increased intraepithelial lymphocyte (IEL) counts were observed in the small-intestinal biopsies of the two reported adult cases, whereas in the paediatric samples hypoplastic crypts were found in the two original cases, and IEL counts were mainly decreased when a cohort of children was investigated.5 Finally, since enterocyte autoantibodies are routinely tested in human blood group O duodenum for diagnostic purposes, it would be of interest to know whether the same autoantibodies detected in the adult patients on monkey substrate also react with the human duodenum. Standard protocols should be undertaken and exchanges of serum samples among centres is needed to validate the detection of the enterocyte autoantibodies. *R Mirakian, P Collins, G F Bottazzo *Department of Immunology, St Bartholomews and Royal London School of Medicine and Dentistry, London E1 2AD, UK
1
2
3
4
5
Corazza GR, Biagi F, Volta U, Andreani ML, De Franceschi L, Gasbarrini G. Autoantimmune enteropathy and villous atrophy in adults. Lancet 1997; 350: 106–09. Mirakian R, Richardson A, Milla PJ, et al. Protracted diarrhoea of infancy: evidence in support of an autoimmune variant. BMJ 1986; 293: 1132–36. Hill SM, Milla PJ, Bottazzo GF, Mirakian R. Autoimmune enteropathy and colitis: is there a generalised disorder? Gut 1991; 32: 36–42. Savage MO, Mirakian R, Wozniak ER, et al. Specific autoantibodies to gut epithelium in two infants with severe protracted diarrhoea. J Pediatr Gastroenterol Nutr 1985; 4: 187–95. Mirakian R, Hill S, Richardson A, Milla PJ, Walker-Smith JA, Bottazzo GF. HLA product expression and lymphocyte subpopulations in jejunum biopsies of children with idiopathic protracted diarrhoea and enterocyte autoantibodies. J Autoimmun 1988; 1: 263–77.
Authors’ reply SIR—We have reviewed the notes of our two adult patients with auto-
960
immune enteropathy. Colonoscopy had been done and multiple biopsies were taken. In both patients the large intestine was normal on endoscopy but the colonic biopsies showed an increase in intraepithelial lymphocytes (26% in patient 1; 49% in patient 2), some epithelial flattening, and absence of subepithelial collagen layer. Thus, according to Lazenby and colleagues 1 our patients also had lymphocytic colitis. We agree that these two cases lend further support to the hypothesis of a generalised gut disorder in patients who have autoimmune enteropathy . 2 Interestingly, adult patients with lymphocytic colitis, refractory coeliac disease, and associated autoimmune disease have been reported.3,4 Perhaps even those patients might have autoimmune enteropathy. As R Mirakian and colleagues point out, the study of the adult form of autoimmune enteropathy has just begun. More data will need to be collected before the adult variant can be compared with the paediatric one. Direct immunofluorescence of small-bowel biopsies and counting of intraepithalial / T-cells are among the first studies that should be carried out. As far as detection of enterocyte autoantibodies in human blood group O duodenum is concerned, the fact that they have been found even on rat intestine5 leads us to think that multiple species specificity for the enterocyte autoantibodies should be tested before any conclusion about optimum conditions. We agree with Mirakian and coworkers that this could be done by validation of enterocyte autoantibody detection through exchange of serum samples between centres. F Biagi, *G R Corazza Department of Internal Medicine, University of L’Aquila, 67100 L’Aquila, Italy
1
2
3
4
5
Lazenby AJ, Yardley JH, Giardiello FM, Jessurun J, Bayless TM. Lymphocytic (“microscopic”) colitis: a comparative histopathologic study with particular reference to collagenous colitis. Hum Pathol 1989; 20: 18–28. Hill SM, Milla PJ, Bottazzo GF, Mirakian R. Autoimmune enteropathy and colitis: is there a generalised autoimmune gut disorder? Gut 1991; 32: 36–42. Giardiello FM, Lazenby AJ, Bayless TM, et al. Lymphocytic (microscopic) colitis: clinicopathologic study of 18 patients and comparison to collagenous colitis. Dig Dis Sci 1989; 34: 1730–38. DuBois RN, Lazenby AJ, Yardley JH, et al. Lymphocytic enterocolitis in patients with “refractory sprue”. JAMA 1989; 262: 935–37. Walker-Smith JA, Unsworth DJ, Hutchins P, Phillips AD, Holborow EJ. Autoantibodies against gut epithelium in child with small-intestinal enteropathy. Lancet 1982; i: 566–67.
Regression of mucosa-associated lymphoid-tissue lymphoma after eradication of Helicobacter pylori SIR—Takayuki Matsumoto and colleagues (July 12, p 115)1 report a case of mucosa-associated lymphoid tissue (MALT) lymphoma of the rectum that regressed after treatment of Helicobacter pylori with omeprazole, amoxycillin, and clarithromycin. They note previous reports of regression of a salivery gland and small-intestinal MALT lymphomas in response to antihelicobacter therapy. Wotherspoon and co-workers2 originally showed that eradication of H pylori was followed by regression of gastric MALT lymphomas. In-vitro studies suggested that the proliferation of low-grade MALT lymphoma cells is driven by Tcells responding to specific H pylori derived antigens, and other investigators3 have shown that this is due to CD40-mediated signalling and Th2-type cytokines.3 Since H pylori colonises only gastrictype mucosa, how can treatment of this organism lead to regression of lymphomas at other sites? The case reported by Fischbach et al4 showed gastric metaplasia with H pylori infection in the duodenal biopsy and might, therefore, be expected to respond to therapy. It is possible that the other patients originally developed gastric MALT lymphomas that subsequently disseminated to non-gastric sites. At these sites, the lymphoma might receive the necessary drive either from H pylori antigens in the blood, or within the intestinal lumen, or from circulating T-cells that have been activated by H pylori antigens in the stomach. Dissemination of gastric MALT lymphoma to the intestine has been demonstrated,5 and is in keeping with the behaviour of lymphoid cells of the mucosal immune system. However, this explanation would imply that the primary gastric lymphoma in these patients was subclinical or had regressed before the patient was investigated. These reports do not, however, necessarily imply an association between H pylori and extra-gastric MALT lymphomas. The antibiotics used to eliminate H pylori are active against other organisms and conceivably might eliminate as yet unidentified agents responsible for the induction and growth of MALT lymphomas outside the stomach. D H Wright Southampton General Hospital, Southampton, Hampshire SO16 6YD, UK
1
Matsumoto T, Iida M, Shimizu M. Regression of mucosa-associated lymphoid-
Vol 350 • September 27, 1997