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Journal of Clinical Immunology May 2024A large proportion of Common variable immunodeficiency (CVID) patients has duodenal inflammation with increased intraepithelial lymphocytes (IEL) of unknown aetiology....
PURPOSE
A large proportion of Common variable immunodeficiency (CVID) patients has duodenal inflammation with increased intraepithelial lymphocytes (IEL) of unknown aetiology. The histologic similarities to celiac disease, lead to confusion regarding treatment (gluten-free diet) of these patients. We aimed to elucidate the role of epigenetic DNA methylation in the aetiology of duodenal inflammation in CVID and differentiate it from true celiac disease.
METHODS
DNA was isolated from snap-frozen pieces of duodenal biopsies and analysed for differences in genome-wide epigenetic DNA methylation between CVID patients with increased IEL (CVID_IEL; n = 5) without IEL (CVID_N; n = 3), celiac disease (n = 3) and healthy controls (n = 3).
RESULTS
The DNA methylation data of 5-methylcytosine in CpG sites separated CVID and celiac diseases from healthy controls. Differential methylation in promoters of genes were identified as potential novel mediators in CVID and celiac disease. There was limited overlap of methylation associated genes between CVID_IEL and Celiac disease. High frequency of differentially methylated CpG sites was detected in over 100 genes nearby transcription start site (TSS) in both CVID_IEL and celiac disease, compared to healthy controls. Differential methylation of genes involved in regulation of TNF/cytokine production were enriched in CVID_IEL, compared to healthy controls.
CONCLUSION
This is the first study to reveal a role of epigenetic DNA methylation in the etiology of duodenal inflammation of CVID patients, distinguishing CVID_IEL from celiac disease. We identified potential biomarkers and therapeutic targets within gene promotors and in high-frequency differentially methylated CpG regions proximal to TSS in both CVID_IEL and celiac disease.
Topics: Humans; DNA Methylation; Common Variable Immunodeficiency; Duodenum; Celiac Disease; Female; Male; Adult; Middle Aged; Epigenesis, Genetic; CpG Islands; Promoter Regions, Genetic; Intraepithelial Lymphocytes; Young Adult; Genome-Wide Association Study; 5-Methylcytosine
PubMed: 38780872
DOI: 10.1007/s10875-024-01726-5 -
Scientific Reports May 2024As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the...
As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the causal relationship between PBC and EHAIDs is unclear. The genome-wide association analyses provided 14 GWAS data for PBC and EHAIDs, and bidirectional, two-sample MR analyses were performed to examine the relationship between PBC and EHAIDs. The analysis using MR provides a strong and meaningful estimation of the bidirectional correlation between PBC and 7 EHAIDs: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, autoimmune hypothyroidism, inflammatory bowel disease and ulcerative colitis of its types. In addition, PBC increases the risk of autoimmune thyroid diseases such as autoimmune hyperthyroidism and Graves' disease, as well as multiple sclerosis and psoriasis. Additionally, PBC is identified as a risk factor for Crohn's disease and Celiac disease. Based on genetic evidence, there may be connections between PBC and specific EHAIDs: not all coexisting EHAIDs induce PBC, and vice versa. This underscores the significance of prioritizing PBC in clinical practice. Additionally, if any liver function abnormalities are observed during treatment or with EHAIDs, it is crucial to consider the possibility of comorbid PBC.
Topics: Humans; Liver Cirrhosis, Biliary; Autoimmune Diseases; Genome-Wide Association Study; Mendelian Randomization Analysis; Colitis, Ulcerative; Arthritis, Rheumatoid; Inflammatory Bowel Diseases; Sjogren's Syndrome; Lupus Erythematosus, Systemic; Genetic Predisposition to Disease; Celiac Disease; Graves Disease; Risk Factors; Crohn Disease; Scleroderma, Systemic; Multiple Sclerosis; Polymorphism, Single Nucleotide; Psoriasis
PubMed: 38773317
DOI: 10.1038/s41598-024-62509-x -
JCEM Case Reports May 2024We report a case of interstitial nephritis, likely secondary to oxalate nephropathy, due to the development of pancreatic exocrine dysfunction after commencement of...
