Alexander A. Navarini

Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice

Psoriasis is a common, relapsing inflammatory skin disease characterized by erythematous scaly plaques. Histological manifestations of psoriasis include keratinocyte dysregulation and hyperproliferation, elongated rete ridges, and inflammatory infiltrates consisting of T cells, macrophages, dendritic cells, and neutrophils. Despite the availability of new effective drugs to treat psoriasis, the underlying mechanisms of pathogenesis are still poorly understood. Recent studies have shown that Aldara cream, used to treat benign skin abnormalities, triggers psoriasis-like disease in humans and mice and have implicated Th17 cells in disease initiation. Using this as a model, we found a predominant role for the Th17 signature cytokines IL-17A, IL-17F, and IL-22 in psoriasiform plaque formation in mice. Using gene-targeted mice, we observed that loss of Il17a, Il17f, or Il22 strongly reduced disease the severity of psoriasis. However, we found that Th17 cells were not the primary source of these pathogenic cytokines. Rather, IL-17A, IL-17F, and IL-22 were produced by a skin-invading population of γδ T cells and RORγt(+) innate lymphocytes. Furthermore, our findings establish that RORγt(+) innate lymphocytes and γδ T cells are necessary and sufficient for psoriatic plaque formation in an experimental disease model that closely resembles human psoriatic plaque formation.

Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling

The liver is known to be a classical immunoprivileged site with a relatively high resistance against immune responses. Here we demonstrate that highly activated liver-specific effector CD8+ T cells alone were not sufficient to trigger immune destruction of the liver in mice. Only additional innate immune signals orchestrated by TLR3 provoked liver damage. While TLR3 activation did not directly alter liver-specific CD8+ T cell function, it induced IFN-alpha and TNF-alpha release. These cytokines generated expression of the chemokine CXCL9 in the liver, thereby enhancing CD8+ T cell infiltration and liver disease in mice. Thus, nonspecific activation of innate immunity can drastically enhance susceptibility to immune destruction of a solid organ.

Inverse correlation between IL-7 receptor expression and CD8 T cell exhaustion during persistent antigen stimulation.

Persistence is a hallmark of infection by viruses such as HIV, hepatitis B virus, hepatitis C virus and LCMV. In the case of LCMV, persistence may often be associated with exhaustion of CD8+ T cells. We demonstrate here that persistent antigen suppressed IL‐7Rα expression and this correlated with T cell exhaustion and reduced expression of the anti‐apoptotic molecule B cell leukemia/lymphoma 2 (Bcl‐2). In contrast, exposure to short‐lived antigen only temporarily suppressed IL‐7Rα expression, failed to induce T cell exhaustion, and primed T cells. Persistent antigen also suppressed IL‐7Rα expression on primed T cells and this correlated with exhaustion of a previously stable primed T cell population. These findings suggest that antigen longevity regulates T cell fate.

Increased susceptibility to bacterial superinfection as a consequence of innate antiviral responses

The reason why severe localized or systemic virus infections enhance and aggravate bacterial superinfection is poorly understood. Here we show that virus-induced IFN type I caused apoptosis in bone marrow granulocytes, drastically reduced granulocyte infiltrates at the site of bacterial superinfection, caused up to 1,000-fold higher bacterial titers in solid organs, and increased disease susceptibility. The finding that the innate antiviral immune response reduces the antibacterial granulocyte defense offers an explanation for enhanced susceptibility to bacterial superinfection during viral disease.

A platelet-mediated system for shuttling blood-borne bacteria to CD8α + dendritic cells depends on glycoprotein GPIb and complement C3

The acquisition of pathogen-derived antigen by dendritic cells (DCs) is a key event in the generation of cytotoxic CD8+ T cell responses. In mice, the intracellular bacterium Listeria monocytogenes is directed from the blood to splenic CD8α+ DCs. We report that L. monocytogenes rapidly associated with platelets in the bloodstream in a manner dependent on GPIb and complement C3. Platelet association targeted a small but immunologically important portion of L. monocytogenes to splenic CD8α+ DCs, diverting bacteria from swift clearance by other, less immunogenic phagocytes. Thus, an effective balance is established between maintaining sterility of the circulation and induction of antibacterial immunity by DCs. Other Gram-positive bacteria also were rapidly tagged by platelets, revealing a broadly active shuttling mechanism for systemic bacteria.

