Clinical characteristics and outcomes of pediatric patients with autoimmune gastritis.

OBJECTIVES: Autoimmune gastritis (AIG) is a rare chronic inflammatory disorder with potential long-term sequelae including gastric neoplasia. There is limited data on the natural history of pediatric AIG. We aimed to characterize the clinical course and outcomes of children with AIG. METHODS: This was a multicenter retrospective study that included pediatric patients diagnosed with AIG between January 1, 2000 and December 31, 2021. Diagnosis of AIG was based on the demonstration of histological corpus-predominant atrophic gastritis, with or without positive antiparietal cell (APCA) or anti-intrinsic factor (IF) antibodies. Demographic, clinical, laboratory, endoscopic, and histologic data were retrieved, along with follow-up data. RESULTS: Thirty-three patients, (23 females [69.7%], median age 12.0 [interquartile range 7.0-15.0] years at diagnosis) were identified. Twenty-two patients (66.7%) had positive APCA and/or anti-IF serology. The most common presenting manifestation was iron deficiency anemia (75%), and accompanying autoimmune disorders were significantly more common in patients with positive serology (62% vs. 18%, p < 0.05). Pseudo-pyloric or intestinal-type metaplasia was present at diagnosis in eight patients (24%), and 11 additional patients (33%) developed metaplasia during a median follow-up time of 27 (17.5-48.3) months. One patient developed a type 1 gastric neuroendocrine tumor. Helicobacter pylori was identified in only one patient, while two patients had prior eradication. Endoscopic and histologic improvements weren't identified in any patients. CONCLUSIONS: AIG should be considered in patients with autoimmunity and resistant iron-deficiency anemia. H. pylori infection may not be associated with pediatric AIG. The development of neuroendocrine tumor in one patient, and the high rates of metaplasia, highlight the importance of surveillance.

WNT2B Deficiency Causes Enhanced Susceptibility to Colitis Due to Increased Inflammatory Cytokine Production.

BACKGROUND & AIMS: Humans with WNT2B deficiency have severe intestinal disease, including significant inflammatory injury, highlighting a critical role for WNT2B. We sought to understand how WNT2B contributes to intestinal homeostasis. METHODS: We investigated the intestinal health of Wnt2b knock out (KO) mice. We assessed the baseline histology and health of the small intestine and colon, and the impact of inflammatory challenge using dextran sodium sulfate (DSS). We also evaluated human intestinal tissue. RESULTS: Mice with WNT2B deficiency had normal baseline histology but enhanced susceptibility to DSS colitis because of an increased early injury response. Although intestinal stem cells markers were decreased, epithelial proliferation was similar to control subjects. Wnt2b KO mice showed an enhanced inflammatory signature after DSS treatment. Wnt2b KO colon and human WNT2B-deficient organoids had increased levels of CXCR4 and IL6, and biopsy tissue from humans showed increased neutrophils. CONCLUSIONS: WNT2B is important for regulation of inflammation in the intestine. Absence of WNT2B leads to increased expression of inflammatory cytokines and increased susceptibility to gastrointestinal inflammation, particularly in the colon.

Principles of Analytic Validation of Immunohistochemical Assays: Guideline Update.

CONTEXT.­: In 2014, the College of American Pathologists developed an evidence-based guideline to address analytic validation of immunohistochemical assays. Fourteen recommendations were offered. Per the National Academy of Medicine standards for developing trustworthy guidelines, guidelines should be updated when new evidence suggests modifications. OBJECTIVE.­: To assess evidence published since the release of the original guideline and develop updated evidence-based recommendations. DESIGN.­: The College of American Pathologists convened an expert panel to perform a systematic review of the literature and update the original guideline recommendations using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS.­: Two strong recommendations, 1 conditional recommendation, and 12 good practice statements are offered in this updated guideline. They address analytic validation or verification of predictive and nonpredictive assays, and recommended revalidation procedures following changes in assay conditions. CONCLUSIONS.­: While many of the original guideline statements remain similar, new recommendations address analytic validation of assays with distinct scoring systems, such as programmed death receptor-1 and analytic verification of US Food and Drug Administration approved/cleared assays; more specific guidance is offered for validating immunohistochemistry performed on cytology specimens.

Clinical presentation and outcomes of Helicobacter heilmannii gastritis in children in the New England region of the United States.

