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• W2162369549 abstract "Background & Aims: Common variable immunodeficiency (CVID) patients can develop an idiopathic inflammatory bowel disease resulting in chronic diarrhea and life-threatening malabsorption. This study was designed to assess the status of the gastrointestinal tract and to define the mucosal immune abnormalities in patients with and without symptomatic gut inflammatory disease. Methods: CVID patients underwent tests of gut absorption, peripheral blood mononuclear cell phenotyping, and upper and lower endoscopy for histology and lamina propria mononuclear cell (LPMC) cytokine production. Results: CVID patients with gastrointestinal symptoms differed from asymptomatic CVID patients by having significantly longer duration of disease and lower body mass index, D-xylose absorption, serum albumin, CD4/CD45RA cells, CD3/CD25 cells, and natural killer cells. Symptomatic CVID patients showed diffuse histologic inflammatory changes in the duodenal and colonic mucosa including villus blunting, increased lamina propria and intraepithelial lymphocytes, and epithelial apoptosis, less frequently seen in asymptomatic patients. LPMCs from symptomatic CVID patients produced significantly higher T-helper (Th) 1 cytokines, interleukin-12, and interferon-γ. Compared with the Th1 cytokines produced by LPMCs from Crohn’s disease, CVID patients did not produce excess amounts of interleukin-23, interleukin-17, or tumor necrosis factor-α. Conclusions: The idiopathic inflammatory bowel disease associated with gastrointestinal symptoms in CVID is a unique combination of diverse histologic findings accompanied by excessive Th1 cytokine production, distinct from that in Crohn’s disease. These data show that human gut mucosal inflammatory disease can occur with excess interleukin-12 and interferon-γ production alone and provide a rationale for developing targeted therapies for this complication of CVID. Background & Aims: Common variable immunodeficiency (CVID) patients can develop an idiopathic inflammatory bowel disease resulting in chronic diarrhea and life-threatening malabsorption. This study was designed to assess the status of the gastrointestinal tract and to define the mucosal immune abnormalities in patients with and without symptomatic gut inflammatory disease. Methods: CVID patients underwent tests of gut absorption, peripheral blood mononuclear cell phenotyping, and upper and lower endoscopy for histology and lamina propria mononuclear cell (LPMC) cytokine production. Results: CVID patients with gastrointestinal symptoms differed from asymptomatic CVID patients by having significantly longer duration of disease and lower body mass index, D-xylose absorption, serum albumin, CD4/CD45RA cells, CD3/CD25 cells, and natural killer cells. Symptomatic CVID patients showed diffuse histologic inflammatory changes in the duodenal and colonic mucosa including villus blunting, increased lamina propria and intraepithelial lymphocytes, and epithelial apoptosis, less frequently seen in asymptomatic patients. LPMCs from symptomatic CVID patients produced significantly higher T-helper (Th) 1 cytokines, interleukin-12, and interferon-γ. Compared with the Th1 cytokines produced by LPMCs from Crohn’s disease, CVID patients did not produce excess amounts of interleukin-23, interleukin-17, or tumor necrosis factor-α. Conclusions: The idiopathic inflammatory bowel disease associated with gastrointestinal symptoms in CVID is a unique combination of diverse histologic findings accompanied by excessive Th1 cytokine production, distinct from that in Crohn’s disease. These data show that human gut mucosal inflammatory disease can occur with excess