COPA syndrome is an autoinflammatory disease, caused by heterozygous variants in the COPA gene. COPA syndrome patients present various manifestations such as interstitial lung disease and arthritis, accompanied with elevation of interferon-stimulated genes （ISGs） expression. COPA gene encodes the alpha subunit of the coatomer protein complex I （COP I）, which is a carrier complex required for retrograde protein trafficking from the Golgi apparatus to the endoplasmic reticulum. The detailed pathogenesis of the disease, however, is unknown and no treatment has been established. Several analyses using cell lines and model mice carrying the COPA syndrome gene variants have revealed that excessive activation of the intracellular DNA sensor pathway is involved in the pathogenesis of COPA syndrome. Here, we review recent findings on the pathogenesis of autoinflammatory diseases caused by dysfunction of the intracellular DNA sensor system, focusing on analyses using mouse models.

 Macrophage activation syndrome （MAS） is defined as secondary hemophagocytic lymphohistiocytois related to rheumatic diseases. Excessive activation of immune system, and overproduction of proinflammatory cytokines play a central role in the pathogenesis of MAS. MAS is a potentially life-threating condition clinically characterized by fever, hepatosplenomegaly, cytopenia, liver injury, hyperferritinemia, coagulopathy, NK cell dysfunction, and expansion of activated macrophages with hemophagocytosis. Although MAS has been associated with most rheumatic diseases, it is most common in systemic juvenile idiopathic arthritis （s-JIA）. Chronic interleukin （IL）-18 exposure inducing overproduction of interferon-γ, suppression of IL-10 production, and secondary suppression of cytolytic function is closely associated to the development of MAS associated with s-JIA. Important role of IL-18 in the pathogenesis of MAS has been brought to attention by the discovery of genetic autoinflammatory diseases with recurrent MAS and massive elevation of serum IL-18 levels including NLRC4 gain of function, XIAP deficiency, and neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash and HLH （NOCARH） syndrome. However, only overproduction of IL-18 cannot induce MAS development. Further studies are necessary to clarify the complex pathogenesis of MAS.

 Newborn screening（NBS）is carried out at public expense for approximately 20 diseases in Japan; however, each prefecture independently conducts additional NBS including several more diseases. Miyazaki Prefecture has optionally included inborn errors of immunity（IEIs）and lysosomal storage diseases since April 2020. We herein report a baby who suffered from B-cell deficiency（BCD）that was identified by NBS conducted in Miyazaki Prefecture. The baby had low levels of kappa-deleting recombination excision circles（KRECs）and was referred to our hospital. Several measurements of CD19-positive B cells in the peripheral blood consistently showed values <2%, leading to the diagnosis of BCD. Periodic immunoglobulin replacement successfully led to a healthy outcome without serious infection developing over a period of more than 17 months. This is the first case of BCD identified by NBS and that underwent prophylactic gamma globulin replacement in Japan. Severe combined immunodeficiency disease and BCD are IEIs known to cause severe sequelae, and patients sometimes die without a correct diagnosis being made; therefore, their early diagnosis and early treatment are extremely important. The inclusion of IEIs in NBS has proven to be cost-effective all over the world. In the future, it is expected that IEIs will be covered by NBS public funds in Japan as well.