OBJECTIVE: To describe the clinical, endoscopic, histologic, and treatment outcomes of Helicobacter heilmannii (H. heilmannii) associated gastritis in children in the New England region of the United States. METHODS: Retrospective study of children (1-18 years) with H. heilmannii identified on gastric mucosal biopsies from two pediatric centers over a 21-year period, January 2000-December 2021. Cases were identified by querying pathology databases at each institution. Demographic and clinical data were obtained from the medical record. Endoscopic and histologic findings were extracted from endoscopy and pathology reports, respectively. RESULTS: Thirty-eight children were diagnosed with H. heilmannii-associated gastritis during the study period. The mean age at diagnosis was 10.1 ± 5.3 years, and 25/38 (66%) cases were male. Abdominal pain (32%) and nausea with or without vomiting (26%) were the most common symptoms. Thirty-two children (84%) had endoscopic findings including gastric nodularity (55%) and erythema (26%). All children had histologic signs of chronic gastritis, including those with normal endoscopic exams. Antibiotic regimens used for treating Helicobacter pylori were frequently prescribed. Of the 17 children who underwent a follow-up endoscopy (range 2-68 months), 15 (88%) did not have H. heilmannii identified on gastric biopsies. CONCLUSION: H. heilmannii was an infrequent but potential cause of epigastric abdominal pain and nausea in our cohort of New England children. While morphologically distinct from H. pylori, the bacteria can result in similar endoscopic and histologic findings of nodularity and chronic gastritis, respectively. The rate of eradication, as assessed by histology following treatment with H. pylori therapies, was below the 90% recommended goal for antimicrobial therapies.

Sclerosing epithelioid fibrosarcoma of bone with hybrid features: clinicopathologic, radiologic, and molecular analysis of three cases.

Sclerosing epithelioid fibrosarcoma (SEF) occurring as a primary bone tumor is exceptionally uncommon. Even more rare are cases of SEF that show morphologic overlap with low-grade fibromyxoid sarcoma (LGFMS). Such hybrid lesions arising within the bone have only rarely been reported in the literature. Due to their variegated histomorphology and non-specific radiologic features, these tumors may pose diagnostic difficulties. Herein we describe three molecularly confirmed primary bone cases of sclerosing epithelioid fibrosarcoma that demonstrated prominent areas showing the features of LGFMS and with areas resembling so-called hyalinizing spindle cell tumor with giant rosettes (HSCTGR). Two patients were female and one was male aged 26, 47, and 16, respectively. The tumors occurred in the femoral head, clavicle, and temporal bone. Imaging studies demonstrated relatively well-circumscribed radiolucent bone lesions with enhancement on MRI. Cortical breakthrough and soft tissue extension were present in one case. Histologically the tumors all demonstrated hyalinized areas with SEF-like morphology as well as spindled and myxoid areas with LGFMS-like morphology. Two cases demonstrated focal areas with rosette-like architecture as seen in HSCTGR. The tumors were all positive for MUC4 by immunohistochemistry and cytogenetics, fluorescence in-situ hybridization, and next-generation sequencing studies identified EWSR1 gene rearrangements confirming the diagnosis in all three cases.Hybrid SEF is exceedingly rare as a primary bone tumor and can be difficult to distinguish from other low-grade spindled and epithelioid lesions of bone. MUC4 positivity and identification of underlying EWSR1 gene rearrangements help support this diagnosis and exclude other tumor types.

A tip-predominant distribution of villous intraepithelial lymphocytes is not specific to celiac disease in children with Marsh I lesions.

OBJECTIVES: To assess if the distribution of villous intraepithelial lymphocytes (IELs) in a pediatric cohort with Marsh I histopathology is specific to celiac disease (CeD). METHODS: Multicenter, retrospective case-control study between January 2001 and December 2019 in children (<18 years) with and without CeD with intraepithelial lymphocytosis and normal villous architecture. Pathology specimens were reviewed by 2 study pathologists who were blinded to the final diagnosis. Morphologic features (villous height to crypt depth ratio [Vh:Cd]) and IELs in the villous tip, top, or bottom half of the villus were quantified. RESULTS: Of the 97 children with Marsh I histopathology identified during the study period, 63 were excluded due to an insufficient number of well-oriented villous-crypt complexes or a Vh:Cd less than 2. Villous IELs were measured in 34 cases (14 CeD, 20 non-CeD controls). There was no difference between the non-CeD and CeD groups in the mean IELs at the villous tip (14.0 ± 7.1 vs 11.7 ± 6.0, P = .31), top (46.4 ± 18.4 vs 38.3 ± 10.8, P = .11), or bottom (29.8 ± 16.8 vs 28.5 ± 12.8, P = .80) half of each villus, respectively. CONCLUSIONS: The distribution of IELs in Marsh I lesions is not specific for CeD.

Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study.

BACKGROUND & AIMS: There is a need to develop safe and effective pharmacologic options for the treatment of celiac disease (CeD); however, consensus on the appropriate design and configuration of randomized controlled trials (RCTs) in this population is lacking. METHODS: A 2-round modified Research and Development/University of California Los Angeles Appropriateness Method study was conducted. Eighteen gastroenterologists (adult and pediatric) and gastrointestinal pathologists voted on statements pertaining to the configuration of CeD RCTs, inclusion and exclusion criteria, gluten challenge, and trial outcomes. Two RCT designs were considered, representing the following distinct clinical scenarios for which pharmacotherapy may be used: trials incorporating a gluten challenge to simulate exposure; and trials evaluating reversal of histologic changes, despite attempted adherence to a gluten-free diet. Each statement was rated as appropriate, uncertain, or inappropriate, using a 9-point Likert scale. RESULTS: For trials evaluating prevention of relapse after gluten challenge, participants adherent to a gluten-free diet for 12 months or more with normal or near-normal-sized villi should be enrolled. Gluten challenge should be FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) free, and efficacy evaluated using histology with a secondary patient-reported outcome measure. For trials evaluating reversal of villus atrophy, the panel voted it appropriate to enroll participants with a baseline villus height to crypt depth ratio ≤2 and measure efficacy using a primary histologic end point. Guidance for measuring histologic, endoscopic, and patient-reported outcomes in adult and pediatric patients with CeD are provided, along with recommendations regarding the merits and limitations of different end points. CONCLUSIONS: We developed standardized recommendations for clinical trial design, eligibility criteria, outcome measures, gluten challenge, and disease evaluations for RCTs in patients with CeD.

Gastric Foveolar Hyperplastic Polyps in 2 Children With Short Bowel Syndrome on Long-Term Teduglutide.

The natural history of short bowel syndrome involves intestinal adaptation wherein the remnant small intestine undergoes histologic and anatomic changes aimed at increasing absorption. Teduglutide-a glucagon-like peptide 2 analog approved for pediatric use in 2019-stimulates this process by causing proliferation of intestinal epithelial cells resulting in increased villous height and crypt depth. Food and Drug Administration approval for pediatric patients followed safety and efficacy studies in children that were limited to 24-week duration. Pediatric-specific postmarketing studies evaluating long-term safety and efficacy are underway. Formation of colorectal polyps has been repeatedly observed in studies of adult patients on long-term teduglutide, including in individuals without endoscopic evidence of polyps before treatment initiation. Recent studies, however, suggest increased risk of small bowel hyperplastic and dysplastic polyp formation with long-term glucagon-like peptide 2 analog use. We report 2 cases of small bowel foveolar hyperplastic polyps found during surveillance endoscopies after 1 year of treatment with teduglutide.

C. difficile intoxicates neurons and pericytes to drive neurogenic inflammation.

Clostridioides difficile infection (CDI) is a major cause of healthcare-associated gastrointestinal infections1,2. The exaggerated colonic inflammation caused by C. difficile toxins such as toxin B (TcdB) damages tissues and promotes C. difficile colonization3-6, but how TcdB causes inflammation is unclear. Here we report that TcdB induces neurogenic inflammation by targeting gut-innervating afferent neurons and pericytes through receptors, including the Frizzled receptors (FZD1, FZD2 and FZD7) in neurons and chondroitin sulfate proteoglycan 4 (CSPG4) in pericytes. TcdB stimulates the secretion of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) from neurons and pro-inflammatory cytokines from pericytes. Targeted delivery of the TcdB enzymatic domain, through fusion with a detoxified diphtheria toxin, into peptidergic sensory neurons that express exogeneous diphtheria toxin receptor (an approach we term toxogenetics) is sufficient to induce neurogenic inflammation and recapitulates major colonic histopathology associated with CDI. Conversely, mice lacking SP, CGRP or the SP receptor (neurokinin 1 receptor) show reduced pathology in both models of caecal TcdB injection and CDI. Blocking SP or CGRP signalling reduces tissue damage and C. difficile burden in mice infected with a standard C. difficile strain or with hypervirulent strains expressing the TcdB2 variant. Thus, targeting neurogenic inflammation provides a host-oriented therapeutic approach for treating CDI.

