- Email: [email protected]
Mucosal IgA defect in primary biliary cirrhosis
508
Letters to the Editor
AJG – Vol. 97, No. 2, 2002
duodenitis, and one had nonspecific chronic colitis (1, 5–9). The pathogenetic mechanism of the association between PV and UC is not clear. Although the antigenic determinant in PV, desmosomal-associated 130-kd glycoprotein, is limited to the stratified squamous epithelium (3, 10), cross-reactivity between antigens in the skin or oral and bowel mucosa has been considered (8). Recently, various serum antibodies against distinct adhesion molecules of the epidermis or dermoepidermal basement membrane zone and T-cell responses have been detected (2, 11). In autoimmune-based disorders genetic predisposition is important. It is well known that HLAs A1, B8, DR3, and DR4 are associated with various autoimmune disorders such as gluten enteropathy, dermatitis herpetiformis, UC, and autoimmune hepatitis. Our patient has the HLA DR4 genotype, which may be significant in the pathogenesis of these disorders in her. In conclusion, we consider that the association of PV and UC may be coincidental or due to cross-reactivity between antigens in the oral mucosa and bowel. It can be considered that an autoimmune disease predisposes to the other autoimmune diseases. Sabite Kacar Orhan Sezgin Tu¨ lin Sahin Gastroenterology Department Tu¨ rkiye Yu¨ ksek Ihtisas Hospital Ankara, Turkey
REFERENCES 1. Prendiville JS, Israel DM, Wood WS, et al. Oral pemphigus vulgaris associated with inflammatory bowel disease and herpetic gingivostomatitis in an 11-year old girl. Pediatr Dermatol 1994;11:145–50. 2. Hertl M. Humoral and cellular autoimmunity in autoimmune skin disorders. Int Arch Allergy Immunol 2000;122:91–100. 3. Pacheco GU, Tovar-Rivera T, Padierna-Olivos L, et al. Altered pattern of connectivity in serum immunoglobulins from pemphigus vulgaris patients. Scand J Immunol 1999;19:424 – 30. 4. Scully C, Paes De Almedia O, Porter SR, et al. Pemphigus vulgaris: The manifestations and long-term management of 55 patients with oral lesions. Br J Dermatol 1999;140:84 –9. 5. Delphino M, Suppa F, Piccirillo A. Pemphigus vulgaris and ulcerative colitis. Dermatology 1986;172:230. 6. Fabbrı P, Emmı L, Vıgnolı L, et al. Pemfigo volgare cronica associato a rettocolite ulcerosa. G Ital Dermatol Venereol 1986;121:355–9. 7. Stone DD. Rectal lesions and toxic dilatation of the colon in a case of pemphigus vulgaris. Dig Dis 1971;16:163– 6. 8. Takizawa H, Watanabe S, Takahashi M, et al. Pemphigus vulgaris with asymptomatic pseudomembranous colitis. Am J Gastroenterol 1996;91:1654 –5. 9. Schwermann M, Lechner W, Elsner C, et al. Pemphigus vulgaris involving duodenum and colon. Z Hautkr 1988;63: 101– 4. 10. Hiroko G, Akiyama M, Yakabi K, et al. Oesophageal involvement in pemphigus vulgaris. Lancet 1999;354:1794. 11. Arnagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies
against a novel epitelial cadhedrin in pemphigus vulgaris, a discase of cell adhesion. Cell 1991;67:869 –77. Reprint requests and correspondence: Sabite Kacar, Ivedik Cad. Ahmet Hikmet Sok., Subay Koop. Evl. 23/7, 06170, Yenimahalle/ Ankara, Turkey. Received May 14, 2001; accepted Sep. 27, 2001.
