Manish Butte

JGH Open. 2025 Apr 17;9(4):e70154. doi: 10.1002/jgh3.70154. eCollection 2025 Apr.

ABSTRACT

BACKGROUND: Lymphomas present a significant challenge in the field of gastrointestinal diseases, often being mistaken for other gastrointestinal tumors or inflammatory bowel disease conditions, causing clinical confusion. Early diagnosis plays a pivotal role in effective treatment. This case highlights the importance of recognizing lymphoproliferative disorders as a rare association of anti-tumor necrosis factor-α (TNF-α) therapy.

CASE PRESENTATION: A 41-year-old man with a 15-year history of Crohn disease on long-term therapy with adalimumab underwent a right hemicolectomy due to a semi-circumferential lesion at the ileocecal valve causing near complete obstruction and severe anemia (Hgb 6.4 g/dL). Previous biopsies of the mass showed an Epstein Barr Virus-positive (EBV+) classic Hodgkin lymphoma (CHL) in Crohn disease. At resection, the lymphoma showed transmural involvement of the ileum and regional lymph nodes.

CONCLUSION: Primary intestinal CHL comprises less than 5% of gastrointestinal lymphomas; CHL arising in the context of Crohn disease is even more rare. Most lymphomas associated with inflammatory bowel disease and/or immunosuppression are non-Hodgkin type. In this case, the long-term treatment with anti-TNF-α and EBV positivity suggested an iatrogenic immunodeficiency-associated lymphoma, an emerging group of lymphoproliferative disorders associated with the increased use of immunosuppressants.

PMID:40255389 | PMC:PMC12006285 | DOI:10.1002/jgh3.70154

J Allergy Clin Immunol Glob. 2025 Mar 8;4(2):100450. doi: 10.1016/j.jacig.2025.100450. eCollection 2025 May.

ABSTRACT

BACKGROUND: Elevation of type I interferon (IFN-I) is characteristic of a group of diseases known as type I interferonopathies. Several technologies are available to monitor IFN-I, but there is no consensus on their routine use in medical laboratories.

OBJECTIVE: We aimed to compare the performance of two technologies for this purpose: NanoString, which monitors messenger RNA expression of interferon-stimulated genes (ISGs), and Simoa, which quantifies IFN-α2 protein in an ultrasensitive way. We also designed a NanoString assay to monitor type II ISGs and tested its value to discriminate clinical conditions.

METHODS: A total of 196 samples from patients with diseases associated or not with IFN-I pathway activation were analyzed by NanoString and Simoa.

RESULTS: The comparison between NanoString IFN-I score and IFN-α2 Simoa revealed a r ² coefficient of 0.55. We identified IFI27, IFI44L, and SIGLEC1 as the ISGs most closely related to IFN-α2 concentration. Nineteen samples had a positive IFN-I score but undetectable IFN-α2. These samples were also positive according to IFN-II score, pointing to IFN-II as the primary ISG inducer in corresponding patients. By measuring IFN-I and IFN-II scores in a subset of patients with systemic lupus erythematosus and systemic juvenile idiopathic arthritis, we identified two subgroups of patients in whom IFN-I and IFN-II were dominant.

CONCLUSION: Both IFN-α2 quantification and NanoString reliably distinguish type I interferonopathies from other diseases. Type I and II interferons induce different transcriptomic signatures in vitro and in vivo, and our results highlight the value of monitoring both IFN-I and IFN-II in interferon-related diseases.

PMID:40242151 | PMC:PMC12002218 | DOI:10.1016/j.jacig.2025.100450

Immunol Res. 2025 Apr 16;73(1):72. doi: 10.1007/s12026-025-09627-4.

