Immunological Reviews

Maternal environmental exposures, particularly during gestation and lactation, significantly influence the immunological development and long-term immunity of offspring. Mammalian immune systems develop through crucial inputs from the environment, beginning in utero and continuing after birth. These critical developmental windows are essential for proper immune system development and, once closed, may not be reopened. This review focuses on the mechanisms by which maternal exposures, particularly to pathogens, diet, and microbiota, impact offspring immunity...

Since their description by Metchnikoff in 1905, phagocytes have been increasingly recognized to be the entities that traffic to sites of infection and inflammation, engulf and kill infecting organisms, and clear out apoptotic debris all the while making antigens available and accessible to the lymphoid organs for future use. Therefore, phagocytes provide the gateway and the first check in host protection and immune response. Disorders in killing and chemotaxis lead not only to infection susceptibility, but also to autoimmunity...

NK cells are short-lived innate lymphocytes that can mediate antigen-independent responses to infection and cancer. However, studies from the past two decades have shown that NK cells can acquire transcriptional and epigenetic modifications during inflammation that result in increased survival and lifespan. These findings blur the lines between the innate and adaptive arms of the immune system, and suggest that the homeostatic mechanisms that govern the persistence of innate immune cells are malleable. Indeed, recent studies have shown that NK cells undergo continuous and strictly regulated adaptations controlling their survival during development, tissue residency, and following inflammation...

The ability of cells of the immune system to acquire features such as increased longevity and enhanced secondary responses was long thought to be restricted to cells of the adaptive immune system. Natural killer (NK) cells have challenged this notion by demonstrating that they can also gain adaptive features. This has been observed in both humans and mice during infection with cytomegalovirus (CMV). The generation of adaptive NK cells requires antigen-specific recognition of virally infected cells through stimulatory NK receptors...

Inborn errors of immunity (IEI) comprise a diverse spectrum of 485 disorders as recognized by the International Union of Immunological Societies Committee on Inborn Error of Immunity in 2022. While IEI are monogenic by definition, they illuminate various pathways involved in the pathogenesis of polygenic immune dysregulation as in autoimmune or autoinflammatory syndromes, or in more common infectious diseases that may not have a significant genetic basis. Rapid improvement in genomic technologies has been the main driver of the accelerated rate of discovery of IEI and has led to the development of innovative treatment strategies...

No abstract text is available yet for this article.

Inborn errors of immunity (IEIs) encompass a diverse spectrum of genetic disorders that disrupt the intricate mechanisms of the immune system, leading to a variety of clinical manifestations. Traditionally associated with an increased susceptibility to recurrent infections, IEIs have unveiled a broader clinical landscape, encompassing immune dysregulation disorders characterized by autoimmunity, severe allergy, lymphoproliferation, and even malignancy. This review delves into the intricate interplay between IEIs and the JAK-STAT signaling pathway, a critical regulator of immune homeostasis...

Severe combined immunodeficiency (SCID) is a rare and life-threatening genetic disorder that severely impairs the immune system's ability to defend the body against infections. Often referred to as the "bubble boy" disease, SCID gained widespread recognition due to the case of David Vetter, a young boy who lived in a sterile plastic bubble to protect him from germs. SCID is typically present at birth, and it results from genetic mutations that affect the development and function of immune cells, particularly T cells and B cells...

Over 200,000 individuals in the United States alone live with Down Syndrome (DS), the most common genetic disorder associated with intellectual disability. DS has a constellation of features across the body, including dysregulation of the immune system. Individuals with DS have both a higher frequency of autoimmunity and more severe infections than the general population, highlighting the importance of understanding the immune system in this population. Individuals with DS present with dysregulation of both the innate and adaptive immune systems...

Inborn errors of immunity (IEI) present a unique paradigm in the realm of gene therapy, emphasizing the need for precision in therapeutic design. As gene therapy transitions from broad-spectrum gene addition to careful modification of specific genes, the enduring safety and effectiveness of these therapies in clinical settings have become crucial. This review discusses the significance of IEIs as foundational models for pioneering and refining precision medicine. We explore the capabilities of gene addition and gene correction platforms in modifying the DNA sequence of primary cells tailored for IEIs...