Pediatric Colonic Xanthomas, a Previously Unreported Colonoscopic Finding.

Gastrointestinal xanthomas are benign, usually sessile, polypoid lesions occasionally incidentally seen in adults, usually in the stomach, but have not been reported in the large intestine in children. We identified xanthomas in the sigmoid colon of the 15-year-old girl confirmed histologically. Our findings suggest that colonic xanthomas may occur as an incidental finding in pediatric patients. They have a characteristic visual and histologic appearance but do not appear to be associated with any symptoms or illness and do not require follow-up.

Patient-derived enteroids provide a platform for the development of therapeutic approaches in microvillus inclusion disease.

Microvillus inclusion disease (MVID), caused by loss-of-function mutations in the motor protein myosin Vb (MYO5B), is a severe infantile disease characterized by diarrhea, malabsorption, and acid/base instability, requiring intensive parenteral support for nutritional and fluid management. Human patient-derived enteroids represent a model for investigation of monogenic epithelial disorders but are a rare resource from MVID patients. We developed human enteroids with different loss-of function MYO5B variants and showed that they recapitulated the structural changes found in native MVID enterocytes. Multiplex immunofluorescence imaging of patient duodenal tissues revealed patient-specific changes in localization of brush border transporters. Functional analysis of electrolyte transport revealed profound loss of Na+/H+ exchange (NHE) activity in MVID patient enteroids with near-normal chloride secretion. The chloride channel-blocking antidiarrheal drug crofelemer dose-dependently inhibited agonist-mediated fluid secretion. MVID enteroids exhibited altered differentiation and maturation versus healthy enteroids. γ-Secretase inhibition with DAPT recovered apical brush border structure and functional Na+/H+ exchange activity in MVID enteroids. Transcriptomic analysis revealed potential pathways involved in the rescue of MVID cells including serum/glucocorticoid-regulated kinase 2 (SGK2) and NHE regulatory factor 3 (NHERF3). These results demonstrate the utility of patient-derived enteroids for developing therapeutic approaches to MVID.

Gastric Intestinal Metaplasia in Children: Natural History and Clinicopathological Correlation.

INTRODUCTION: Gastric intestinal metaplasia (GIM) is defined as the replacement of the normal gastric epithelium by intestinal-type epithelium. GIM is considered a preneoplastic lesion for gastric adenocarcinoma in adults and is found in 25% of Helicobacter pylori ( H pylori ) exposed adults. However, the significance of GIM in pediatric gastric biopsies is still unknown. METHODS: We conducted a retrospective study of children with GIM on gastric biopsies at Boston Children's Hospital between January 2013 and July 2019. Demographic, clinical, endoscopic, and histologic data were collected and compared to age and sex-matched cohort without GIM. Gastric biopsies were reviewed by the study pathologist. GIM was classified as complete/incomplete based on Paneth cell presence or absence and limited/extensive based on its distribution in the antrum or both antrum and corpus. RESULTS: Of 38 patients with GIM, 18 were male (47%), mean age of detection was 12.5 ± 5.05 years (range, 1-18 years). The most common histologic was chronic gastritis (47%). Complete GIM was present in 50% (19/38) and limited GIM was present in 92% (22/24). H pylori was positive in 2 patients. Two patients had persistent GIM on repeat esophagogastroduodenoscopy (2/12). No dysplasia or carcinoma was identified. Proton-pump inhibitor use and chronic gastritis were more common in GIM patients compared to control ( P = 0.02). CONCLUSION: Most children with GIM had low-risk histologic subtype (complete/limited) for gastric cancer; GIM was rarely associated with H pylori gastritis in our cohort. Larger multicenter studies are needed to better understand outcomes and risk factors in children with GIM.

WNT2B Deficiency Causes Increased Susceptibility to Colitis in Mice and Impairs Intestinal Epithelial Development in Humans.