ABSTRACT

The major histocompatibility complex (MHC) encompasses a group of genes critical for immune system regulation. In humans, these molecules are referred to as human leukocyte antigens (HLA) due to their initial discovery in human leukocytes. Class I molecules present antigens to CD8 + T cells, while Class II molecules present to CD4 + T cells. Here we report a patient who had a background of parental consanguinity and a family history suggestive of immunodeficiency. He presented with clinical symptoms including fever, septic arthritis, recurrent moniliasis. Preliminary diagnostic tests revealed hypogammaglobulinemia and CD4 lymphopenia. Further immunological assessment indicated extremely low expression levels of HLA molecules: HLA ABC at 5% and HLA DR at 0%. Genetic analysis showed a mutation in the regulatory factor X5 (RFX5) gene, leading to a combined immunodeficiency diagnosis. Consequently, hematopoietic stem cell transplantation (HSCT) was planned. Regulatory factor X5plays a pivotal role in immune function by transactivating genes critical for the expression of MHC Class I and Class II molecules, as well as beta- 2-microglobulin (B2M). MHC Class I transcription is controlled indirectly by RFX5, and the RFX5 gene mutation in the patient likely caused the markedly reduced expression of HLA ABC in addition to HLA DR. Combined HLA-ABC and HLA-DR expression analyses via flow cytometry may serve as a valuable diagnostic tool for identifying RFX5-related immunodeficiency at an early stage, facilitating timely genetic testing and appropriate clinical management.

PMID:40240550 | DOI:10.1007/s12026-025-09627-4

Hematol Oncol Clin North Am. 2025 Apr 15:S0889-8588(25)00027-9. doi: 10.1016/j.hoc.2025.03.002. Online ahead of print.

ABSTRACT

The main indication for allogeneic HSCT in children is primary/familial HLH but indications in adults are diverse, including malignancy-associated HLH. Matched related donors have historically been the preferred stem cell source (if not sharing predisposing genetics) followed closely by unrelated donors, but haploidentical transplants are proving feasible. Choice of conditioning regimen between myeloablative and reduced-intensity (RIC) involves trade-offs between early toxicity, particularly veno-occlusive disease, and additional cellular infusions to address graft failure or poor chimerism. Allogeneic HSCT for HLH is most successful when primary disease is under control, so coordination between initial/salvage therapy and transplant initiation is key.

PMID:40240177 | DOI:10.1016/j.hoc.2025.03.002

Lab Invest. 2025 Apr 14:104174. doi: 10.1016/j.labinv.2025.104174. Online ahead of print.

ABSTRACT

WHIM syndrome is a rare primary immunodeficiency disorder predominantly caused by germline CXCR4 variants. Bone marrow (BM) evaluation showing myelokathexis helps to establish the diagnosis of WHIM syndrome, but unfamiliarity with pertinent diagnostic features and variability in morphologic and clinical findings may result in disease under-recognition. We characterize the clinical, BM and peripheral blood (PB) features of 30 patients with germline CXCR4 variants, including genotype-phenotype analysis and correlation between morphologic features and functional CXCR4 receptor internalization defect. We also examine PB features of a mouse model of WHIM syndrome (Cxcr4^+/1013), and examine WHIM syndrome and WHIM mouse PB morphologic changes after CXCR4 antagonist therapy. Carboxy-terminal nonsense/frameshift CXCR4 variants were associated with myelokathectic neutrophil morphology in 32-80% (median: 66%) and 4-14% (median: 9%) of total neutrophils in the BM and PB, respectively. In contrast, myelokathectic neutrophils were infrequent in five missense CXCR4 variants (three CXCR4^D84H; two CXCR4^S341Y). Compared to neutropenic controls, carboxy-terminal CXCR4 nonsense/frameshift variants were associated with >10% BM or >5% PB myelokathectic neutrophils (100% specific; 100% (BM) or 93% (PB) sensitive), as well as more frequent neutrophil apoptosis (BM p=0.0093; PB p<0.0001), dysmorphic/vacuolated eosinophils (BM p=0.012; PB p<0.0001), neutrophil vacuolization (BM p<0.0001), and non-paratrabecular neutrophil clusters in the BM (p=0.0059). BM myeloid hyperplasia occurred in 54% of carboxy-terminal CXCR4 nonsense/frameshift variants and no controls. BM myelokathectic neutrophil percentage correlated with the functional CXCR4 internalization defect (p≤0.0042). Like humans, WHIM mice (Cxcr4^+/1013) demonstrated circulating myelokathectic-like neutrophils with nuclear hypersegmentation. CXCR4 antagonist therapy in patients with WHIM syndrome (n=5) and mice increased both morphologically normal and myelokathectic neutrophils in PB. We demonstrate notable genotype-phenotype heterogeneity between CXCR4 variants and myelokathexis, which correlates with functional CXCR4 internalization defect. The morphologic features of WHIM syndrome may be subtle, resulting in misdiagnosis. We describe key morphologic features that are useful to facilitate diagnosis.