Mucosal IgA Defect in Primary Biliary Cirrhosis TO THE EDITOR: The pathogenic mechanisms leading to selective damage of bile ducts in primary biliary cirrhosis (PBC) are still unknown. However, the apparent restriction of tissue damage to epithelial cells capable of transcytosing IgA has led to the suggestion that transcytosis of the IgA subtype of antimitochondrial antibodies (AMAs) may play an important role in the pathogenesis of PBC (1). In this view, the IgA class of AMAs can bind to mitochondrial antigens, resulting in cellular disruption. Recent studies have demonstrated the presence of AMAs in saliva of PBC patients (2, 3). Moreover, it has been observed that PBC patients have anti–pyruvate dehydrogenase complex IgA in their saliva, suggesting that this is predominantly secretory IgA reaching the saliva through the active process of epithelial transcytosis (4). Furthermore, a recent article showed that AMAs of the IgA isotype are secreted into urine from the uroepithelium of PBC patients (5). These important studies prompted us to address the critical question of whether IgA transport may be altered in patients with PBC in the site of the main trafficking—that is, the intestinal mucosa. Twenty-three patients with PBC and normal IgA levels underwent upper endoscopies for clinical purposes (20 female and three male; nine having histological stage II; five, stage III; and nine, stage IV). Seventeen patients with functional dyspepsia served as controls. During endoscopy, after informed consent, seven distal duodenum biopsies were taken and processed for 1) microscopic assessment; 2) in vitro organ culture system, according to the method described by Browning and Trier (6) with minor modifications [the enterocyte height before and after 24-h culture was measured at ⫻40 magnification, according to Howdle (7)]; and 3) immunohistochemical staining using polyclonal antiIgA (Dako, Glostrup, Denmark) and antihuman secretory component (IgA-SC) (Sigma Poole, Dorset, United Kingdom). Evaluation was based on the intensity of staining of the cells, which was scored as follows: 0 ⫽ absent, 1 ⫽ weak staining, 2 ⫽ moderate staining, 3 ⫽ a very strong staining. The enterocyte height was always normal (mean ⫽ 35.0 ⫾ 3.3 m), and the brush border was well defined. In the culture, the mean of enterocyte height in PBC did not differ from that of controls (35.0 ⫾ 3.3 m, vs 34.4 ⫾ 3.4 m in controls at the baseline, and 28.1 ⫾ 2.8 m vs 28.9 ⫾
AJG – February, 2002
Letters to the Editor
509
Table 1. Immunohistochemistry for IgA-SC and Total IgA in PBC Patients and in Controls
PBC Controls
IgA-SC (Villus)– Positive Subjects
IgA-SC (Villus) (Mean Score)
IgA-SC (Crypt)– Positive Subjects
IgA-SC (Crypt) (Mean Score)
Total IgAPositive Subjects
Total IgA (Mean Score)
8 17
1.2 ⫾ 0.5* 2.8 ⫾ 1.2
17 17
1.3 ⫾ 0.5* 3.2 ⫾ 0.9
23 17
2.5 ⫾ 0.7 2.4 ⫾ 0.6
* p ⬍ 0.002.
