Inborn errors of immunity underlying a susceptibility to pyogenic infections: from innate immune system deficiency to complex phenotypes

BackgroundPyogenic bacteria are associated with a wide range of clinical manifestations, ranging from common and relatively mild respiratory and cutaneous infections to life-threatening localized or systemic infections, such as sepsis and profound abscesses. Despite vaccination and the widespread use of effective antibiotic treatment, severe infection is still observed in a subset of affected patients.ObjectivesWe aim to summarize the available data regarding inborn errors of immunity that result in a high risk of severe pyogenic infections.SourcesCase series, as well as review and original articles on human genetic susceptibility to pyogenic infections were examined.ContentWe review host-associated factors resulting in inborn errors of immunity and leading to a susceptibility to pyogenic infections, including deficiency in major components of the immune system (e.g., neutrophils, complement, immunoglobulin, and spleen function) and novel monogenic disorders resulting in specific susceptibility to pyogenic infection. Specifically, innate immune system deficiency involving toll-like receptors and associated signaling typically predispose to a narrow spectrum of bacterial diseases in otherwise healthy people, making a diagnosis more difficult to suspect and confirm. More complex syndromes, such as hyper IgE syndrome, are associated with a high risk of pyogenic infections due to an impairment of the interleukin-6 or -17 signaling, demonstrating the pivotal role of these pathways in controlling bacterial infections.ImplicationsIn clinical practice, awareness of such conditions is essential, especially in the pediatric setting, to avoid a potentially fatal diagnostic delay, set the most proper and prompt treatment, and ensure prevention of severe complications.     

Genetic susceptibility to viral disease in humans

BackgroundDuring the past decades, studies on patients with severe viral infections have revealed rare inborn errors of immunity (IEIs) underlying these diseases. This has led to important new insights into the molecular genetics and immunological mechanisms governing susceptibility to viral infection in humans.ObjectivesHerein, the current knowledge on major IEIs predisposing to severe or chronic viral infections are described and discussed, and the clinical implications of these findings for individualized prophylaxis and treatment are outlined.SourcesThe review is based on a broad literature search, including relevant studies primarily based on patients, supported by experimental molecular models in vitro or in mice, to characterize the pathophysiological mechanism governing these disease conditions.ContentCurrent concepts and principles of genetic predisposition to viral infections in humans are described with a major focus on defects related to innate immune responses and new concepts of constitutive immune mechanisms. The topic therefore spans from seminal studies on the human genetics of herpesvirus infections in the central nervous system, severe influenza, and disease after vaccination with live attenuated viral vaccines, to genetic resistance to viral infection.ImplicationsPast and present studies of patients with IEIs conferring vulnerability to viral infections have taught us important lessons on protective innate and adaptive antiviral immunity in humans. Such knowledge also has important clinical implications, allowing development of prophylactic and therapeutic solutions to prevent or dampen the clinical consequences of insufficient or dysregulated antiviral immunity in patients. Collectively, such measures are likely to improve patient management at an individualized level and help societies reduce the disease burden from viral infections.     

Primary immunodeficiencies of protective immunity to primary infections

The vast majority of primary immunodeficiencies (PIDs) predispose affected individuals to recurrent or chronic infectious diseases, because they affect protective immunity to both primary and secondary or latent infections. We discuss here three recently described groups of PIDs that seem to impair immunity to primary infections without compromising immunity to secondary and latent infections. Patients with mutations in IL12B or IL12RB1 typically present mycobacterial disease in childhood with a favorable progression thereafter. Cross-protection between mycobacterial infections has even been observed. Patients with mutations in IRAK4 or MYD88 suffer from pyogenic bacterial diseases, including invasive pneumococcal diseases in particular. These diseases often recur, although not always with the same serotype, but the frequency of these recurrences tails off, with no further infections observed from adolescence onwards. Finally, mutations in UNC93B1 and TLR3 are associated with childhood herpes simplex encephalitis, which strikes only once in most patients, with almost no recorded cases of more than two bouts of this disease. Unlike infections in patients with other PIDs, the clinical course of which typically deteriorates with age even if appropriate treatment is given, the prognosis of patients with these three newly described PIDs tends to improve spontaneously with age, provided, of course, that the initial infection is properly managed. In other words, although life-threatening in early childhood, these new PIDs are associated with a favorable outcome in adulthood. They provide proof-of-principle that infectious diseases of childhood striking only once may result from single-gene inborn errors of immunity.     

