ABSTRACT
BACKGROUND: Protein-losing enteropathy (PLE) is a severe complication of the Fontan circulation. There is increasing discussion about whether lymphatic dysregulation is involved as pathomechanism of PLE. This investigation focuses on the interplay between alteration of lymphatic cells and immunologic pathway alterations. METHODS: Micro-ribonucleic acid (miRNA) expression profiling was performed in 49 patients (n = 10 Fontan patients with PLE, n = 30 Fontan patients without PLE, and n = 9 patients with dextro-transposition of the great arteries (dTGA). miRNA pathway analysis was performed to identify significantly enriched pathways. To determine lymphocyte populations and subtypes multiparameter flow cytometry was used. RESULTS: miRNAs pathway analysis of Fontan patients with PLE revealed 20 significantly changed networks of which four of the ten largest were associated with immunologic processes. This finding is supported by significant T cell deficiency with decreased CD4+ count (p = 0.0002), altered CD4 +/CD8+ ratio, and significantly modified CD4+ (p < 0.0001) and CD8+ (p = 0.0002) T cell differentiation toward effector and terminal differentiated T cells in Fontan patients with PLE. Analyses of CD4+ T cell subsets demonstrated significantly increased frequencies of CD4+ CD25+ CD127- regulatory T cells (Treg) in Fontan patients with PLE (p = 0.0011). CONCLUSION: PLE in Fontan patients is associated with severe lymphopenia, T cell deficiency, significant alterations of T cell differentiation, and increased Treg frequency reflecting an immune status of chronic inflammation and shortened protection against pathogens and autoimmunity. These cellular alterations seemed to be dysregulated by several miRNA controlled immunological pathways.
Subject(s)
Cell Differentiation , Fontan Procedure/adverse effects , Heart Defects, Congenital/surgery , Lymphopenia/immunology , Protein-Losing Enteropathies/immunology , T-Lymphocyte Subsets/immunology , Adolescent , Animals , Autoimmunity , Case-Control Studies , Child , Child, Preschool , Databases, Factual , Female , Gene Expression Profiling , Gene Regulatory Networks , Humans , Immunophenotyping , Infant , Lymphopenia/diagnosis , Lymphopenia/genetics , Lymphopenia/microbiology , Male , Mice , MicroRNAs/genetics , Phenotype , Protein-Losing Enteropathies/diagnosis , Protein-Losing Enteropathies/genetics , Transcriptome , Treatment Outcome , Young AdultABSTRACT
Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Complement Activation/drug effects , Complement C5/antagonists & inhibitors , Complement Inactivating Agents/therapeutic use , Energy Metabolism/drug effects , Hypoproteinemia/drug therapy , Immunity, Innate/drug effects , Protein-Losing Enteropathies/drug therapy , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Biomarkers/blood , CD55 Antigens/deficiency , CD55 Antigens/genetics , Complement C5/metabolism , Complement Inactivating Agents/adverse effects , Complement Inactivating Agents/pharmacokinetics , Genetic Predisposition to Disease , Humans , Hypoproteinemia/genetics , Hypoproteinemia/immunology , Hypoproteinemia/metabolism , Mutation , Phenotype , Protein-Losing Enteropathies/genetics , Protein-Losing Enteropathies/immunology , Protein-Losing Enteropathies/metabolism , Treatment OutcomeABSTRACT
A 24-year-old woman with a medical history of chronic lower extremity oedema, abdominal pain, diarrhoea and recurrent pulmonary infections presented with sepsis from right lower extremity cellulitis. Blood cultures grew Morganella morganii Laboratory evaluation revealed lymphopaenia, hypogammaglobulinaemia, a low CD4+ T-cell count and nutritional deficiencies resulting from protein-losing enteropathy (PLE). CT showed small bowel wall thickening in the jejunum and ileum. Primary intestinal lymphangiectasia (PIL) was the likely diagnosis that explained her PLE and immunodeficiencies. Video capsule endoscopy is an important diagnostic tool for distal small bowel pathology and confirmed patchy areas of lymphangiectasia of the jejunum and ileum. Secondary causes of lymphangiectasia were ruled out. Clinically significant immunodeficiency from PIL has not been frequently documented, and this case adds to the literature of rare infections associated with PIL. Treatment with intravenous antibiotics resolved her septicaemia, while dietary modifications improved her oedema, abdominal pain and diarrhoea.