interleukin-12 and interferon-γ production alone and provide a rationale for developing targeted therapies for this complication of CVID. Common variable immunodeficiency (CVID), the most common symptomatic primary immunodeficiency, is characterized by failure of B-cell differentiation and decreased production of immunoglobulins. The major manifestations of this syndrome include suppurative sinopulmonary infections, infections of the gastrointestinal (GI) tract, autoimmunity (eg, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and other organ-specific autoimmune syndromes), and an increased incidence of lymphoproliferative processes that may predispose to neoplasia. Therapy is aimed primarily at restoring immunoglobulin levels with the administration of intravenous pooled immunoglobulin (IVIG); however, although this therapy clearly decreases the frequency and severity of infections, it has no apparent effect on associated autoimmune disease or neoplasia risk. GI manifestations of CVID suggestive of autoimmunity unrelated to infections occur in upwards of 10% of patients.1Cunningham-Rundles C. Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients.Clin Immunol. 1999; 92: 34-48Crossref PubMed Scopus (1290) Google Scholar, 2Sneller M. Strober W. Eisenstein E. Jaffe J. Cunningham-Rundles C. NIH Conference: new insights into common variable immunodeficiency.Ann Intern Med. 1993; 118: 720-730Crossref PubMed Scopus (231) Google Scholar Symptoms generally include chronic diarrhea, weight loss, and effects of micronutrient deficiencies because of malabsorption. Histologic abnormalities in the gastric, small bowel, and colonic mucosa include increased intraepithelial and lamina propria lymphocytes, epithelial cell apoptosis, and small intestine villus blunting. The GI symptoms persist and progress despite ongoing IVIG therapy, and effective treatment has not been established. Immune abnormalities in CVID are not limited to deficient antibody production. Disturbances in T-cell function3Fischer M.B. Hauber I. Eggenbauer H. Thon V. Lokaj J. Wolf H.M. Mannhalter J.W. Eibl M.M. Activation of CVID patients’ T cells with conventional antigens and superantigens.Immunodeficiency. 1993; 4: 15-16PubMed Google Scholar, 4Fischer M.B. Hauber I. Eggenbauer H. Thon V. Vogel E. Schaffer E. Lokaj J. Litzman J. Wolf H.M. Mannhalter J.W. Eibl M.M. A defect in the early phase of T-cell receptor-mediated T-cell activation in patients with common variable immunodeficiency.Blood. 1994; 84: 4234-4241PubMed Google Scholar, 5North M. Webster A.D.B. Farrant J. Defects in proliiferative responses of T cells from patients with common variable immunodeficiency on direct activation of protein kinase C.Clin Exp Immunol. 1991; 85: 198-201Crossref PubMed Scopus (37) Google Scholar, 6Brugnoni D. Airo P. Lebovitz M. Malacarne F. Ugazio A.G. Notarangelo L.D. Plebani A. Cattaneo R. CD4+ cells from patients with common variable immunodeficiency have a reduced ability of CD40 ligand membrane expression after in vitro stimulation.Pediatr Allergy Immunol. 1996; 7: 176-179Crossref PubMed Scopus (12) Google Scholar, 7Farrington M. Grosmaire L.S. Nonoyama S. Fischer S.H. Hollenbaugh D. Ledbetter J.A. Noelle R.J. Aruffo A. Ochs H.D. CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency.Proc Natl Acad Sci U S A. 1994; 91: 1099-1103Crossref PubMed Scopus (215) Google Scholar, 8Kondratenko I. Amlot P.L. Webster A.D. Farrant J. Lack of specific antibody response in common variable immunodeficiency (CVID) associated with failure in production of antigen-specific T-memory cells.Clin Exp Immmunol. 1997; 108: 9-13Crossref PubMed Scopus (82) Google Scholar, 9Stagg A.J. Funauchi M. Knight S.C. Webster A.D. Farrant J. Failure in antigen responses by T cells from patients with common variable immunodeficiency (CVID).Clin Exp Immunol. 