Manish Butte

J Exp Med. 2025 May 5;222(5):e20241047. doi: 10.1084/jem.20241047. Epub 2025 Apr 15.

ABSTRACT

The last decades have brought a rapid expansion of the number of primary disorders related to the polyubiquitination pathways in humans. Most of these disorders manifest with two seemingly contradictory clinical phenotypes: autoinflammation, immunodeficiency, or both. We provide an overview of the molecular pathogenesis of these disorders, and their role in inflammation and infection. By focusing on data from human genetic diseases, we explore the complexities of the polyubiquitination pathways and the corresponding clinical phenotypes of their deficiencies. We offer a road map for the discovery of new genetic etiologies. By considering the triggers that induce inflammation, we propose autoinflammation and immunodeficiency as continuous clinical phenotypes.

PMID:40232244 | DOI:10.1084/jem.20241047

Front Immunol. 2025 Mar 28;16:1510365. doi: 10.3389/fimmu.2025.1510365. eCollection 2025.

ABSTRACT

Inborn errors of immunity (IEI), a diverse group of rare inborn disorders involving over 500 genes, pose diagnostic challenges despite next-generation sequencing advancements. Accurate molecular diagnosis is crucial for personalized treatment. This study aimed to assess the complementary role of genome and transcriptome sequencing in improving diagnostic yield for inborn errors of immunity. A cohort of 37 suspected IEI cases mainly consisting of predominantly primarily antibody deficiency (PAD) (27/37) underwent genome and transcriptome sequencing. We validated transcriptome sequencing analysis using positive controls and showed limitations of current methods. Among the 37 IEI cases, genetic etiology was identified in 14% (5/37). Genome and transcriptome sequencing prompted diagnostic changes in three initially diagnosed common variable immunodeficiency (CVID)/PAD cases, including showing RAS-associated autoimmune leukoproliferative disorder presenting as a novel CVID mimic disorder. The spectrum of identified pathogenic variants included STAT1, ADA2, SH2D1A, NRAS, and NR2F1. A complex structural variant in SH2D1A was characterized, demonstrating the significance of transcriptome sequencing in clarifying the genomic findings. While genome and transcriptome sequencing provided critical insights and allowed to provide correct diagnosis for at least 14% of the patients, the overall improvement in diagnostic yield over exome sequencing is limited. Transcriptome sequencing proved efficient in variant effect interpretation. Our findings underscore the evolving landscape of primary immunodeficiency genetics, necessitating ongoing exploration for novel genes and atypical phenotypes. The integration of genome and transcriptome sequencing holds promise but requires further refinement to enhance the diagnostic yield.

PMID:40226629 | PMC:PMC11986850 | DOI:10.3389/fimmu.2025.1510365

Methods Mol Biol. 2025;2904:159-177. doi: 10.1007/978-1-0716-4414-0_12.

ABSTRACT

CD8⁺ T cells are a vital branch of the adaptive immune response. They are necessary for an effective antiviral and anticancer immunity, which is mediated through their cytotoxic effector functions. CD8⁺ T cell activation, proliferation, and effector functions are dependent on a complex network of Ca²⁺ signalling pathways involving both Ca²⁺ release and Ca²⁺ entry. Dysregulation of intracellular Ca²⁺ signalling pathways has been linked to immunodeficiencies including severe combined immunodeficiency syndrome (SCID), highlighting the need to study both Ca²⁺ dynamics and cytotoxic effector function in patient-derived CD8⁺ T cells. The following protocol describes a workflow for the isolation of primary human CD8⁺ T cells and their activation using bispecific T cell engagers (BiTEs). This allows for a simultaneous assessment of both Ca²⁺ dynamics and cytotoxicity through a target cell line presenting an epitope recognized by the BiTE.

PMID:40220233 | DOI:10.1007/978-1-0716-4414-0_12

J Patient Rep Outcomes. 2025 Apr 12;9(1):42. doi: 10.1186/s41687-025-00876-3.