PMID:40239948 | DOI:10.1016/j.labinv.2025.104174

Pediatr Allergy Immunol. 2025 Apr;36(4):e70090. doi: 10.1111/pai.70090.

ABSTRACT

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity response to the allergens of Aspergillus fumigatus, which is the most frequently isolated fungus from the sputum of cystic fibrosis (CF) patients. Because a low number of Th17 lymphocytes is associated with the risk of fungal infections, we investigated inflammatory markers, Th17 cells, and T-cell polarization in CF patients with ABPA.

METHODS: We analyzed the levels of inflammatory markers, blood counts, chemokines, cytokines, and T cell subsets in blood and sputum of CF subjects to elucidate the immunological factors associated with CF patients with Aspergillus fumigatus (AF) positive sputum (AFS⁺) or with ABPA.

RESULTS: We observed that AFS+ patients have higher sputum and blood IL-6 levels than AF-negative sputum (AFS^–) patients. Analysis of blood memory T-helper subsets associated with Th1, Th2, and Th17 polarization among circulating CD45RA-/CD4+ memory T-cell subsets showed higher numbers of CCR4⁺/CCR6⁺/CXCR3^– and CCR4⁺/CCR6⁺/CXCR3⁺ memory CD4 cells in AFS+ compared to AFS^– subjects. Further analysis of Th17-related subsets and IL-17 secreting T cells in subjects with AFS+ showed that those with ABPA have statistically significantly lower levels of Th17 cells as compared to those without ABPA.

CONCLUSION: In CF, AF airway colonization is associated with increased blood counts of Th17-related subsets. However, CF patients with ABPA exhibit lower numbers of CCR4+/CCR6+/CXCR3+ memory CD4 cells and IL-17-secreting CD4 cells compared to control subjects and CF patients without AF sensitization.

PMID:40238087 | DOI:10.1111/pai.70090

J Clin Immunol. 2025 Apr 16;45(1):86. doi: 10.1007/s10875-025-01878-y.

ABSTRACT

Unexplained neurological symptoms can pose a diagnostic challenge in patients with inborn errors of immunity (IEI) where the aetiology can be varied, and diverse pathologies may require contrasting treatments. Brain biopsy, the process of sampling brain tissue directly, has historically provided histological and microbiological information and can now be exploited for deep metagenomic next generation analysis (mNGS). We conducted a retrospective analysis of clinical and diagnostic data on paediatric patients with IEI who had a brain biopsy between 2010 and 2022 at a UK tertiary centre where 14 patients fulfilled our search criteria. We report on clinical characteristics, adverse events and the additional impact of mNGS of brain biopsies, where these were conducted. We found that brain biopsy enabled diagnostics with manageable complications in most cases, either by tissue or metagenomics analysis (n = 11/14, 79%). We found that mNGS analysis improved the diagnostic yield of brain biopsy in 29% of IEI cases (n = 4/14). Brain biopsy enabled a change in management in 71% of cases (n = 10/14). This series provides compelling evidence for the safe and purposeful use of brain biopsy in children with IEI.

PMID:40237937 | DOI:10.1007/s10875-025-01878-y

JCEM Case Rep. 2025 Apr 15;3(5):luaf068. doi: 10.1210/jcemcr/luaf068. eCollection 2025 May.