1994; 96: 48-53Crossref PubMed Scopus (87) Google Scholar, 10Jaffe J.S. Strober W. Sneller M.C. Functional abnormalities of CD8+ T cells define a unique subset of patients with common variable immunodeficiency.Blood. 1993; 82: 192-201PubMed Google Scholar, 11Serrano D. Becker K. Cunningham-Rundles C. Mayer L. Characterization of the T-cell receptor repertoire in patients with common variable immunodeficiency: oligoclonal expansion of CD8(+) T cells.Clin Immunol. 2000; 97: 248-258Crossref PubMed Scopus (43) Google Scholar, 12Wright J.J. Wagner D.K. Blaese R.M. Hagengruber C. Waldmann T.A. Fleisher T.A. Characterization of common variable immunodeficiency: identification of a subset of patients with distinctive immunophenotypic and clinical features.Blood. 1990; 76: 2046-2051PubMed Google Scholar, 13Waldmann T.A. Broder S. Blaese R.M. Durm M. Blackman M. Strober W. Role of suppressor cells in pathogenesis of common variable hypogammaglobulinemia.Lancet. 1974; 2: 609-616Abstract PubMed Scopus (480) Google Scholar and in the innate immune system14Cambronero R. Sewell W.A.C. North M.E. Webster A.D.B. Farrant J. Up-regulation of IL-12 in monocytes: a fundamental defect in common variable immunodeficiency.J Immunol. 2000; 164: 488-494PubMed Google Scholar, 15Cunningham-Rundles C. Radigan L. Deficient IL-12 and dendritic cell function in common variable immue deficiency.Clin Immunol. 2005; 115: 147-153Crossref PubMed Scopus (84) Google Scholar, 16Bayry J. Lacroix-Desmazes S. Kazatchkine M.D. Galicier L. Lepelletier Y. Webster D. Levy Y. Eibl M.M. Oskenhendler E. Hermine O. Kaveri S.V. Common variable immunodeficiency is associated with defective functions of dendritic cells.Blood. 2004; 104: 2441-2443Crossref PubMed Scopus (127) Google Scholar, 17Scott-Taylor T.H. Green M.R.J. Eren E. Webster A.D.B. Monocyte derived dendritic cell responses in common variable immunodeficiency.Clin Exp Immmunol. 2004; 138: 484-490Crossref PubMed Scopus (50) Google Scholar have also been described. In this study, we compare the gut function and histology, peripheral blood mononuclear cell phenotypes, and lamina propria mononuclear cell (LPMC) cytokine production in CVID patients with GI symptoms to symptom-free CVID patients. We show that CVID patients with GI symptoms have a malabsorptive syndrome associated with excess T-helper (Th1) cytokine secretion by LPMCs that differs in some key aspects from that occurring in Th1-mediated Crohn’s disease. Eligible patients with a diagnosis of common variable immunodeficiency (according to established criteria)18Chapel H. Geha R. Rosen F. IUIS PID (Primary Immmunodeficiencies) Classification Committee Primary immunodeficiencies: an update.Clin Exp Immmunol. 2003; 132: 9-15Crossref PubMed Scopus (109) Google Scholar were either 10 years of age or older (with chronic diarrhea or unexplained weight loss greater than 5% of total body weight over the previous 6 months) or were older than 18 years (without GI symptoms). Eligible patients also had negative stool testing for pathogens (Salmonella, Shigella, Yersinia, Campylobacter, Vibrio, Escherichia coli O157/H7, Cryptosporidia, Cyclospora, Microsporidia, and Giardia) and Clostridia difficile toxin, negative hydrogen breath test, were on no immunomodulatory agents for the preceding 4 months, and were human immunodeficiency virus (HIV) negative. Crohn’s disease patients with moderately active disease who underwent identical colonoscopy and biopsy procedures for harvest and assay of LPMC cytokine production were used as a comparison group. All protocol and consent procedures were approved by the National