2.3 m after 24 h). IgA-SC was widely and homogeneously expressed in the cytoplasm of enterocytes of the crypts and all villi in control patients. Conversely, an absence of the IgA-SC expression in the villi was noticed in 15 of 23 PBC patients; the remaining eight showed significant reductions in the staining score relative to controls (Table 1). No difference was observed in the total IgA expression in the two groups of patients; in particular, IgA staining was observed along the basolateral side of the enterocyte membrane, resulting in a widening of the cell-to-cell junction. To our knowledge, this is the first communication to pinpoint an in situ IgA secretion defect in the intestinal epithelium of PBC patients. This reduced expression of IgA-SC on enterocytes in the absence of histological abnormalities could reflect a reduced local immune response. If this is so, this model would help to explain the mechanism and tropism of tissue damage in PBC. Several hypotheses could explain this defect. First of all, our results could be explained by a deficient synthesis or plasma membrane expression of polymeric immunoglobulin receptor (pIgR). This hypothesis is supported by an experimental model used by Shimada et al. (8), who generated a knockout mouse for pIgR, which revealed a lack of intestinal expression of IgA-SC and increased serum IgA levels. Secondly, a defect in IgA-SC binding, possibly through the J chain, to the pIgR might be suggested. A deficiency in J chain production could severely hinder the intestinal transport of IgA, as observed in J chain knockout mice (9), where disruption of the J chain gene caused a remarkable increase in serum IgA concentration. The defect of binding of IgA-SC to the pIgR might also be due to the formation of antibodies directed against the J chain (10). The ability of IgA autoantibodies from patients with PBC to penetrate and bind to their intracellular target was examined in an elegant experimental study by Malmborg et al. (11), who assessed the ability of serum IgA from PBC patients to penetrate cells using Madine-Darby canine kidney cells transfected with the human IgA receptor (MadineDarby canine kidney pIgR). The IgA from PBC patients colocalized with pyruvate dehydrogenase complex E2 (the major autoantigen of PBC) inside the cells. It may be that, during the transcytosis process, IgA is somehow directed toward the mitochondria or that IgA binds the mitochondrial enzyme during its migration of the mitochondria. However, to be elucidated, these hypotheses require further studies. In conclusion, an in situ defect of IgA secretion may be suggested, possibly in the binding of IgA-SC to the pIgR. The mucosal IgA defect might consequently alter mucosal
immunity, allowing several antigens to adhere to and penetrate the epithelium. Annarosa Floreani, M.D. Anna Baragiotta, M.D. Daniela Pizzuti, Ph.D. Diego Martines, M.D. Attilio Cecchetto, M.D. Silvia Chiarelli, M.D. Department of Surgical and Gastroenterological Sciences, Institute of Pathology, and Department of Surgical and Oncological Sciences University of Padova Padova, Italy
REFERENCES 1. Gershwin ME, Ansari AA, Mackay IR, et al. Primary biliary cirrhosis: An orchestrated immune response against epithelial cells. Immunol Rev 2000;174:210 –25. 2. Yeaman SJ, Kirby JA, Jones DEJ. Autoreactive responses to pyruvate dehydrogenase complex in the pathogenesis of primary biliary cirrhosis. Immunol Rev 2000;174:238 – 49. 3. Reynoso-Paz S, Leung PSC, Van de Water J, et al. Evidence for a locally driven mucosal response and the presence of mitochondrial antigens in saliva in primary biliary cirrhosis. Hepatology 2000;31:24 –9. 4. Palmer JM, Doshi M, Kirby JA, et al. Secretory autoantibodies in primary biliary cirrhosis (PBC). Clin Exp Immunol 2000; 122:423– 8. 5. Tanaka A, Nalbandian G, Leung PS, et al. Mucosal immunity and primary biliary cirrhosis: Presence of antimitochondrial antibodies in urine. Hepatology 2000;32:910 –5. 6. Browning TH, Trier JS. Organ culture of mucosal biopsies of human small intestine. J Clin Invest 1969;48:1423–32. 7. Howdle PD, Corazza GR, Bullen AW, Losowsky MS. Gluten sensitivity of small intestinal mucosa in vitro: Quantitative assessment of histological change. Gastroenterology 1981;80: 442–50. 8. Shimada S, Kawaguchi-Miyashita M, Kushiro A, et al. Generation of polymeric immunoglobulin receptor-deficient mouse with marked reduction of secretory IgA. J Immunol 1999;163:5367–73. 9. Hendrickson BA, Conner DA, Ladd DJ, et al. Altered hepatic transport of immunoglobulin A in mice lacking the J chain. J Exp Med 1995;182:1905–11. 10. Vaerman JP, Langendries AE, Giffroy DA, et al. Antibodies against the human J chain inhibits polymeric Ig receptormediated biliary and epithelial transport of human polymeric IgA. Eur J Immunol 1998;28:171– 82. 11. Malmborg A-C, Shultz DB, Luton F, et al. Penetration and co-localization in MDCK cell mitochondria of IgA derived from patients with primary biliary cirrhosis. J Autoimmun 1998;11:573– 80.
