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New Insights into Immune Dysregulation Disorders
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New Insights into Immune Dysregulation Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 20 April 2026 | Viewed by 14894

Special Issue Editor

Dr. Francesco Saettini

E-Mail Website
Guest Editor
Centro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Interests: inborn errors of immunity; primary immunodeficiencies; clinical immunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Special Issue entitled "New Insights into Immune Dysregulation Disorders" in the International Journal of Molecular Sciences will present groundbreaking research on the molecular mechanisms of immune dysregulation disorders, encompassing autoimmune conditions, primary immunodeficiencies, and autoinflammatory disorders. It will highlight advancements in understanding specific genes, signalling pathways, and molecular interactions in the pathogenesis of these disorders. Advanced techniques, such as next-generation sequencing, CRISPR gene editing, and omics (proteomics, lipidomics, and metabolomics), will be utilised to uncover new molecular targets and biomarkers for early diagnosis and treatment. This Special Issue will discuss how this knowledge will lead to precision medicine approaches, including targeted biologics and gene therapies, aimed at restoring immune balance. By focusing on the molecular level of these conditions, this Special Issue aims to pave the way for novel therapeutic interventions that could significantly improve patient outcomes.

Dr. Francesco Saettini
Guest Editor

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Keywords

  • immune dysregulation disorders
  • autoimmune conditions
  • primary immunodeficiencies
  • autoinflammatory disorders

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Published Papers (6 papers)

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Research

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13 pages, 658 KB  
Communication
Expanding the Spectrum of Selective IgM Deficiency: From Infections to Immune Dysregulation
by Rebecca Fumagalli and Francesco Saettini
Int. J. Mol. Sci. 2025, 26(18), 9003; https://doi.org/10.3390/ijms26189003 - 16 Sep 2025
Viewed by 955
Abstract
IgM plays a central role in early immune responses, yet the clinical significance of its deficiency remains poorly defined. Current diagnostic criteria focus on selective IgM deficiency (sIgMD), characterized by persistently low IgM concentrations and recurrent infections, potentially overlooking patients with isolated IgM [...] Read more.
IgM plays a central role in early immune responses, yet the clinical significance of its deficiency remains poorly defined. Current diagnostic criteria focus on selective IgM deficiency (sIgMD), characterized by persistently low IgM concentrations and recurrent infections, potentially overlooking patients with isolated IgM deficiency and non-infectious manifestations. In this retrospective study, we analyzed a pediatric cohort with isolated IgM deficiency, irrespective of infectious history. Clinical features—including cytopenia, lymphoproliferation, autoimmunity, allergy, and inflammation—were similarly distributed in patients with and without infections. Importantly, 26% of patients received a molecular diagnosis consistent with inborn errors of immunity (IEIs), including several without recurrent infections. Longitudinal analysis revealed a dynamic course of IgM concentrations over time, allowing classification into chronic, intermittent, progressive, and resolved subtypes. These findings challenge the current definition of sIgMD, highlight the limitations of relying solely on infectious history, and suggest that isolated IgM deficiency may represent a broader and heterogeneous immunological phenotype. Molecular testing and extended follow-up may help identify underlying inborn errors of immunity and clarify long-term risks, even in patients initially lacking infectious complications. A redefinition of IgM deficiency is warranted. Full article
(This article belongs to the Special Issue New Insights into Immune Dysregulation Disorders)
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16 pages, 1452 KB  
Article
Genetic Landscape of Non-Remitting Neutropenia in Children and Chronic Idiopathic Neutropenia in Adults
by Alice Grossi, Grigorios Tsaknakis, Francesca Rosamilia, Marta Rusmini, Paolo Uva, Isabella Ceccherini, Maria Carla Giarratana, Diego Vozzi, Irene Mavroudi, Carlo Dufour, Helen A. Papadaki and Francesca Fioredda
Int. J. Mol. Sci. 2025, 26(14), 6929; https://doi.org/10.3390/ijms26146929 - 18 Jul 2025
Viewed by 824
Abstract
Non-remitting neutropenia in children and chronic idiopathic neutropenia (CIN) in adults have been described previously as peculiar subgroups of neutropenic patients carrying similar clinical and immunological features. The present collection comprising 25 subjects (16 adults and 9 children) mostly affected with mild (84%) [...] Read more.
Non-remitting neutropenia in children and chronic idiopathic neutropenia (CIN) in adults have been described previously as peculiar subgroups of neutropenic patients carrying similar clinical and immunological features. The present collection comprising 25 subjects (16 adults and 9 children) mostly affected with mild (84%) and moderate (16%) neutropenia aimed to identify the underlying (possibly common) genetic background. The phenotype of these patients resemble the one described previously: no severe infections, presence of rheumathological signs, leukopenia in almost all patients and lymphocytopenia in one-third of the cohort. The pediatric patients did not share common genes with the adults, based on the results of the multisample test, while some singular variants in neutropenia potentially associated with immune dysregulation likely consistent with the phenotype were found. SPINK5, RELA and CARD11 were retrieved and seem to be consistent with the clinical picture characterized by neutropenia associated to immune dysregulation. The enrichment and burden tests performed in comparison with a control group underline that the products of expression by the variants involved belong to the autoimmunity and immune regulation pathways (i.e., SPINK5, PTPN22 and PSMB9). Even with the limitation of this study’s low number of patients, these results may suggest that non-remitting neutropenia and CIN in adults deserve deep genetic study and enlarged consideration in comparison with classical neutropenia. Full article
(This article belongs to the Special Issue New Insights into Immune Dysregulation Disorders)
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18 pages, 3771 KB  
Article
Neutrophil Diversity (Immature, Aged, and Low-Density Neutrophils) and Functional Plasticity: Possible Impacts of Iron Overload in β-Thalassemia
by Kritsanawan Sae-Khow, Awirut Charoensappakit and Asada Leelahavanichkul
Int. J. Mol. Sci. 2024, 25(19), 10651; https://doi.org/10.3390/ijms251910651 - 3 Oct 2024
Cited by 10 | Viewed by 2851
Abstract
Neutrophil dysfunction is a form of immune suppression in patients with β-thalassemia (Beta-thal), although data on this are limited. In this study, blood from patients and healthy volunteers was analyzed. Flow cytometry analysis demonstrated an increase in immature neutrophils (CD16− CD62L+) and aged [...] Read more.
Neutrophil dysfunction is a form of immune suppression in patients with β-thalassemia (Beta-thal), although data on this are limited. In this study, blood from patients and healthy volunteers was analyzed. Flow cytometry analysis demonstrated an increase in immature neutrophils (CD16− CD62L+) and aged (senescent) neutrophils (CD16+ CD62L−) in Beta-thal patients compared to healthy volunteers. The Beta-thal neutrophils demonstrated less prominent chemotaxis and phagocytosis than healthy neutrophils at the baseline. With phorbol myristate acetate (PMA) or lipopolysaccharide (LPS) stimulations, some of the indicators, including the flow cytometry markers (CD11b, CD62L, CD66b, CD63, apoptosis, and reactive oxygen species) and neutrophil extracellular traps (NETs; detected by anti-citrullinated histone 3 immunofluorescence), were lower than the control. Additionally, low-density neutrophils (LDNs), which are found in the peripheral blood mononuclear cell (PBMC) fraction, were observed in Beta-thal patients but not in the control group. The expression of CD11b, CD66b, CD63, arginase I, and ROS in LDNs was higher than the regular normal-density neutrophils (NDNs). The proliferation rate of CD3+ T cells isolated from the PBMC fraction of healthy volunteers was higher than that of the cells from patients with Beta-thal. The incubation of red blood cell (RBC) lysate plus ferric ions with healthy NDNs transformed the NDNs into the aged neutrophils (decreased CD62L) and LDNs. In conclusion, iron overload induces neutrophil diversity along with some dysfunctions. Full article
(This article belongs to the Special Issue New Insights into Immune Dysregulation Disorders)
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Review