Institute of Allergy and Infectious Disease Institutional Review Board. After signing the informed consent, patients had a review of the documentation of their diagnosis, HIV antibody and viral load test, stool examination, and hydrogen breath test. Eligible patients then returned to the NIH Clinical Center for a history and physical, complete hematology and biochemistry blood tests, peripheral blood lymphocyte phenotyping, craniocaudal spleen size by ultrasound, D-xylose absorption test (25 g by mouth [PO], blood samples taken before ingestion and 1 hour afterward; lower limit of normal for serum D-xylose 1 hour postingestion is 25 mg/dL),19Craig R.M. Atkinson A.J. D-xylose testing: a review.Gastroenterology. 1988; 95: 223-231Abstract PubMed Google Scholar and a 48-hour stool collection for fat (collection delimited by carmine red capsule ingestion 48 hours apart during 60- to 100-g fat diet/24 hours with calorie count). Patients also underwent esophagogastroduodenoscopy and colonoscopy to obtain duodenal and colonic biopsy specimens for histology and preparation of LPMCs for cytokine production. These studies were completed within 4 weeks of enrollment and just before the patient’s next IVIG administration was due. Endoscopic biopsy specimens were fixed in 10% formalin prior to paraffin embedding and routine staining with H&E. Biopsy specimens were reviewed by a GI pathologist who was masked to the clinical status of the patients. Biopsy specimens were labeled as nodular lymphoid hyperplasia (NLH) if germinal centers were present, intraepithelial lymphocytosis (IEL) if there were greater than 5 lymphocytes per 20 epithelial cells, and noted for apoptosis if there were greater than 5 apoptotic epithelial cells per 10 glands. LPMCs were prepared using a modification of a previously described procedure.20Fuss I.J. Heller F. Boirivant M. Leon F. Yoshida M. Fichtner-Feigl S. Yang Z. Exley M. Kitani A. Blumberg R.S. Mannon P. Strober W. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis.J Clin Invest. 2004; 113: 1490-1497Crossref PubMed Scopus (653) Google Scholar Cytokines were measured by ELISA from supernatants of cultured cells after stimulation with antibodies to CD2 or CD3 plus CD28 (T-cell stimulus) and Staphylococcus aureus Cowan 1, interferon-γ, and CD40 ligand trimer (antigen-presenting cell stimulus).21Jain A. Atkinson T.P. Lipsky P.E. Slater J.E. Nelson D.L. Strober W. Defects of T-cell effector function and post-thymic maturation in X-linked hyper-IgM syndrome.J Clin Invest. 1999; 103: 1151-1158Crossref PubMed Scopus (94) Google Scholar Peripheral blood cells (3 mL EDTA anticoagulated samples) were stained for 3-color flow cytometry using a whole-blood lysis method and analyzed on a FACScan (Becton Dickinson Biosciences [BD], San Jose, CA) using Cellquest software (BD). T cells and T-cell subsets were identified by directly conjugated monoclonal antibodies anti-CD3, anti-CD4, anti-CD8, anti-CD5 and CD57/CD8; B cells by anti-CD19 and anti-CD20; and natural killer (NK) cells by a combination of anti-CD16 and anti-CD56, evaluated on CD3-negative lymphocytes; T-cell activation markers by anti-CD25 and anti-HLA-DR; memory T cells by anti-CD45RO; naïve T cells by anti-CD45RA; memory B cells by anti-CD27; directly conjugated, murine IgG1 was used to ascertain background staining. All monoclonal antibodies were obtained from Becton Dickinson Biosciences, with the exception of anti-CD4, anti-CD8, and anti-CD45RA (Beckman-Coulter, Brea, CA) and anti-CD45RO (Dako, Carpinteria, CA). Lymphocytes were identified using anti-CD45/anti-CD14 (BD), and a lymphocyte gate was established using forward and side scatter. List mode parameters were collected for 106 lymphocytes. To