6 0 9 1 10 1 1089.2 ⫾ 381.1 2316.7 ⫾ 579.4 11/1.83 5/1.11
Period
Years 1991–1996 Years 1997–2001
4/3/4 5/0/0
2 0
57.2 ⫾ 33.1 134.2 ⫾ 43.1
No. of Patients With AIDS
No. of Patients Chronically Treated With Cotrimoxazole Mean Neutrophil Count at Diagnosis (Cells/L ⫾ SD) No. of Patients With Lethal Outcomes
Mean CD4⫹ Lymphocyte Count at Diagnosis (Cells/L ⫾ SD)
TO THE EDITOR: Although bacterial infections represented frequent complications of HIV disease, their overall morbidity and mortality remarkably dropped thanks to the highly active antiretroviral therapy (HAART)–related immunoreconstitution (1). However, Campylobacter spp infection, infrequently described even in the pre-HAART era—around 50 reported cases with prevalence of prolonged and/or relapsing diarrhea, nearly 30 cases of bacteremia (2– 8), and anecdotal episodes of atypical or focal disease (9)— continues to occur, probably because of the multiple modes of transmission of these organisms (alimentary, direct, or sexual) (2, 6), so that Campylobacter was recognized as the most frequent enteric pathogen in a crosssectional bacteriological survey also including asymptomatic patients (6). To re-evaluate the role of Campylobacter disease after HAART introduction, all cases of patients with at least one microbial isolation associated with consistent GI and/or systemic signs and symptoms were retrospectively retrieved, among the ⬃1000 patients referring every year to our tertiary care center since 1991. The 16 identified patients (11 males and five females, aged 35.6 ⫾ 5.2 yr) did not show demographic differences when compared with the whole HIV-infected population observed by us in the last decade, whereas more frequent HIV sexual exposure was detected (12 cases of 16, p ⬍ 0.005 compared with the entire cohort). The HAART’s introduction in late 1996 caused a significant drop in the absolute frequency of campylobacteriosis (odds ratio ⫽ 1.79 [1.38 ⬍ OR ⬍ 2.33], p ⬍ 0.0001), but also a notable modification of its clinical features (Table 1). A hematogenous dissemination has not occurred since 1997, compared with the seven episodes diagnosed until 1996 (four of them represented by a bacteremic enteritis) (p ⬍ 0.03). Intestinal findings (diarrhea, nausea, and abdominal discomfort) were similar to those in the general population, but systemic involvement (febrile bacteremia with or without enteric involvement) was observed only before HAART introduction (p ⬍ 0.03) and proved undistinguishable from any other HIV-related septic complication, although two extremely rare lethal cases of isolated hospital-acquired septicemia were previously reported by us (10). The concurrent immunodeficiency (as expressed by mean CD4⫹ lymphocyte and absolute neutrophil counts) and the stage of underlying disease were
No. of Patients With Enteric/ Hematogenous/ Associated Involvement
Enteric and Disseminated Campylobacter Species Infection During HIV Disease: A Persisting but Significantly Modified Association in the HAART Era
No. of Episodes/ No. of Episodes per 1000 Patient Years
Reprint requests and correspondence: Annarosa Floreani, M.D., Div. Gastroenterologia, Via Giustiniani, 2, 35128 Padova, Italy. Received July 12, 2001; accepted Sep. 27, 2001.
