Abstract
BackgroundImmunosenescence is the age-related decline and dysfunction of protective immunity leading to a marked increase in the risk of infections, autoimmune disease, and cancer. The majority of studies have focused on immunosenescence in the systemic immune system; information concerning the effect of aging on intestinal immunity is limited. Isolated lymphoid follicles (ILFs) are newly appreciated dynamic intestinal lymphoid structures that arise from nascent lymphoid tissues, or cryptopatches (CP), in response to local inflammatory stimuli. ILFs promote "homeostatic" responses including the production of antigen-specific IgA, thus playing a key role in mucosal immune protection. ILF dysfunction with aging could contribute to immunosenescence of the mucosal system, and accordingly we examined phenotypic and functional aspects of ILFs from young (2 month old) and aged (2 year old) mice.ResultsWe observed that aged mice have increased numbers of ILFs and increased numbers of structures corresponding to an early stage of CPs transforming into ILFs. The cellular composition of ILFs in aged mice is altered with a smaller B-lymphocyte population and an increased T-lymphocyte population. The ILF T-lymphocyte population is notable by the presence of CD4+ CD8αα+ T-lymphocytes, which are absent from the systemic compartment. The smaller B-lymphocyte population in ILFs from aged mice is directly correlated with decreased mRNA and protein expression of CCL20 and CXCL13, two chemokines that play crucial roles in recruiting B-lymphocytes into ILFs. Aged mice had elevated levels of serum and fecal immunoglobulins and despite the decreased B-lymphocyte population, ILFs from aged mice displayed increased IgA production. The immunoglobulin repertoire was skewed in aged mice, and ILFs demonstrated a repertoire usage similar to that of the systemic pool in both young and aged mice.ConclusionsHere we observed that ILF development, cellular composition, and immunoglobulin production are altered with aging suggesting that ILF dysfunction contributes to mucosal immunosenescence.
Highlights
Immunosenescence is the age-related decline and dysfunction of protective immunity leading to a marked increase in the risk of infections, autoimmune disease, and cancer
As CP progress to become Isolated lymphoid follicles (ILFs) they become infiltrated with a substantial population of dendritic cells [23], and the presence of CD11c+ clusters can be used to identify stages of solitary intestinal lymphoid tissue (SILT) ranging from CP progressing to immature ILFs to fully developed mature ILFs
ILFs can range from lymphocyte containing cellular clusters encompassing the crypt and extending up the villi to more organized aggregates having a follicular appearance possessing an overlying follicle associated epithelium (FAE)
Summary
Immunosenescence is the age-related decline and dysfunction of protective immunity leading to a marked increase in the risk of infections, autoimmune disease, and cancer. Bacterial and viral infections in the lungs, skin, and urinary tract become more common [5,6,7] Compounding this susceptibility to infection, the rates of seroconversion after prophylactic vaccination decrease proportionally with advancing age [8,9]. Age is an important risk factor for colon cancer, the third most deadly cancer in the United States Coincident with this decline is an increased incidence of individuals diagnosed with inflammatory bowel disease in their seventh decade of life, demonstrating a tendency toward the development of inappropriate mucosal immune responses with aging [15,16]
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