calculate absolute numbers of each lymphocyte subset, the percentage of cells staining positive was multiplied by the absolute peripheral blood lymphocyte count, which was determined by a Celldyne 3500 (Abbott, Santa Clara, CA). Peripheral blood from healthy adult controls was stained and analyzed to establish 95% confidence interval normal ranges. Differences between mean and median values were tested for significance by the unpaired t test and Mann–Whitney U test, respectively. The Mann–Whitney U test was used when group values were not normally distributed and transformation failed to yield a normal distribution. Thirteen CVID patients completed the study procedures over a period from April 2002 to October 2005. One patient was enrolled in both the asymptomatic and symptomatic groups after disease progression. Eight patients (5 female) had GI symptoms: 7 with chronic diarrhea (4 with weight loss) and 1 with weight loss alone. These symptomatic patients were diagnosed with CVID 15.3 ± 2.4 years before participation, had been receiving IVIG for 14.5 ± 2.5 years, and had an average duration of gastrointestinal symptoms for 5.3 ± 2.1 years. The 6 patients (3 female) without GI symptoms were diagnosed with CVID 5.9 ± 3.6 years earlier and had been receiving IVIG for 5.9 ± 3.6 years. The groups were similar in age (see Table 1). Those with GI symptoms had significantly lower body mass indices consistent with their significantly lower D-xylose absorption (and symptomatic patients tended to show worse steatorrhea). In addition, serum albumin was significantly lower in symptomatic patients compared with asymptomatic patients. Neither C-reactive protein nor erythrocyte sedimentation rate was elevated in either group. In general, both groups had splenomegaly,22Frank K. Linhart P. Kortsik C. Wohlenberg H. Sonographic determination of spleen size: normal dimensions in adults with a healthy spleen.Ultraschall Med. 1986; 7: 134-137Crossref PubMed Google Scholar but spleen size (craniocaudal length measured by ultrasonography) was larger in the symptomatic group (these differences did not reach significance).Table 1Demographic and Clinical Characteristics of CVID Patients With and Without Gastrointestinal SymptomsGI symptoms (n = 8)No GI symptoms (n = 6)P valueAge (y)46.3 ± 2.943.7 ± 4.3.61Duration of CVID (y)15.3 ± 2.45.9 ± 3.6.04Body mass index22.6 ± 1.428.2 ± 1.3.02D-xylose absorption (mg/dL)13.6 ± 2.633.9 ± 6.3.0124 hour stool fat excretion (% ingested fat)19.2 ± 7.5 (n = 7)4.8 ± 1.2 (n = 3).39Erythrocyte sedimentation rate (mm/hr)9.4 ± 1.98 ± 2.8.68Spleen size (cm)19.5 ± 2.414.2 ± 2.3.15Serum iron (μg/dL)38.4 ± 9.663.2 ± 11.7.14Serum transferrin (mg/dL)255 ± 17.5250.5 ± 12.7.83Iron saturation (%)14.4 ± 2.725.4 ± 17.5.06Serum albumin (mg/dL)3.2 ± 0.23.8 ± 0.1.04NOTE. Values are mean ± standard error of mean. Open table in a new tab NOTE. Values are mean ± standard error of mean. Endoscopy in both patient groups showed an unremarkable appearance of the mucosa in the duodenum and the colon. There were no gross mucosal abnormalities or endoscopic findings of nodular lymphoid hyperplasia. Patchy erythema seen in the stomachs of some patients was consistent with a nonspecific gastritis. There were several significant differences in peripheral blood immune cell phenotype distribution between CVID patients with GI symptoms compared with those without symptoms (Table 2). Total CD3+, CD4+, and CD8+ T-cell numbers tended to be lower in symptomatic patients, but these differences were not significant except for the lower numbers of naïve CD4+ T cells (CD45RA+ T cells). Similarly, although total B-cell numbers and CD20+/CD27+ cells were lower in patients with GI symptoms, this difference was