AJG – Vol. 97, No. 2, 2002
No. of Patients Experiencing Recurrences
Letters to the Editor
Table 1. A Comparison of Some Epidemiological, Clinical, Laboratory, Therapeutic, and Outcome Features of Our Patients With HIV-Associated Campylobacteriosis, Before (Years 1991–1996) and After (1997–2001) the Introduction of HAART as the Standard Antiretroviral Treatment
510
Letters to the Editor
AJG – Vol. 97, No. 2, 2002
duodenitis, and one had nonspecific chronic colitis (1, 5–9). The pathogenetic mechanism of the association between PV and UC is not clear. Although the antigenic determinant in PV, desmosomal-associated 130-kd glycoprotein, is limited to the stratified squamous epithelium (3, 10), cross-reactivity between antigens in the skin or oral and bowel mucosa has been considered (8). Recently, various serum antibodies against distinct adhesion molecules of the epidermis or dermoepidermal basement membrane zone and T-cell responses have been detected (2, 11). In autoimmune-based disorders genetic predisposition is important. It is well known that HLAs A1, B8, DR3, and DR4 are associated with various autoimmune disorders such as gluten enteropathy, dermatitis herpetiformis, UC, and autoimmune hepatitis. Our patient has the HLA DR4 genotype, which may be significant in the pathogenesis of these disorders in her. In conclusion, we consider that the association of PV and UC may be coincidental or due to cross-reactivity between antigens in the oral mucosa and bowel. It can be considered that an autoimmune disease predisposes to the other autoimmune diseases. Sabite Kacar Orhan Sezgin Tu¨ lin Sahin Gastroenterology Department Tu¨ rkiye Yu¨ ksek Ihtisas Hospital Ankara, Turkey
REFERENCES 1. Prendiville JS, Israel DM, Wood WS, et al. Oral pemphigus vulgaris associated with inflammatory bowel disease and herpetic gingivostomatitis in an 11-year old girl. Pediatr Dermatol 1994;11:145–50. 2. Hertl M. Humoral and cellular autoimmunity in autoimmune skin disorders. Int Arch Allergy Immunol 2000;122:91–100. 3. Pacheco GU, Tovar-Rivera T, Padierna-Olivos L, et al. Altered pattern of connectivity in serum immunoglobulins from pemphigus vulgaris patients. Scand J Immunol 1999;19:424 – 30. 4. Scully C, Paes De Almedia O, Porter SR, et al. Pemphigus vulgaris: The manifestations and long-term management of 55 patients with oral lesions. Br J Dermatol 1999;140:84 –9. 5. Delphino M, Suppa F, Piccirillo A. Pemphigus vulgaris and ulcerative colitis. Dermatology 1986;172:230. 6. Fabbrı P, Emmı L, Vıgnolı L, et al. Pemfigo volgare cronica associato a rettocolite ulcerosa. G Ital Dermatol Venereol 1986;121:355–9. 7. Stone DD. Rectal lesions and toxic dilatation of the colon in a case of pemphigus vulgaris. Dig Dis 1971;16:163– 6. 8. Takizawa H, Watanabe S, Takahashi M, et al. Pemphigus vulgaris with asymptomatic pseudomembranous colitis. Am J Gastroenterol 1996;91:1654 –5. 9. Schwermann M, Lechner W, Elsner C, et al. Pemphigus vulgaris involving duodenum and colon. Z Hautkr 1988;63: 101– 4. 10. Hiroko G, Akiyama M, Yakabi K, et al. Oesophageal involvement in pemphigus vulgaris. Lancet 1999;354:1794. 11. Arnagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies
against a novel epitelial cadhedrin in pemphigus vulgaris, a discase of cell adhesion. Cell 1991;67:869 –77. Reprint requests and correspondence: Sabite Kacar, Ivedik Cad. Ahmet Hikmet Sok., Subay Koop. Evl. 23/7, 06170, Yenimahalle/ Ankara, Turkey. Received May 14, 2001; accepted Sep. 27, 2001.