We report a case of interstitial nephritis, likely secondary to oxalate nephropathy, due to the development of pancreatic exocrine dysfunction after commencement of pasireotide for acromegaly. Pasireotide is known to impair insulin secretion but can also impair pancreatic exocrine function, hypothezised to result from high-affinity binding of somatostatin receptors 1, 2, 3, and 5. This has been an advantage in postoperative tissue anastomoses after pancreatic surgery, but exocrine insufficiency has not been reported when used for the treatment of acromegaly. A 73-year-old woman, diagnosed with acromegaly, was unable to achieve biochemical control despite 2 surgical resections of an invasive mammosomatotroph pituitary tumor and treatment with cabergoline and maximal-dose lanreotide. The tumor expressed somatostatin receptor type 5 but not somatostatin receptor type 2, predicting good response from pasireotide, which was commenced at 40 mg every 4 weeks. IGF-1 rapidly normalized, but the patient presented with nausea, anorexia, and acute kidney injury. Renal biopsy revealed acute-on-chronic interstitial nephritis, with numerous oxalate crystals. Increased fecal fat globules were noted on fat stain (3+), supporting malabsorption as an etiology of secondary enteric hyperoxaluria. Renal function recovered to near baseline over months following pasireotide withdrawal and high-dose glucocorticoids.
PubMed: 38770226
DOI: 10.1210/jcemcr/luae071 -
Indian Journal of Pathology &... May 2024We report an unusual case of jejunal strongyloidiasis presenting as chronic malabsorption and intractable small bowel diarrhea in an immunocompetent adolescent boy who...
We report an unusual case of jejunal strongyloidiasis presenting as chronic malabsorption and intractable small bowel diarrhea in an immunocompetent adolescent boy who posed a diagnostic challenge for pathologists, radiologists, and gastroenterologists. Histopathology revealed chronic active colitis and was consistent with the clinicoradiological diagnosis of Crohn's colitis but nonresponse to immunomodulators warranted full-thickness jejunal biopsy through laparotomy which showed numerous larvae and eggs of Strongyloides. There is a need to increase the awareness of Strongyloides colitis given its high rate of misdiagnosis and mortality as the correct diagnosis can avoid a fatal outcome of this curable disease.
PubMed: 38769818
DOI: 10.4103/ijpm.ijpm_298_23 -
Clinical Immunology (Orlando, Fla.) Jul 2024The gluten-free diet for celiac disease (CeD) is restrictive and often fails to induce complete symptom and/or mucosal disease remission. Central to CeD pathogenesis is...
UNLABELLED
The gluten-free diet for celiac disease (CeD) is restrictive and often fails to induce complete symptom and/or mucosal disease remission. Central to CeD pathogenesis is the gluten-specific CD4+ T cell that is restricted by HLA-DQ2.5 in over 85% of CeD patients, making HLA-DQ2.5 an attractive target for suppressing gluten-dependent immunity. Recently, a novel anti-HLA-DQ2.5 antibody that specifically recognizes the complexes of HLA-DQ2.5 and multiple gluten epitopes was developed (DONQ52).
OBJECTIVE
To assess the ability of DONQ52 to inhibit CeD patient-derived T-cell responses to the most immunogenic gluten peptides that encompass immunodominant T cell epitopes.
METHODS
We employed an in vivo gluten challenge model in patients with CeD that affords a quantitative readout of disease-relevant gluten-specific T-cell responses. HLA-DQ2.5+ CeD patients consumed food containing wheat, barley, or rye for 3 days with collection of blood before (D1) and 6 days after (D6) commencing the challenge. Peripheral blood mononuclear cells were isolated and assessed in an interferon (IFN)-γ enzyme-linked immunosorbent spot assay (ELISpot) testing responses to gluten peptides encompassing a series of immunodominant T cell epitopes. The inhibitory effect of DONQ52 (4 or 40 μg/mL) was assessed and compared to pan-HLA-DQ blockade (SPVL3 antibody).
RESULTS
In HLA-DQ2.5+ CeD patients, DONQ52 reduced T cell responses to all wheat gluten peptides to an equivalent or more effective degree than pan-HLA-DQ antibody blockade. It reduced T cell responses to a cocktail of the most immunodominant wheat epitopes by a median of 87% (IQR 72-92). Notably, DONQ52 also substantially reduced T-cell responses to dominant barley hordein and rye secalin derived peptides. DONQ52 had no effect on T-cell responses to non-gluten antigens.
CONCLUSION
DONQ52 can significantly block HLA-DQ2.5-restricted T cell responses to the most highly immunogenic gluten peptides in CeD. Our findings support in vitro data that DONQ52 displays selectivity and broad cross-reactivity against multiple gluten peptide:HLA-DQ2.5 complexes. This work provides proof-of-concept multi-specific antibody blockade has the potential to meaningfully inhibit pathogenic gluten-specific T-cell responses in CeD and supports ongoing therapeutic development.