not statistically significant. Interestingly, significantly larger proportions of CD3+ and CD4+ cells from symptomatic patients expressed the human leukocyte antigen (HLA) DR activation/maturation marker, but they also had significantly fewer CD3+/CD25+ cells. Last, CVID patients with GI symptoms had significantly lower numbers of NK cells (CD16/CD56/CD3−) compared with patients without GI symptoms, and this number was also below the normal reference range.Table 2Peripheral Blood Lymphocyte Phenotype Results From CVID Patients With and Without Gastrointestinal SymptomsReference rangeGI symptoms (n = 8)No GI symptoms (n = 6)P valueCD3832–2028854 ± 1321245 ± 173.10CD4480–1339559 ± 94779 ± 84.14CD8351–911294 ± 67445 ± 68.16T4/T8 ratio0.8–3.33 ± 0.82.3 ± 0.4.51CD45RO/CD4196–522407 ± 100395 ± 35.93CD45RO/CD833–19291 ± 23108 ± 20.64CD45RA/CD457–48142 ± 18132 ± 37.03CD45RA/CD853–41378 ± 21133 ± 44.22CD4/DR0–85103 ± 2652 ± 8.16CD4/DR %0–5.211 ± 23.6 ± 0.8.006CD3/DR0–291203 ± 41148 ± 41.39CD3/DR %0–15.120 ± 29 ± 2.007CD3/CD25193–1248245 ± 46580 ± 95.005CD3/CD25 %14–4326 ± 437 ± 4.07CD2088–33092 ± 28148 ± 13.16CD1994–37897 ± 30151 ± 13.20CD20/CD2711–11816 ± 1058 ± 30.18CD16/CD56/CD3−120–49067 ± 16165 ± 47.04CD16/CD56/CD3+19–22198 ± 26136 ± 47.46NOTE. Values in columns 3 and 4 are mean ± standard error of mean. Open table in a new tab NOTE. Values in columns 3 and 4 are mean ± standard error of mean. CVID patients with gastrointestinal symptoms exhibited histologic changes in the duodenum (Table 3 and Figure 1). These included villus blunting and flattening/atrophy (7/8 patients), an increased number of intraepithelial lymphocytes (IEL) (7/8 patients), and the appearance of polymorphonuclear cells in the lamina propria (2/8 patients). Every biopsy specimen that displayed increased IELs also had increased lamina propria lymphocytes. Interestingly, the colonic mucosa in these symptomatic patients was also noted to have a high frequency of inflammatory changes. This consisted of an increased number of lamina propria lymphocytes or polymorphonuclear cells (5/8 patients) and included the presence of cryptitis and crypt abscesses in 1 patient and granulomas or granuloma-like lesions in the lamina propria of 2 other patients. As in the duodenum, there was an increase in the number of intraepithelial lymphocytes (6/8 patients) in the colon, but the latter differed from the duodenum in that colonic epithelium also exhibited notable epithelial apoptosis (3/8 patients), and the colonic lamina propria exhibited a higher frequency of prominent lymphoid follicles consistent with lymphoid hyperplasia (5/8 patients).Table 3Histologic Findings on Endoscopic Biopsy of CVID Patients With and Without Gastrointestinal SymptomsLocation of biopsiesDuodenumColonStomachPatients with GI symptoms (Patient no.) 1Villus blunting, IEL, increased lamina propria lymphocytesNo lesionNo lesion 2Villus blunting, IEL, increased lamina propria lymphocytesIEL, patchy, NLH, granulomaIntestinal metaplasia 3Villus blunting, IEL, increased lamina propria lymphocytesNLHNot biopsied 4Villus blunting, IEL, patchy increased lamina propria lymphocytesIEL, increased lamina propria lymphocytes, NLHChronic gastritis 5Villus blunting, IEL, increased lamina propria lymphocytesIEL, architectural distortion, mild neutrophilic infiltrate with cryptitis and crypt abscessLymphoid aggregates without germinal centers 6IEL, patchy, increased lamina propria lymphocytes, intact villiIEL, patchy, marked apoptosis, neutrophilic infiltrate, focal NLHNo lesion 7Villus atrophy, focal neutrophilic infiltrate with reactive atypia, apoptosis, patchyIEL, patchy, apoptosis neutrophilic infiltrate, focal, tubular adenomaNo lesion 8Villus blunting, IEL, increased