Mendelian susceptibility to mycobacterial disease: Genetic,immunological, and clinical features of inborn errors of IFN-γ immunity

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy individuals with no overt abnormalities in routine hematological and immunological tests. MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis, and more rarely to infections with other intramacrophagic bacteria, fungi, or parasites, and even, perhaps, a few viruses. Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, and CYBB) genes have been discovered. The high level of allelic heterogeneity has already led to the definition of 18 different disorders. The nine gene products are physiologically related, as all are involved in IFN-γ-dependent immunity. These disorders impair the production of (IL12B, IL12RB1, IRF8, ISG15, NEMO) or the response to (IFNGR1, IFNGR2, STAT1, IRF8, CYBB) IFN-γ. These defects account for only about half the known MSMD cases. Patients with MSMD-causing genetic defects may display other infectious diseases, or even remain asymptomatic. Most of these inborn errors do not show complete clinical penetrance for the case-definition phenotype of MSMD. We review here the genetic, immunological, and clinical features of patients with inborn errors of IFN-γ-dependent immunity.     

Trained innate immunity and resistance to Mycobacterium tuberculosis infection

BackgroundSome individuals, even when heavily exposed to an infectious tuberculosis patient, develop neither active nor latent tuberculosis infection (LTBI). This ‘early clearance’ of Mycobacterium tuberculosis is associated with a history of bacillus Calmette–Guérin (BCG) vaccination. As BCG vaccination can boost innate immune responses through a process termed ‘trained immunity’, we hypothesize that BCG-induced trained innate immunity contributes to early clearance of M. tuberculosis.ObjectivesWe describe the epidemiological evidence and biological concepts of early clearance and trained immunity, and the possible relation between these two processes through BCG vaccination.SourcesRelevant data from published reports up to November 2018 were examined in the conduct of this review.ContentSeveral observational studies and one recent randomized trial support the concept that boosting innate immunity contributes to protection against M. tuberculosis infection, with BCG vaccination providing approximately 50% protection. The molecular mechanisms mediating early clearance remain largely unknown, but we propose that trained immunity, characterized by epigenetic and metabolic reprogramming of innate immune cells such as monocytes or macrophages, is at least partially responsible for eliminating the mycobacteria and inducing early clearance.ImplicationsFuture studies should examine if BCG revaccination increases early clearance of M. tuberculosis through induction of trained immunity. Epigenetic or metabolic modulation may further boost BCG-induced trained innate immunity to promote tuberculosis prevention. New tuberculosis vaccine candidates should also be examined for their capacity to improve protection against M. tuberculosis infection and induce trained immunity.     

Co-stimulate or Co-inhibit Regulatory T Cells,Which Side to Go?

ABSTRACT

Co-stimulatory and co-inhibitory molecules direct the “second signal,” which largely determines the outcome of the “first signal” generated by the interaction of T cell receptor (TCR) with cognate MHC–peptide complex. The co-stimulatory and co-inhibitory signals are key mechanistic contributors to the regulation of adaptive immunity, especially the T cell–mediated immune response. Regulatory T cells (Tregs) are a special population of T cells, which unlike other T cells function as “attenuators” to suppress T cell immunity. Dysregulation of either the “second signal” or Tregs leads to an unbalanced immune system, which can result in a range of immune-related disorders, including autoimmune diseases, chronic infections, and tumors. In contrast, precise manipulation of these two systems offers tremendous clinical opportunities to treat these same diseases. Co-stimulatory and co-inhibitory molecules modulate immunity at molecular level, whereas Tregs delicately control the immune response at cellular level. Accumulating evidence has demonstrated that these two regulatory strategies converge and synergize with each other. This review discusses recent progress on the roles of co-stimulatory and co-inhibitory signals in the context of Tregs.     

Are hepatitis B virus “subgenotypes” defined accurately?

BackgroundRecently, several novel hepatitis B virus (HBV) subgenotypes have been introduced that do not meet proper definition of “subgenotypes”. In particular for HBV genotype A, such novel subgenotypes have been reported.ObjectiveTo comprehensively reanalyse all HBV subgenotypes A, and to propose a novel, consistent alternative for HBV classification.Study designAll HBV full-length genome subgenotypes A1–A6 were reanalysed using phylogenetic reconstruction and genetic distance calculation in order to study their evolutionary relationships.ResultsPhylogenetic analysis based on the complete genome sequence of subgenotype A strains revealed four distinct clusters supported by high bootstrap values, whereas only the three groups A1, A2 and A6 could be assigned as subgenotypes. Previously introduced subgenotype A3, “tentative A4” and A5 clustered together in one main branch and were designated as “quasi-subgenotypes”. Also genetic distances failed to classify these three groups as definite subgenotypes. These results advocate for a new classification of HBV genotype A into subgenotype A1, A2, “quasi-subgenotype A3” and A4.ConclusionDetailed phylogenetic analysis of the complete genome sequences demonstrates that some of available HBV genotype A strains may not be considered as definite “subgenotypes”. These strains, which are mainly of African origin, could be considered as “quasi-subgenotypes” which puts them in between the “clade” and “subgenotype” definition. Geographical origin may have a key role in further classification of HBV subgenotypes.     

