Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease characterized by intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold [1][2][3][4] . FCAS was previously mapped to a 10-cM region on chromosome 1q44 (refs. 5,6). Muckle-Wells syndrome (MWS; MIM 191900), which also maps to chromosome 1q44, is an autosomal-dominant periodic fever syndrome with a similar phenotype except that symptoms are not precipitated by cold exposure and that sensorineural hearing loss is frequently also present [6][7][8] . To identify the genes for FCAS and MWS, we screened exons in the 1q44 region for mutations by direct sequencing of genomic DNA from affected individuals and controls. This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS. This gene, called CIAS1, is expressed in peripheral blood leukocytes and encodes a protein with a pyrin domain 9-11 , a nucleotide-binding site (NBS, NACHT subfamily 12 ) domain and a leucine-rich repeat (LRR) motif region 13 , suggesting a role in the regulation of inflammation and apoptosis.We previously identified a locus for FCAS on chromosome 1q44 between markers D1S423 and D1S2682 (ref. 5). We developed a physical contig of bacterial artificial chromosomes (BACs) and P1-derived artificial chromosomes and narrowed the critical region to less than 1 Mb using haplotype analysis (data not shown). We used ESTs mapping to this region and The four-generation family with FCAS (family 1; Fig. 1) has an apparent de novo mutation that first appeared in subject 4 on a chromosome inherited from her mother. Only the affected members of subsequent generations of the family (subjects 5, 9 and 11) inherited this chromosome. We found a missense mutation in subject 4 that segregated with the disease haplotype in subsequent generations (subjects 5, 9 and 11). This mutation was not present in either of her parents (subjects 1 and 2), even though the unaffected mother (subject 2) possessed the haplotype that segregates with disease in this family.The other two families with FCAS (families 2 and 3) also had different missense mutations in the same exon; these were present in all affected family members (Fig. 2). In the one family studied with affected members with a diagnosis of MWS (family 4), both affected individuals had sensorineural hearing loss (Fig. 2). This family also had a missense mutation in the same exon as the families with FCAS. As in family 1, the phenotype of family 4 resulted from a de novo mutation. The unaffected mother (DNA was not available from the father) in family 4 possessed the haplotype that segregates with the disease in subsequent generations (data not shown), but she did not have the mutation that was found in all of the affected family members. These missense mutations were not found in any unaffected individuals in thes...

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Recent years have witnessed an explosion of interest in the innate immune system. Questions about how the innate immune system senses infection and empowers a protective immune response are being answered at the molecular level. These basic science discoveries are being translated into a more complete understanding of the central role innate immunity plays in the pathogenesis of many human infectious and inflammatory diseases. It is particularly exciting that we are already seeing a return on these scientific investments with the emergence of novel therapies to harness the power of the innate immune system. In this review we explore the defining characteristics of the innate immune system, and through more detailed examples, we highlight recent breakthroughs that have advanced our understanding of the role of innate immunity in human health and disease.

Background Cysteinyl leukotrienes contribute to asthma pathogenesis, in part through CysLT1 receptor (CysLT1R). Recently discovered lineage-negative type 2 innate lymphoid cells (ILC2) potently produce IL-5 and IL-13. Objectives We hypothesized that lung ILC2 may be activated by leukotrienes through CysLT1R. Methods ILC2 (Thy 1.2+ lineage-negative lymphocytes) and CysLT1R were detected in the lungs of WT, STAT6−/−, and RAG2−/− mice by flow cytometry. Levels of Th2 cytokines were measured in purified lung ILC2 stimulated with leukotriene D4 (LTD4) in the presence or absence of the CysLT1R antagonist montelukast. Calcium influx was measured by Fluo-4 intensity. Intranasal LTD4 and LTE4 were administered to naive mice and levels of ILC2 IL-5 production determined. Finally, LTD4 was co-administered with Alternaria repetitively to RAG2−/− mice (have ILC2) and IL-7R−/− mice (lack ILC2) and total ILC2 numbers, proliferation (Ki-67+) and BAL eosinophils measured. Results CysLT1R was expressed on lung ILC2 from WT, RAG2−/−, and STAT6−/−naïve and Alternaria-challenged mice. In vitro, LTD4 induced ILC2 to rapidly generate high levels of IL-5 and IL-13 within six hours of stimulation. Interestingly, LTD4, but not IL-33, induced high levels of IL-4 by ILC2. LTD4 administered in-vivo rapidly induced ILC2 IL-5 production that was significantly reduced by montelukast pre-treatment. Finally, LTD4 potentiated Alternaria-induced eosinophilia as well as ILC2 accumulation and proliferation. Conclusions We present novel data that CysLT1R is expressed on ILC2 and LTD4 potently induces CysLT1R-dependent ILC2 production of IL-4, IL-5, and IL-13. Additionally, LTD4 potentiates Alternaria-induced eosinophilia and ILC2 proliferation and accumulation.

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In this pilot study, a 6-week regimen of the AIC vaccine appeared to offer long-term clinical efficacy in the treatment of ragweed allergic rhinitis. (ClinicalTrials.gov number, NCT00346086 [ClinicalTrials.gov] .).

Recognition of microbial components by APCs and their activation through Toll-like receptors (TLR) leads to the induction of adaptive immune responses. In this study, we show that activation of TLR2 by its synthetic ligand Pam3Cys, in contrast to activation of TLR9 by immunostimulatory DNA (ISS-ODN), induces a prominent Th2-biased immune response. Activation of APCs by Pam3Cys resulted in the induction of Th2-associated effector molecules like IL-13, and IL-1β, GM-CSF and up-regulation of B7RP-1, but low levels of Th1-associated cytokines (IL-12, IFNα, IL-18, IL-27). Accordingly, TLR2 ligands aggravated experimental asthma. These data indicate that the type of TLR stimulation during the initial phase of immune activation determines the polarization of the adaptive immune response and may play a role in the initiation of Th2-mediated immune disorders, such as asthma.