This issue of the International Reviews of Immunology is again dedicated to primary and acquired immunodeficiencies, some of the underlying molecular and cellular mechanisms, as well as their relationship with genetic, environmental factors and other categories of diseases.
The lead article by Yazdani et al. provides a very comprehensive state of the art of what is currently known relative to defects in signaling-associated molecules in patients with common variable immunodeficiency (CVID). In this review, defects of cell signaling associated molecules at three levels, of surface, cytoplasmic and nuclear molecules, are highlighted. They comprise genetic defects of key B and T cell signaling pathways, as well as Toll-like-receptor (TLR) pathways that influence both innate and adaptive immunity. TLR-related pathway defects present an enormous interest from both theoretical and practical standpoints. Multiple studies have identified defective TLR7 and TLR9 signaling in B-cells and plasmacytoid dendritic cells (pDCs) from CVID patients. Analysis of genetic defects in TLR9, a sensor of unmethylated DNA of bacterial origin, uncovered the key role of this pathway in initiating and sustaining a robust B cell response against microbial antigens such as capsular polysaccharides, including driving hypersomatic mutation, class-switch recombination, and plasma cell differentiation. Furthermore, protracted or repeated bacterial infections in CVID patients could be due to defects downstream of TLRs, such as NEMO, and are correlated with impaired B-cell differentiation and increased frequency of encapsulated pyogenic bacterial infections. The authors discuss extensively the connection between CVID and immunopathology, as well as the defects of the B cell receptor complex comprising CD19, CD21 and CD81, and of other costimulatory molecules including ICOS, CD20, BAFFR and TACI. All of these defects resulted in decreased immunoglobulin production and reduction of memory B-cells, along with some manifestations of autoimmunity. In addition to defects in innate immune and B cell signaling pathways, the authors discuss T cell signaling pathways that can contribute to CVID: lymphocyte-specific cytosolic tyrosine kinase (LCK), zeta-chain-associated protein 70 kD (ZAP-70), inositol-1,4,5-triphosphate (IP3), the guanine nucleotide exchange factor (Vav), the Ras-related C3 botulinum toxin substrate 2 (RAC2), phospholipase Cγ2 (PLCγ2), CARD-containing MAGUK protein 1 (CARMA1), extracellular signal-regulated kinases (ERK), as well as other molecules that affect the development and functionality of T cells. Finally, the authors review the evidence to date on the role of NF-kB and DNA repair system in CVID.
In a second review, D'Assante et al. review the links between ectodermal disorders and a subset of primary immunodeficiencies. Primary immunodeficiencies (PIDs) include a heterogeneous group of mostly monogenic diseases characterized by functional developmental alterations of the immune system. Skin and skin annexa abnormalities may be a warning sign of immunodeficiency since both the epidermal and thymic epithelia have ectodermal origin. Thus, genetic abnormalities that affect the ectodermal layer could influence both systems: skin/mucosa and immune. This review focuses on the most common immune disorders associated with ectodermal alterations: Hyper-IgE Syndrome (HIES), characterized by severe eczema and susceptibility to infections; Ectodermal Dysplasia (ED), a group of rare disorders that affect tissues of ectodermal origin; a category of diseases associated with NEMO mutations (Hypoidrotic ED [HED], and X-linked HED); alterations in the transcription factor FOXN1 gene expressed in the mature thymic and skin epithelia, with drastic effect on T cell development and associated with ectodermal abnormalities such as alopecia and nail dystrophy. The relationship between the immune system and epithelial tissues is intriguing and complex, as skin explants have been shown to sustain some T cell differentiation in the absence of functional thymus.
A subcategory of immunodeficiencies of interest is represented by primary immunodeficiencies with elevated IgE. Trine Mogensen describes in detail this affliction characterized by elevated IgE and termed “Hyper-IgE syndrome” (HIES). In addition to the elevated levels of IgE, patients with this condition display a spectrum of infections by staphylococci and fungi, and even viruses, particularly affecting skin and lungs. This set of diseases have also a non-infectious phenotype, comprising musculoskeletal, vascular, and neurological abnormalities due to mutations in STAT3, DOCK8, TYK2, and PGM3 molecules. Thus, the increased levels of IgE represent only one aspect of a multifaceted syndrome that affects immune and non-immune tissues alike, as the gene defects are upstream of lymphoid tissue ontogenesis and control development of a variety of organs in addition to the differentiation and function of various immune cells.
Changing the topic, Seyed Hossein Aalaei-andabili and Nima Rezaei discuss the emerging role of MicroRNAs (MiRs) in regulating the immune system development and function in context of immunesenescence. As the human aging process is a complex process with pivotal changes in gene expression of biological pathways, immune system dysfunctions have been recognized in senescence. The authors performed a systematic meta-analysis of the literature connecting MiRs with immunosenescence. Out of 46 articles of interest, 12 studies were found to be directly relevant to this subject. MiRs appear to be involved in the regulation of the aging process of the immune system primarily by controlling the life span of the immune cells through genes involved in apoptosis. An interesting connection between the NF-kB pathway and promoter activity of MiRs regulating immune cells is showcased by the authors.
Last but not least, Jorge Cervantes and Bo-Young Hong discuss a poorly understood topic, dysbiosis and immune dysregulation in outer space. In space, the relative sterility and extreme environmental stresses such as microgravity and cosmic radiation can compromise the balance between the human body and human microbiome that should provide a continuous tonic stimulation to the immune system. In addition to environmental stresses, cortisol increases paralleling the strenuous and stressful nature of the work in space does also have a deleterious impact on the immune system. The authors perform a meta-analysis of the published literature on this topic and conclude that a key pre-emptive strategy is to maintain an adequate balanced microbiome that would provide an appropriate direct and indirect defense against horizontal transmission of pathogens or invasion by pre-existing colonizing pathogenic microbes.
The next issues of the journal will approach a broad range of topics of interest to our readership, such as the interface between cancer and immunity, immune regulating molecules and novel aspects related to the innate immunity.