Monogenic autoimmunity

Abstract

Monogenic autoimmune syndromes provide a rare yet powerful glimpse into the fundamental mechanisms of immunologic tolerance. Such syndromes reveal not only the contribution of an individual breakpoint in tolerance but also patterns in the pathogenesis of autoimmunity. Disturbances in innate immunity, a system built for ubiquitous sensing of danger signals, tend to generate systemic autoimmunity. For example, defects in the clearance of self-antigens and chronic stimulation of type 1 interferons lead to the systemic autoimmunity seen in C1q deficiency, SPENCDI, and AGS. In contrast, disturbances of adaptive immunity, which is built for antigen specificity, tend to produce organ-specific autoimmunity. Thus, the loss of lymphocyte homeostasis, whether through defects in apoptosis, suppression, or negative selection, leads to organ-specific autoimmunity in ALPS, IPEX, and APS1. We discuss the unique mechanisms of disease in these prominent syndromes as well as how they contribute to the spectrum of organ-specific or systemic autoimmunity. The continued study of rare variants in autoimmune disease will inform future investigations and treatments directed at rare and common autoimmune diseases alike.

Figure 1.

Type 1 interferons are activated in the systemic autoimmunity seen with SPENCDI and AGS. The plasmacytoid dendritic cell (pDC) is one of the primary sensors and producers of type 1 interferons (IFN-α/β), providing self-amplification of interferon-mediated signaling. Exogenous nucleic acids in the form of viral infection activate TLR signaling through endosomal processing coupled to TLR7 and TLR9 signaling. Intracellular nucleic acids from exogenous viral sources can also be sensed through the intracellular RIG1/MDA5 system. These pathways converge on the activation of interferon regulatory factors (IRFs) that then translocate to the nucleus to activate transcription of type 1 interferons. These events occur in concert with IFN-a/p activation of the IFNAR (IFN-a receptor), resulting in JAK1-STAT-mediated signal transduction to upregulate several interferon-inducible genes through the combined action of IRFs and STAT1,2. The AGS and SPENCDI syndromes highlight mechanisms at two levels that can lead to chronic activation of type 1 interferon signaling with potential for systemic autoimmunity. In AGS, the TREX1, RNaseH2 complex, and SAMHD1 proteins are thought to mediate degradation of endogenous nucleic acids, such as ssDNAs (single-stranded DNAs) and RNA:DNA duplexes. In the absence of these functions, endogenous nucleic acids can accumulate and, through a yet-to-be-identified sensor, lead to activation of IRFs. In SPENCDI, deficiency of TRAP (tartrate-resistant acid phosphatase) leads to accumulation of hyperphosphorylated forms of iOPN (intracellular osteopontin). In pDCs, phosphorylated iOPN acts as an adaptor molecule in complex with MyD88 to activate TLR9 signaling. Notably, iOPN selectively couples TLR9 signal to IRF7 activation instead of NF-kB. Thus, accumulation of phosphorylated iOPN can lead to skewing of TLR9 signaling to type 1 interferon activation. As sensors of exogenous and endogenous nucleic acids as well as apoptotic debris (not shown in figure), pDCs can induce and amplify type 1 interferon signals to produce systemic autoimmunity. The resulting production of type 1 interferons can also act upon T cells, B cells, and DCs to promote a network of responses, leading to autoimmunity (reviewed in 31).

Figure.2

Domain structure of the FOXP3 protein. The N-terminal half of the protein houses a repressor domain important for the binding and inhibition of the NFAT (nuclear factor of activated T cells) transcription factors. Consistent with its function as a transcription factor, the protein also contains a zinc finger domain (ZnF) and leucine zipper (Zip), followed by a C-terminal canonical forkhead domain that mediates DNA binding

Figure 3.

Domain structure of the AIRE protein. Several domains within the protein share homology with components of transcriptional regulatory elements. The N terminus of AIRE consists of a homogeneously staining region (HSR) that is thought to mediate homodimerization of the protein and is followed by a nuclear localization sequence (NLS). Overlapping the HSR is a putative caspase-recruitment domain (CARD) that is also predicted to mediate homotypic protein oligomerization with other CARDs, although other CARD-carrying partners of AIRE have yet to be identified. It remains to be seen if these two domain designations mediate all the same functions. The SAND domain, so named for its homology to the DNA-binding domain of the Spl00 family of proteins (Spl00, AIRE, NucP4l/75, and DEAF-1), occupies the central portion of the protein. Four LXXLL (X being any amino acid) transcriptional coactivation motifs are distributed throughout the protein ( gray bars). The C terminus consists of two plant homeodomains (PHD1, PHD2) thought to mediate differential binding to histone marks and a proline-rich region (PRR) that is hypothesized to mediate transactivation as seen in other transcription factors. Over 60 mutations in AIRE have been documented, scattered throughout the protein. The G228W mutation lies within the SAND domain, as shown (asterisk).