The Humoral Response in TCR α–/– Mice. Can γδ‐T Cells Support the Humoral Immune Response?

An optimal humoral response requires T-cell help; however, it has been questioned if this help comes exclusively from alphabeta-T cells or whether gammadelta-T cells also contribute. We have attempted to answer this question by studying the humoral response in T-cell receptor alpha-chain knockout (alpha-/-) mice, which lack the alphabetaT cell subset. Two model antigens were used to characterize the response: the thymus-independent (TI) antigen native dextran B512 (Dx), and the thymus-dependent (TD) antigen heat shock protein (HSP65) from Mycobacterium tuberculosis. When challenged with Dx, the alpha-/- mice elicited a strong antibody response and formed rudimentary germinal centres (GCs), a T-cell dependent reaction. In contrast, the humoral response to HSP65 was poor. However, alpha-/- mice became primed when challenged with HSP65, because when supplemented with wild-type thymocytes, the antigen-primed animals were able to mount a stronger response than the nonprimed ones when challenged with HSP65. A crucial step seems to be the collaboration between gammadeltaT cells and antigen presenting cells (APCs), as splenocytes from alpha-/- mice were able to respond to HSP65 in an environment containing primed-APCs. Based on these results, we propose a model for B-cell activation in the alpha-/- mice.     

Inhibitory oligodeoxynucleotides − therapeutic promise for systemic autoimmune diseases?

Recent studies have shed new light on a possible link between the innate activation of plasmocytoid dendritic cells and marginal zone B cells and the pathogenesis of systemic lupus erythematosus. Animal studies have identified that this response requires the Toll-like receptor 9 (TLR9). Engagement of the TLR9 by various ligands, including non-canonical CpG-motifs, can cause or aggravate pathogenic autoantibody production and cytokine secretion in lupus. Attempts to neutralize this activity either by blocking the acidification of the endosomal compartment with chloroquine and related compounds, or by preventing the interaction between the CpG-DNA sequences and TLR9 using inhibitory oligonucleotides could be a promising therapeutic option for lupus.     

Feeling “Pooped” and “Run Down?”: Fatigue Experiences in Latino Cancer Patients

The purpose of this study was to describe fatigue and the utility of the Multidimensional Fatigue Symptom Inventory‐Short Form (MFSI‐SF) to assess fatigue among Latino cancer patients. Twenty‐two female and thirteen male Latino cancer patients participated in one of seven focus groups that took place in the southern California USA‐Mexico border region. Participants were asked to describe their fatigue experiences; participants also completed the MFSI‐SF and provided feedback about the items. Content analyses indicate that there are gender differences in the salience of the challenges that fatigue poses. Men tended to focus on physical symptoms, whereas women tended to focus on the impairment in role fulfillment. Findings have implications for intervention and health education efforts in Latino cancer patients.     

γδ T‐cell lymphomas: a homogeneous entity?

gammadelta T-cells comprise an immunologically distinct lymphoid population, characterized by specific morphological, phenotypical and functional properties. Therefore it seems reasonable to speculate that neoplasms derived from this particular T-cell subset display distinct features. Indeed, the prototype gammadelta T-cell lymphoma, hepatosplenic T-cell lymphoma constitutes a unique clinicopathological entitity which is intimately associated with a gammadelta T-cell phenotype. However, gammadelta T-cell lymphomas have also been described in other extranodal sites where, unlike reactive gammadelta T-cells and hepatosplenic gammadelta T-cell lymphomas, they display an important morphological heterogeneity. Moreover, these nonhepatosplenic gammadelta T-cell lymphomas are essentially not that different from their alphabeta T-cell receptor for antigen (TCR)-expressing counterparts and thus may be incorporated in the established T-cell lymphoma subclasses. However, subtle differences regarding their histopathological appearance as well as their biological behaviour indicate that further studies to determine the exact significance of TCR expression are required. Such inquiries may contribute to the general understanding of T-cell lymphomagenesis in general, which is still obscure.     

Radiation‐guided breast sentinel lymph node biopsies – is a handling delay for radiation protection necessary?

Singleton M, Firth M, Stephenson T, Morrison G & Baginska J
(2012) Histopathology  61, 277–282 Radiation‐guided breast sentinel lymph node biopsies – is a handling delay for radiation protection necessary? Aims: Radiation‐guided sentinel lymph node (SLN) biopsy is a well‐established procedure in many countries. However, histopathology protocols in different centres specify widely differing sample handling delays of between 0 and 72 h. Introducing a delay reduces the radiation exposure of pathologists, but has a detrimental effect on the quality and validity of histology. This study aims to show that a sample handling delay is not justified by the radiation doses to pathologists handling samples received directly from surgery. Methods and results: Radiation doses to the body and hands of pathologists handling samples delivered directly from theatres were measured using personal dose meters. These measurements were supplemented by dose assessments undertaken using dose‐rate measurements at 1 cm and 30 cm from Tc‐99m sources to simulate the processing of samples. The study has shown that radiation doses arising from a zero delay in sample handling represent a negligible radiation risk to pathologists and are well within relevant limits specified in the Ionising Radiations Regulations 1999. Conclusions: This study supports adoption of a zero‐delay SLN histopathology protocol. Centres must, however, complete a risk assessment that accounts for local practice and adopt simple precautions to keep doses to pathologists as low as reasonably achievable.     

Post‐CPAP sleepiness – a specific syndrome?