Subject(s)
Agammaglobulinemia/immunology , Bacteremia/immunology , Enterobacteriaceae Infections/immunology , Lymphangiectasis, Intestinal/diagnosis , Morganella morganii/isolation & purification , Protein-Losing Enteropathies/immunology , Administration, Intravenous , Agammaglobulinemia/blood , Agammaglobulinemia/diagnosis , Anti-Bacterial Agents/administration & dosage , Bacteremia/diagnosis , Bacteremia/drug therapy , Bacteremia/microbiology , Biopsy , CD4 Lymphocyte Count , Capsule Endoscopy , Enterobacteriaceae Infections/diagnosis , Enterobacteriaceae Infections/drug therapy , Enterobacteriaceae Infections/microbiology , Female , Humans , Ileum/diagnostic imaging , Ileum/pathology , Immunoglobulin A/blood , Immunoglobulin A/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , Jejunum/diagnostic imaging , Jejunum/pathology , Lymphangiectasis, Intestinal/blood , Lymphangiectasis, Intestinal/complications , Lymphangiectasis, Intestinal/immunology , Morganella morganii/immunology , Protein-Losing Enteropathies/blood , Protein-Losing Enteropathies/diagnosis , Tomography, X-Ray Computed , Young AdultSubject(s)
Intestinal Mucosa/metabolism , Protein-Losing Enteropathies/etiology , Undifferentiated Connective Tissue Diseases/complications , Vascular Endothelial Growth Factor A/metabolism , Biopsy , Female , Fluorescent Antibody Technique , Glucocorticoids/therapeutic use , Humans , Immunosuppressive Agents/therapeutic use , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Middle Aged , Protein-Losing Enteropathies/drug therapy , Protein-Losing Enteropathies/immunology , Protein-Losing Enteropathies/metabolism , Treatment Outcome , Undifferentiated Connective Tissue Diseases/drug therapy , Undifferentiated Connective Tissue Diseases/immunology , Undifferentiated Connective Tissue Diseases/metabolism , Up-RegulationSubject(s)
Adalimumab/adverse effects , Biological Products/adverse effects , Duodenal Ulcer/microbiology , Duodenum/microbiology , Histoplasmosis/microbiology , Ileum/microbiology , Immunocompromised Host , Protein-Losing Enteropathies/microbiology , Psoriasis/drug therapy , Adult , Antifungal Agents/therapeutic use , Biopsy , Duodenal Ulcer/diagnosis , Duodenal Ulcer/drug therapy , Duodenum/diagnostic imaging , Duodenum/drug effects , Endoscopy, Gastrointestinal , Histoplasmosis/diagnosis , Histoplasmosis/drug therapy , Histoplasmosis/immunology , Humans , Ileum/diagnostic imaging , Ileum/drug effects , Male , Protein-Losing Enteropathies/diagnosis , Protein-Losing Enteropathies/drug therapy , Protein-Losing Enteropathies/immunology , Psoriasis/diagnosis , Psoriasis/immunology , Tomography, X-Ray Computed , Treatment Outcome , Wound HealingABSTRACT
OBJECTIVE: To comprehensively characterize the immunologic characteristics of patients with protein-losing enteropathy (PLE) post-Fontan and compare them with patients without PLE post-Fontan. STUDY DESIGN: Patients with PLE post-Fontan and age-matched controls post-Fontan were prospectively studied with laboratory markers of immune function. Infectious history was obtained by interview and chart review. The groups' demographics, cardiac history, immune characteristics, and infection history were compared using appropriate 2-group statistics. RESULTS: A total of 16 patients enrolled (8 patients with PLE and 8 controls). All patients with PLE had lymphopenia compared with 25% of controls (P = .01). All patients with PLE had markedly depressed CD4 T cell counts (median 58 cells/µL) compared with controls (median 450 cells/µL, P = .0002); CD4% was also low in the PLE group (12.3%) and normal in control (36.9%, P = .004). Both groups had mildly depressed CD8 T cells and normal to slightly elevated natural killer and B-cell subsets. A majority of patients with PLE (62.5%) had negative titers to measles, mumps, and rubella vaccination, compared with no control Fontan with a negative titer (P = .03). Despite profoundly low CD4 counts, the frequency of infection was not different between groups with no reported opportunistic infections. CONCLUSIONS: Patients with Fontan-associated PLE have extensive quantitative immune abnormalities, particularly CD4 deficiency. These immune abnormalities are similar to those found in non-Fontan patients with PLE caused by intestinal lymphangiectasia.