ABSTRACT

BACKGROUND: There is a lack of clear evidence pointing to a fit-for-purpose instrument to measure impacts on health-related quality of life (HRQoL) in adult and adolescent patients with hereditary angioedema (HAE). The purpose of this study was to determine whether the Angioedema Quality of Life Questionnaire (AE-QoL) is content valid and appropriate for capturing the impact of HAE attacks on HRQoL in both adults and adolescents with HAE.

METHODOLOGY: This study used one-on-one, audio-recorded, cognitive debriefing interviews employing think-aloud and verbal probing approaches to evaluate the relevance, comprehensibility, and comprehensiveness of the AE-QoL in this patient population. All data were quality checked then coded and analyzed using inductive and deductive approaches.

RESULTS: This study included 10 adolescents and 12 adults with HAE in the United States. Overall, participants had positive impressions of the AE-QoL, finding the length and recall period appropriate, and the response options clear and easy to understand. Some reported minor concerns with the instructions, but none that prevented them from completing the instrument. Participants found the instrument relevant to their experiences with HAE, noting that items that were not personally relevant were still important to ask. Overall, participants found the AE-QoL comprehensible and comprehensive, although some participants, primarily adolescents, reported being unfamiliar with the word “leisure,” making it difficult to answer the item asking about impact of attacks on “leisure time.” Adolescents also reported that questions about school-related impacts were missing and would be important to ask about specifically.

CONCLUSIONS: This study presents evidence that supports the content validity of the AE-QoL in adult and adolescent patients with HAE. While revisions could be considered prior to using the instrument with samples of adolescent patients with HAE, in general, adolescents and adults with HAE found the measure relevant, comprehensive, and comprehensible.

PMID:40220084 | DOI:10.1186/s41687-025-00876-3

Ann Med Surg (Lond). 2025 Mar 18;87(4):2473-2476. doi: 10.1097/MS9.0000000000003164. eCollection 2025 Apr.

ABSTRACT

INTRODUCTION AND IMPORTANCE: Common Variable Immunodeficiency (CVID) is a rare primary immunodeficiency with complex presentations, including recurrent infections and autoimmune diseases. Given its rarity and overlapping symptoms with other gastrointestinal and infectious conditions, it is often overlooked. This case underscores the importance of considering CVID as a differential diagnosis when evaluating patients with recurrent infections and persistent gastrointestinal manifestations. It highlights the complexities of diagnosing and managing multifaceted, multisystemic disorders and reinforces the need for a personalized approach to treatment. We present a 68-year-old male with recurrent infections, gastrointestinal symptoms, and a family history of autoimmune disease and consanguinity. Initially diagnosed with malabsorption syndrome, the patient was later found to have ulcerative colitis (UC) and CVID.

CASE PRESENTATION: A 68-year-old Asian male with a history of recurrent pulmonary infections, chronic diarrhea, and fatigue presented with a family history of autoimmune diseases. Investigations revealed a marked reduction in immunoglobulin levels, leading to the diagnosis of CVID. Further investigations, including a colonoscopy, confirmed the presence of UC. The patient was treated with intravenous immunoglobulin (IVIG), corticosteroids, and azathioprine. The patient’s condition stabilized, and his infection frequency reduced significantly.

DISCUSSION: This case illustrates the complexity of diagnosing CVID, particularly when accompanied by autoimmune disorders like UC. The patient’s overlapping symptoms of chronic infection, gastrointestinal distress and lack of proper follow through led to delayed diagnosis and treatment.

CONCLUSION: This case underscores the importance of considering CVID in patients with recurrent infections and unexplained gastrointestinal symptoms, particularly when there is a family history of autoimmune diseases.

PMID:40212137 | PMC:PMC11981455 | DOI:10.1097/MS9.0000000000003164

Iran J Allergy Asthma Immunol. 2025 Mar 10;24(2):187-197. doi: 10.18502/ijaai.v24i2.18147.