Deliberate removal of T cell help improves virus-neutralizing antibody production

The B cell response to lymphocytic choriomeningitis virus is characterized by a CD4+ T cell–dependent polyclonal hypergammaglobulinemia and delayed formation of virus-specific neutralizing antibodies. Here we provide evidence that, paradoxically, because of polyclonal B cell activation, virus-specific T cell help impairs the induction of neutralizing antibody responses. Experimental reduction in CD4+ T cell help in vivo resulted in potent neutralizing antibody responses without impairment of CD8+ T cell activity. These unexpected consequences of polyclonal B cell activation may affect vaccine strategies and the treatment of clinically relevant chronic bacterial, parasitic and viral infections in which hypergammaglobulinemia is regularly found.

IL-1β drives inflammatory responses to propionibacterium acnes in vitro and in vivo.

Acne vulgaris is potentially a severe skin disease associated with colonization of the pilo-sebaceous unit by the commensal bacterium Propionibacterium acnes and inflammation. P. acnes is considered to contribute to inflammation in acne, but the pathways involved are unclear. Here we reveal a mechanism that regulates inflammatory responses to P. acnes. We show that IL-1β mRNA and the active processed form of IL-1β are abundant in inflammatory acne lesions. Moreover, we identify P. acnes as a trigger of monocyte-macrophage NLRP3-inflammasome activation, IL-1β processing and secretion that is dependent on phagocytosis, lysosomal destabilization, reactive oxygen species, and cellular K+ efflux. In mice, inflammation induced by P. acnes is critically dependent on IL-1β and the NLRP3 inflammasome of myeloid cells. These findings show that the commensal P. acnes-by activating the inflammasome-can trigger an innate immune response in the skin, thus establishing the NLRP3-inflammasome and IL-1β as possible therapeutic targets in acne.

Extraintestinal Manifestations of Inflammatory Bowel Disease

Abstract:Extraintestinal manifestations (EIM) in inflammatory bowel disease (IBD) are frequent and may occur before or after IBD diagnosis. EIM may impact the quality of life for patients with IBD significantly requiring specific treatment depending on the affected organ(s). They most frequently affect joints, skin, or eyes, but can also less frequently involve other organs such as liver, lungs, or pancreas. Certain EIM, such as peripheral arthritis, oral aphthous ulcers, episcleritis, or erythema nodosum, are frequently associated with active intestinal inflammation and usually improve by treatment of the intestinal activity. Other EIM, such as uveitis or ankylosing spondylitis, usually occur independent of intestinal inflammatory activity. For other not so rare EIM, such as pyoderma gangrenosum and primary sclerosing cholangitis, the association with the activity of the underlying IBD is unclear. Successful therapy of EIM is essential for improving quality of life of patients with IBD. Besides other options, tumor necrosis factor antibody therapy is an important therapy for EIM in patients with IBD.

Interrupting IL-6–receptor signaling improves atopic dermatitis but associates with bacterial superinfection

*Some of the patients who experienced sedation moved along the sedation score scale during the observation period (eg, a patient could have started with a sedation score of 3, then received a score of 1 when heavily sedated, then moved up to a score of 2 while gradually getting more alert, and ended the observation period again with a score of 3). Therefore these patients received more than 1 sedation score, and this explains why the percentages of the scores sum to greater than 100. All subjects started or ended the observation period with this score. J ALLERGY CLIN IMMUNOL NOVEMBER 2011 1128 LETTERS TO THE EDITOR

Innate immune-induced depletion of bone marrow neutrophils aggravates systemic bacterial infections

Neutrophils are the most abundant leukocytes in circulation and provide a primary innate immune defense function against bacterial pathogens before development of a specific immune response. These specialized phagocytes are short lived (12–24 hours) and continuously replenished from bone marrow. We found that if the host is overwhelmed by a high inoculum of Listeria monocytogenes, neutrophils are depleted despite high granulocyte-colony stimulating factor induction. In contrast to a low-dose innocuous L. monocytogenes infection, high-dose Listeria challenge blocks neutrophil recruitment to infectious abscesses and bacterial proliferation is not controlled, resulting in lethal outcomes. Administering synthetic TLR2-ligand or heat-killed bacteria during the innocuous L. monocytogenes infection reproduced these effects, once again leading to overwhelming bacterial propagation. The same stimuli also severely aggravated Salmonella typhimurium, Staphylococcus aureus, and Streptococcus pyogenes systemic infection. These data implicate systemic innate immune stimulation as a mechanism of bone marrow neutrophil exhaustion which negatively influences the outcome of bacterial infections.