lamina propria lymphocytes, apoptosis neutrophilic infiltrate, NLHIEL, apoptosis, NLH, granuloma neutrophilic infiltrateChronic active gastritis Intestinal metaplasia, focalPatients without GI symptoms (Patient no.) 9Intact villi, lymphoid aggregate without germinal centersApoptosis, patchy, lymphoid aggregate, edemaNot biopsied 10No lesionNeutrophilic infiltrate, focal,Chronic gastritis, mildNLH, edema 11Intact villi, increased lymphocytes in lamina propriaIncreased lymphocytes in lamina propria, NLHChronic gastritis, mild 12No lesionEdemaIEL, chronic active gastritis 13Intact villi, IEL, increased lymphocytes in lamina propriaIncreased lymphocytes in lamina propria, IEL, apoptosis, architectural distortion, mildNot biopsied 14Intact villi, IEL, patchyIEL, NLH, architectural distortion, mild, neutrophilic infiltrate, focal, tubular adenomaActive gastritis, focalIEL, intraepithelial lymphocytes; NLH, nodular lymphoid hyperplasia. Open table in a new tab IEL, intraepithelial lymphocytes; NLH, nodular lymphoid hyperplasia. CVID patients without gastrointestinal symptoms exhibited both normal histology and microscopic evidence of inflammation. In the duodenum, normal histology was seen in 3 of 6 patients, but there was no evidence of villus blunting or flattening in any asymptomatic patient. Chronic duodenitis (increased lymphocytes in the lamina propria) was seen in 2 patients, and 2 had an increase in intraepithelial lymphocytes. However, in the colonic mucosa of these asymptomatic CVID patients, evidence of inflammation was noted in 4 of 6, with findings of chronic active colitis and chronic colitis. Increased intraepithelial lymphocytes were noted in 2 patients, and increased epithelial apoptosis was noted in 2 patients. In addition, lymphoid aggregates consistent with lymphoid hyperplasia were seen in 3 patients. In general, any inflammatory changes in the colonic mucosa of any CVID patient were diffuse, in that biopsy specimens from different anatomic areas sampled showed consistent changes. LPMC from CVID patients with GI symptoms produced greatly increased amounts of Th1 cytokines compared with cells from patients without GI symptoms. Thus, as shown in Figure 2, LPMC from the duodenal and colonic mucosa of symptomatic patients when stimulated in vitro with Staphylococcal aureus Cowan 1, interferon-γ, and CD40 trimer produced more IL-12 p70, 356 ± 135 pg/mL and 274 ± 77 pg/mL (mean ± SEM) from the duodenum and colon, respectively, compared with 14 ± 9 pg/mL and 4 ± 4 pg/mL from asymptomatic patients. This increase in IL-12 production was accompanied by comparable increases in the IL-12-induced “downstream” Th1 cytokine, IFN-γ; LPMC of symptomatic patients when stimulated with anti-CD2/anti-CD28 produced greatly increased amounts of IFN-γ (10,364 ± 1808 pg/mL and 14,112 ± 7118 pg/mL from the duodenum and colon of symptomatic patients, respectively) compared with LPMC from the duodenum and colon of asymptomatic patients (662 ± 213 pg/mL and 1078 ± 503 pg/mL, respectively). In contrast, as shown in Figure 2, LPMC from both symptomatic and asymptomatic patients produce equivalently low amounts of IL-23 when stimulated with SAC/IFN-γ/CD40 trimer and IL-17 when stimulated with anti-CD2/anti-CD28. Furthermore, as seen in Figure 3, there were no significant differences between the 2 patient groups in the duodenal or colonic LPMC production of IL-4, IL-10, TNF-α, or IL-6. We compared the profile of colonic LPMC Th1 cytokine production from symptomatic CVID patients to that of Crohn’s disease patients with active colonic inflammation who were previously studied by us in an identical fashion to the CVID patients.23Mannon P.J. Fuss I.J. Mayer L. Elson C.O. Sandborn