Splenic small B‐cell lymphoma with predominant red pulp involvement: a diffuse variant of splenic marginal zone lymphoma?

AIMS: Splenic marginal zone lymphoma (SMZL) has been characterized by a micronodular pattern of infiltration, biphasic cytology, follicular replacement and the presence of marginal zone differentiation. Here we describe four cases with some distinctive features, such as diffuse splenic infiltration, lack of micronodules, marginal zone cytology, p53 inactivation and cutaneous involvement. METHODS AND RESULTS: In the course of a review of cases of SMZL, we recognized the existence of a subset of four cases of splenic B-cell lymphoma, with predominantly red pulp involvement, absence of follicular replacement, and a monomorphous population of tumoral cells resembling marginal zone B-cells, with scattered nucleolated blast cells. The immunophenotype (bcl2+, CD5-, CD10-, CD43-, CD23-, cyclin D1-, IgD- (3/4)) was consistent with SMZL. Bone marrow infiltration (4/4) and peripheral blood involvement (2/4) showed similar findings to those described for SMZL in these locations. However, unlike classical SMZL, 2/4 had cutaneous involvement, and 4/4 cases showed either p53 mutation or anomalous p53 staining (p53+, p21-). CONCLUSIONS; In spite of a diffuse pattern of splenic infiltration, cutaneous involvement and p53 alterations, these cases have findings that overlap with those corresponding to classic SMZL (symptomatology, morphology of bone marrow, lymph nodes, peripheral blood involvement, and immunophenotype). We suggest that these cases be considered a putative variant of SMZL.     

Immunological decision‐making: how does the immune system decide to mount a helper T‐cell response?

Aberrant T-cell responses underpin a range of diseases, including asthma and allergy and autoimmune diseases. Pivotal immune elements of these diseases are the development of antigen-specific effector T-helper type 2 (Th2) cells, Th1 cells, or the recently defined Th17 cells that are associated with the clinical features and disease progression. In order to identify crucial processes in the pathogenesis of these diseases it is critical to understand how the development of these T cells occurs. The phenotype of a polarized T-cell that differentiates from a naïve precursor is determined by the complex interaction of antigen-presenting cells with naïve T cells and involves a multitude of factors, including the dominant cytokine environment, costimulatory molecules, type and load of antigen presented and a plethora of signaling cascades. The decision to take the immune response in a certain direction is not made by one signal alone, instead many different elements act synergistically, antagonistically and through positive feedback loops to activate a Th1, Th2, or Th17 immune response. The elucidation of the mechanisms of selection of T-cell phenotype will facilitate the development of therapeutic strategies to intervene in the development of deleterious T-cell responses. This review will focus on the pathways and key factors responsible for the differentiation of the various subsets of effector CD4 T cells. We will primarily discuss what is known of the Th1 and Th2 differentiation pathways, while also reviewing the emerging research on Th17 differentiation.     

Can alternative epitope mapping approaches increase the impact of B‐cell epitopes in food allergy diagnostics?

In vitro allergy diagnostics are currently based on the detection of specific IgE binding on intact allergens or a mixture thereof. This approach has drawbacks as it may yield false‐negative and/or false‐positive results. Thus, we reviewed the impact of known B‐cell epitopes of food allergens to predict transience or persistence, tolerance or allergy and the severity of an allergic reaction and to examine new epitope mapping strategies meant to improve serum‐based allergy diagnostics. Recent epitope mapping approaches have been worthwhile in epitope identification and may increase the specificity of allergy diagnostics by using epitopes predominately recognized by allergic patients in some cases. However, these approaches did not lead to discrimination between clinically relevant and irrelevant epitopes so far, since the polyclonal serum IgE‐binding epitope spectrum seems to be too individual, independent of the disease status of the patients. New epitope mapping strategies are necessary to overcome these obstacles. The use of patient‐derived monoclonal antibodies instead of patient sera for functional characterization of clinically relevant and irrelevant epitope combinations, distinguished by their ability to induce degranulation, might be a promising approach to gain more insight into the allergic reaction and to improve serum‐based allergy diagnostics.     

T‐cell migration: a naive paradigm?

Naive T cells have long been thought to recirculate exclusively between secondary lymphoid organs via the lymph and blood. Evidence is now emerging that this view may be too simplistic and that naive T cells routinely traffic through non-lymphoid organs in a manner similar to that of memory T cells, albeit in lower numbers. This represents a fundamental shift in the current paradigm of T-cell migration through different types of tissue. This review summarizes these recent findings, along with the similarities and differences in migratory properties of naive and memory T cells, and discusses how and why naive T cells might access non-lymphoid tissues.     

CD117 expression in diffuse large B‐cell lymphomas: Fact or fiction?

