Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment but strongly interacts with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on micro- and astroglia and trigger an innate immune response, characterized by the release of inflammatory mediators, which contribute to disease progression and severity. Genome wide analysis suggests that several genes, which increase the risk for sporadic Alzheimer's disease en-code for factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity are likely to interfere with the immunological processes of the brain and further promote disease progression. This re-view provides an overview on the current knowledge and focuses on the most recent and exciting findings. Modulation of risk factors and intervention with the described immune mechanisms are likely to lead to future preventive or therapeutic strategies for Alzheimer's disease.

More than any other cytokine family, the interleukin (IL)-1 family is closely linked to the innate immune response. This linkage became evident upon the discovery that the cytoplasmic domain of the IL-1 receptor type I is highly homologous to the cytoplasmic domains of all Toll-like receptors (TLRs). Thus, fundamental inflammatory responses such as the induction of cyclooxygenase type 2, increased expression of adhesion molecules, or synthesis of nitric oxide are indistinguishable responses of both IL-1 and TLR ligands. Both families nonspecifically affect antigen recognition and lymphocyte function. IL-1beta is the most studied member of the IL-1 family because of its role in mediating autoinflammatory diseases. Although the TLR and IL-1 families evolved to assist in host defense against infection, unlike the TLR family, the IL-1 family also includes members that suppress inflammation, both specifically within the IL-1 family but also nonspecifically for TLR ligands and the innate immune response.

To understand the role of the proinflammatory cytokine interleukin-1 (IL-1) in disease, investigators have studied how production of the different members of the IL-1 family is controlled, the various biologic activities of IL-1, the distinct and various functions of the IL-1 receptor (IL-1R) family, and the complexity of intracellular signaling. Mice deficient in IL-1Beta, IL-1Beta converting enzyme, and IL-1R type I have also been studied. Humans have been injected with IL- 1 (either IL-1alpha or IL-1beta) for enhancing bone marrow recovery and for cancer treatment. The IL-1-specific receptor antagonist (IL-1Ra) has also been tested in clinical trials. The topics discussed in this review include production and activities of IL-1 and IL-1Ra molecules, the effects of IL-1 on gene expression, functions of cell-bound and soluble IL-1 receptors, the importance of the IL-1R accessory protein, newly discovered signal transduction pathways, naturally occurring cytokines limiting IL-1 production or activity, the effects of blocking cyclooxygenase and nitric oxide, and the outcomes of IL-1 and IL-1 Ra in human trials. Special attention is paid to IL-1beta converting enzyme and programmed cell death. The roles of IL-1 in hematopoiesis, leukemia, atherosclerosis, and growth of solid tumors are also discussed. This is a lengthy review, with 586 citations chosen to illustrate specific areas of interest rather than a compendium of references. At the end of each section, a short commentary summarizes what the author considers established or controversial topics linking the biology of IL-1 to mechanisms of disease.

More than any other cytokine family, the IL-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each IL-1 receptor family member contains the Toll-IL-1-receptor domain. This domain is also present in each Tolllike receptor, the receptors that respond to microbial products and viruses. Since Toll-IL-1-receptor domains are functional for both receptor families, responses to the IL-1 family are fundamental to innate immunity. Of the 11 members of the IL-1 family, IL-1␤ has emerged as a therapeutic target for an expanding number of systemic and local inflammatory conditions called autoinflammatory diseases. For these, neutralization of IL-1␤ results in a rapid and sustained reduction in disease severity. Treatment for autoimmune diseases often includes immunosuppressive drugs whereas neutralization of IL-1␤ is mostly anti-inflammatory. Although some autoinflammatory diseases are due to gain-of-function mutations for caspase-1 activity, common diseases such as gout, type 2 diabetes, heart failure, recurrent pericarditis, rheumatoid arthritis, and smoldering myeloma also are responsive to IL-1␤ neutralization. This review summarizes acute and chronic inflammatory diseases that are treated by reducing IL-1␤ activity and proposes that disease severity is affected by the anti-inflammatory members of the IL-1 family of ligands and receptors. (Blood. 2011;117(14):3720-3732) IntroductionSince the 1996 publication in Blood of "Biologic Basis for Interleukin-1 in Disease," 1 there have been several major advances in understanding a role for IL-1 in the pathogenesis of disease. Because of its property as a hematopoietic factor, IL-1 was administered to patients to improve recovery after BM transplantation (human responses to IL-1 were reviewed in detail in 1996). 1 Effective in reducing the duration of thrombocytopenia and leukopenia, recipients of IL-1 therapy experienced unacceptable signs and symptoms of systemic inflammation, including hypotension. Therefore, attention was initially focused on blocking IL-1 activity in sepsis with the use of the naturally occurring IL-1 receptor antagonist (IL-1Ra), now known by its generic name anakinra. There were 3 controlled trials of anakinra in human sepsis. Although in each trial there was a reduction in 28-day all-causes mortality compared with placebo-treated patients, the reductions did not reach statistical significance. 2 The failure of blocking IL-1 to significantly reduce mortality in septic shock is not unusual, because most anticytokines and anti-inflammatory agents have also failed in sepsis trials (reviewed in Eichacker et al 3 ).Subsequently, attention focused on blocking IL-1 in noninfectious, chronic inflammatory conditions, such as rheumatoid arthritis. Anakinra is approved for reducing the signs and symptoms of rheumatoid arthritis and slows the progressive joint destructive characteristics of the disease. Anakinra has also been administered to patients with smoldering/indolent myeloma at high risk o...