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J Allergy Clin Immunol. 2024 Dec 27:S0091-6749(24)02416-3. doi: 10.1016/j.jaci.2024.12.1082. Online ahead of print.

ABSTRACT

BACKGROUND: Heterozygous immunoproteasome subunit beta-type 10 (PSMB10) mutations can cause severe combined immunodeficiency (SCID) and Omenn syndrome (OS). Hematopoietic stem cell transplantation in these patients is associated with severe complications and poor immune reconstitution, often resulting in death.

OBJECTIVE: To perform immunological and molecular characterization of an infant with a PSMB10 heterozygous variant.

METHODS: A heterozygous variant in PSMB10 (p.G201R) was identified in the index but not her parents. Detailed immunophenotyping and functional studies, including flow cytometry, immunoblotting, and T-cell development in artificial thymic organoids (ATO), were performed.

RESULTS: The patient presented with severe B-, NK-, as well as T-cell lymphopenia, with a progressive increase in memory CD4+ and loss of CD8+ T-cells, diminished Vbeta family diversity, and abnormal IL-7 signaling. Immunoproteasome protein expression (PSMB10 and 9) was markedly reduced in the patient’s cells, including PBMCs, EBV-transformed B cells, and fibroblasts, the mutation likely acting in a dominant negative fashion. Patient CD34+ cells showed a normal early T-cell development but slightly impaired generation of CD3+TCRαβ+ cells in ATO, and human thymus single cell RNA sequencing demonstrated that PSMB10 is expressed in different subsets of cortical and medullary thymic epithelial cells. Collectively, these data indicate that PSMB10 mutations affect positive selection of CD8 T-cells, generation of a diverse T-cell repertoire, and negative selection of autoreactive T-cells.

CONCLUSION: The PSMB10 G201R variant is associated with reduced immunoproteasome expression levels that appear to play vital roles in hematopoietic and extra-hematopoietic immune system development and function. PSMB10-associated thymoproteasome dysfunction leads to impaired thymopoiesis and the development of SCID and OS, suggesting possible benefit from thymus implantation.

PMID:39734035 | DOI:10.1016/j.jaci.2024.12.1082

J Clin Immunol. 2024 Dec 27;45(1):59. doi: 10.1007/s10875-024-01853-z.

ABSTRACT

Inborn errors of immunity (IEI) are a heterogenous group of rare monogenic disorders that affect innate or adaptive immunity, resulting in susceptibility to life-threatening infections and autoimmunity. Allogeneic hematopoietic cell transplantation (HCT) is a valuable curative option for children with IEI. We conducted a retrospective single-center study on the outcome of HCT in children with IEI. Primary outcome was overall survival (OS). We gathered data from 55 patients underwent HCT in the period 2014 to 2023. The indications for HCT were CGD (n = 14), HLH (n = 12), SCID (n = 10), and others (n = 19). Median age at HCT was 3 years (range 0.1-17). Donors were HLA-matched related (n = 27), haploidentical (n = 24), and cord (n = 4). The conditioning regimens were myeloablative (n = 34), reduced intensity (n = 18), or no conditioning (n = 3). After a median follow-up of 43 months (range 13-120), 2-year OS was 93%, 2-year EFS 79% and 2 year GvHD-free relapse-free survival (GRFS) was 69%. Univariate analysis showed that bone marrow source was significantly associated with better EFS and GRFS. Cumulative incidence of grade 2-4 acute and moderate/severe chronic GvHD were 21% and 13%, respectively. Incidence of graft failure was 13%. In conclusion, HCT is feasible and curative in children with IEI. Early diagnosis and referral in addition to timely treatment can further improve outcomes.

PMID:39729175 | DOI:10.1007/s10875-024-01853-z

J Family Med Prim Care. 2024 Nov;13(11):5067-5071. doi: 10.4103/jfmpc.jfmpc_664_24. Epub 2024 Nov 18.

ABSTRACT

BACKGROUND: Bell’s palsy (BP) is a cranial nerve disorder in which unilateral or bilateral paralysis of the facial nerve occurs. The study aims to study BP’s characteristics, including its clinical manifestations, prognosis, and complications among adult patients aged 18 years and above.