Mucosal IgA Defect in Primary Biliary Cirrhosis TO THE EDITOR: The pathogenic mechanisms leading to selective damage of bile ducts in primary biliary cirrhosis (PBC) are still unknown. However, the apparent restriction of tissue damage to epithelial cells capable of transcytosing IgA has led to the suggestion that transcytosis of the IgA subtype of antimitochondrial antibodies (AMAs) may play an important role in the pathogenesis of PBC (1). In this view, the IgA class of AMAs can bind to mitochondrial antigens, resulting in cellular disruption. Recent studies have demonstrated the presence of AMAs in saliva of PBC patients (2, 3). Moreover, it has been observed that PBC patients have anti–pyruvate dehydrogenase complex IgA in their saliva, suggesting that this is predominantly secretory IgA reaching the saliva through the active process of epithelial transcytosis (4). Furthermore, a recent article showed that AMAs of the IgA isotype are secreted into urine from the uroepithelium of PBC patients (5). These important studies prompted us to address the critical question of whether IgA transport may be altered in patients with PBC in the site of the main trafficking—that is, the intestinal mucosa. Twenty-three patients with PBC and normal IgA levels underwent upper endoscopies for clinical purposes (20 female and three male; nine having histological stage II; five, stage III; and nine, stage IV). Seventeen patients with functional dyspepsia served as controls. During endoscopy, after informed consent, seven distal duodenum biopsies were taken and processed for 1) microscopic assessment; 2) in vitro organ culture system, according to the method described by Browning and Trier (6) with minor modifications [the enterocyte height before and after 24-h culture was measured at ⫻40 magnification, according to Howdle (7)]; and 3) immunohistochemical staining using polyclonal antiIgA (Dako, Glostrup, Denmark) and antihuman secretory component (IgA-SC) (Sigma Poole, Dorset, United Kingdom). Evaluation was based on the intensity of staining of the cells, which was scored as follows: 0 ⫽ absent, 1 ⫽ weak staining, 2 ⫽ moderate staining, 3 ⫽ a very strong staining. The enterocyte height was always normal (mean ⫽ 35.0 ⫾ 3.3 m), and the brush border was well defined. In the culture, the mean of enterocyte height in PBC did not differ from that of controls (35.0 ⫾ 3.3 m, vs 34.4 ⫾ 3.4 m in controls at the baseline, and 28.1 ⫾ 2.8 m vs 28.9 ⫾
AJG – February, 2002
Letters to the Editor
509
Table 1. Immunohistochemistry for IgA-SC and Total IgA in PBC Patients and in Controls
PBC Controls
IgA-SC (Villus)– Positive Subjects
IgA-SC (Villus) (Mean Score)
IgA-SC (Crypt)– Positive Subjects
IgA-SC (Crypt) (Mean Score)
Total IgAPositive Subjects
Total IgA (Mean Score)
8 17
1.2 ⫾ 0.5* 2.8 ⫾ 1.2
17 17
1.3 ⫾ 0.5* 3.2 ⫾ 0.9
23 17
2.5 ⫾ 0.7 2.4 ⫾ 0.6
* p ⬍ 0.002.