The molecular immunology of human susceptibility to fungal diseases: lessons from single gene defects of immunity

Introduction: Fungal diseases are a threat to human health. Therapies targeting the fungus continue to lead to disappointing results. Strategies targeting the host response represent unexplored opportunities for innovative treatments. To do so rationally requires the identification and neat delineation of critical mechanistic pathways that underpin human antifungal immunity. The study of humans with single-gene defects of the immune system, i.e. inborn errors of immunity (IEIs), provides a foundation for these paradigms.

Areas covered: A systematic literature search in PubMed, Scopus, and abstracts of international congresses was performed to review the history of genetic resistance/susceptibility to fungi and identify IEIs associated with fungal diseases. Immunologic mechanisms from relevant IEIs were integrated with current definitions and understandings of mycoses to establish a framework to map out critical immunobiological pathways of human antifungal immunity.

Expert opinion: Specific immune responses non-redundantly govern susceptibility to their corresponding mycoses. Defining these molecular pathways will guide the development of host-directed immunotherapies that precisely target distinct fungal diseases. These findings will pave the way for novel strategies in the treatment of these devastating infections.     

A proposed nosology of inborn errors of metabolism

PurposeWe propose a nosology for inborn errors of metabolism that builds on their recent redefinition.MethodsWe established a strict definition of criteria to develop a self-consistent schema for inclusion of a disorder into the nosology.ResultsWe identified 1015 well-characterized inborn errors of metabolism described in the literature. In addition, there are 111 less well-characterized conditions that may be inborn errors but do not meet strict criteria for inclusion in the current nosology.ConclusionWe provide a master list of all currently recognized inborn errors of metabolism grouped according to their pathophysiological basis, with the hope of setting a standard against which new errors should be defined, as well as to promote awareness and foster collaboration in the area. With the rapid advances in the field of genetics in recent years, it is likely that this nosology will need to be updated in the near future, a process that will benefit from broader input and collaboration of experts in the field to improve future versions of the proposed classification.     

Parasite-based interventions in systemic lupus erythematosus (SLE): A systematic review

BackgroundThe hygiene hypothesis proposed in 1989 expresses that allergic and infectious diseases are inversely related. Accordingly, it has been demonstrated that infection with some microorganisms such as parasites and helminths can provide a potential immunity and prevent the onset of some life-threatening autoimmune diseases like systemic lupus erythematosus (SLE). Therefore, in this comprehensive study, we systematically reviewed and discussed the use of live parasites or parasitic products in the treatment of mouse models of SLE.MethodsThe present systematic review was performed using the following search terms: (“systemic lupus erythematosus” OR “SLE” OR “lupus”) AND (“parasite” OR “protozoa” OR “helminths” OR “worms” OR “helminth” OR “worm”) in PubMed, Scopus, and Web of Science online databases. We included studies reporting the effect of any intervention using parasites or parasitic-based products on animal models of SLE, which were published until January 20th, 2021 without any language or date restrictions. For each included study, we extracted the authors' names, publication year, type of animal, number of groups, types of intervention, sample size, changes in immunologic cells, auto-Abs, cytokines, and blood cells count, urine analysis, histological analysis of kidney/spleen/liver, outcome and survival. (PROSPERO CRD42020160460).ResultsA total of 17 eligible articles were included in this systematic review. Sixteen out of the 17 studies reported immunomodulating changes in immunologic cells, cytokines, and/or auto-Abs in mouse models of SLE after using parasitic interventions compared to not-infected or control groups. Moreover, 14 studies reported decreased level of proteinuria and/or favorable kidney, liver, or spleen histological changes.ConclusionIn conclusion, we have demonstrated that parasites like Hymenolepis microstoma, TPC and ES-62 from Acanthocheilonema viteae, Plasmodium chabaudi, Schistosoma mansoni, and Toxoplasma gondii have favorable immunomodulating effects on SLE outcomes in lupus-prone mice.     