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26 pages, 964 KB  
Review
Gulf War Illness, Fibromyalgia, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Overlap in Common Symptoms and Underlying Biological Mechanisms: Implications for Future Therapeutic Strategies
by David Mantle, Joan Carles Domingo, Beatrice Alexandra Golomb and Jesús Castro-Marrero
Int. J. Mol. Sci. 2025, 26(18), 9044; https://doi.org/10.3390/ijms26189044 - 17 Sep 2025
Cited by 1 | Viewed by 3208
Abstract
Although Gulf War Illness (GWI), fibromyalgia (FM), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID have distinct origins, in this article we have reviewed evidence that these disorders comprise a group of so-called low-energy associated disorders with overlapping common symptoms underlying pathology. In [...] Read more.
Although Gulf War Illness (GWI), fibromyalgia (FM), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID have distinct origins, in this article we have reviewed evidence that these disorders comprise a group of so-called low-energy associated disorders with overlapping common symptoms underlying pathology. In particular, evidence for mitochondrial dysfunction, oxidative stress, inflammation, immune dysregulation, neuroendocrine dysfunction, disrupted brain–gut-microbiome axis, apoptosis/ferroptosis and telomere shortening as common features in the pathogenesis of these disorders has been identified. Given the role of coenzyme Q10 (CoQ10) in promoting normal mitochondrial function, as an antioxidant, antiinflammatory and antiapoptotic and antiferroptotic agent, there is a rationale for supplementary CoQ10 in the management of these disorders. The reported benefits of supplementary CoQ10 administration in GWI, FM, ME/CFS and long COVID have been reviewed; the potential benefit of supplementary CoQ10 in reducing telomere shortening and improving the efficiency of stem cell transfer relevant has also been identified as promising therapeutic strategies in these disorders. This review advances beyond previous systematic reviews and consensus statements on overlapping similar symptoms and underlying biological pathomechanisms in these complex disorders. Full article
(This article belongs to the Special Issue New Insights into Immune Dysregulation Disorders)
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22 pages, 1544 KB  
Review
Interaction Between Neutrophils and Elements of the Blood–Brain Barrier in the Context of Multiple Sclerosis and Ischemic Stroke
by Anna Nowaczewska-Kuchta, Dominika Ksiazek-Winiarek and Andrzej Glabinski
Int. J. Mol. Sci. 2025, 26(9), 4437; https://doi.org/10.3390/ijms26094437 - 7 May 2025
Cited by 4 | Viewed by 3299
Abstract
The blood–brain barrier (BBB) is a semi-permeable membrane in physiological conditions, but in pathologies like multiple sclerosis (MS) and ischemic stroke (IS), its permeability increases. In this review, we focus on neutrophils and their interaction with cellular components of the BBB: endothelial cells [...] Read more.
The blood–brain barrier (BBB) is a semi-permeable membrane in physiological conditions, but in pathologies like multiple sclerosis (MS) and ischemic stroke (IS), its permeability increases. In this review, we focus on neutrophils and their interaction with cellular components of the BBB: endothelial cells (EC), pericytes (PC), and astrocytes (AC). Nowadays, neutrophils receive more attention, mostly due to advanced research techniques that show the complexity of their population. Additionally, neutrophils have the ability to secrete extracellular vesicles (EVs), reactive oxygen species (ROS) and cytokines, which both destroy and restore the BBB. Astrocytes, PCs, and ECs also have dual roles in the pathogenesis of MS and IS. The interaction between neutrophils and cellular components of the BBB provides us with a wider insight into the pathogenesis of common diseases in the central nervous system. Further, we comprehensively review knowledge about the influence of neutrophils on the BBB in the context of MS and IS. Moreover, we describe new therapeutic strategies for patients with MS and IS like cell-based therapies and therapies that use the neutrophil function. Full article
(This article belongs to the Special Issue New Insights into Immune Dysregulation Disorders)
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Other

