Immunological Reviews

Severe combined immune deficiency due to adenosine deaminase deficiency (ADA SCID) is an inborn error of immunity with pan-lymphopenia, due to accumulated cytotoxic adenine metabolites. ADA SCID has been treated using gene therapy with a normal human ADA gene added to autologous hematopoietic stem cells (HSC) for over 30 years. Iterative improvements in vector design, HSC processing methods, and clinical HSC transplant procedures have led nearly all ADA SCID gene therapy patients to achieve consistently beneficial immune restoration with stable engraftment of ADA gene-corrected HSC over the duration of observation (as long as 20 years)...

Common variable immunodeficiency (CVID) is a heterogenous disease category created to distinguish late-onset antibody deficiencies from early-onset diseases like agammaglobulinemia or more expansively dysfunctional combined immunodeficiencies. Opinions vary on which affected patients should receive a CVID diagnosis which confuses clinicians and erects reproducibility barriers for researchers. Most experts agree that CVID's most indeliable feature is defective germinal center (GC) production of isotype-switched, affinity-maturated antibodies...

Infectious susceptibility is a component of many inborn errors of immunity. Nevertheless, antibiotic use is often used as a surrogate in history taking for infectious susceptibility, thereby disadvantaging patients who present with viral infections as their phenotype. Further complicating clinical evaluations are unusual manifestations of viral infections which may be less familiar that the typical respiratory viral infections. This review covers several unusual viral phenotypes arising in patients with inborn errors of immunity and other settings of immune compromise...

FOXP3 gene is a key transcription factor driving immune tolerance and its deficiency causes immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome (IPEX), a prototypic primary immune regulatory disorder (PIRD) with defective regulatory T (Treg) cells. Although life-threatening, the increased awareness and early diagnosis have contributed to improved control of the disease. IPEX currently comprises a broad spectrum of clinical autoimmune manifestations from severe early onset organ involvement to moderate, recurrent manifestations...

The essential role of B cells is to produce protective immunoglobulins (Ig) that recognize, neutralize, and clear invading pathogens. This results from the integration of signals provided by pathogens or vaccines and the stimulatory microenvironment within sites of immune activation, such as secondary lymphoid tissues, that drive mature B cells to differentiate into memory B cells and antibody (Ab)-secreting plasma cells. In this context, B cells undergo several molecular events including Ig class switching and somatic hypermutation that results in the production of high-affinity Ag-specific Abs of different classes, enabling effective pathogen neutralization and long-lived humoral immunity...

Cancer arises from the growth and division of uncontrolled erroneous cells. Programmed cell death (PCD), or regulated cell death (RCD), includes natural processes that eliminate damaged or abnormal cells. Dysregulation of PCD is a hallmark of cancer, as cancer cells often evade cell death and continue to proliferate. Exosomes nanoscale extracellular vesicles secreted by different types of cells carrying a variety of molecules, including nucleic acids, proteins, and lipids, to have indispensable role in the communication between cells, and can influence various cellular processes, including PCD...

The cellular stress and immunity cycle is a cornerstone of organismal homeostasis. Stress activates intracellular and intercellular communications within a tissue or organ to initiate adaptive responses aiming to resolve the origin of this stress. If such local measures are unable to ameliorate this stress, then intercellular communications expand toward immune activation with the aim of recruiting immune cells to effectively resolve the situation while executing tissue repair to ameliorate any damage and facilitate homeostasis...

Ferroptosis is a novel form of programmed cell death morphologically, genetically, and biochemically distinct from other cell death pathways and characterized by the accumulation of iron-dependent lipid peroxides and oxidative damage. It is now understood that ferroptosis plays an essential role in various biological processes, especially in the metabolism of iron, lipids, and amino acids. Gastric cancer (GC) is a prevalent malignant tumor worldwide with low early diagnosis rates and high metastasis rates, accounting for its relatively poor prognosis...

Necroptosis is generally considered as an inflammatory cell death form. The core regulators of necroptotic signaling are receptor-interacting serine-threonine protein kinases 1 (RIPK1) and RIPK3, and the executioner, mixed lineage kinase domain-like pseudokinase (MLKL). Evidence demonstrates that necroptosis contributes profoundly to inflammatory respiratory diseases that are common public health problem. Necroptosis occurs in nearly all pulmonary cell types in the settings of inflammatory respiratory diseases...

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Neutrophils are important in the context of innate immunity and actively contribute to the progression of diverse autoimmune disorders. Distinct death mechanisms of neutrophils may exhibit specific and pivotal roles in autoimmune diseases and disease pathogenesis through the orchestration of immune homeostasis, the facilitation of autoantibody production, the induction of tissue and organ damage, and the incitement of pathological alterations. In recent years, more studies have provided in-depth examination of various neutrophil death modes, revealing nuances that challenge conventional understanding and underscoring their potential clinical utility in diagnosis and treatment...