Inborn errors of IL-12/23- and IFN-γ-mediated immunity: molecular, cellular, and clinical features

Mendelian susceptibility to mycobacterial diseases confers predisposition to clinical disease caused by weakly virulent mycobacterial species in otherwise healthy individuals. Since 1996, disease-causing mutations have been found in five autosomal genes (IFNGR1, IFNGR2, STAT1, IL12B, IL12BR1) and one X-linked gene (NEMO). These genes display a high degree of allelic heterogeneity, defining at least 13 disorders. Although genetically different, these conditions are immunologically related, as all result in impaired IL-12/23-IFN-γ-mediated immunity. These disorders were initially thought to be rare, but have now been diagnosed in over 220 patients from over 43 countries worldwide. We review here the molecular, cellular, and clinical features of patients with inborn errors of the IL-12/23-IFN-γ circuit.     

Trained innate immunity

The innate immune system acts rapidly in an identical and nonspecific way every time the body is exposed to pathogens. As such, it cannot build and maintain immunological memory to help prevent reinfection. Researchers contend that trained immunity is influenced by intracellular metabolic pathways and epigenetic remodeling. The purpose of this review was to explore the topic of trained innate immunity based on the results of relevant previous studies. This systematic review entailed identifying articles related to trained innate immunity. The sources were obtained from PubMed using different search terms that included “trained innate immunity,” “trained immunity,” “trained,” “innate,” “immunity,” and “immune system.” Boolean operators were used to combine terms and phrases. A review of previous study results revealed that little is currently known about the molecular and cellular processes that mediate or induce a trained immune response in animals. However, it is believed that alterations in the phenotypes of cell populations and the numbers of specific cells may play a critical role in mediating the trained immune response. Increasing evidence shows that the protective processes and actions that occur during a secondary infection are not entirely linked to the adaptive immune system. Instead, these events also involve heightened activation of innate immune cells. While trained innate immune cells may have a shorter memory, they assist in the fight against pathogens and provide cross-protection. Identification of the mechanisms and molecules that underlie trained innate immunity has highlighted important features of the human immune response. Such advances continue to open doors for future research on how the body responds to disease-causing pathogens.

     

Introduction: One health and emerging infectious diseases

Those infectious diseases that have increased in the past two decades or that threaten to emerge are considered emerging infectious diseases. Many of these diseases are acquired through contact with plants, insects and animals. “One health” acknowledges the interconnectedness of environment, plant, animal and human health. The introduction to this issue of Seminars in Diagnostic Pathology gives the definition of emerging and reemerging infectious diseases, explores the concept of “One Health”, explains the evolution of testing for infectious agents as it relates to emerging infections, and considers the difficulties in predicting which and where the next emerging infection will occur.     

Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes

The genetic dissection of various human infectious diseases has led to the definition of inborn errors of human STAT1 immunity of four types, including (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD gain of STAT1 activity. The two types of AR STAT1 defect give rise to a broad infectious phenotype with susceptibility to intramacrophagic bacteria (mostly mycobacteria) and viruses (herpes viruses at least), due principally to the impairment of IFN-γ-mediated and IFN-α/β-mediated immunity, respectively. Clinical outcome depends on the extent to which the STAT1 defect decreases responsiveness to these cytokines. AD STAT1 deficiency selectively predisposes individuals to mycobacterial disease, owing to the impairment of IFN-γ-mediated immunity, as IFN-α/β-mediated immunity is maintained. Finally, AD gain of STAT1 activity is associated with autoimmunity, probably owing to an enhancement of IFN-α/β-mediated immunity. More surprisingly, it is also associated with chronic mucocutaneous candidiasis, through as yet undetermined mechanisms involving an inhibition of the development of IL-17-producing T cells. Thus, germline mutations in human STAT1 define four distinct clinical disorders. Various combinations of viral, mycobacterial and fungal infections are therefore allelic at the human STAT1 locus. These experiments of Nature neatly highlight the clinical and immunological impact of the human genetic dissection of infectious phenotypes.     