ABSTRACT

Ataxia Telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disease caused by mutations in the ataxia telengiectasia mutated (ATM) gene. The gene is on chromosome 11q22-23 and codes for the protein kinase ATM, which plays an essential role in DNA damage repair. In this study, we review the clinical characteristics of 13 A-T patients, 2 of whom displayed novel mutations. Thirteen patients with ataxia-telangiectasia from 10 unrelated families were referred to Immunology, Asthma and Allergy Research Institute, Tehran, Iran. After clinical confirmation, blood samples were collected from the patients and their parents. Genetic analysis for 8 patients was conducted using whole-exome sequencing; in the other 3 patients, polymerase chain reaction was used, followed by sequencing. We identified 11 different mutations in the ATM gene. Two patients had mutations as compound heterozygous, while 9 other patients were homozygous for the mutations. Among these, 2 likely pathogenic mutations (ie, c.2639-1G>A and c.7940_7970del​TTCCAGCAGA​CCAGCCAATT​ACTAAACTTAA) have not been reported. Our study highlights the significance of next-generation sequencing techniques in identifying novel ATM mutations in A-T patients. Although all reported A-T mutations reside in 1 gene, the absence of a mutation hotspot for this gene necessitates the use of next-generation sequencing techniques. Specifically, we identified 2 mutations that have not been reported previously, emphasizing the importance of continued research in this area. This study provides new insights into the genetic underpinnings of A-T and underscores the potential clinical implications of identifying novel mutations.

PMID:40211499 | DOI:10.18502/ijaai.v24i2.18147

Clin Lab. 2025 Apr 1;71(4). doi: 10.7754/Clin.Lab.2025.250224.

ABSTRACT

BACKGROUND: Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, immune dysfunction, and neurologic abnormalities.

METHODS: This paper aims to provide a detailed understanding of the clinical presentation, laboratory examination, genetic basis, EEG/MRI, diagnostic challenges, and current management strategies for CHS through a new case report and a analysis of the current literature.

RESULTS: The analysis of the case report and literature indicates that CHS requires vigilant clinical observation for early diagnosis and effective treatment. The analysis highlights the necessity for advanced therapies that are both more efficient and cost-effective, given the current limitations in treatment options.

CONCLUSIONS: The study concludes that further research is needed to develop more efficient and economical therapies for CHS that can enhance patient outcomes. The development of such therapies will be crucial in addressing the unmet needs of patients with this rare genetic disorder.

PMID:40209792 | DOI:10.7754/Clin.Lab.2025.250224

Arerugi. 2025;74(2):73-77. doi: 10.15036/arerugi.74.73.

ABSTRACT

Hereditary angioedema (HAE) is a rare genetic disease characterized by recurrent episodes of temporary organ swelling. Here, we report a case of HAE type III who experienced recurrent acute abdominal pain after starting low-dose estrogen therapy. Genetic analysis by Sanger sequencing led to the identification of a recurrent heterozygous missense variant c.988A>G (p.K330E) in the plasminogen (PLG) gene of the patient. This variant was previously found in her elder sister who also had the disease. She was treated with tranexamic acid as a long-term prophylactic. Her attacks did not increase during her pregnancy. We managed the patient with intravenous injection of C1-INH preparation before and after delivery. As the frequency of attacks increased after delivery and after the resumption of menstruation, the dose of tranexamic acid was increased, and a subcutaneous injection of lanadelumab was started.While the severity of attacks reduced, she experienced the attacks once or twice a month. After switching from lanadelumab to twice-weekly subcutaneous injections of C1-inhibitor (C1-INH), she had no attacks requiring additional treatment, although she had several minor attacks. To establish appropriate treatment for HAE type III, accumulation of cases, determination of the causative gene in each case, and elucidation of the pathology are warranted.

PMID:40204483 | DOI:10.15036/arerugi.74.73

Comp Biochem Physiol C Toxicol Pharmacol. 2025 Apr 7:110202. doi: 10.1016/j.cbpc.2025.110202. Online ahead of print.

