Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling.

Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown.

cGAS surveillance of micronuclei links genome instability to innate immunity.

DNA is strictly compartmentalized within the nucleus to prevent autoimmunity; despite this, cyclic GMP-AMP synthase (cGAS), a cytosolic sensor of double-stranded DNA, is activated in autoinflammatory disorders and by DNA damage. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells.

Enteric helminth-induced type I interferon signaling protects against pulmonary virus infection through interaction with the microbiota.

Background: Helminth parasites have been reported to have beneficial immunomodulatory effects in patients with allergic and autoimmune conditions and detrimental consequences in patients with tuberculosis and some viral infections. Their role in coinfection with respiratory viruses is not clear.

Objective: Here we investigated the effects of strictly enteric helminth infection with Heligmosomoides polygyrus on respiratory syncytial virus (RSV) infection in a mouse model.

Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis.

Compaction of chromosomes is essential for accurate segregation of the genome during mitosis. In vertebrates, two condensin complexes ensure timely chromosome condensation, sister chromatid disentanglement, and maintenance of mitotic chromosome structure. Here, we report that biallelic mutations in NCAPD2, NCAPH, or NCAPD3, encoding subunits of these complexes, cause microcephaly.

Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response.

Aicardi-Goutières syndrome (AGS) provides a monogenic model of nucleic acid-mediated inflammation relevant to the pathogenesis of systemic autoimmunity. Mutations that impair ribonuclease (RNase) H2 enzyme function are the most frequent cause of this autoinflammatory disorder of childhood and are also associated with systemic lupus erythematosus. Reduced processing of eitherRNA:DNAhybrid or genome-embedded ribonucleotide substrates is thought to lead to activation of a yet undefined nucleic acid-sensing pathway.

TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions.

Cathelicidin host defence peptide augments clearance of pulmonary Pseudomonas aeruginosa infection by its influence on neutrophil function in vivo.

Cathelicidins are multifunctional cationic host-defence peptides (CHDP; also known as antimicrobial peptides) and an important component of innate host defence against infection. In addition to microbicidal potential, these peptides have properties with the capacity to modulate inflammation and immunity. However, the extent to which such properties play a significant role during infection in vivo has remained unclear.

Effector and central memory T helper 2 cells respond differently to peptide immunotherapy.

Peptide immunotherapy (PIT) offers realistic prospects for the treatment of allergic diseases, including allergic asthma. Much is understood of the behavior of naive T cells in response to PIT. However, treatment of patients with ongoing allergic disease requires detailed understanding of the responses of allergen-experienced T cells.

RNA:DNA hybrids are a novel molecular pattern sensed by TLR9.

The sensing of nucleic acids by receptors of the innate immune system is a key component of antimicrobial immunity. RNA:DNA hybrids, as essential intracellular replication intermediates generated during infection, could therefore represent a class of previously uncharacterised pathogen-associated molecular patterns sensed by pattern recognition receptors. Here we establish that RNA:DNA hybrids containing viral-derived sequences efficiently induce pro-inflammatory cytokine and antiviral type I interferon production in dendritic cells.

Republished: novel insights into immune and inflammatory responses to respiratory viruses.

Viral lower respiratory tract infection (LRTI) can lead to severe disease at all ages, but with the exception of influenza vaccination, prevention is not available for most respiratory viruses, hence, effective, disease-limiting therapy is urgently required. To enable the development of novel effective therapeutic approaches, we need to improve understanding of the pathological mechanisms of viral LRTI. Here, we will discuss recently gained new insight into early, innate immune and inflammatory responses to respiratory viruses by airway epithelial cells and mucosal immune cells.

Combination peptide immunotherapy based on T-cell epitope mapping reduces allergen-specific IgE and eosinophilia in allergic airway inflammation.

Peptide immunotherapy using soluble peptides containing allergen-derived immunodominant T-cell epitopes holds therapeutic promise for allergic asthma. Previous studies in BALB/c mice using the immunodominant peptide epitope of chicken ovalbumin (p323-339) have been unable to demonstrate therapeutic effects in ovalbumin-induced allergic airway inflammation. We have previously shown that intravenous application of p323-339 can effectively tolerise p323-339-reactive T cells in a non-allergic model in C57BL/6 mice.

Novel insights into immune and inflammatory responses to respiratory viruses.

Viral lower respiratory tract infection (LRTI) can lead to severe disease at all ages, but with the exception of influenza vaccination, prevention is not available for most respiratory viruses, hence, effective, disease-limiting therapy is urgently required. To enable the development of novel effective therapeutic approaches, we need to improve understanding of the pathological mechanisms of viral LRTI. Here, we will discuss recently gained new insight into early, innate immune and inflammatory responses to respiratory viruses by airway epithelial cells and mucosal immune cells.

Peptide immunotherapy for childhood allergy - addressing translational challenges.

Allergic sensitisation usually begins early in life. The number of allergens a patient is sensitised to can increase over time and the development of additional allergic conditions is increasingly recognised. Targeting allergic disease in childhood is thus likely to be the most efficacious means of reducing the overall burden of allergic disease.

Inhibition of eosinophil migration by lactoferrin.

Eosinophilic granulocytes are innate effector cells that are important in immune responses against helminth parasitic infections and contribute towards the pathology associated with allergic inflammatory conditions, including allergic rhinitis and asthma. Their recruitment to inflammatory sites occurs in response to chemotactic and activation signals, such as eotaxin and interleukin-5, and is a tightly controlled process. However, the mechanisms that counterbalance these positive chemoattractive processes, thereby preventing excessive eosinophil infiltration, have received little attention.

Distinct T cell recognition of naturally processed and cryptic epitopes within the immunodominant 35-55 region of myelin oligodendrocyte glycoprotein.

We have assessed the complexity in T cell recognition of the immunodominant 35-55 region of myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. Immunization with the p35-55 peptide generated two types of T cell, recognizing either a cryptic, or a naturally-processed epitope. Clear differences in the recognition of residues within a core sequence of 40-48 were observed.