Autoantibodies targeting type I interferons: Prevalence,mechanisms of induction,and association with viral disease susceptibility

The type I IFN (IFN-I) system is essential to limit severe viral disease in humans. Thus, IFN-I deficiencies are associated with serious life-threatening infections. Remarkably, some rare individuals with chronic autoimmune diseases develop neutralizing autoantibodies (autoAbs) against IFN-Is thereby compromising their own innate antiviral defenses. Furthermore, the prevalence of anti-IFN-I autoAbs in apparently healthy individuals increases with age, such that ∼4% of those over 70 years old are affected. Here, I review the literature on factors that may predispose individuals to develop anti-IFN-I autoAbs, such as reduced self-tolerance caused by defects in the genes AIRE, NFKB2, and FOXP3 (among others), or by generally impaired thymus function, including thymic involution in the elderly. In addition, I discuss the hypothesis that predisposed individuals develop anti-IFN-I autoAbs following “autoimmunization” with IFN-Is generated during some acute viral infections, systemic inflammatory events, or chronic IFN-I exposure. Finally, I highlight the enhanced susceptibility that individuals with anti-IFN-I autoAbs appear to have towards viral diseases such as severe COVID-19, influenza, or herpes (e.g., varicella-zoster virus, herpes simplex virus, cytomegalovirus), as well as adverse reactions to live-attenuated vaccines. Understanding the mechanisms underlying development and consequences of anti-IFN-I autoAbs will be key to implementing effective prophylactic and therapeutic measures.     

Dissecting innate immunity by germline mutagenesis

The innate arm of our immune system is the first line of defence against infections. In addition, it is believed to drive adaptive immune responses, which help fight pathogens and provide long-term memory. As such, the innate immune system is instrumental for protection against pathogens that would otherwise destroy their host. Although our understanding of the innate immune components involved in pathogen sensing and fighting is improving, it is still limited. This is particularly exemplified by increased documentation of innate immune deficiencies in humans that often result in high and recurrent susceptibility to infections or even death, without the genetic cause being evident. To provide further insight into the mechanisms by which pathogen sensing and eradication occur, several strategies can be used. The current review focuses on the forward genetic approaches that have been used to dissect innate immunity in the fruit fly and the mouse. For both animal models, forward genetics has been instrumental in the deciphering of innate immunity and has greatly improved our understanding of how we respond to invading pathogens.     

Achieving the “triple aim” for inborn errors of metabolism: a review of challenges to outcomes research and presentation of a new practice-based evidence framework

Across all areas of health care, decision makers are in pursuit of what Berwick and colleagues have called the “triple aim”: improving patient experiences with care, improving health outcomes, and managing health system impacts. This is challenging in a rare disease context, as exemplified by inborn errors of metabolism. There is a need for evaluative outcomes research to support effective and appropriate care for inborn errors of metabolism. We suggest that such research should consider interventions at both the level of the health system (e.g., early detection through newborn screening, programs to provide access to treatments) and the level of individual patient care (e.g., orphan drugs, medical foods). We have developed a practice-based evidence framework to guide outcomes research for inborn errors of metabolism. Focusing on outcomes across the triple aim, this framework integrates three priority themes: tailoring care in the context of clinical heterogeneity; a shift from “urgent care” to “opportunity for improvement”; and the need to evaluate the comparative effectiveness of emerging and established therapies. Guided by the framework, a new Canadian research network has been established to generate knowledge that will inform the design and delivery of health services for patients with inborn errors of metabolism and other rare diseases.Genet Med 2013:15(6):415–422     

Role of inflammatory dendritic cells in innate and adaptive immunity

The major role of cells of the dendritic family in immunity and tolerance has been amply documented. Since their discovery in 1973, these cells have gained increasing interest from immunologists, as they are able to detect infectious agents, migrate to secondary lymphoid tissue, and prime naive T lymphocytes, thereby driving immune responses. Surprisingly, they can also have the opposite function, that is, preventing immune responses, as they are involved in central and peripheral tolerance. Most dendritic cells (DCs) derive from a common precursor and do not arise from monocytes and are considered “conventional” DCs. However, a new population of DCs, namely “inflammat‐ory” DCs, has recently been identified, which is not present in the steady state but differentiates from monocytes during infection/inflammation. In this review, we summarize the role of these “inflammatory” DCs in innate and adaptive immunity.     

Chlamydia trachomatis infection: host immune responses and potential vaccines

Chlamydia trachomatis causes genital tract infections that affect men, women, and children on a global scale. This review focuses on innate and adaptive immune responses in the female reproductive tract (FRT) to genital tract infections with C. trachomatis. It covers C. trachomatis infections and highlights our current knowledge of genital tract infections, serovar distribution, infectious load, and clinical manifestations of these infections in women. The unique features of the immune system of the FRT will be discussed and will include a review of our current knowledge of innate and adaptive immunity to chlamydial infections at this mucosal site. The use of animal models to study the pathogenesis of, and immunity to, Chlamydia infection of the female genital tract will also be discussed and a review of recent immunization and challenge experiments in the murine model of chlamydial FRT infection will be presented.