Background The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in host defense against infections. Disseminated infection caused by BCG vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected individuals, the etiology of disseminated BCG disease is unexplained. Methods We investigated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, requiring hematopoietic stem cell transplantation. We also studied two otherwise healthy adults with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic cells compartments in these three persons and sequenced candidate genes, mutation of which could plausibly confer susceptibility to BCG disease. Results We detected two distinct disease-causing mutations affecting the transcriptional regulator IRF8. Both K108A and T80A mutations impair IRF8 transcriptional activity by disrupting IRF8 interaction with DNA. Mutation K108E was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. Mutation T80A was associated with an autosomal dominant milder immunodeficiency and a selective depletion of CD11c+ CD1c+ circulating dendritic cells. Conclusions These findings define a new class of human primary immunodeficiency, affecting the differentiation of mononuclear phagocytes. They also demonstrate that human IRF8 is critically required for the development of monocytes and dendritic cells and for anti-mycobacterial immunity.

Scrub typhus is a life-threatening zoonosis caused by Orientia tsutsugamushi organisms that are transmitted by the larvae of trombiculid mites. Endemic scrub typhus was originally thought to be confined to the so called "tsutsugamushi triangle" within the Asia-Pacific region. In 2006, however, two individual cases were detected in the Middle East and South America, which suggested that the pathogen was present farther afield. Here, we report three autochthonous cases of scrub typhus caused by O. tsutsugamushi acquired on Chiloé Island in southern Chile, which suggests the existence of an endemic focus in South America. (Funded by the Chilean Comisión Nacional de Investigación Científica y Tecnológica and the Wellcome Trust.).

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in about 1/100,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and 1/2,500 other individuals, is much more frequent in patients with tuberculosis than in ethnicity-adjusted controls (p = 8.37×10−8, odds ratio = 89.31 [95%CI: 14.7–1,725]). We also show that the frequency of P1104A in Europeans has decreased significantly, from about 9% to 4.2%, over the last 4,000 years, consistent with purging of this variant by endemic tuberculosis. Moreover, we show that catalytically inactive P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Finally, we show that catalytically competent TYK2 is critical for IL-23 but not IL-12 responses, whereas catalytically competent JAK2 is redundant for both. Homozygosity for the P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.

Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory T1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a mice lack cDC2s, have CD4 T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory T1* cells.