Following treatment with continuous positive airway pressure (CPAP), some patients with obstructive sleep apnoea (OSA) remain sleepy despite effective CPAP and attention to other diagnoses that can provoke sleepiness. It is unclear if this residual sleepiness is an irreversible result of their previous OSA and merits consideration for pharmacological treatment or simply because of the many and varied causes of sleepiness normally found in the community. We have measured levels of sleepiness, using the Epworth Sleepiness Score (ESS), in 572 patients on CPAP and compared them with a control group of 525 subjects from a community survey, which would have included the usual lifestyle reasons for sleepiness as well as any undiagnosed sleep disorders. There was no difference in the percentage of patients with an ESS >10 in the CPAP group compared with the controls (16.1 versus 14.3, P = 0.54). Thus, although there clearly are sleepy patients within the CPAP group, the prevalence is no higher than in the community. We question whether so-called 'post-CPAP sleepiness' should be regarded as any more abnormal and worthy of treatment than a 'normal' population. Post-CPAP sleepiness as a specific disorder may not exist.     

MR1‐restricted Vα19i T cells – a second population recognizing lipid antigens?

There is increasing evidence that T cells recognizing lipid antigens contribute to the immunological regulation of different disease conditions including autoimmunity. The best-known subset is CD1d-restricted lipid-reactive T cells characterized by the expression of an invariant TCRalpha chain. Much less is known about the biology of another invariant T cell subset, which is restricted to the MHC class I-like molecule MR1. A beneficial role of MR1-restricted T cells has been suggested in a mouse EAE model. However, the nature of antigens that can be presented by MR1 to this invariant T cell subset remained largely unclear. An article in this issue of the European Journal of Immunology presents strong indications that derivatives of alpha-mannosyl ceramide (alpha-ManCer), i.e. glycolipids, can serve as ligands for MR1-restricted invariant T cells. In addition to that, the structure of the alpha-ManCer sphingosine chain influences the Th1-Th2 polarization of the cytokine response. These important new findings will foster further research on the identity of physiological ligands for MR1-restricted T cells and on their relation with immunoregulation. See accompanying article: (http://dx.doi.org/10.1002/eji.200636689).     

Syndiotactic Poly(propylene) from [Me2Si(3,6‐di‐tert‐butyl‐9‐fluorenyl)(N‐tert‐butyl)]TiCl2–Based Catalysts: Chain‐End or Enantiotopic‐Sites Stereocontrol?

The origin of the syndiotactic selectivity in propene polymerization of a typical bridged fluorenyl‐amido catalyst, namely [Me₂Si(3,6‐di‐tert‐butyl‐9‐fluorenyl)(N‐tert‐butyl)]TiCl₂ ( 1 ), activated with methylaluminoxane or [HMe₂N(C₆H₅)][B(C₆F₅)₄]/Al(i‐butyl)₃, was investigated by means of 150 MHz ¹³C NMR spectroscopic microstructural polymer analysis. The asymmetric induction was traced unambiguously to enantiotopic‐sites control. Compared with the better‐known cyclopentadienyl‐fluorenyl ansa‐zirconocenes, 1 turned out to be almost identically enantioselective (in agreement with computer modeling), but less stereoselective because of a higher propensity to undergo site epimerization. This results in a chain microstructure with large predominance of m over mm stereodefects, deceptively similar to that of syndiotactic poly(propylene) produced under chain‐end control.

Methyl region of the 150 MHz ¹³C NMR spectrum of a poly(propylene) sample prepared with catalyst system 1 /borate/TIBAl.     

B‐type suppression: A role played by “regulatory B cells” or “regulatory plasma cells”?

B‐cell depletion can improve disease in some patients with rheumatoid arthritis or multiple sclerosis, indicating the pathogenic contribution of B cells to autoimmunity. However, studies in mice have demonstrated that B cells have immunosuppressive functions as well, with IL‐10 being a critical mediator of B‐cell‐mediated suppression. IL‐10‐secreting B cells have been shown to promote disease remission in some mouse models of autoimmune disorders. Human B cells also produce IL‐10, and evidence is accumulating that human IL‐10‐producing B cells might inhibit immunity. There is considerable interest in identifying the phenotype of B cells providing IL‐10 in a suppressive manner, which would facilitate the analysis of the molecular mechanisms controlling this B‐cell property. Here, we review current knowledge on the B‐cell subpopulations found to provide suppressive functions in mice, considering both the pathological context in which they were identified and the signals that control their induction. We discuss the phenotype of B cells that have IL‐10‐dependent regulatory activities in mice, which leads us to propose that antibody‐secreting cells are, in some cases at least, the major source of B‐cell‐derived regulatory IL‐10 in vivo. Anti‐inflammatory cytokine production by antibody‐secreting cells offers a novel mechanism for the coordination of innate and humoral immune responses.     

Therapeutic anti‐integrin (α4 and αL) monoclonal antibodies: two‐edged swords?

Anti-alpha4 and anti-alphaL integrin chain monoclonal antibodies have shown a clear-cut beneficial effect in different animal models of autoimmune and inflammatory disorders as well as in human diseases, including multiple sclerosis, inflammatory bowel disease, and psoriasis. It has been widely assumed that this therapeutic effect is mainly consequence of the blockade of leucocyte adhesion to endothelium, inhibiting thus their extravasation and the inflammatory phenomenon. However, it is evident that both alpha4beta1 (very late antigen-4) and alphaLbeta2 (leucocyte function-associated antigen-1) integrins have additional important roles in other immune phenomena, including the formation of the immune synapse and the differentiation of T helper 1 lymphocytes. Therefore, it is very feasible that the long-term administration of blocking agents directed against these integrins to patients with inflammatory/autoimmune conditions may have undesirable or unexpected effects.