METHODS: A retrospective study of adult patients diagnosed with BP in a primary care setting] [January 2015 to December 2022].

RESULTS: The study included a total number of 92 patients with an incidence rate of 23 cases per 100,000 people. The mean age was 43.52 years. The most common symptoms reported were dropping of the mouth at 38.9%, loss of forehead muscle movement at 24.4%, loss of nasolabial fold at 22.2%, loss of facial expressions at 20%, and headache at 18.9%. Immunodeficiency affected 2.3% of the patients. The management of patients involved the use of steroids in 76.1% and the use of antiretroviral medications in 48.9%. Physiotherapy was used in 29.5%. The complete recovery rate during the first year was 90.8%. The rate of complete recovery within two years was 96.9%.

CONCLUSION: The incidence of BP in the region seems to be similar to the incidence rate reported elsewhere in the world. The use of antiviral therapy seems to be high despite the controversy around the use of antivirals in the management of BP. The majority of patients with BP recover within the first year.

PMID:39722915 | PMC:PMC11668478 | DOI:10.4103/jfmpc.jfmpc_664_24

Cent Eur J Immunol. 2024;49(3):300-307. doi: 10.5114/ceji.2024.142340. Epub 2024 Sep 20.

ABSTRACT

This study presents a detailed clinical case of a 10-year-old boy with a history of prolonged cough, fever, and delayed diagnosis of bronchiectasis. Review of the case revealed that the child has had recurrent bronchitis, otitis media, skin allergies, and viral warts since early childhood, indicating persistent immune system abnormalities. Imaging studies, including pulmonary and sinus CT scans, show significant bronchiectasis accompanied by infections and sinusitis. Immunological assessment revealed abnormalities in immunoglobulin levels and T-cell distribution, suggesting a potential immune deficiency. Whole exome sequencing did not identify any genetic variants highly associated with and definitively pathogenic for bronchiectasis but detected a compound heterozygous missense mutation c.420A>T (p.R140S) in the IL2RG gene, linked to primary combined immunodeficiency (CID), a clinical phenotype rarely reported in China due to this gene mutation. This case report not only enhances our understanding of CID but also provides a new addition to the genetic landscape of CID both domestically and internationally, aiding in earlier diagnosis and treatment of such diseases in clinical practice. During the 18-month follow-up period, the child was unable to participate in physical activities, and experienced recurrent rhinitis, sinusitis, and warts. The child’s current weight and height are 30 kg and 140 cm, respectively.

PMID:39720273 | PMC:PMC11664801 | DOI:10.5114/ceji.2024.142340

Adv Biomed Res. 2024 Nov 30;13:112. doi: 10.4103/abr.abr_134_23. eCollection 2024.

ABSTRACT

BACKGROUND: The relationship between inborn errors of immunity (IEIs) and COVID-19 severity and incidence rates remains unclear due to limited and diverse data. This study aimed to address this gap by identifying specific IEIs associated with an increased risk of severe COVID-19 or a predisposition to severe disease before vaccination.

MATERIALS AND METHODS: Data were collected from the medical records of 15 patients with various IEIs, supplemented by interviews with individuals from an IEIs registry who had experienced COVID-19 before vaccination.

RESULTS: Among the participants, only three patients (20%) experienced severe-prolonged COVID-19. Notably, this severity was predominantly observed in two male patients with Bruton’s disease (BD) and one female patient with autosomal recessive hypogammaglobinemia. Moderate and severe COVID-19 cases were equally distributed (13.33%). In the female subgroup, one patient with common variable immunodeficiency and another with combined immunodeficiency experienced moderate and severe COVID-19, respectively. Conversely, both male patients with moderate and severe COVID-19 had BD.

CONCLUSION: Despite the limited number of severe cases, the absence of cytokine storm manifestation suggests potential protective mechanisms, possibly due to intravenous immunoglobulin therapy and inherent deficiencies within cytokine-producing cells (B and T cells). While IEIs may not be significant risk factors for COVID-19, they offer promising avenues for further research into therapeutic strategies targeting specific immune system components to mitigate severe COVID-19.