Subject(s)
CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Fontan Procedure/adverse effects , Heart Defects, Congenital/surgery , Lymphopenia/epidemiology , Protein-Losing Enteropathies/immunology , CD4 Lymphocyte Count , Case-Control Studies , Child , Child, Preschool , Female , Heart Defects, Congenital/blood , Heart Defects, Congenital/immunology , Humans , Immunoglobulin Isotypes/blood , Infant , Male , Prospective Studies , Protein-Losing Enteropathies/bloodABSTRACT
The syndrome of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) is a rare disorder caused by mutations in the FOXP3 gene. Diarrhea, diabetes and dermatitis are the hallmark of the disease, with a typical onset within the first months of life. We describe the case of a twelve-year old male affected by a very late-onset IPEX with intractable enteropathy, which markedly improved after starting Sirolimus as second-line treatment. This case suggests that IPEX should always be considered in the differential diagnosis of watery intractable diarrhea, despite its unusual onset.
Subject(s)
Diarrhea/etiology , Genetic Diseases, X-Linked/complications , Polyendocrinopathies, Autoimmune/complications , Protein-Losing Enteropathies/complications , T-Lymphocytes, Regulatory/immunology , Child , Diarrhea/immunology , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/immunology , Humans , Male , Mutation , Polyendocrinopathies, Autoimmune/genetics , Polyendocrinopathies, Autoimmune/immunology , Protein-Losing Enteropathies/genetics , Protein-Losing Enteropathies/immunology , SyndromeABSTRACT
A 28-year-old woman previously diagnosed to have Down syndrome presented with a one-month history of severe hypoalbuminemia, lower extremity edema, and diarrhea. Her urine was negative for protein. She was diagnosed with immune-mediated protein-losing enteropathy (PLE) based on clinical findings, protein loss evident on (99m)Technetium-labeled human serum albumin scintigraphy, and IgM and complement C3 deposition in the duodenum. She did not exhibit any manifestations of collagen diseases. A dramatic remission was achieved and maintained with corticosteroid administration. This is the first report of immune-mediated PLE in a patient with Down syndrome.
Subject(s)
Down Syndrome/complications , Protein-Losing Enteropathies/diagnosis , Protein-Losing Enteropathies/immunology , Adult , Diarrhea/etiology , Edema/etiology , Female , Glucocorticoids/therapeutic use , Humans , Hypoalbuminemia/etiology , Prednisolone/therapeutic use , Protein-Losing Enteropathies/drug therapyABSTRACT
OBJECTIVE: To estimate the prevalence of perinuclear antineutrophilic cytoplasmic autoantibodies (pANCA) in the serum of healthy Soft Coated Wheaten Terriers (SCWTs) in the United Kingdom and to identify potential risk factors and heritability patterns associated with a positive result for pANCA. ANIMALS: 188 SCWTs (age range, 18 months to 14.3 years). PROCEDURES: Blood samples were obtained from SCWTs in various locations in England. Serum was tested for pANCA by use of an immunofluorescence assay, and total protein and albumin concentrations were determined. Pedigrees were evaluated to identify close relatives that had protein-losing enteropathy (PLE) or protein-losing nephropathy (PLN). RESULTS: 39 of 188 (20.7%) dogs, including young dogs, had positive results for pANCA. Dogs had significantly higher odds of having positive results for pANCA if they had at least 1 littermate that had PLE or PLN (odds ratio, 12.1) or if they had at least 1 full sibling from another litter known to be affected with PLE or PLN (odds ratio, 4.0). CONCLUSIONS AND CLINICAL RELEVANCE; This study revealed a high prevalence of pANCA in the serum of a representative sample of healthy SCWTs in the United Kingdom and a significant association between positive results for pANCA and a diagnosis of PLE or PLN in a sibling.