W.J. Present D. Dolin B. Goodman N. Groden C. Hornung R.L. Quezado M. Yang J. Neurath M.F. Salfeld J. Veldman G.M. Schwertschlag U. Strober W. Anti-interleukin-12 antibody for active Crohn’s disease.N Engl J Med. 2004; 351: 2069-2079Crossref PubMed Scopus (750) Google Scholar, 24Fuss I.J. Becker C. Yang Z.Q. Groden C. Hornung R.L. Heller F. Neurath M.F. Strober W. Mannon P.J. Both IL-12p70 and IL-23 are synthesized during active Crohn’s disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody.Inflamm Bowel Dis. 2006; 12: 9-15Crossref PubMed Scopus (279) Google Scholar When compared with the colonic LPMC cytokine production from Crohn’s disease patient biopsy specimens (Figure 4), CVID patients with symptomatic gut inflammation showed similarly elevated IL-12 and INF-γ, but CVID patient colonic LPMC produced very little IL-23, IL-17, and TNF-α.Figure 3Cytokine production by lamina propria mononuclear cells in CVID patients. Tumor necrosis factor-α, interleukin-10, interleukin-4, and interleukin-6 secretion from LPMC obtained from duodenal and colonic endoscopic biopsies from CVID patients with (n = 8) and without (n = 6) gastrointestinal symptoms. Boxes show median and 25th and 75th percentile, and bars show the range. There were no significant differences based on the Mann–Whitney U test.View Large Image Figure ViewerDownload (PPT)Figure 4Comparison of cytokine production by colonic lamina propria mononuclear cells from CVID and Crohn’s disease patients. Interleukin-12, interferon-γ, interleukin-23, interleukin-17, tumor necrosis factor-α, and interleukin-6 secretion from LPMCs obtained from colonic endoscopic biopsies from CVID patients with gastrointestinal symptoms (n = 8) and Crohn’s disease patients (n = 9) with active inflammation. Results of Mann–Whitney U tests are shown for significant differences.View Large Image Figure ViewerDownload (PPT) In one case, we were able to study the same patient who developed chronic GI symptoms after the initial evaluation as an asymptomatic subject (Table 3, patients 5 and 13). The initial studies revealed a D-xylose absorption of 18 mg/dL, evidence of microscopic inflammation (increased lamina propria and intraepithelial lymphocytes, colonic crypt architectural distortion, and apoptosis), and colonic LPMC cytokine production of 216 pg/mL INF-γ and no IL-12 Twenty-one months later, after 3 months of chronic diarrhea and weight loss, repeat studies showed D-xylose absorption of 6.7 mg/dL, additional gut histologic changes included blunted duodenal villi and a neutrophilic infiltrate in the colonic mucosa, and colonic LPMC cytokine production increased to 9781 pg/mL INF-γ and 89 pg/mL IL-12. The data presented above clearly associate specific immune abnormalities with a unique clinical subgroup of CVID patients: those with malabsorption accompanying gut inflammation. Patients with common variable immunodeficiency who develop symptomatic noninfectious GI inflammation differ from asymptomatic CVID patients in 2 important ways. First, their clinical presentation is notable for a significantly longer duration of CVID and lower body mass indices, deficient absorption of D-xylose, and lower concentrations of serum albumin. Second, these patients possess characteristic functional and phenotypic immune cell abnormalities not seen in CVID patients without symptomatic gut inflammatio" @default.
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• W2162369549 date "2006-09-01" @default.
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• W2162369549 title "Excess IL-12 but not IL-23 Accompanies the Inflammatory Bowel Disease Associated With Common Variable Immunodeficiency" @default.
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