Topics: Humans; Celiac Disease; Glutens; HLA-DQ Antigens; Antibodies, Bispecific; Female; Epitopes, T-Lymphocyte; Adult; Male; CD4-Positive T-Lymphocytes; Peptides; Middle Aged; T-Lymphocytes; Interferon-gamma; Immunodominant Epitopes; Diet, Gluten-Free
PubMed: 38768856
DOI: 10.1016/j.clim.2024.110259 -
Cureus Apr 2024Biermer's disease (BD) or pernicious anemia (PA) is an autoimmune atrophic gastritis characterized by the absence of intrinsic factor (IF) secretion, leading to...
Biermer's disease (BD) or pernicious anemia (PA) is an autoimmune atrophic gastritis characterized by the absence of intrinsic factor (IF) secretion, leading to malabsorption of vitamin B12 in the ileum. Its clinical manifestations are primarily hematological, with neuropsychiatric and cardiovascular manifestations being less common. We present the case of a patient with PA diagnosed based on neurological and cardiovascular complications. The patient, a 56-year-old man with no specific medical history, presented with an episode of melena without other associated digestive symptoms. He also complained of memory and gait disturbances. Clinical examination revealed a cerebellar ataxia with impaired proprioceptive and vibratory sensitivity, and a swollen and red right lower limb with a positive Homan sign. The blood count showed macrocytic anemia. Gastroscopy revealed flattened fundic folds resembling a fundus appearance, and histopathological examination confirmed fundic atrophic gastritis with pseudopyloric metaplasia and lymphoplasmacytic infiltration. Anti-intrinsic factor antibodies were positive, while anti-parietal cell antibodies were negative. Vitamin B12 levels were severely low, and vitamin B9 levels were normal. TSH and HbA1c levels were within normal ranges. The abdominal CT scan showed no abnormalities. Lower limb Doppler ultrasound confirmed the diagnosis of deep vein thrombosis (DVT). Cardiac evaluation revealed sinus bradycardia suggestive of secondary dysautonomia. Therapeutically, the patient was started on vitamin B12 supplementation and anticoagulant therapy for DVT, resulting in a good clinical and biological outcome.
PubMed: 38765343
DOI: 10.7759/cureus.58601 -
Pediatric Rheumatology Online Journal May 2024Vitamin C deficiency, or scurvy, is rare but poses risks for children with poor diets, limited resources, or malabsorption issues. It may also be common in children with...
BACKGROUND
Vitamin C deficiency, or scurvy, is rare but poses risks for children with poor diets, limited resources, or malabsorption issues. It may also be common in children with restrictive or selective dietary habits in children with global developmental delay, autism spectrum disorder, and physical disabilities. Symptoms include fatigue, irritability, joint and muscle pain, joint swellings, edema, swollen gums, easy bruising, and delayed wound healing. Early recognition and prompt intervention are essential to prevent the progression of symptomatic vitamin C deficiency in children.
CASE PRESENTATION
We present a case of a 13-year-old boy with developmental delay secondary to Lennox Gastaut syndrome referred for suspected recurrent, severe, and atypical IgA vasculitis. He presented with irritability, loss of appetite, petechial and ecchymotic lower limb lesions, unilateral gum swelling, severe arthritis, peripheral oedema, severe weight loss, anaemia, and raised inflammatory markers. Multiple investigations were performed before the diagnosis of scurvy was made. A surgical finding of friable gingival tissue with multiple loose teeth, a skin biopsy with follicular hyperkeratosis and extravasated perifollicular red blood cells, and a typical X-ray finding led to the diagnosis of scurvy.
CONCLUSION
Scurvy should be given careful consideration as a differential diagnosis in patients presenting with musculoskeletal issues, mucocutaneous complaints, and constitutional symptoms such as malaise, asthenia, irritability, and loss of appetite. A focused and detailed dietary history looking for a lack of good sources of vitamin C can be an easy indicator of this differential. Imaging studies revealing the typical features can also help make the diagnosis. Pathology of the skin revealing pathognomonic features can add to the certainty of the diagnosis. In the absence of all else, the rapid response to treatment with an appropriate dose of vitamin C has a diagnostic and therapeutic role.