Cell death can be executed through distinct subroutines. PANoptosis is a unique inflammatory cell death modality involving the interactions between pyroptosis, apoptosis, and necroptosis, which can be mediated by multifaceted PANoptosome complexes assembled via integrating components from other cell death modalities. There is growing interest in the process and function of PANoptosis. Accumulating evidence suggests that PANoptosis occurs under diverse stimuli, for example, viral or bacterial infection, cytokine storm, and cancer...

Antigen cross-priming of CD8+ T cells is a critical process necessary for the effective expansion and activation of CD8+ T cells endowed with the ability to recognize and destroy tumor cells. The cross-presentation of tumor antigens to cross-prime CD8+ T cells is mainly mediated, if not only, by a subset of professional antigen-presenting cells termed type-1 conventional dendritic cells (cDC1). The demise of malignant cells can be immunogenic if it occurs in the context of premortem stress. These ways of dying are termed immunogenic cell death (ICD) and are associated with biochemical features favoring cDC1 for the efficient cross-priming of tumor antigens...

The failure to resolve inflammation underpins to several prevalent diseases, like atherosclerosis, and so identifying ways to boost resolution is unmet clinical needs. The resolution of inflammation is governed by several factors such as specialized pro-resolving mediators (SPMs) that counter-regulate pro-inflammatory pathways and promote tissue repair without compromising host defense. A major function of nearly all SPMs is to enhance the clearance of dead cells or efferocytosis. As such, phagocytes, such as macrophages, are essential cellular players in the resolution of inflammation because of their ability to rapidly and efficiently clear dead cells...

Copper is an essential nutrient for maintaining enzyme activity and transcription factor function. Excess copper results in the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), which correlates to the mitochondrial tricarboxylic acid (TCA) cycle, resulting in proteotoxic stress and eliciting a novel cell death modality: cuproptosis. Cuproptosis exerts an indispensable role in cancer progression, which is considered a promising strategy for cancer therapy. Cancer immunotherapy has gained extensive attention owing to breakthroughs in immune checkpoint blockade; furthermore, cuproptosis is strongly connected to the modulation of antitumor immunity...

The process of neutrophil extracellular traps (NETs) formation, called NETosis, is a peculiar death modality of neutrophils, which was first observed as an immune response against bacterial infection. However, recent work has revealed the unique biology of NETosis in facilitating tumor metastatic process. Neutrophil extracellular traps released by the tumor microenvironment (TME) shield tumor cells from cytotoxic immunity, leading to impaired tumor clearance. Besides, tumor cells tapped by NETs enable to travel through vessels and subsequently seed distant organs...

Digestive tract cancers (DTC) belong to the most investigated family of tumors. The incidence, prevalence, and mortality rate of DTC remain high, especially for patients with pancreatic cancer. Even though immunotherapy such as immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid cancer types, ICI are still restricted to a very small group of patients and seem to be more efficacious in combination with chemotherapy. Cellular immunotherapy such as CAR T-cell therapy has entered clinical routine in hematological malignancies with outstanding results...

Non-small-cell lung cancer (NSCLC), which has a high rate of metastatic spread and drug resistance, is the most common subtype of lung cancer. Therefore, NSCLC patients have a very poor prognosis and a very low chance of survival. Human cancers are closely linked to regulated cell death (RCD), such as apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. Currently, small-molecule compounds targeting various types of RCD have shown potential as anticancer treatments. Moreover, RCD appears to be a specific part of the antitumor immune response; hence, the combination of RCD and immunotherapy might increase the inhibitory effect of therapy on tumor growth...

Neuropathic pain is a common and debilitating modality of chronic pain induced by a lesion or disease of the somatosensory nervous system. Albeit the elucidation of numerous pathophysiological mechanisms and the development of potential treatment compounds, safe and reliable therapies of neuropathic pain remain poor. Multiple stress/cell death pathways have been shown to be implicated in neuroinflammation during neuropathic pain. Here, we summarize the current knowledge of stress/cell death pathways and present an overview of the roles and molecular mechanisms of stress/cell death pathways in neuroinflammation during neuropathic pain, covering intrinsic and extrinsic apoptosis, autophagy, mitophagy, ferroptosis, pyroptosis, necroptosis, and phagoptosis...

Cancer cells undergoing immunogenic cell death (ICD) can initiate adaptive immune responses against dead cell-associated antigens, provided that (1) said antigens are not perfectly covered by central tolerance (antigenicity), (2) cell death occurs along with the emission of immunostimulatory cytokines and damage-associated molecular patterns (DAMPs) that actively engage immune effector mechanisms (adjuvanticity), and (3) the microenvironment of dying cells is permissive for the initiation of adaptive immunity...