Subject(s)
Antibodies, Antineutrophil Cytoplasmic/blood , Autoantibodies/blood , Dog Diseases/immunology , Kidney Diseases/veterinary , Protein-Losing Enteropathies/veterinary , Animals , Dog Diseases/blood , Dog Diseases/epidemiology , Dogs , England , Female , Fluorescent Antibody Technique, Indirect/veterinary , Kidney Diseases/complications , Kidney Diseases/epidemiology , Kidney Diseases/immunology , Male , Pedigree , Prevalence , Protein-Losing Enteropathies/complications , Protein-Losing Enteropathies/epidemiology , Protein-Losing Enteropathies/immunology , Risk FactorsABSTRACT
We first report a case of protein losing enteropathy in severe atopic dermatitis in an exclusively breast-fed 5-month-old infant. Protein losing enteropathy was confirmed by fecal alpha1-antitrypsin clearance test and imaged successfully by 99mTc-human serum albumin scintigraphy. The present case highlights that protein losing enteropathy in severe infantile atopic dermatitis is being a topic of concern and also an issue even in exclusive breast feeding patients.
Subject(s)
Breast Feeding/adverse effects , Dermatitis, Atopic/complications , Protein-Losing Enteropathies/complications , Dermatitis, Atopic/diagnosis , Dermatitis, Atopic/immunology , Humans , Infant , Infant Formula , Male , Protein-Losing Enteropathies/diagnosis , Protein-Losing Enteropathies/immunology , Severity of Illness IndexABSTRACT
Several studies have suggested that T cell-producing permeability factors might lead to proteinuria in minimal change nephrotic syndrome (MCNS). However, it is still unclear whether T-cell abnormalities cause MCNS. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder of the immune regulation system, which leads to severe autoimmune phenomena including autoimmune enteropathy, atopic dermatitis with high levels of serum immunoglobulin E (IgE), type 1 diabetes mellitus (T1DM), and severe infection such as sepsis, which frequently result in death within the first 2 years of life. This disease is caused by mutations in the FOXP3 gene that result in the defective development of regulatory T (Treg) cells. This report describes a 5-year-old boy with IPEX syndrome with a 3 bp deletion in the FOXP3 gene (c.748-750delAAG, p.250K.del) and a paucity of CD4(+) CD25(+) FOXP3(+) T cells. The boy's condition was complicated by MCNS in addition to many IPEX-related manifestations, such as atopic dermatitis, T1DM, enteropathy, sepsis and hemolytic anemia. This is the first report of IPEX syndrome complicated by MCNS, and our findings imply that Treg cell dysfunction may be crucial for the development of MCNS.
Subject(s)
Genetic Diseases, X-Linked , Nephrotic Syndrome/complications , Polyendocrinopathies, Autoimmune , Protein-Losing Enteropathies , CD4-Positive T-Lymphocytes/metabolism , Child, Preschool , Cyclosporine/therapeutic use , DNA/genetics , DNA/isolation & purification , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/immunology , Gene Deletion , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/immunology , Humans , Immunosuppressive Agents/therapeutic use , Interleukin-2 Receptor alpha Subunit/metabolism , Male , Methylprednisolone/therapeutic use , Nephrotic Syndrome/prevention & control , Polyendocrinopathies, Autoimmune/genetics , Polyendocrinopathies, Autoimmune/immunology , Protein-Losing Enteropathies/genetics , Protein-Losing Enteropathies/immunology , Secondary Prevention , Sequence Analysis, DNA , T-Lymphocytes, Regulatory/immunology , Treatment OutcomeABSTRACT
Protein-losing gastroenteropathy (PLGE) is a rare manifestation of primary Sjögren's syndrome (SS). We report a case of a 41-year-old Japanese man, who is the first male patient, with PLGE associated with primary SS. Although serum anti-SSA and SSB antibodies were detected, he had no subjective sicca symptoms. He had multiple annular erythema: a characteristic skin manifestation of Asian SS patients. A diagnosis of PLGE was made from results of (99m)Tc-labelled albumin scintigraphy and a faecal alpha-1-antitrypsin clearance test. Intravenous administration of high-dose glucocorticoid was not effective, but pulse methylprednisolone therapy alleviated disease manifestations. As all cases of PLGE associated with primary SS have been reported from East Asia, this complication could be essentially limited to Asian patients.