Topics: Humans; Scurvy; Male; Adolescent; Diagnosis, Differential; Ascorbic Acid; IgA Vasculitis
PubMed: 38760753
DOI: 10.1186/s12969-024-00992-2 -
Medicine May 2024Sickle Cell Anemia (SCA) is a hereditary hemoglobinopathy characterized by chronic hemolytic anemia, vaso-occlusive events, and a wide range of clinical complications.... (Review)
Review
Sickle Cell Anemia (SCA) is a hereditary hemoglobinopathy characterized by chronic hemolytic anemia, vaso-occlusive events, and a wide range of clinical complications. Malnutrition, often an underexplored aspect of this complex condition, plays a critical role in disease management and overall patient well-being. This publication provides a comprehensive review of the prevalence, impact, and interventions related to malnutrition in individuals with SCA. A thorough literature review reveals the multifaceted challenges faced by SCA patients in maintaining adequate nutrition. The pathophysiology of SCA, involving chronic inflammation, oxidative stress, and hypermetabolism, contributes to increased nutritional requirements and altered dietary patterns. Factors such as reduced appetite, nutrient malabsorption, dietary restrictions, and socioeconomic disparities further exacerbate the risk of malnutrition. Malnutrition is a prevalent issue among individuals with SCA, affecting patients of different age groups and disease severities. Nutritional deficiencies, including vitamins, minerals, and essential nutrients, are common in this population. The impact of malnutrition on disease outcomes is significant, with associations between nutrient status and complications such as pain crises, infections, and impaired quality of life. This paper also reviews nutritional interventions aimed at addressing malnutrition in SCA patients. While dietary counseling, supplementation, and personalized nutrition plans have shown promise in improving nutritional status, challenges such as patient adherence and access to healthcare must be addressed to optimize their effectiveness.
Topics: Humans; Anemia, Sickle Cell; Malnutrition; Prevalence; Quality of Life; Nutritional Status
PubMed: 38758879
DOI: 10.1097/MD.0000000000038164 -
PeerJ 2024An increased level of interleukin-17A and interleukin-18 in the serum and intestinal mucosa of celiac disease patients reflecting the severity of villous atrophy and...
BACKGROUND
An increased level of interleukin-17A and interleukin-18 in the serum and intestinal mucosa of celiac disease patients reflecting the severity of villous atrophy and inflammation was documented. Thus, the objective of this study was to evaluate the concentrations of salivary-17A, interleukin-1 beta, and interleukin-18 in patients with celiac disease who are on a gluten-free diet, both with and without periodontitis, and to compare these levels with those in healthy individuals.
METHODS
The study involved 23 participants with serologically confirmed celiac disease (CD) and 23 control subjects. The CD patients had been following a gluten-free diet (GFD) for a minimum of 1 year and had no other autoimmune disorders. The research involved collecting demographic data, conducting periodontal examinations, gathering unstimulated whole saliva, and performing enzyme-linked immunosorbent assays to measure salivary interleukin-17A, interleukin-1 beta, and interleukin-18 levels. Spearman's correlation analysis was utilized to explore the relationships between CD markers in patients on a GFD and their periodontal clinical findings.
RESULTS
The periodontal findings indicated significantly lower values in celiac disease patients adhering to a gluten-free diet compared to control subjects ( = 0.001). No significant differences were found in salivary IL-17A, IL-18, and IL-1B levels between celiac disease patients and control subjects. Nevertheless, the levels of all interleukins were elevated in periodontitis patients in both the celiac and control groups. The IL-1 Beta level was significantly higher in periodontitis patients compared to non-periodontitis patients in the control group ( = 0.035). Significant negative correlations were observed between serum IgA levels and plaque index (r = -0.460, = 0.010), as well as gingival index (r = -0.396, = 0.030) in CD patients on a gluten-free diet.
CONCLUSION
Celiac disease patients on gluten-free diet exhibited better periodontal health compared to control subjects. However, increased levels of salivary IL-17A, IL-18 and IL-1B levels were associated with periodontitis. Additionally, serum IgA level was significantly inversely associated with periodontitis clinical manifestations and with salivary inflammatory mediators in CD patients on GFD.
Topics: Humans; Celiac Disease; Interleukin-17; Male; Female; Interleukin-18; Saliva; Adult; Periodontitis; Diet, Gluten-Free; Interleukin-1beta; Case-Control Studies; Middle Aged; Biomarkers; Young Adult
PubMed: 38756445
DOI: 10.7717/peerj.17374