PMID:39717240 | PMC:PMC11665184 | DOI:10.4103/abr.abr_134_23

Ann Allergy Asthma Immunol. 2024 Dec 21:S1081-1206(24)01739-3. doi: 10.1016/j.anai.2024.12.016. Online ahead of print.

ABSTRACT

Inborn Errors of Immunity are a rapidly expanding group of monogenetic disorders affecting the immune system. Advancements in genetic testing and functional validation studies have accelerated the pace of IEI gene discovery and mechanism of disease, particularly in the past five years. To keep up with this rapid expansion, the International Union of Immunological Societies (IUIS) Expert Committee has periodically, since 1999, released updated IEI classifications with corresponding genotypic and phenotypic catalogues with its most recent update in 2022.1-5 Now there are over 485 monogenetic disorders of the immune system described among 10 main groups of classification. This article reviews recent clinical developments in IEI, including a closer look at some of the more recently described IEI disorders. In particular we highlight a few disorders with the following clinical phenotypes of IEI: severe atopy, immunodeficiency with immune dysregulation, immune dysregulation with lymphoproliferation, autoinflammation, and innate phenotype. To aid the clinician, we also provide a diagnostic approach to use when there is suspicion of IEI and a discussion of management and treatment.

PMID:39716531 | DOI:10.1016/j.anai.2024.12.016

J Clin Immunol. 2024 Dec 23;45(1):58. doi: 10.1007/s10875-024-01835-1.

ABSTRACT

BACKGROUND: Activated Phosphoinositide 3-Kinase (PI3K) δ Syndrome (APDS), an inborn error of immunity due to upregulation of the PI3K pathway, leads to recurrent infections and immune dysregulation (lymphoproliferation and autoimmunity).

METHODS: Clinical and genetic data of 28 APDS patients from 25 unrelated families were collected from fifteen Italian centers.

RESULTS: Patients were genetically confirmed with APDS-1 (n = 20) or APDS-2 (n = 8), with pathogenic mutations in the PIK3CD or PIK3R1 genes. The median age at diagnosis was 15.5 years, with a median follow-up of 74 months (range 6-384). The main presenting symptoms were respiratory tract infections alone (57%) or associated with lymphoproliferation (17%). Later, non-clonal lymphoproliferation was the leading clinical sign (86%), followed by respiratory infections (79%) and gastrointestinal complications (43%). Malignant lymphoproliferative disorders, all EBV-encoding RNA (EBER)-positive at the histological analysis, occurred in 14% of patients aged 17-19 years, highlighting the role of EBV in lymphomagenesis in this disorder. Diffuse large B-cell lymphoma was the most frequent. Immunological work-up revealed combined T/B cell abnormalities in most patients. Treatment strategies included immunosuppression and PI3K/Akt/mTOR inhibitor therapy. Rapamycin, employed in 36% of patients, showed efficacy in controlling lymphoproliferation, while selective PI3Kδ inhibitor leniolisib, administered in 32% of patients, was beneficial on both infections and immune dysregulation. Additionally, three patients underwent successful HSCT due to recurrent infections despite ongoing prophylaxis or lymphoproliferation poorly responsive to Rapamycin.

CONCLUSIONS: This study underscores the clinical heterogeneity and challenging diagnosis of APDS, highlighting the importance of multidisciplinary management tailored to individual needs and further supporting leniolisib efficacy.

PMID:39714594 | DOI:10.1007/s10875-024-01835-1

World J Methodol. 2024 Dec 20;14(4):96380. doi: 10.5662/wjm.v14.i4.96380. eCollection 2024 Dec 20.