Background and aims: WNT2B is a canonical Wnt ligand previously thought to be fully redundant with other Wnts in the intestinal epithelium. However, humans with WNT2B deficiency have severe intestinal disease, highlighting a critical role for WNT2B. We sought to understand how WNT2B contributes to intestinal homeostasis. Methods: We investigated the intestinal health of Wnt2b knock out (KO) mice. We assessed the impact of inflammatory challenge to the small intestine, using anti-CD3χ antibody, and to the colon, using dextran sodium sulfate (DSS). In addition, we generated human intestinal organoids (HIOs) from WNT2B-deficient human iPSCs for transcriptional and histological analyses. Results: Mice with WNT2B deficiency had significantly decreased Lgr5 expression in the small intestine and profoundly decreased expression in the colon, but normal baseline histology. The small intestinal response to anti-CD3χ antibody was similar in Wnt2b KO and wild type (WT) mice. In contrast, the colonic response to DSS in Wnt2b KO mice showed an accelerated rate of injury, featuring earlier immune cell infiltration and loss of differentiated epithelium compared to WT. WNT2B-deficient HIOs showed abnormal epithelial organization and an increased mesenchymal gene signature. Conclusion: WNT2B contributes to maintenance of the intestinal stem cell pool in mice and humans. WNT2B deficient mice, which do not have a developmental phenotype, show increased susceptibility to colonic injury but not small intestinal injury, potentially due to a higher reliance on WNT2B in the colon compared to the small intestine.WNT2B deficiency causes a developmental phenotype in human intestine with HIOs showing a decrease in their mesenchymal component and WNT2B-deficient patients showing epithelial disorganization. Data Transparency Statement: All RNA-Seq data will be available through online repository as indicated in Transcript profiling. Any other data will be made available upon request by emailing the study authors.

Therapy Development for Microvillus Inclusion Disease using Patient-derived Enteroids.

Microvillus Inclusion Disease (MVID), caused by loss-of-function mutations in the motor protein Myosin Vb (MYO5B), is a severe infantile disease characterized by diarrhea, malabsorption, and acid-base instability, requiring intensive parenteral support for nutritional and fluid management. Human patient-derived enteroids represent a model for investigation of monogenic epithelial disorders but are a rare resource from MVID patients. We developed human enteroids with different loss-of function MYO5B variants and showed that they recapitulated the structural changes found in native MVID enterocytes. Multiplex Immunofluorescence imaging of patient duodenal tissues revealed patient-specific changes in localization of brush border transporters. Functional analysis of electrolyte transport revealed profound loss of Na + /H + exchange (NHE) activity in MVID patient enteroids with near-normal chloride secretion. The chloride channel-blocking anti-diarrheal drug, Crofelemer, dose-dependently inhibited agonist-mediated fluid secretion. MVID enteroids exhibited altered differentiation and maturation versus healthy enteroids. Inhibition of Notch signaling with the γ-secretase inhibitor, DAPT, recovered apical brush border structure and functional Na + /H + exchange activity in MVID enteroids. Transcriptomic analysis revealed potential pathways involved in the rescue of MVID cells including serum- and glucocorticoid-induced protein kinase 2 (SGK2), and NHE regulatory factor 3 (NHERF3). These results demonstrate the utility of patient-derived enteroids for developing therapeutic approaches to MVID. Conflict-of-interest statement: The authors have declared that no conflict of interest exists.

Factors Associated With Chronic Intestinal Inflammation Resembling Inflammatory Bowel Disease in Pediatric Intestinal Failure: A Matched Case-Control Study.

BACKGROUND AND AIMS: There is a subset of intestinal failure patients with associated chronic intestinal inflammation resembling inflammatory bowel disease. This study aimed to evaluate factors associated with chronic intestinal inflammation in pediatric intestinal failure. METHODS: This was a single-center retrospective case-control study of children <18 years old with intestinal failure. Cases were defined by abnormal amounts of chronic intestinal inflammation on biopsies. Children with diversion colitis, eosinophilic colitis, or isolated anastomotic ulceration were excluded. Cases were matched 1:2 to intestinal failure controls based on sex, etiology of intestinal failure, and duration of intestinal failure. Multivariable conditional logistic regression was used to compare clinical factors between cases and controls, accounting for clustering within matched sets. A subgroup analysis was performed assessing factors associated with escalation of anti-inflammatory therapy. RESULTS: Thirty cases were identified and matched to 60 controls. On univariate analysis, longer parenteral nutrition (PN) duration (1677 vs 834 days, P = 0.03), current PN use (33.3% vs 20.0%, P = 0.037), and culture-proven bacterial overgrowth (53.3% vs 31.7%, P = 0.05) were associated with chronic intestinal inflammation. On multivariable analysis, no variable reached statistical significance. On subgroup analysis, duration of intestinal failure, location of inflammation, and worst degree of inflammation on histology were associated with escalation of therapy. CONCLUSIONS: PN dependence and intestinal dysbiosis are associated with chronic intestinal inflammation in children with intestinal failure. Severity of inflammation is associated with escalation of therapy. Further analysis is needed to assess these associations and the efficacy of treatments in this population.

