The Humoral Immune Response Is Initiated in Lymph Nodes by B Cells that Acquire Soluble Antigen Directly in the Follicles

Pape, Kathryn A.; Catron, Drew M.; Itano, Andrea; Jenkins, Marc K.

doi:10.1016/j.immuni.2007.02.011

Cited by 316 publications

(313 citation statements)

References 43 publications

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“…Presentation of enriched i.p.-injected OVA may have allowed particularly efficient stimulation and suppressive activity of T reg in the spleen. The conduit system of LN appears to be more efficient at enriching antigen arriving through the afferent lymphatics [40]. In our system, autoantigen was restricted to the pancreas and thus could reach via afferent lymphatics only the PLN.…”

Section: Discussionmentioning

confidence: 89%

CD25⁺ T_reg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

Ludwig‐Portugall¹,

Hamilton‐Williams²,

Gotot³

et al. 2009

Eur J Immunol

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To study B-cell tolerance against non-lymphoid tissue autoantigens, we generated transgenic rat insulin promoter (RIP)-OVA/hen egg lysozyme (HEL) mice expressing the model antigens, OVA and HEL, in pancreatic islets. Their vaccination with OVA or HEL induced far less auto-Ab titers compared with non-transgenic controls. Depletion of CD25 + cells during immunization completely restored auto-Ab production, but did not affect antibodies against a foreign control antigen. Depletion at later time-points was not effective. OVA-specific CD25 + FoxP3 + T reg were more frequent in the autoantigen-draining pancreatic LN than in other secondary lymphatics of RIP-OVA/HEL mice. Consistently, B cells were suppressed in that LN and also in the spleen, which is known to concentrate circulating antigen, such as the antigens used for vaccination. Suppression involved preventing expansion of autoreactive B cells in response to autoantigen, reducing antibody production per B-cell and isotype changes. These findings demonstrate that CD25 + T reg suppress auto-Ab production against non-lymphoid tissue antigens in an antigenspecific manner.Key words: Auto-antibodies . B cells . Tolerance . Transgenic mice . T reg IntroductionAutoreactive B cells are controlled by a series of self-tolerance mechanisms. The first checkpoint incapacitates B cells of high affinity to autoantigen in the bone marrow, by receptor editing [1,2] or central deletion [1][2][3][4]. Self-reactive low-affinity B cells enter the periphery and can constitute up to 5-20% of circulating mature B cells in healthy individuals [5,6]. Therefore, further peripheral checkpoints exist, such as deletion [1,2,7] or anergy [1,8,9]. Anergic B cells are arrested in the transitional T2 developmental stage, followed by their death [10]. B cells also die in response to continuous antigen binding [11] and BCR signaling [9].Auto-Ab production by autoreactive B cells that survive these checkpoints can be avoided by extrinsic regulation [1], like the absence of T cell help resulting from central T-cell tolerance, which appears to be more efficient than central B-cell tolerance [12]. Th cells are required for B-cell survival [1], class switching, Ig synthesis and somatic hypermutation [6,13,14]. The latter process not only further increases BCR diversity but may also generate self-reactive B cells, with an even higher risk for autoimmunity, because after somatic hypermutation, B cells are long-lived and produce high-affinity Ab [15]. Thus, additional tolerance mechanisms seem to be required for maintaining peripheral B-cell tolerance, such as active suppression [6].In addition to T-cell suppression, T reg have also been proposed to control antibody production, since auto-Ab titers in B-cellmediated disease models were associated with decreased numbers or functionality of T reg , and because depletion of T reg aggravated disease [16,17]. The role of T reg in antibody production against non-lymphoid tissue autoantigens is unresolved. In rat insulin promoter (RIP)-mOVA mice expressing the mo...

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Section: Discussionmentioning

confidence: 89%

CD25⁺ T_reg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

Ludwig‐Portugall¹,

Hamilton‐Williams²,

Gotot³

et al. 2009

Eur J Immunol

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“…Further in support of the lymph node as a target, the humoral response is apparently initiated by lymph-node B cells, which take up antigen directly in the lymph-node follicles, rather than by migrating B cells or by dendritic cells, indicating that lymph-node targeting may be advantageous for protective antibody-generating vaccines 11 . This approach has not been widely investigated, and it remains to be determined how the T-cell response differs when initiated by peripherally activated dendritic cells and when initiated by lymph-node dendritic cells, as well as how the chemokine balance shifts in the lymph node and how this ultimately affects the long-term response.…”

