Mechanisms for Decreased Function of B Cells in Aged Mice and Humans

Abstract The immune system has been known for some time to be compromised in aged individuals, e.g., both mice and humans, and in both humoral and cellular responses. Our studies have begun to elucidate intrinsic B lymphocyte defects in Ig class switch recombination, activation-induced cytidine deaminase, and E47 transcription factor expression. These defects occur in both mice and humans. Our studies have also shown that tristetraprolin is one of the key players in regulating the decreased E47 mRNA stability in aged B lymphocytes. These and current studies should lead to improvements in B lymphocyte function in aged populations

Physical location of the human immunoglobulin lambda-like genes, 14.1, 16.1, and 16.2

The human immunoglobulin lambda-like ( IGLL ) genes, which are homologous to the human immunoglobulin lambda ( IGL ) light chain genes, are expressed only in pre-B cells and are involved in B cell development. Three IGLL genes, 14.1, 16.1, and 16.2 are present in humans as opposed to one, λ5 ( Igll ), found in the mouse. To precisely map the location of the human IGLL genes in relation to each other and to the human IGL gene locus, at 22q11.1–2, a somatic cell hybrid panel and pulsed field gel electrophoresis (PFGE) were used. Hybridization with a λ-like gene-specific DNA probe to somatic cell hybrids revealed that these genes reside on 22q11.2 between the breakpoint cluster region ( BCR ) and the Ewing sarcoma breakpoint at 22q12 and that gene 16.1 was located distal to genes 14.1 and 16.2 . Gene 14.1 was found by PFGE to be proximal to 16.2 by at least 30 kilobases (kb). A 210 kb Not I fragment containing genes 14.1 and 16.2 is adjacent to a 400 kb Not I fragment containing the BCR locus, which is just distal to the IGL-C ( IGL constant region) genes. We have determined that the IGLL genes 14.1 and 16.2 are approximately 670 kb and 690 to 830 kb distal, respectively, to the 3′-most IGL-C gene in the IGL gene locus, IGL-C7 . We thus show the first physical linkage of the IGL and the IGLL genes, 14.1 and 16.2 . We discuss the relevance of methylation patterns and CpG islands to expression, and the evolutionary significance of the IGLL gene duplications. Consistent with the GenBank nomenclature, these human IGLL genes will be referred to as IGLL1 (14.1) , IGLL2 (16.2) , and IGLL3 (16.1) , reflecting their position on chromosome 22, as established by this report.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46751/1/251_2004_Article_BF00184519.pd

The Impact of Obesity and Metabolic Syndrome on Vaccination Success

The increase in the prevalence of obesity represents a worldwide phenomenon which is associated with several chronic diseases. In this review, we summarize published data showing how obesity, alone or together with the metabolic syndrome, induces defects in B cells similar to those induced by aging, contributes to systemic and B cell intrinsic inflammation and increases the secretion of autoimmune antibodies. We show that obese individuals contract more bacterial, viral, and fungal infections as compared to lean controls. These include periodontal, cutaneous, gastric, and respiratory tract infections, as well as postsurgical infections occurring after solid organ transplantation and surgeries for weight loss. Moreover, because obese individuals have a compromised immune system, they respond poorly to vaccination against influenza, hepatitis B, tetanus, and rabies. The results in this review highlight the importance to vaccinate individuals with obesity and/or with metabolic syndrome to prevent morbidity from vaccine-preventable diseases

Aging Impairs Murine B Cell Differentiation and Function in Primary and Secondary Lymphoid Tissues

Age-related changes in humoral immunity are responsible for the reduced vaccine responses observed in elderly individuals. Although aging has been shown to affect T cells, dendritic cells and macrophages and these effects significantly impact humoral responses, intrinsic alterations in B cells also occur. We here provide an overview of age-related changes in mouse B cells. In particular, we summarize data from the literature showing age-related changes in B cell differentiation in the bone marrow, in B cell marker expression and cell survival in the periphery and in the ability to make specific antibodies in both splenic and mucosal tissues. Moreover, we summarize the results from our studies showing that the ability to undergo class switch recombination, the enzyme activation-induced cytidine deaminase and the transcription factor E47 are all decreased in stimulated B cells from old mice. The defects presented in this review for aged B cells should allow the discovery of strategies for improvement of humoral immune responses in both humans and mice in the near future

Obesity Accelerates Age Defects in Mouse and Human B Cells

Obesity, similar to aging, is associated with chronic low-grade systemic inflammation, known as inflammaging, and represents a significantly higher risk for developing chronic diseases typical of old age. Immune cells are recruited to the obese adipose tissue (AT) by chemotactic molecules secreted by non-immune and immune cells in the AT, both contributing to the release of several pro-inflammatory mediators that fuel local and systemic inflammation, to the refractory response of immune cells to further and stimulation and to the induction of autoimmune B cells with potentially pathogenic repertoires. In terms of molecular mechanisms involved, leptin, an adipokine secreted primarily by adipocytes, has been proposed to be involved in the reduced generation of protective antibodies, and in the increased generation of autoimmune antibodies, further supporting the concept that obesity accelerates age defects. Leptin has also been shown to induce intrinsic B cell inflammation and B cell immunosenescence. The results presented in this review highlight the importance of weight reduction programs to improve immunity and reduce the risk for developing chronic diseases in obese and older individuals

Age effects on mouse and human B cells

Our laboratory has contributed to the areas of B cell receptor (BCR) and pre-BCR gene identification and transcription and has focused on the problem of the aged immune system in mice and humans for the last 15 years. We have found biomarkers for the decrease in B cell function in aged mice and humans. These include decreases in immunoglobulin (Ig) class switch (e.g., IgM to IgG), decreases in the enzyme AID (activation-induced cytidine deaminase) and decreases in the transcription factor E47. The E47 mRNA stability is decreased in old B cells due to decreased phospho-MAPKinase and phospho-TTP (tristetraprolin). Inflammation, e.g., TNF-α, which increases with age, impacts B cells directly by increasing their TNF-α and NF-κB and leads to the above decreased pathway. Both class switch and affinity maturation are decreased in elderly responses to the influenza vaccine and biomarkers we have found (numbers and percentages of switched memory B cells and AID in stimulated B cells in culture) can predict a beneficial or decreased immune response to the vaccine. Current and future avenues to improve the humoral immune response in the elderly are discussed

Adipose Tissue Inflammation Induces B Cell Inflammation and Decreases B Cell Function in Aging

Aging is the greatest risk factor for developing chronic diseases. Inflamm-aging, the age-related increase in low-grade chronic inflammation, may be a common link in age-related diseases. This review summarizes recent published data on potential cellular and molecular mechanisms of the age-related increase in inflammation, and how these contribute to decreased humoral immune responses in aged mice and humans. Briefly, we cover how aging and related inflammation decrease antibody responses in mice and humans, and how obesity contributes to the mechanisms for aging through increased inflammation. We also report data in the literature showing adipose tissue infiltration with immune cells and how these cells are recruited and contribute to local and systemic inflammation. We show that several types of immune cells infiltrate the adipose tissue and these include macrophages, neutrophils, NK cells, innate lymphoid cells, eosinophils, T cells, B1, and B2 cells. Our main focus is how the adipose tissue affects immune responses, in particular B cell responses and antibody production. The role of leptin in generating inflammation and decreased B cell responses is also discussed. We report data published by us and by other groups showing that the adipose tissue generates pro-inflammatory B cell subsets which induce pro-inflammatory T cells, promote insulin resistance, and secrete pathogenic autoimmune antibodies