353 www.expert-reviews.com ISSN 1744-666X © 2010 Expert Reviews Ltd 10.1586/ECI.10.16 Key Paper Evaluation Streptococcus pyogenes infections are among the most common microbial challenges in human life. They manifest in a wide spectrum of patho- logic conditions, ranging from pharyngitis to localized purulent skin lesions or, less frequently, in life-threatening conditions such as necrotiz- ing fasciitis and septic/toxic shock syndrome [1,2] . The actual outcome of infections always depends on the balance between the strength of the viru- lence factors of the pathogen and the defense mechanisms of the host. Therefore, studying fac- tors that possibly inluence this balance might provide insight into the mechanistic components of infectious diseases, which may in turn help us to design appropriate therapeutic approaches to treat them. Animal models are especially useful for such studies because many components of dis- ease development, susceptibility and modulation of cellular function cannot be properly monitored or controlled in the human population. Infection of ‘susceptible’ mice (e.g., C3H or CBA strains) with S. pyogenes leads to fulminant systemic bacterial growth, a generalized inlam- matory reaction and, eventually, to the death of the animals within a period of a few days [3] . Septic C3H mice produce large amounts of proin- lammatory cytokines, such as IL-1a and IFN-g, and nitric oxide within 48 h postinoculation, and suffer serious liver damage after 72 h [4] . T cells of C3H mice exhibit extensive proliferation in response to S. pyogenes products [4] . Innate immune cells (macrophages, dendritic cells and natural killer cells) play pivotal roles in the defense against S. pyogenes [5–7] . In summary, this mouse model represents a very severe and fulminant form of systemic streptococcal infection. Immunosenescence is a complex, age- related decline of immune functions affect- ing both innate and adaptive immunity [8–11] . Consequently, elderly individuals are at a higher risk of succumbing to infections, tumors or autoimmunity [9–12] . Innate immunity is affected at multiple levels in aged individu- als [8,10] . Neutrophils and macrophages exhibit Ferenc Boldizsar 1 , Katalin Mikecz 2 and Tibor T Glant †2 1 Department of Immunology and Biotechnology, University of Pécs, Pécs, Szigeti út 12, H-7624 Pécs, Hungary 2 Section of Molecular Medicine, Departments of Orthopedic Surgery, Biochemistry, and Medicine (Section of Rheumatology), Rush University Medical Center, 1735 West Harrison, Cohn Research Bld, Chicago, IL 60612, USA † Author for correspondence: Tel.: +1 312 942 9733 Fax: +1 312 942 8828 tglant@rush.edu Evaluation of: Goldmann O, Lehne S, Medina E. Age-related susceptibility to Streptococcus pyogenes infection in mice: underlying immune dysfunction and strategy to enhance immunity. J. Pathol. 220(5), 521–529 (2010). Immunosenescence is a pathophysiological event in the aging process, which probably represents the greatest danger to an individual; diminished immune functions and altered immunoregulation lead to increased susceptibility to infections, autoimmunity and increased frequency of tumors in the elderly. Immunosenescence affects the functions of both innate immune cells (such as neutrophils, macrophages and dendritic cells) and cells involved in adaptive immunity (T and B lymphocytes). A number of methods have been developed to monitor age-related abnormalities in inbred murine strains, including physiologial and immunological tests, and a variety of genetic and epigenetic assays. Various animal models enable investigation of certain aspects of the aging process, and also allow for testing of immune-modulating agents that might ‘rejuvenate’ the cellular functions altered by aging. Although short-term experiments with targeted compounds to replenish certain cell types or restore cellular functions may present impressive results of ‘rejuvenation’ of innate immunity (reduced susceptibility to an infectious agent), to date, immunosenescence still remains a phenomenological term with limited etiologic information at the cellular and molecular levels. KEYWORDS: adaptive immunity • aging • epigenome • immunosenescence • infection • innate immunity Immunosenescence and its potential modulation: lessons from mouse models Expert Rev. Clin. Immunol. 6(3), 353–357 (2010) For reprint orders, please contact reprints@expert-reviews.com