Subject(s)
Gastrointestinal Tract/immunology , Gastrointestinal Tract/physiopathology , Protein-Losing Enteropathies/immunology , Protein-Losing Enteropathies/physiopathology , Sjogren's Syndrome/complications , Adult , Albumins/metabolism , Asian People/ethnology , Erythema/ethnology , Erythema/immunology , Erythema/physiopathology , Gastrointestinal Tract/diagnostic imaging , Humans , Japan , Male , Metabolic Clearance Rate , Methylprednisolone/therapeutic use , Protein-Losing Enteropathies/ethnology , Racial Groups , Radionuclide Imaging , Sjogren's Syndrome/ethnology , Sjogren's Syndrome/immunology , Treatment Outcome , alpha 1-Antitrypsin/metabolismABSTRACT
OBJECTIVE: To evaluate perinuclear anti-neutrophilic cytoplasmic autoantibody (pANCA) status in Soft Coated Wheaten Terriers (SCWTs) and SCWT-Beagle crossbred dogs and to correlate pANCA status of dogs with clinicopathologic variables of protein-losing enteropathy (PLE), protein-losing nephropathy (PLN), or both. ANIMALS: 13 SCWTs and 8 SCWT-Beagle crossbred dogs in a research colony and a control group comprising 7 dogs with X-linked hereditary nephropathy and 12 healthy SCWTs > 9 years old. PROCEDURES: Samples were obtained from dogs in the research colony every 6 months. At each sample-collection time point, serum concentrations of albumin, globulin, creatinine, and urea nitrogen; fecal concentration of alpha-proteinase inhibitor; and urinary protein-to-creatinine ratios were determined and correlated with pANCA status. RESULTS: 20 of 21 dogs in the research colony had positive results for pANCAs at a minimum of 2 time points, and 18 of 21 dogs had definitive evidence of disease. None of the control dogs had positive results for pANCAs. A positive result for pANCAs was significantly associated with hypoalbuminemia, and pANCAs preceded the onset of hypoalbuminemia on an average of 2.4 years. Sensitivity and specificity for use of pANCAs to predict development of PLE or PLN were 0.95 (95% confidence interval, 0.72 to 1.00) and 0.8 (95% confidence interval, 0.51 to 0.95), respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Most dogs in this study affected with PLE, PLN, or both had positive results for pANCAs before clinicopathologic evidence of disease was detected. Thus, pANCAs may be useful as an early noninvasive test of disease in SCWTs.
Subject(s)
Antibodies, Antineutrophil Cytoplasmic/blood , Autoantibodies/blood , Dog Diseases/immunology , Kidney Diseases/veterinary , Protein-Losing Enteropathies/veterinary , Animals , Dog Diseases/blood , Dogs , Kidney Diseases/etiology , Kidney Diseases/immunology , Protein-Losing Enteropathies/complications , Protein-Losing Enteropathies/immunology , Species SpecificityABSTRACT
Type 1 diabetes (T1D) is associated with autoimmune thyroid disease (AIT), celiac disease (CD), Addison's disease (AD), and other autoimmune diseases. These diseases can occur simultaneously in defined syndromes with distinct pathophysiology and characteristics: autoimmune polyendocrine syndromes (APSs) and the immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX). APSs were initially defined as a multiple endocrine gland insufficiency associated to an autoimmune disease in a patient. APS-1 is characterized by the evidence of chronic candidiasis, chronic hypoparathyroidism, AD and T1D could be present as part of this syndrome. The combination of autoimmune adrenal insufficiency with AIT and/or type 1 autoimmune diabetes mellitus defines APS-2. AIT associated to other autoimmune diseases (excluding AD and/or hypoparathyroidism) are the main characteristics of APS-3. Different clinical combinations of autoimmune diseases which were not included in the previous groups are the characteristics of APS-4. IPEX is a recessive disorder characterized by the neonatal onset of T1D, infections, enteropathy, thrombocytopenia and anemia, as well as endocrinopathy, eczema and cachexia. These disorders are not common, but their consequences can be life threatening when the diagnosis is overlooked, and the treatment is the same prescribed for isolated disease presentation.
