Editorial: Autoimmunity and Chronic Inflammation in Early Life

Non-communicable diseases such as cardiovascular diseases, metabolic disease and chronic inflammatory diseases are often attributed to an interplay between genetic predispositions and imprinting mechanisms early in life. In a simplified concept, the fetal development is characterized by the acquisition of immuno-tolerance towards maternal and self-antigens, whereas the neonatal period reflects the acquisition of immune-defense against potentially harmful environmental antigen. Immune development involves a complex cross talk of immune cells in various organs that is influenced by environmental antigen (1–3). During infancy and childhood, autoimmune diseases and chronic inflammation coincide with an exponential diversification of the adaptive immune system, causing potentially life-long consequences. Interestingly, the earlier hypothesis of an “immunodeficiency of immaturity” had to be partially revised since it has become clear that inflammatory states in the neonate, e.g. in the context of sepsis, represent a lack of controlling inflammation rather than a failure to mount inflammation. Thus, hyperinflammatory states can occur even in the very immature organism and can lay the ground for autoimmunity or various conditions of chronic inflammation. This knowledge may affect therapeutic approaches. In this Research Topic, we have called for publications that relate to clinical or molecular aspects of aberrant immune responses in pediatric patients. Here we briefly present the 12 contributions that comprise six Original Research articles, three (mini) reviews and three case reports. The contributions can be grouped into three sections:


INTRODUCTION
Non-communicable diseases such as cardiovascular diseases, metabolic disease and chronic inflammatory diseases are often attributed to an interplay between genetic predispositions and imprinting mechanisms early in life. In a simplified concept, the fetal development is characterized by the acquisition of immuno-tolerance towards maternal and self-antigens, whereas the neonatal period reflects the acquisition of immune-defense against potentially harmful environmental antigen. Immune development involves a complex cross talk of immune cells in various organs that is influenced by environmental antigen (1)(2)(3). During infancy and childhood, autoimmune diseases and chronic inflammation coincide with an exponential diversification of the adaptive immune system, causing potentially life-long consequences. Interestingly, the earlier hypothesis of an "immunodeficiency of immaturity" had to be partially revised since it has become clear that inflammatory states in the neonate, e.g. in the context of sepsis, represent a lack of controlling inflammation rather than a failure to mount inflammation. Thus, hyperinflammatory states can occur even in the very immature organism and can lay the ground for autoimmunity or various conditions of chronic inflammation. This knowledge may affect therapeutic approaches.
In this Research Topic, we have called for publications that relate to clinical or molecular aspects of aberrant immune responses in pediatric patients. Here we briefly present the 12 contributions that comprise six Original Research articles, three (mini) reviews and three case reports. The contributions can be grouped into three sections:  diagnoses that can be grouped into inflammasomopathies (42%), non-inflammasome related conditions (48%) and type 1 interferonopathies (10%). 76% of the patients presented with skin disorders, making this the most common clinical clue to autoimmune diseases. In contrast, Chinello et al. address a new complication in a rare autoimmune disease by presenting a pediatric patient with lipopolysaccharide-responsive-beigelinked-anchor-protein (LRBA) deficiency that developed acute cervical longitudinally transverse myelitis. Chen et al. report a patient with symptoms of intestinal Behcet's disease that was associated with novel heterozygous mutation in the TNFAIP gene, potentially linking intestinal Behcet's disease with Haploinsufficiency A20.

FROM MOLECULAR MECHANISMS TO AUTOIMMUNE PHENOTYPES
Haploinsufficiency A20 (HA20) has recently been identified as one potential molecular mechanism of autoimmunity. In an analysis of 89 patients with this rare condition, Chen et al. present the typical clinical manifestations associated with HA20: Recurrent oral ulcers and fever episodes, gastrointestinal and genital ulcers as well as skin lesions are the hallmarks that can help clinicians to initiate targeted diagnostics in patients that often suffer a long odyssey prior to a correct diagnosis and therapy.

CONCLUDING REMARKS
The article collection of the Research Topic gives an up-to-date overview on the clinical manifestations and molecular mechanisms of autoimmunity and chronic inflammation in early life. Thus, in the jungle of "diagnostic chameleons", clinicians may find important hints for linking characteristic symptoms with autoimmune diseases. On the other hand, basic researchers find a thorough overview of the current knowledge on disease mechanism that should inspire research projects in the field of diagnostics and novel therapeutic concepts.

AUTHOR CONTRIBUTIONS
MZ wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.

FUNDING
This study was supported by BMBF PRIMAL study (01GL1746D) to MZ.