ABSTRACT

Inborn errors of immunity (IEI) disorders, formerly primary immune deficiency diseases, are a heterogeneous group of disorders with variable hereditary transitions, clinical manifestations, complications and varying disease severity. Many of the clinical symptoms, signs and complications in IEI patients can be attributed to inflammatory and immune dysregulatory processes due to loss of microbial diversity (dysbiosis). For example, in common variable immunodeficiency patients, the diversity of bacteria, but not fungi, in the gut microbiota has been found to be reduced and significantly altered. Again, this was associated with a more severe disease phenotype. Compromise of the STAT3/Th17 pathway in hyper-IgE syndrome may lead to dysbiosis of the oral microbiota in these patients, causing Candida albicans to switch from commensal to pathogenic. Modification of the microbiota can be used as a therapeutic approach in patients with IEI. Prebiotics, probiotics, postbiotics and fecal microbiota transplantation can be used to restore the balance of the gut microbiota and reduce pathogenicity in IEI patients. Clinical trials are currently underway to understand the impact of this dysbiosis on the phenotype of IEI diseases and its role in their treatment.

PMID:39712559 | PMC:PMC11287548 | DOI:10.5662/wjm.v14.i4.96380

Front Immunol. 2024 Dec 5;15:1477499. doi: 10.3389/fimmu.2024.1477499. eCollection 2024.

ABSTRACT

BACKGROUND: According to the WHO’s recommendation for developing countries, Bacillus Calmette-Guerin (BCG) vaccination has been implemented in some countries as part of national vaccination programs at birth. Although it is generally considered safe, some complications may occur; including BCGitis (local) or BCGosis (systemic), ranging from mild like local abscesses to fatal impediments like osteomyelitis and disseminated BCG infection. This study aimed to determine the spectrum of inborn errors of immunity (IEI) in BCG-vaccinated neonates experiencing local or systemic complications.

METHODS: In this cross-sectional study, we investigated Iranian children referred to the Immunology, Asthma, and Allergy Research Institute (IAARI) between 2007-2023 for suspected immunodeficiency. Medical history was recorded, and primary screening tests for immunodeficiency were conducted for all cases. For suspected cases, more advanced immunologic investigations were performed to reach a definitive diagnosis. Furthermore, the study incorporated the documented genetic findings of the patients under investigation. All patients with inborn error of immunity who had a history of BCG vaccine complications within the first year of vaccination were enrolled in the study.

RESULTS: We investigated 3,275 cases suspected of IEI, identifying197 patients with both IEI and BCG vaccine complications. Among these, 127 (64.5%) were male. Symptoms began at or before 3 months of age in 64.8% of the cases, and parental consanguinity was reported in 79.2%. Genetic diagnoses were confirmed in 108 patients. Of the 197 patients, 108 (54.8%) had BCGitis, while 89 (45.2%) experienced systemic complications (BCGosis). A family history of IEI, BCG-related complications, and unexplained deaths were observed in 20.3%, 12.2%, and 29.9% of cases, respectively. Furthermore, 46.2% had at least one of these three risk factors in their history.

CONCLUSIONS: Early BCG vaccine complications may indicate an underlying immunodeficiency, particularly when there is a positive family history of BCG complications, immunodeficiency, or unexplained deaths. Nation-wide vaccination protocols should address this issue by delaying inoculation to allow for immunological screening of suspected immunodeficient patients, thereby preventing BCG vaccine-related morbidity and mortality.

PMID:39712030 | PMC:PMC11659753 | DOI:10.3389/fimmu.2024.1477499

Respiration. 2024 Dec 19:1-23. doi: 10.1159/000543146. Online ahead of print.

ABSTRACT

During the COVID-19 pandemic the effectiveness of vaccines against SARS-CoV-2 in immunodeficient patients did not only affect the individual risk of these vulnerable patients but endangered the selection of new variants of concern due to prolonged virus shedding by these patients. In a tertiary center for pulmonary diseases, we investigated the immune response of 11 patients with primary humoral immunodeficiency and 13 healthy controls on the humoral and cellular level after full vaccination with a mRNA or vector vaccine against SARS-CoV-2. In the majority of patients (73%), we found antibodies against the Spike protein above the thresh-old of positivity. Likewise, patients showed a promising cellular response: the upregulated production of INFγ, TNFα and CXCL10 by T cells did not differ from the response of healthy controls. These results stress the importance to further discern an adequate immunological correlate of protection and the need to follow the effect of booster immunizations in this population at risk.

PMID:39701048 | DOI:10.1159/000543146