CD117 (KIT) is expressed in a variety of hematopoietic neoplasms but there are a paucity of data regarding its expression in diffuse large B-cell lymphomas (DLBCL). The purpose of the present paper was to describe the authors' experience of two CD117+ DLBCL (one of follicle center-cell origin and one nasal Epstein-Barr virus (EBV)- plasmablastic lymphoma associated with lytic bone lesions), as determined by tissue immunohistochemistry and flow cytometry. The CD117 expression in DLBCL was further evaluated using tissue microarrays and seven additional plasmablastic lymphomas, using two commercially available anti-CD117 antibodies (Ab-1, Oncogene and A4502, DakoCytomation). Membranous +/- cytoplasmic staining was seen with Ab-1 in 24/65 (37%) DLBCL, including 21/56 microarray DLBCL, two index cases, and 1/7 additional plasmablastic lymphomas, with persistent staining in 13% of microarray DLBCL despite preincubation with KIT peptide. However, A4502 had only membranous staining of the index cases and one additional EBV- plasmablastic lymphoma with medullary disease. The present study suggests that (i) CD117 expression can be detected sporadically in DLBCL of follicle center-cell origin and a subset of plasmablastic lymphomas; (ii) staining for CD117 might help in identifying EBV- plasmablastic lymphomas associated with bone marrow involvement; and (iii) CD117 antibodies should be carefully validated prior to use, because non-specific staining, as observed with Ab-1, could lead to false-positive results.     

Schimke immuno-osseous dysplasia: a cell autonomous disorder?

SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like protein 1) encodes a SWI/SNF ATP-dependent chromatin remodeling protein. Mutations in SMARCAL1 cause the autosomal-recessive multisystem disorder Schimke immuno-osseous dysplasia (SIOD); this suggests that the SMARCAL1 protein is involved in the development or maintenance of multiple organs. Disease within these many tissues could arise by a cell autonomous or a cell non-autonomous mechanism. Consistent with a cell autonomous mechanism, we did not find any disease recurrence in transplanted organs or protection of other tissues by the organ grafts. In order to better understand the role of SMARCAL1 during normal development and in the pathogenesis of SIOD, we characterized the spatial and temporal expression of the murine homolog (Smarcal1). The Smarcal1 mRNA and protein were expressed throughout development and in all tissues affected in patients with SIOD including the bone, kidney, thymus, thyroid, tooth, bone marrow, hair, eye, and blood vessels. Significantly, the expression profile of Smarcal1 in the mouse has led us to reexamine and identify novel pathology in our patient population resulting in changes in the clinical management of SIOD. The expression of Smarcal1 in affected tissues and the non-recurrence of disease in grafted organs lead us to hypothesize a cell autonomous function for SMARCAL1 and to propose tissue-specific mechanisms for the pathophysiology of SIOD.     

Accelerating the induction of Fas‐mediated T cell apoptosis: a strategy for transplant tolerance?

Acute allograft rejection is primarily a consequence of clonal expansion of donor-specific T cells with specificity for donor antigen. Immunosuppression current involves the administration of toxic drugs that limit lymphoproliferation, but this treatment is not antigen-specific and allows opportunistic infection. An ideal strategy would be production of donor-specific T cell tolerance in the presence of an otherwise intact and functional T cell repertoire. Methods to enhance normal apoptotic clearance of activated T cells might contribute to development of this state. This study focuses on manipulation in vitro of Fas-mediated T cell apoptosis and compares two methods to enhance the extent and kinetics for clearance of activated T cells. First, the CD4 coreceptor was cross-linked in the presence and absence of Fas-stimulation. It was found that CD4 cross-linking potently induced apoptosis, even in the absence of Fas stimulation. Resting and activated T cells were susceptible to this treatment, precluding the development of antigen-specific tolerance after T cell activation. In a second system, T cells were treated with two staurosporine analogues, Bisindolylmaleimide (Bis) III and VIII and apoptosis was induced by stimulation of Fas. Resting T cells remained resistant to Fas-mediated apoptosis, but treatment of mitogen or alloantigen-activated cells with either Bis III or VIII caused a synergistic increase in apoptosis. These agents also reduced the period of resistance to Fas-mediated apoptosis after T cell activation, possibly by reducing expression of c-FLIP, allowing early activation of caspase 8 in alloreactive T cells. Development of this strategy might provide a route to the induction of specific tolerance after organ transplantation.     

Chromatin assembly factor‐1 (CAF‐1)‐mediated regulation of cell proliferation and DNA repair: a link with the biological behaviour of squamous cell carcinoma of the tongue?