Subject(s)
Diabetes Mellitus, Type 1/complications , Polyendocrinopathies, Autoimmune/complications , Addison Disease/complications , Addison Disease/immunology , Adult , Celiac Disease/complications , Celiac Disease/immunology , Chronic Disease , Diabetes Mellitus, Type 1/immunology , Female , Genetic Diseases, X-Linked/complications , Genetic Diseases, X-Linked/immunology , Humans , Male , Polyendocrinopathies, Autoimmune/immunology , Protein-Losing Enteropathies/complications , Protein-Losing Enteropathies/immunology , SyndromeABSTRACT
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome is a rare X-linked disorder that usually presents in early childhood with immune enteropathy, diabetes mellitus, and other autoimmune complications. The disease is caused by mutations in the forkhead box P3 gene, a transcription factor that is essential for the development and function of regulatory T cells. This population of cells plays an essential role in controlling immune responses and preventing autoimmunity. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome is often initially treated with immunosuppressive drugs, but only allogeneic hematopoietic stem cell transplantation has offered the possibility of cure. We recently performed an unrelated donor transplant in a child with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome by using a reduced-intensity conditioning regimen. This transplant provided a rare opportunity to gain valuable insight into the regeneration of the immune system after transplantation. Clinical recovery was associated with the emergence of regulatory T cell populations, the majority of which expressed memory phenotype markers and raised important questions about the origin and longevity of the FOXP3(+) regulatory T cell pool.
Subject(s)
Forkhead Transcription Factors/metabolism , Genetic Diseases, X-Linked/therapy , Peripheral Blood Stem Cell Transplantation/methods , Polyendocrinopathies, Autoimmune/diagnosis , Polyendocrinopathies, Autoimmune/therapy , T-Lymphocytes, Regulatory/immunology , Follow-Up Studies , Forkhead Transcription Factors/genetics , Gene Expression , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/immunology , Graft Survival , Humans , Infant , Male , Polyendocrinopathies, Autoimmune/genetics , Polymerase Chain Reaction , Protein-Losing Enteropathies/genetics , Protein-Losing Enteropathies/immunology , Protein-Losing Enteropathies/therapy , Risk Assessment , Syndrome , T-Lymphocytes, Regulatory/metabolism , Transplantation, Homologous , Treatment OutcomeABSTRACT
Três entidades clínicas distintas, causadas por desarranjos genéticos, estão associadas a múltiplas desordens auto-imunes: síndrome linfoproliferativa auto-imune, poliendocrinopatias auto-imunes (APSs) e desregulação imune, poliendocrinopatia, enteropatia ligada ao X (IPEX). O diabetes melito auto-imune ou tipo 1 (DM1) pode estar presente nas APSs e na IPEX. A APS-1 caracteriza-se pela associação de candidíase crônica, hipoparatireoidismo e insuficiência adrenal auto-imune ou idiopática (doença de Addison), no entanto, o diabetes melito tipo 1 pode estar presente em até 12 por cento dos casos. A APS-2 inclui a doença de Addison (sempre presente), a doença tireoidiana auto-imune e o diabetes melito tipo 1, enquanto na APS-3 a doença tireoidiana se associa a outra doença imunológica, excluindo a insuficiência adrenal e o hipoparatireoidismo, e a APS-4 é composta por combinações diferentes das descritas anteriormente. Já a IPEX caracteriza-se por alteração rara da regulação auto-imune que resulta doenças auto-imunes de início precoce, envolvendo pâncreas, tireóide, intestino com diarréia secretora grave, eczema e anemia. O diagnóstico e o tratamento das doenças componentes das poliendocrinopatias e da IPEX são semelhantes ao da patologia na forma isolada.