A 72-Year-Old Woman with Fatigue and Shortness of Breath.

A 72-Year-Old Woman with Fatigue and Shortness of BreathA 72-year-old woman presented for evaluation of fatigue, dyspnea on exertion, and weight loss. How do you approach the evaluation, and what is the most likely diagnosis?

Serrated Polyposis Syndrome in a Young Adolescent Patient.

Serrated polyps are pathological neoplastic lesions in the colon with subtle gross morphology leading to underreporting during colonoscopy. While detection rates are increasing in average-risk adult screening colonoscopy, the rate of detection during pediatric colonoscopy is unknown. Serrated polyposis syndrome is characterized by the presence of multiple serrated polyps in the colon and an increased risk of developing colorectal cancer. Cancer prevention relies on early recognition, endoscopic clearance of all polyps > 5 mm, and continued interval surveillance or prophylactic colectomy. We report the diagnosis and management of serrated polyposis syndrome in a young adolescent patient and highlight the subtle features of serrated polyps that may go unrecognized leading to underreporting in childhood.

Pediatric Gastrointestinal Histopathology in Patients With Tetratricopeptide Repeat Domain 7A (TTC7A) Germline Mutations: A Rare Condition Leading to Multiple Intestinal Atresias, Severe Combined Immunodeficiency, and Congenital Enteropathy.

Mutations in the tetratricopeptide repeat domain 7A (TTC7A) gene are a rare cause of congenital enteropathy that can result in significant morbidity. TTC7A deficiency leads to disruption of the intestinal epithelium. The histopathology of this condition has been partly described in case reports and clinical studies. This manuscript describes an in-depth investigation of the pediatric gastrointestinal pathology of the largest histologically examined cohort with confirmed TTC7A mutations reported to date and, for the first time, compared the findings to age-matched and sex-matched control patients with intestinal atresia not thought to be associated with TTC7A mutations. Hematoxylin and eosin-stained slides of endoscopically obtained mucosal biopsies and surgical resection specimens from 7 patients with known TTC7A mutations were examined retrospectively. The microscopic findings were found to be on a spectrum from atresia-predominant to those with predominantly epithelial abnormalities. Several unique histopathologic characteristics were observed when compared with controls. These included neutrophilic colitis and prominent lamina propria eosinophilia throughout the gastrointestinal tract. Striking architectural abnormalities of the epithelium were observed in 4 of the 7 patients. The 5 patients with intestinal atresia demonstrated hypertrophy and disorganization of the colonic muscularis mucosae accompanied by bland spindle cell nodules within the intestinal wall. The components of the latter were further elucidated using immunohistochemistry, and we subsequently hypothesize that they represent obliterated mucosa with remnants of the muscularis mucosae. Finally, atrophic gastritis was noted in 4 patients. In conclusion, the unique histopathologic characteristics of TTC7A mutation-associated enteropathy described herein more fully describe this novel disease entity in infants who present with congenital enteropathy or enterocolitis.

Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor 𝛋B kinase alpha (IKKα).

Inhibitor of nuclear factor kappa B kinase alpha (IKKα) is critical for p100/NF-κB2 phosphorylation and processing into p52 and activation of the noncanonical NF-κB pathway. A patient with recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine and liver was found to have a homozygous p.Y580C mutation in the helix-loop-helix domain of IKKα. The mutation preserves IKKα kinase activity but abolishes the interaction of IKKα with its activator NF-κB­inducing kinase and impairs lymphotoxin-ß­driven p100/NF-κB2 processing and VCAM1 expression. Homozygous IKKαY580C/Y580C mutant mice phenocopy the patient findings; lack marginal zone B cells, germinal centers, and antigen-specific T cell response to cutaneous immunization; have impaired Il17a expression; and are susceptible to cutaneous Staphylococcus aureus infection. In addition, these mice demonstrate a severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, a restricted TCRVß repertoire, a selective expansion of potentially autoreactive T cell clones, a decreased frequency of regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells coinciding with organ damage. Hence, this study identifies IKKα deficiency as a previously undescribed cause of primary immunodeficiency with associated autoimmunity.