Jump to: Research, Review

12 pages, 2822 KB  
Case Report
Multiple Tumors in a Patient with Interleukin-2-Inducible T-Cell Kinase Deficiency: A Case Report
by Michela Di Filippo, Ramona Tallone, Monica Muraca, Lisa Pelanconi, Francesca Faravelli, Valeria Capra, Patrizia De Marco, Marzia Ognibene, Simona Baldassari, Paola Terranova, Virginia Livellara, Valerio Gaetano Vellone, Maurizio Miano, Loredana Amoroso and Andrea Beccaria
Int. J. Mol. Sci. 2024, 25(23), 13181; https://doi.org/10.3390/ijms252313181 - 7 Dec 2024
Viewed by 1834
Abstract
Immune dysregulation in Inborn Errors of Immunity (IEI) shows a broad phenotype, including autoimmune disorders, benign lymphoproliferation, and malignancies, driven by an increasing number of implicated genes. Recent findings suggest that childhood cancer survivors (CCSs) may exhibit immunological abnormalities potentially linked to an [...] Read more.
Immune dysregulation in Inborn Errors of Immunity (IEI) shows a broad phenotype, including autoimmune disorders, benign lymphoproliferation, and malignancies, driven by an increasing number of implicated genes. Recent findings suggest that childhood cancer survivors (CCSs) may exhibit immunological abnormalities potentially linked to an underlying IEI, along with a well-known increased risk of subsequent malignancies due to prior cancer treatments. We describe a patient with two composite heterozygous pathogenic variants in the interleukin-2-inducible T-cell kinase (ITK) gene and a history of multiple tumors, including recurrent Epstein–Barr virus (EBV)-related nodular sclerosis and Hodgkin’s lymphoma (NSHL), associated with unresponsive multiple hand warts, immune thrombocytopenia, and an impaired immunological profile (CD4+ lymphocytopenia, memory B-cell deficiency, reduction in regulatory T-cells, and B-cell- and T-cell-activated profiles). In our case, ITK-related immune dysregulation and prior exposure to oncological treatments seem to have simultaneously intervened in the same individual, leading to the development of a unique clinical profile. It is essential to raise awareness of the two-way association between immune dysregulation disorders and multiple tumors. Full article
(This article belongs to the Special Issue New Insights into Immune Dysregulation Disorders)
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