ABSTRACT

Cantú syndrome involves fetal polyhydramniosis, congenital hypertrichosis, and macrosomia. Distinctive features include acromegaloid features with broad nasal bridge and macroglossia as well as cardiac abnormalities, including patent ductus arteriosus. We present a case in a male patient, who presented with cardiac abnormalities in childhood, but was diagnosed with the syndrome in adulthood after many years of atypical symptoms such as multiple endocrinopathies and infection susceptibility. He had surgery for a patent ductus arteriosus in early childhood. During adulthood, he developed idiopathic pericarditis. Extensive rheumatological investigations were made, and in parallel, several endocrinopathies were found. These included thyroiditis with subsequent hypothyroidism, idiopathic partial hypocortisolism, and GH insufficiency. In addition, he had mild neutropenia and required hospitalization twice because of Streptococcus pyogenes infections. Immunodeficiency screening has not revealed a specific primary immunodeficiency, yet transient neutropenia, low count of CD8+ effector memory T cells, as well as lymphocyte responses, was seen during bacteremia. The diagnose was made after a trio-whole genome sequencing identified a pathogenic missense variant of the gene ABCC9 (c.3460C > T;p. (Arg1154Trp)) causing Cantú syndrome.

PMID:40236613 | PMC:PMC11997666 | DOI:10.1210/jcemcr/luaf068

Ann Rheum Dis. 2025 Apr 9:S0003-4967(25)00084-6. doi: 10.1016/j.ard.2025.01.028. Online ahead of print.

ABSTRACT

OBJECTIVES: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease despite being a rare disease for many rheumatologists. These evidence-based recommendations update the ones issued in 2016 to account for the recent developments in the field and aim to guide rheumatologists and other health professionals in the treatment and follow-up of patients with FMF.

METHODS: A multidisciplinary panel was assembled, including rheumatologists, internists, paediatricians, a nephrologist, an occupational therapist, a physiotherapist, 2 methodologists, and 2 patient representatives, all from the Eastern Mediterranean area and Europe. Several systematic reviews were performed on the pharmacological treatment of FMF and its complications. The previous recommendations were revised considering the updated evidence, and the new levels of evidence were incorporated. The agreement with the recommendations was obtained through a Delphi survey.

RESULTS: The final set comprises 4 overarching principles and 12 recommendations, each presented with its degree of agreement (0-10), level of evidence, and rationale. The degree of agreement was greater than 9/10 in all instances, and the level of evidence improved in most updated statements. Improving adherence is emphasised as an important aspect in several statements. These new recommendations include a priority set, quality indicators, and other suggested implementation strategies.

CONCLUSIONS: This article presents a set of widely accepted recommendations for treating and monitoring FMF, supported by the best available evidence and expert opinion. These recommendations are valuable for guiding physicians in caring for patients with FMF.

PMID:40234174 | DOI:10.1016/j.ard.2025.01.028

Proc Natl Acad Sci U S A. 2025 Apr 22;122(16):e2414002122. doi: 10.1073/pnas.2414002122. Epub 2025 Apr 15.

ABSTRACT

CD20 is a four-transmembrane protein expressed at the surface of B cells from late pro-B cells to memory B cells, with the exception of plasma cells. Its expression pattern makes it an attractive therapeutic target for different B cell malignancies and autoimmune diseases. Despite the clinical success of CD20-targeting antibodies, the biology of the CD20 protein is still not well understood. We investigated CD20 binding partners in the membrane of human B cells using immunoprecipitation followed by mass spectrometry analysis. We identified a molecular interaction between CD70 and CD20, and confirmed this using proximity ligation assays. CD20-CD70 spatiotemporal colocalization was validated at the plasma membrane of B cells using high-resolution microscopy. Cell surface expression of CD70 was found to be enhanced upon CD20 overexpression, suggesting a role for CD20 in stabilizing CD70 at the B cell membrane. Moreover, we observed impaired B-T cell synapse formation and defective recruitment of CD70 to the immunological synapse in the absence of CD20. Impaired synapse formation was confirmed by deleting CD20 in primary B cells, and analysis of B cells from a CD20-deficient patient. Finally, CD20-deletion resulted in diminished T cell activation and cytokine secretion. Together, this study demonstrates that CD20 interacts with CD70 at the B cell membrane, and that CD20 is required for immune synapse formation between B and T cells and consequent T cell activation.

PMID:40232798 | DOI:10.1073/pnas.2414002122