ABSTRACT

The impact of polycyclic aromatic hydrocarbons (PAHs) on the immune function of marine animals has garnered significant attention. C. farrei is frequently exposed to pollutants and has only innate immunity. To delve more deeply into the immunotoxicity mechanism of PAHs in C. farrei, its hemocytes were cultured in vitro as they were the primary drivers of immune activities. The autophagy and apoptosis of hemocytes are essential components of the immune response. The exposure of pollutant, autophagy and apoptosis of immune cells are often disrupted, leading to immunodeficiency. In aquatic animals, the mechanism of autophagy and apoptosis in hemocytes remains unclear, and the crosstalk between the two needs to be further investigated. To evaluate the mechanism of autophagy and apoptosis of hemocytes in vitro, 0 μM, 1 μM, 2.5 μM or 5 μM Benzopyrene (B[a]p) was chosen. Experimental results demonstrated that B[a]P triggered autophagosome formation, but also caused significant damage to lysosomes, resulting in a compromised autophagic flux. B[a]P causes an increase in apoptosis levels in hemocytes of C. farreri by affecting the transcriptional level of AIF. To further explore the crosstalk mechanism between the two, activator and inhibitor of autophagy were used. After adding autophagy activator or inhibitor, the present results indicated that Lysosomal function determined the patency of autophagic flux. When massive autophagosomes accumulate, it leads to a much higher rate of apoptosis through caspase-dependent apoptotic pathway. Lysosomal damage further leads to apoptosis and inhibit autophagy. In the B[a]P-treated group, immunological parameters were markedly decreased due to autophagy and apoptosis of hemocytes. The immunotoxicity mechanism of B[a]P in C. farreri hemocytes was investigated in present study, which enriched the immunotoxicity network.

PMID:40203950 | DOI:10.1016/j.cbpc.2025.110202

Int J Surg Case Rep. 2025 Apr 7;130:111277. doi: 10.1016/j.ijscr.2025.111277. Online ahead of print.

ABSTRACT

INTRODUCTION AND IMPORTANCE: Osteomyelitis, an inflammatory condition of the bone, poses significant challenges in clinical management due to its multifactorial etiology and variable presentation. Understanding the underlying mechanisms, risk factors, and biological processes is essential for improving treatment outcomes. Through this paper, we present an exceptionally rare case of “bilateral” aggressive osteomyelitis affecting the mandible, resulting in significant bone loss on both sides. Additionally, we review the literature to explore the causes of this disease and the factors contributing to its occurrence, aiming to understand its pathogenesis and improve prevention and treatment methods.

CASE PRESENTATION: A 58-year-old male presented to our oral and maxillofacial department with a chief complaint of intense pain on both sides of the mandible, persisting for over 12 days. According to the patient, several months ago, the pain varied from mild to moderate, but recently it has increased dramatically. His medical history revealed enlarged lymphatic nodes on both sides of the neck. Consequently, the patient underwent a surgical procedure under general anesthesia to remove the enlarged nodes, followed by chemotherapy, and then 24 sessions of radiotherapy. After a while, the patient began to experience pain of varying intensity, and ulcers appeared, which increased in size over time.

DISCUSSION: After confirming the diagnosis of osteomyelitis, we identified the radiation and chemotherapy to which the patient was exposed as the primary reason for the worsening of the condition. in addition, the injury to both sides of the mandible indicates two possibilities: the first is that the patient has a predisposition to develop osteomyelitis (due to genetic factors, possible ischemia, etc.), and the second is that radiological doses he received was excessive, combined with the immunodeficiency resulting from chemotherapy, contributed to the condition.

CONCLUSION: Research on jaw osteomyelitis highlights a complex interplay of factors that contribute to the development of this condition. Overall, effective prevention and management strategies should address these diverse causes.

PMID:40203624 | DOI:10.1016/j.ijscr.2025.111277