The thymus is the primary site of T-cell development, enabling generation, and selection of a diverse repertoire of T cells that recognize non-self, whilst remaining tolerant to self- antigens. Severe congenital disorders of thymic development (athymia) can be fatal if left untreated due to infections, and thymic tissue implantation is the only cure. While newborn screening for severe combined immune deficiency has allowed improved detection at birth of congenital athymia, thymic disorders acquired later in life are still underrecognized and assessing the quality of thymic function in such conditions remains a challenge...

Human autoantibodies (auto-Abs) neutralizing type I IFNs were first discovered in a woman with disseminated shingles and were described by Ion Gresser from 1981 to 1984. They have since been found in patients with diverse conditions and are even used as a diagnostic criterion in patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1). However, their apparent lack of association with viral diseases, including shingles, led to wide acceptance of the conclusion that they had no pathological consequences...

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...

From studies of individual families to global collaborative efforts, the NLRP3 inflammasome is now recognized to be a key regulator of innate immunity. Activated by a panoply of pathogen-associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18. Initially discovered as the cause of the autoinflammatory spectrum of cryopyrin-associated periodic syndrome (CAPS), NLRP3 is now also known to play a role in more common diseases including cardiovascular disease, gout, and liver disease...

Inflammatory bowel diseases (IBD) are multifactorial diseases which are caused by the combination of genetic predisposition, exposure factors (environmental and dietary), immune status, and dysbiosis. IBD is a disease which presents at any age, ranging from newborns to the elderly. The youngest of the pediatric IBD population have a more unique presentation and clinical course and may have a different etiology. Very early onset IBD (VEOIBD) patients, designated as those diagnosed prior the age of 6, have distinct features which are more frequent in this patient population including increased incidence of monogenetic causes for IBD (0%-33% depending on the study)...

Hemophagocytic lymphohistiocytosis (HLH) is a disorder that has been recognized since the middle of the last century. In recent decades, increasing understanding of the genetic roots and pathophysiology of HLH has led to improved diagnosis and treatment of this once universally fatal disorder. HLH is best conceptualized as a maladaptive state of excessive T cell activation driving life-threatening myeloid cell activation, largely via interferon-gamma (IFN-γ). In familial forms of HLH (F-HLH), inherited defects of lymphocyte cytotoxic biology underlie excessive T cell activation, demonstrating the importance of the perforin/granzyme pathway as a negative feedback loop limiting acute T cell activation in response to environmental factors...

No abstract text is available yet for this article.

Dendritic cells (DCs) are myeloid cells bridging the innate and adaptive immune system. By cross-presenting tumor-associated antigens (TAAs) liberated upon spontaneous or therapy-induced tumor cell death to T cells, DCs occupy a pivotal position in the cancer immunity cycle. Over the last decades, the mechanisms linking cancer cell death to DC maturation, have been the focus of intense research. Growing evidence supports the concept that the mere transfer of TAAs during the process of cell death is insufficient to drive immunogenic DC maturation unless this process is coupled with the release of immunomodulatory signals by dying cancer cells...

Germline human heterozygous STAT1 gain-of-function (GOF) variants were first discovered a common cause of chronic mucocutaneous candidiasis (CMC) in 2011. Since then, numerous STAT1 GOF variants have been identified. A variety of clinical phenotypes, including fungal, viral, and bacterial infections, endocrine disorders, autoimmunity, malignancy, and aneurysms, have recently been revealed for STAT1 GOF variants, which has led to the expansion of the clinical spectrum associated with STAT1 GOF. Among this broad range of complications, it has been determined that invasive infections, aneurysms, and malignancies are poor prognostic factors for STAT1 GOF...

Inborn errors of immunity (IEI) or primary immune deficiencies (PIDD) are caused by variants in genes encoding for molecules that are relevant to the innate or adaptive immune response. To date, defects in more than 450 different genes have been identified as causes of IEI, causing a constellation of heterogeneous clinical manifestations ranging from increased susceptibility to infection, to autoimmunity or autoinflammation. IEI that are mainly characterized by autoinflammation are broadly classified according to the inflammatory pathway that they predominantly perturb...