Section: Tissue and Cellular Targetsmentioning

confidence: 99%

Materials engineering for immunomodulation

Hubbell

Thomas

Swartz

2009

Nature

502

428

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The engineering of materials that can modulate the immune system is an emerging field that is developing alongside immunology. For therapeutic ends such as vaccine development, materials are now being engineered to deliver antigens through specific intracellular pathways, allowing better control of the way in which antigens are presented to one of the key types of immune cell, T cells. Materials are also being designed as adjuvants, to mimic specific 'danger' signals in order to manipulate the resultant cytokine environment, which influences how antigens are interpreted by T cells. In addition to offering the potential for medical advances, immunomodulatory materials can form well-defined model systems, helping to provide new insight into basic immunobiology.The term 'immunobioengineering' is used to describe efforts by immunologists and engineers to design materials, delivery vehicles and molecules both to manipulate and to better understand the immune system. Examples are the engineering of material surfaces to induce or prevent complement activation, the engineering of adjuvants to activate the immune system, the engineering of antigen or adjuvant carriers for subunit vaccine delivery, and the engineering of microenvironments to determine the interaction kinetics of mature dendritic cells and naive T cells. These advances not only will contribute to prophylactic vaccine strategies for infectious diseases but also are likely to affect immunotherapeutics, particularly for cancer, and new approaches to prevent or treat allergies and autoimmune diseases. The field is rapidly evolving along with advances in our understanding of immunology and is also contributing to our knowledge of basic immunology.In this Review, we describe the current state of immunobioengineering as it intersects with the field of materials science, and we give a perspective on its current and future directions. We focus on materials for immunomodulation, particularly with respect to dendritic-cell modulation. We begin by providing a brief introduction to the targets for delivery: the types of cell that materials are being designed to target, the tissues in which those cells reside, the intracellular compartments within those cells, and the influence that delivery to those particular compartments has on immunological outcome. We then discuss the biomolecular payloads used to activate immune cells and the design of the materials used to deliver those 'danger' signals along with, in the context of vaccination, antigens. Finally, we highlight materials approaches that are being developed to explore basic immunological function, especially how dendritic cells and T cells interact. Tissue and cellular targetsAs the general goals of immunobioengineering are to probe and manipulate the immune system, we start with a general discussion of tissue, cellular and subcellular targets -what we want to target and why -to guide the design principles discussed below.The immune cells most frequently targeted include B cells, macrophages and dendritic cells, wh...

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“…Lymphatic vessels bring peripheral antigens and antigen presenting cells (APCs) like dendritic cells (DCs) to lymph nodes (LNs) where adaptive immunity can be initiated. This occurs either from lymph-borne antigen capture by B cells and lymph node resident APCs [2][3][4], or by the more classical route of peripherally-activated DC migration to the LN and activation of resident T cells [5]. Lymph nodes are also important centers for the maintenance of tolerance to self-antigens [4,[6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

Lund

Swartz

2010

J Mammary Gland Biol Neoplasia

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Research in lymphatic biology and cancer immunology may soon intersect as emerging evidence implicates the lymphatics in the progression of chronic inflammation and autoimmunity as well as in tumor metastasis and immune escape. Like the blood vasculature, the lymphatic system comprises a highly dynamic conduit system that regulates fluid homeostasis, antigen transport and immune cell trafficking, which all play important roles in the progression and resolution of inflammation, autoimmune diseases, and cancer. This review presents emerging evidence that lymphatic vessels are active modulators of immunity, perhaps fine-tuning the response to adjust the balance between peripheral tolerance and immunity. This suggests that the tumor-associated lymphatic vessels and draining lymph node may be important in tumor immunity which in turn governs metastasis.

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The Humoral Immune Response Is Initiated in Lymph Nodes by B Cells that Acquire Soluble Antigen Directly in the Follicles

Cited by 316 publications

References 43 publications

CD25⁺ T_reg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

CD25⁺ T_reg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

Materials engineering for immunomodulation

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

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The Humoral Immune Response Is Initiated in Lymph Nodes by B Cells that Acquire Soluble Antigen Directly in the Follicles

Cited by 316 publications

References 43 publications

CD25+ Treg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

CD25+ Treg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

Materials engineering for immunomodulation

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

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CD25⁺ T_reg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

CD25⁺ T_reg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens