Maackia amurensis seed lectin (MASL) ameliorates articular cartilage destruction and increases movement velocity of mice with TNFα induced rheumatoid arthritis.

Up to 70 million people around the world suffer from rheumatoid arthritis. Current treatment options have varied efficacy and can cause unwanted side effects. New approaches are needed to treat this condition.

American Association of Immunologists Recommendations for an Undergraduate Course in Immunology.

Identifying the "essential" components of an undergraduate immunology lecture course can be daunting because of the varying postgraduate pathways students take. The American Association of Immunologists Education Committee commissioned an Ad Hoc Committee, representing undergraduate, graduate, and medical institutions as well as the biotechnology community, to develop core curricular recommendations for teaching immunology to undergraduates. In a reiterative process involving the American Association of Immunologists teaching community, 14 key topics were identified and expanded to include foundational concepts, subtopics and examples, and advanced subtopics, providing a flexible list for curriculum development and avenues for higher-level learning.

Differential cellular composition of human palatine and pharyngeal tonsils.

Objective: The goal of this study was to gain a better understanding of the potential functional specialization of palatine and pharyngeal tonsils, by comparing their cellular composition in paired specimens from a large cohort of adenotonsillectomy patients.

Design: Resident B cell, T cell, dendritic cell, and stromal cell subsets were characterized using multicolor flow cytometry in palatine and pharyngeal tonsil specimens from 27 patients, age 2-34 years.

Results: Paired comparisons showed highly significant intra-individual differences in resident cell subsets of palatine and pharyngeal tonsils.

Animal models of rheumatoid pain: experimental systems and insights.

Severe chronic pain is one of the hallmarks and most debilitating manifestations of inflammatory arthritis. It represents a significant problem in the clinical management of patients with common chronic inflammatory joint conditions such as rheumatoid arthritis, psoriatic arthritis and spondyloarthropathies. The functional links between peripheral inflammatory signals and the establishment of the neuroadaptive mechanisms acting in nociceptors and in the central nervous system in the establishment of chronic and neuropathic pain are still poorly understood, representing an area of intense study and translational priority.

Chronic exposure to tumor necrosis factor in vivo induces hyperalgesia, upregulates sodium channel gene expression and alters the cellular electrophysiology of dorsal root ganglion neurons.

The goal of these studies was to investigate the links between chronic exposure to the pro-inflammatory cytokine tumor necrosis factor (TNF), hyperalgesia and the excitability of dorsal root ganglion (DRG) sensory neurons. We employed transgenic mice that constitutively express TNF (TNFtg mice), a well-established model of chronic systemic inflammation. At 6 months of age, TNFtg mice demonstrated increased sensitivity to both mechanical and thermal heat stimulation relative to aged-matched wild-type controls.

Brief Report: Treatment of Tumor Necrosis Factor-Transgenic Mice With Anti-Tumor Necrosis Factor Restores Lymphatic Contractions, Repairs Lymphatic Vessels, and May Increase Monocyte/Macrophage Egress.

Objective: Recent studies have demonstrated that there is an inverse relationship between lymphatic egress and inflammatory arthritis in affected joints. As a model, tumor necrosis factor (TNF)-transgenic mice develop advanced arthritis following draining lymph node (LN) collapse, and loss of lymphatic contractions downstream of inflamed joints. It is unknown if these lymphatic deficits are reversible.

Increased numbers of CD23(+) CD21(hi) Bin-like B cells in human reactive and rheumatoid arthritis lymph nodes.

A unique population of CD23(+) CD21(high) B cells in inflamed nodes (Bin) has been shown to accumulate in lymph nodes (LNs) draining inflamed joints of TNF-transgenic (TNF-tg) mice. Bin cells contribute to arthritis flare in mice by distorting node architecture and hampering lymphatic flow, but their existence in human inflamed LNs has not yet been described. Here, we report the characterization of resident B-cell populations in fresh popliteal lymph nodes (PLNs) from patients with severe lower limb diseases (non-RA) and rheumatoid arthritis (RA) patients, and from banked, cryopreserved reactive and normal human LN single cell suspension samples.

The CD27-CD70 pathway and pathogenesis of autoimmune disease.

Objective: To critically examine current evidence regarding the role of the CD27-CD70 pathway in the pathophysiology of autoimmune disease with a focus on understanding the contributions of this pathway as a potential new therapeutic target for systemic lupus erythematosus and rheumatoid arthritis.

Methods: A PubMed search for articles was conducted using the following key words: ("CD27" OR "CD70") AND ("autoimmune disease" OR "systemic lupus erythematosus" OR "rheumatoid arthritis"). The search was limited to publications in English and included human and animal studies.

TNF signals are dispensable for the generation of CD23+ CD21/35-high CD1d-high B cells in inflamed lymph nodes.

Tumor necrosis factor (TNF) is a key cytokine in rheumatoid arthritis (RA) pathogenesis, as underscored by the clinical effectiveness of TNF antagonists. While several of TNF's key targets in RA are well understood, its many pleiotropic effects remain to be elucidated. TNF-transgenic mice develop inflammatory-erosive arthritis associated with disruption of draining lymph node histology and function, and accumulation of B cells with unique phenotypic and functional features consistent with contribution to pathogenesis (B cells in inflamed nodes, Bin).

Baseline CXCL10 and CXCL13 levels are predictive biomarkers for tumor necrosis factor inhibitor therapy in patients with moderate to severe rheumatoid arthritis: a pilot, prospective study.

Background: TNF inhibitors have been used as a treatment for moderate to severe RA patients. However, reliable biomarkers that predict therapeutic response to TNF inhibitors are lacking. In this study, we investigated whether chemokines may represent useful biomarkers to predict the response to TNF inhibitor therapy in RA.

Peroxisome proliferator-activated receptor γ B cell-specific-deficient mice have an impaired antibody response.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARγ, a ligand-activated transcription factor, has important anti-inflammatory and antiproliferative functions, and it has been associated with diseases including diabetes, scarring, and atherosclerosis, among others. PPARγ is expressed in most bone marrow-derived cells and influences their function.

Efficacy of B cell depletion therapy for murine joint arthritis flare is associated with increased lymphatic flow.

Objective: B cell depletion therapy ameliorates rheumatoid arthritis by mechanisms that are incompletely understood. Arthritis flare in tumor necrosis factor (TNF)-transgenic mice is associated with efferent lymph node (LN) "collapse," triggered by B cell translocation into lymphatic spaces and decreased lymphatic drainage. The aim of this study was to examine whether the efficacy of B cell depletion therapy is associated with restoration of lymphatic drainage due to removal of obstructing nodal B cells.

CD23+ CD21(high) CD1d(high) B cells in inflamed lymph nodes are a locally differentiated population with increased antigen capture and activation potential.

CD23(+)CD21(high)CD1d(high) B cells in inflamed nodes (Bin cells) accumulate in the lymph nodes (LNs) draining inflamed joints of the TNF-α-transgenic mouse model of rheumatoid arthritis and are primarily involved in the significant histological and functional LN alterations that accompany disease exacerbation in this strain. In this study, we investigate the origin and function of Bin cells. We show that adoptively transferred GFP(+) sorted mature follicular B (FoB) cells home preferentially to inflamed LNs of TNF-α-transgenic mice where they rapidly differentiate into Bin cells, with a close correlation with the endogenous Bin fraction.

CD23(+)/CD21(hi) B-cell translocation and ipsilateral lymph node collapse is associated with asymmetric arthritic flare in TNF-Tg mice.

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease with episodic flares in affected joints. However, how arthritic flare occurs only in select joints during a systemic autoimmune disease remains an enigma. To better understand these observations, we developed longitudinal imaging outcomes of synovitis and lymphatic flow in mouse models of RA, and identified that asymmetric knee flare is associated with ipsilateral popliteal lymph node (PLN) collapse and the translocation of CD23(+)/CD21(hi) B-cells (B-in) into the paracortical sinus space of the node.

Long-term immunologically competent human peripheral lymphoid tissue cultures in a 3D bioreactor.

Peripheral lymphoid organs (PLOs), the primary sites of development of adaptive immune responses, display a complex structural organization reflecting separation of cellular subsets (e.g., T and B lymphocytes) and functional compartments which is critical for immune function.

Expanded CD23(+)/CD21(hi) B cells in inflamed lymph nodes are associated with the onset of inflammatory-erosive arthritis in TNF-transgenic mice and are targets of anti-CD20 therapy.

Anti-CD20 B cell depletion therapy (BCDT) is very effective for some patients with rheumatoid arthritis (RA); however the pathogenic role of B lymphocytes in RA and the primary targets of BCDT are unknown. The human TNF transgenic (hTNF-Tg) mouse model of RA displays a chronic, progressive disease that spreads from distal to proximal joints and is generally considered to be adaptive immune system independent. We have previously reported that knee arthritis in hTNF-Tg mice is accompanied by structural and functional changes of the adjoining popliteal lymph node (PLN), detectable by contrast-enhanced magnetic resonance imaging.

Susceptibility to autoimmunity and B cell resistance to apoptosis in mice lacking androgen receptor in B cells.

Estrogens have been linked to a higher female incidence of autoimmune diseases. The role of androgen and the androgen receptor (AR) in autoimmune diseases, however, remains unclear. Here we report that the lack of AR in B cells in different strains of mice, namely general AR knockout, B cell-specific AR knockout, and naturally occurring testicular feminization mutation AR-mutant mice, as well as castrated wild-type mice, results in increased B cells in blood and bone marrow.

The biologic properties of leukemias arising from BCR/ABL-mediated transformation vary as a function of developmental origin and activity of the p19ARF gene.

Recent reports have shown that upon expression of appropriate oncogenes, both stem cells and more differentiated progenitor populations can serve as leukemia-initiating cells. These studies suggest that oncogenic mutations subvert normal development and induce reacquisition of stem-like features. However, no study has described how specific mutations influence the ability of differentiating cell subsets to serve as leukemia-initiating cells and if varying such cellular origins confers a functional difference.

Requirement for enhancer specificity in immunoglobulin heavy chain locus regulation.

The intronic Emicro enhancer has been implicated in IgH locus transcription, VDJ recombination, class switch recombination, and somatic hypermutation. How Emicro controls these diverse mechanisms is still largely unclear, but transcriptional enhancer activity is thought to play a central role. In this study we compare the phenotype of mice lacking the Emicro element (DeltaEmicro) with that of mice in which Emu was replaced with the ubiquitous SV40 transcriptional enhancer (SV40eR mutation) and show that SV40e cannot functionally complement Emu loss in pro-B cells.

Localization and differential expression of activation-induced cytidine deaminase in the amphibian Xenopus upon antigen stimulation and during early development.

As in mammals, B cell maturation in the amphibian Xenopus involves somatic hypermutation (SHM) and class switch recombination to diversify the B cell receptor repertoire in response to Ag stimulation. Unlike mammals, however, the resulting increase in Ab affinity is poor in Xenopus, which is possibly related to the absence of germinal centers and a suboptimal selection mechanism of SHM. In mammals, both SHM and class switch recombination are mediated by the activation-induced cytidine deaminase enzyme and under Ag-dependent regulation.

Leukemia stem cells in a genetically defined murine model of blast-crisis CML.

Myeloid leukemia arises from leukemia stem cells (LSCs), which are resistant to standard chemotherapy agents and likely to be a major cause of drug-resistant disease and relapse. To investigate the in vivo properties of LSCs, we developed a mouse model in which the biologic features of human LSCs are closely mimicked. Primitive normal hematopoietic cells were modified to express the BCR/ABL and Nup98/HoxA9 translocation products, and a distinct LSC population, with the aberrant immunophenotype of lineage(-), Kit(+/-), Flt3(+), Sca(+), CD34(+), and CD150(-), was identified.

Structural phylogenetic analysis of activation-induced deaminase function.

In mammals, activation-induced deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) of Ig genes. SHM and CSR activities require separate regions within AID. A chromosome region maintenance 1 (CRM1)-dependent nuclear export signal (NES) at the AID C terminus is necessary for CSR, and has been suggested to associate with CSR-specific cofactors.