Type 1 diabetes (T1D) is associated with autoimmune thyroid disease (AIT), celiac disease (CD), Addison's disease (AD), and other autoimmune diseases. These diseases can occur simultaneously in defined syndromes with distinct pathophysiology and characteristics: autoimmune polyendocrine syndromes (APSs) and the immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX). APSs were initially defined as a multiple endocrine gland insufficiency associated to an autoimmune disease in a patient. APS-1 is characterized by the evidence of chronic candidiasis, chronic hypoparathyroidism, AD and T1D could be present as part of this syndrome. The combination of autoimmune adrenal insufficiency with AIT and/or type 1 autoimmune diabetes mellitus defines APS-2. AIT associated to other autoimmune diseases (excluding AD and/or hypoparathyroidism) are the main characteristics of APS-3. Different clinical combinations of autoimmune diseases which were not included in the previous groups are the characteristics of APS-4. IPEX is a recessive disorder characterized by the neonatal onset of T1D, infections, enteropathy, thrombocytopenia and anemia, as well as endocrinopathy, eczema and cachexia. These disorders are not common, but their consequences can be life threatening when the diagnosis is overlooked, and the treatment is the same prescribed for isolated disease presentation.
Subject(s)
Adult , Female , Humans , Male , Diabetes Mellitus, Type 1/complications , Polyendocrinopathies, Autoimmune/complications , Addison Disease/complications , Addison Disease/immunology , Chronic Disease , Celiac Disease/complications , Celiac Disease/immunology , Diabetes Mellitus, Type 1/immunology , Genetic Diseases, X-Linked/complications , Genetic Diseases, X-Linked/immunology , Polyendocrinopathies, Autoimmune/immunology , Protein-Losing Enteropathies/complications , Protein-Losing Enteropathies/immunology , SyndromeABSTRACT
A 3-year-old boy developed transient protein-losing gastroenteropathy associated with cytomegalovirus (CMV) infection. Both IgG and IgM antibodies to CMV were positive in a serologic blood test. Upper gastrointestinal endoscopy showed multiple erosions throughout the body of the stomach, without enlarged gastric folds. Histological examination of the biopsy specimens indicated eosinophilic gastroenteritis and CMV infection. The patient had complete resolution without specific therapy for CMV in four weeks. An allergic reaction as well as CMV infection played important roles in the pathogenesis of this case.
Subject(s)
Antibodies, Viral/blood , Cytomegalovirus Infections/complications , Cytomegalovirus/immunology , Eosinophilia/complications , Food Hypersensitivity/complications , Gastroenteritis/complications , Immunocompetence , Protein-Losing Enteropathies/virology , Child, Preschool , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/pathology , Eosinophilia/immunology , Eosinophilia/pathology , Eosinophilia/virology , Food Hypersensitivity/immunology , Food Hypersensitivity/pathology , Gastroenteritis/immunology , Gastroenteritis/pathology , Gastroenteritis/virology , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Male , Protein-Losing Enteropathies/immunology , Protein-Losing Enteropathies/pathology , Stomach/immunology , Stomach/pathology , Stomach/virologyABSTRACT
Cow's milk protein enteropathy is a symptom complex that composed of severe diarrhoea and malnutrition. This disorder is caused by non-immunoglobulin E-mediated food allergy. Its clinical features and natural course have been explained in many reports, of different types of cow's milk and soy reactions. In the present article, we describe a newborn patient who presented with chronic diarrhoea and failure to thrive diagnosed as cow's milk protein enteropathy. The duodenal biopsy revealed granulomatous duodenitis which has not been described before. Her clinical and pathological findings responded well to cow's milk elimination. We suggest that food allergies should be considered in differential diagnosis of patients with chronic diarrhoea and failure to thrive.