2.3 m after 24 h). IgA-SC was widely and homogeneously expressed in the cytoplasm of enterocytes of the crypts and all villi in control patients. Conversely, an absence of the IgA-SC expression in the villi was noticed in 15 of 23 PBC patients; the remaining eight showed significant reductions in the staining score relative to controls (Table 1). No difference was observed in the total IgA expression in the two groups of patients; in particular, IgA staining was observed along the basolateral side of the enterocyte membrane, resulting in a widening of the cell-to-cell junction. To our knowledge, this is the first communication to pinpoint an in situ IgA secretion defect in the intestinal epithelium of PBC patients. This reduced expression of IgA-SC on enterocytes in the absence of histological abnormalities could reflect a reduced local immune response. If this is so, this model would help to explain the mechanism and tropism of tissue damage in PBC. Several hypotheses could explain this defect. First of all, our results could be explained by a deficient synthesis or plasma membrane expression of polymeric immunoglobulin receptor (pIgR). This hypothesis is supported by an experimental model used by Shimada et al. (8), who generated a knockout mouse for pIgR, which revealed a lack of intestinal expression of IgA-SC and increased serum IgA levels. Secondly, a defect in IgA-SC binding, possibly through the J chain, to the pIgR might be suggested. A deficiency in J chain production could severely hinder the intestinal transport of IgA, as observed in J chain knockout mice (9), where disruption of the J chain gene caused a remarkable increase in serum IgA concentration. The defect of binding of IgA-SC to the pIgR might also be due to the formation of antibodies directed against the J chain (10). The ability of IgA autoantibodies from patients with PBC to penetrate and bind to their intracellular target was examined in an elegant experimental study by Malmborg et al. (11), who assessed the ability of serum IgA from PBC patients to penetrate cells using Madine-Darby canine kidney cells transfected with the human IgA receptor (MadineDarby canine kidney pIgR). The IgA from PBC patients colocalized with pyruvate dehydrogenase complex E2 (the major autoantigen of PBC) inside the cells. It may be that, during the transcytosis process, IgA is somehow directed toward the mitochondria or that IgA binds the mitochondrial enzyme during its migration of the mitochondria. However, to be elucidated, these hypotheses require further studies. In conclusion, an in situ defect of IgA secretion may be suggested, possibly in the binding of IgA-SC to the pIgR. The mucosal IgA defect might consequently alter mucosal
immunity, allowing several antigens to adhere to and penetrate the epithelium. Annarosa Floreani, M.D. Anna Baragiotta, M.D. Daniela Pizzuti, Ph.D. Diego Martines, M.D. Attilio Cecchetto, M.D. Silvia Chiarelli, M.D. Department of Surgical and Gastroenterological Sciences, Institute of Pathology, and Department of Surgical and Oncological Sciences University of Padova Padova, Italy
REFERENCES 1. Gershwin ME, Ansari AA, Mackay IR, et al. Primary biliary cirrhosis: An orchestrated immune response against epithelial cells. Immunol Rev 2000;174:210 –25. 2. Yeaman SJ, Kirby JA, Jones DEJ. Autoreactive responses to pyruvate dehydrogenase complex in the pathogenesis of primary biliary cirrhosis. Immunol Rev 2000;174:238 – 49. 3. Reynoso-Paz S, Leung PSC, Van de Water J, et al. Evidence for a locally driven mucosal response and the presence of mitochondrial antigens in saliva in primary biliary cirrhosis. Hepatology 2000;31:24 –9. 4. Palmer JM, Doshi M, Kirby JA, et al. Secretory autoantibodies in primary biliary cirrhosis (PBC). Clin Exp Immunol 2000; 122:423– 8. 5. Tanaka A, Nalbandian G, Leung PS, et al. Mucosal immunity and primary biliary cirrhosis: Presence of antimitochondrial antibodies in urine. Hepatology 2000;32:910 –5. 6. Browning TH, Trier JS. Organ culture of mucosal biopsies of human small intestine. J Clin Invest 1969;48:1423–32. 7. Howdle PD, Corazza GR, Bullen AW, Losowsky MS. Gluten sensitivity of small intestinal mucosa in vitro: Quantitative assessment of histological change. Gastroenterology 1981;80: 442–50. 8. Shimada S, Kawaguchi-Miyashita M, Kushiro A, et al. Generation of polymeric immunoglobulin receptor-deficient mouse with marked reduction of secretory IgA. J Immunol 1999;163:5367–73. 9. Hendrickson BA, Conner DA, Ladd DJ, et al. Altered hepatic transport of immunoglobulin A in mice lacking the J chain. J Exp Med 1995;182:1905–11. 10. Vaerman JP, Langendries AE, Giffroy DA, et al. Antibodies against the human J chain inhibits polymeric Ig receptormediated biliary and epithelial transport of human polymeric IgA. Eur J Immunol 1998;28:171– 82. 11. Malmborg A-C, Shultz DB, Luton F, et al. Penetration and co-localization in MDCK cell mitochondria of IgA derived from patients with primary biliary cirrhosis. J Autoimmun 1998;11:573– 80.