AIMS: Squamous cell carcinoma (SCC) of the tongue shows aggressive behaviour and a poor prognosis. Clinicopathological parameters fail to provide reliable prognostic information, so the search continues for new molecular markers for this tumour. Chromatin assembly factor-1 (CAF-1) plays a major role in chromatin assembly during cell replication and DNA repair and has been proposed as a new proliferation marker. The aim of this study was to investigate its expression in SCC of the tongue. METHODS AND RESULTS: The immunohistochemical expression of the p60 and p150 subunits of CAF-1 were evaluated in a series of SCCs of the tongue. The findings were correlated with the expression of proliferation cell nuclear antigen (PCNA) and patients' clinicopathological and follow-up data. CAF-1/p60 was expressed in all the tumours, whereas CAF-1/p150 was down-regulated in a number of cases. Overexpression of CAF-1/p60 and down-regulation of CAF-1/p150 identified SCCs with poor outcome, in addition to the classical prognostic parameters. CONCLUSIONS: Simultaneous CAF-1-mediated deregulation of cell proliferation and DNA repair takes place in aggressive SCC of the tongue. Therefore, the evaluation of CAF-1 expression may be a valuable tool for evaluation of the biological behaviour of these tumours. This may be relevant to the introduction of improved follow-up protocols and/or alternative therapeutic regimens.     

Intrusions related to obsessive‐compulsive disorder: a question of content or context?

The aim of the current study was to investigate whether intrusions of individuals with obsessive‐compulsive disorder (OCD) and nonclinical individuals differed in content and in context of occurrence. The results suggest that although the intrusions of OCD and nonclinical individuals are similar in content, they differ in their context of occurrence. Chi square analyses revealed that the intrusions of nonclinical participants were more likely to be directly linked than indirectly linked to observations in the here and now, whereas the intrusions of participants with OCD were more prone to be indirectly linked than directly linked to triggers in the environment at the time they occurred. The implications of the results for cognitive models of OCD are discussed. © 2009 Wiley Periodicals, Inc. J Clin Psychol 65: 1–14, 2009.     

Autoimmune disease: is it a disorder of the microenvironment?

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease that involves several vital organs including the cardiovascular system, joints, and kidneys. The pathology is characterized by accumulation of autoreactive lymphocytes that attack the patients' own tissues, secretion of autoantibodies and deposition of immune complexes in vital organs. Chronic widespread inflammation is the hallmark of SLE and the target of current therapy. According to recent theories, intonating immune circuits of inflammatory cytokines and immune cells constitute highly specialized targets for SLE therapy, which nonetheless consists for the most part of anti-inflammatory medications and cytotoxic drugs. For advanced autoimmune disorders, cell therapy aiming at introducing "healthy" stem cells has been promising, keeping in mind that in its current state, stem cell therapy is reserved for the most advanced diseases refractory to traditional therapy. Ongoing studies in our laboratories examined the role of the bone marrow microenvironment, in particular, mesenchymal stem cells (MSCs) in the etiopathogenesis of SLE. Specifically, we are testing the hypothesis that, in human SLE mouse model, marrow MSCs are defective structurally and functionally. Preliminary data indicate that structural and functional defects in MSC population from an autoimmune mouse model for human SLE may contribute to this pathology and consequently present a target for cell therapy.     

Gap junctions: a novel route for direct cell–cell communication in the immune system?

Functional gap junctions are found in thymus, bone marrow and lymph node microenvironments; formed by connexins, they allow the passage of small molecules between adjacent cells. Various experimental approaches have indicated the existence of heterocellular gap junctions between lymphocytes and microenvironmental cells in these organs. Here, Luiz Alves and colleagues discuss the suggestion that they represent an additional route for cell–cell communication in the immune system.     

Exercise and the immune system: a model of the stress response?

Exercise influences natural immunity, T- and B-cell functions, and cytokine responses, through circulatory (hemodynamic) changes and by endocrine hormones secreted in response to physical stress. The magnitude of the effects on the immune system reflects the intensity, duration and chronicity of the exercise. In this review, Laurie Hoffman-Goetz and Bente KlarlundPedersen suggest that exercise-immune interactions can be viewed as a subset of stress immunology.     

Aging of the immune system: a risk factor for autoimmunity?

Aging of the immune system, or immunosenescence, is characterized by changes in T cell subsets, cellular and molecular level alterations and thymic atrophy, resulting in a decline of T and B cell function. These alterations have been shown to be accompanied by a loss of ability to recognize "self" and "foreign" antigens. Therefore the development of autoimmune responses like production of autoantibodies has been hypothesized to be secondary to thymus involution with a decline of na?ve T cells and accumulation of clonal T cells with activation due to "neoantigens" during the aging process. Altered apoptosis and altered T cell homeostasis have been emphasized to promote a chronic inflammatory state and lead to the concept of a immune-risk phenotype. However, it has to be proven which kinds of mechanisms turn the immune system to manifest autoimmune disease and how speculated defects in T cell differentiation and interaction leading to premature aging of the immune system may contribute to the development of autoimmune diseases.