Subject(s)
Diarrhea/immunology , Duodenitis/diagnosis , Enterocytes/pathology , Failure to Thrive/immunology , Milk Hypersensitivity/diet therapy , Milk Hypersensitivity/diagnosis , Protein-Losing Enteropathies/immunology , Animals , Biopsy , Cattle , Duodenitis/complications , Duodenitis/diet therapy , Duodenitis/pathology , Female , Humans , Infant, Newborn , Milk Hypersensitivity/complications , Protein-Losing Enteropathies/diet therapy , Protein-Losing Enteropathies/pathologyABSTRACT
IPEX syndrome is a rare, inherited condition characterized by immune dysfunction, polyendocrinopathy, enteropathy, and X-linked recessive inheritance. Patients typically present in infancy with severe diarrhea and failure to thrive. Most children die by 1 year of age without therapy. The diagnosis is established by genetic analysis, which often takes several weeks to complete and can sometimes delay crucial immunosuppressive treatment. We attempted to develop a screening tool that allows rapid identification of patients with IPEX syndrome using immunocytochemical staining of FOXP3+ cells in bowel biopsies. We found that 2 patients with classic IPEX syndrome due to protein-truncating mutations in FOXP3 had markedly decreased staining of FOXP3+ T cells in the lamina propria and lymphoid aggregates. One patient with a mild, late-onset presentation and a missense mutation in FOXP3 had intact staining of FOXP3+ cells. This screening test provides a valuable tool for diagnosing IPEX syndrome in extremely ill patients who may not tolerate a delay in therapeutic intervention.
Subject(s)
Forkhead Transcription Factors , Genetic Diseases, X-Linked/diagnosis , Genetic Testing , Polyendocrinopathies, Autoimmune/diagnosis , Protein-Losing Enteropathies/diagnosis , Case-Control Studies , Child , Child, Preschool , Endoscopy , Fatal Outcome , Follow-Up Studies , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Frameshift Mutation , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/immunology , Genetic Diseases, X-Linked/pathology , Genetic Diseases, X-Linked/surgery , Genetic Diseases, X-Linked/therapy , Humans , Immunohistochemistry , Immunosuppressive Agents/therapeutic use , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Intestine, Large/surgery , Male , Mucous Membrane/metabolism , Mucous Membrane/pathology , Mutation, Missense , Polyendocrinopathies, Autoimmune/genetics , Polyendocrinopathies, Autoimmune/immunology , Polyendocrinopathies, Autoimmune/pathology , Polyendocrinopathies, Autoimmune/surgery , Polyendocrinopathies, Autoimmune/therapy , Protein-Losing Enteropathies/genetics , Protein-Losing Enteropathies/immunology , Protein-Losing Enteropathies/pathology , Protein-Losing Enteropathies/surgery , Protein-Losing Enteropathies/therapy , Retrospective Studies , Sirolimus/therapeutic use , Syndrome , T-Lymphocytes/metabolism , Time Factors , Treatment OutcomeABSTRACT
The nonclassical MHC class-I molecule, FcRn, salvages both IgG and albumin from degradation. Here we introduce a mechanism-based kinetic model for human to quantify FcRn-mediated recycling of both ligands based on saturable kinetics and data from the literature using easily measurable plasma concentrations rather than unmeasurable endosomal concentrations. The FcRn-mediated fractional recycling rates of IgG and albumin were 142% and 44% of their fractional catabolic rates, respectively. Clearly, FcRn-mediated recycling is a major contributor to the high endogenous concentrations of these two important plasma proteins. While familial hypercatabolic hypoproteinemia is caused by complete FcRn deficiency, the hypercatabolic IgG deficiency of myotonic dystrophy could be explained, based on the kinetic analyses, by a normal number of FcRn with lowered affinity for IgG but normal affinity for albumin. A simulation study demonstrates that the plasma concentrations of IgG and albumin could be dynamically controlled by both FcRn-related and -unrelated parameters.