6 0 9 1 10 1 1089.2 ⫾ 381.1 2316.7 ⫾ 579.4 11/1.83 5/1.11
Period
Years 1991–1996 Years 1997–2001
4/3/4 5/0/0
2 0
57.2 ⫾ 33.1 134.2 ⫾ 43.1
No. of Patients With AIDS
No. of Patients Chronically Treated With Cotrimoxazole Mean Neutrophil Count at Diagnosis (Cells/L ⫾ SD) No. of Patients With Lethal Outcomes
Mean CD4⫹ Lymphocyte Count at Diagnosis (Cells/L ⫾ SD)
TO THE EDITOR: Although bacterial infections represented frequent complications of HIV disease, their overall morbidity and mortality remarkably dropped thanks to the highly active antiretroviral therapy (HAART)–related immunoreconstitution (1). However, Campylobacter spp infection, infrequently described even in the pre-HAART era—around 50 reported cases with prevalence of prolonged and/or relapsing diarrhea, nearly 30 cases of bacteremia (2– 8), and anecdotal episodes of atypical or focal disease (9)— continues to occur, probably because of the multiple modes of transmission of these organisms (alimentary, direct, or sexual) (2, 6), so that Campylobacter was recognized as the most frequent enteric pathogen in a crosssectional bacteriological survey also including asymptomatic patients (6). To re-evaluate the role of Campylobacter disease after HAART introduction, all cases of patients with at least one microbial isolation associated with consistent GI and/or systemic signs and symptoms were retrospectively retrieved, among the ⬃1000 patients referring every year to our tertiary care center since 1991. The 16 identified patients (11 males and five females, aged 35.6 ⫾ 5.2 yr) did not show demographic differences when compared with the whole HIV-infected population observed by us in the last decade, whereas more frequent HIV sexual exposure was detected (12 cases of 16, p ⬍ 0.005 compared with the entire cohort). The HAART’s introduction in late 1996 caused a significant drop in the absolute frequency of campylobacteriosis (odds ratio ⫽ 1.79 [1.38 ⬍ OR ⬍ 2.33], p ⬍ 0.0001), but also a notable modification of its clinical features (Table 1). A hematogenous dissemination has not occurred since 1997, compared with the seven episodes diagnosed until 1996 (four of them represented by a bacteremic enteritis) (p ⬍ 0.03). Intestinal findings (diarrhea, nausea, and abdominal discomfort) were similar to those in the general population, but systemic involvement (febrile bacteremia with or without enteric involvement) was observed only before HAART introduction (p ⬍ 0.03) and proved undistinguishable from any other HIV-related septic complication, although two extremely rare lethal cases of isolated hospital-acquired septicemia were previously reported by us (10). The concurrent immunodeficiency (as expressed by mean CD4⫹ lymphocyte and absolute neutrophil counts) and the stage of underlying disease were
No. of Patients With Enteric/ Hematogenous/ Associated Involvement
Enteric and Disseminated Campylobacter Species Infection During HIV Disease: A Persisting but Significantly Modified Association in the HAART Era
No. of Episodes/ No. of Episodes per 1000 Patient Years
Reprint requests and correspondence: Annarosa Floreani, M.D., Div. Gastroenterologia, Via Giustiniani, 2, 35128 Padova, Italy. Received July 12, 2001; accepted Sep. 27, 2001.
AJG – Vol. 97, No. 2, 2002
No. of Patients Experiencing Recurrences
Letters to the Editor
Table 1. A Comparison of Some Epidemiological, Clinical, Laboratory, Therapeutic, and Outcome Features of Our Patients With HIV-Associated Campylobacteriosis, Before (Years 1991–1996) and After (1997–2001) the Introduction of HAART as the Standard Antiretroviral Treatment
510