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The clonal selection theory (CST) is the centrepiece of the current paradigm used to explain immune recognition and memory. Throughout the past decades, the original CST had been expanded and modified to explain new experimental evidences since its original publication by Burnet. This gave origin to new paradigms that govern experimental immunology nowadays, such as the associative recognition of antigen model and the stranger/danger signal model. However, these new theories also do not fully explain experimental findings such as natural autoimmune immunoglobulins, idiotypic networks, low and high dose tolerance, and dual‐receptor T and B cells. To make sense of these empirical data, some authors have been trying to change the paradigm of immune cognition using a systemic approach, analogies with brain processing and concepts from second‐order cybernetics. In the present paper, we review the CST and some of the theories/hypotheses derived from it, focusing on immune recognition. We point out their main weaknesses and highlight arguments made by their opponents and believers. We conclude that, until now, none of the proposed theories can fully explain the totality of immune phenomena and that a theory of everything is needed in immunology. [ABSTRACT FROM AUTHOR]

Prolymphocytic leukaemias of B and T cell subtype are rare diseases. Despite recent advances in immunophenotyping and molecular cytogenetics, leading to a better understanding of the underlying cell biology of the prolymphocytic leukaemias, prognosis for these patients remains poor. Purine analogues and monoclonal antibodies have shown efficacy in B-cell prolymphocytic leukaemia although further studies are warranted. Monoclonal antibody therapy with alemtuzumab has significantly improved outcome in T-cell prolymphocytic leukaemia (T-PLL) but responses are still transient and further disease progression is inevitable. While allogeneic stem cell transplant is an attractive option, due to the older age group of T-PLL patients the morbidity and mortality associated with the procedure is significant. [ABSTRACT FROM AUTHOR]

To evaluate the clinical significance of CD21S expression of diffuse large B-cell lymphoma (DLBCL) tumour cells, we compared their clinical features, immunophenotype, response to therapy and outcome in relation to CD21S expression. Between 1987 and 1999, frozen sections from 240 DLBCL cases were examined for CD21S expression by immunohistochemical methods. CD21S expression was detected on the tumour cells of 87 (36%) cases. The median age of the CD21S+ DLBCL cases was 65 years (range: 17–84 years), the male–female ratio was 42:45, and they showed the following clinical features: Eastern Cooperative Oncology Group score >1 in 14%, lactate dehydrogenase greater than normal levels in 38%, extranodal sites >1 in 14%, stages III/IV disease at diagnosis in 29%, B symptoms in 17%, and a high/high–intermediate International Prognostic Index (IPI) in 23%. They also showed a better overall survival ( P = 0·00001, log-rank test) and a better complete remission rate ( P = 0·00004, chi-square test) than CD21S− DLBCL. Moreover, CD21S+ DLBCL showed a better survival than CD21S− DLBCL for both low/low–intermediate and high/high–intermediate risk categories of IPI ( P = 0·045 and P = 0·0016 respectively). Multivariate analysis identified CD21S expression as an independent factor for survival when compared with the five IPI factors. These findings indicate that CD21S expression of DLBCL tumour cells is a useful prognostic factor for survival. [ABSTRACT FROM AUTHOR]

Disease progression in B-cell chronic lymphocytic leukaemia (B-CLL) is determined by the interplay between proliferation kinetics in the proliferating compartment and cell death in the accumulating compartment. Improving our knowledge of cell cycle regulation in B-CLL cells might therefore be important for identifying therapeutic targets. Cyclin E was detected by Western blotting in purified B-CLL cells from peripheral blood samples of all 12 patient tested but not in normal peripheral blood B cells. While cyclin-dependent kinase 2 (cdk2) expression was similar in different samples, p27 and cyclin E expression was highly variable. We further investigated the regulation of p27, cyclin E and cdk2 in an in vitro model of cycling B-CLL cells. Cyclin E and cdk2 expression was increased in B-CLL cells stimulated with a CpG-oligodeoxynucleotide and interleukin-2, while p27 expression rapidly declined. This was accompanied by the increased formation of cyclin E–cdk2 complexes, which were able to phosphorylate Histone H1 in vitro. Pharmacological inhibition of cdk2 activity with Roscovitine-inhibited thymidine incorporation and Histone H1 phosphorylation. We conclude that further evaluation of cyclin E and p27 in peripheral blood cells might help to identify prognostic subgroups. In addition, inhibition of Cyclin E–cdk2 activity by Roscovitine might be a new therapeutic strategy in B-CLL. [ABSTRACT FROM AUTHOR]

The Ikaros transcription factor has been shown to play an important role in the differentiation of both myeloid and lymphoid lineages. Mice heterozygous for a dominant negative (DN) ikaros isoform develop T-cell leukaemia and lymphoma with 100% penetrance. Overexpression of DN Ikaros isoforms has been reported in some forms of leukaemia, such as childhood acute myelomonocytic and monocytic leukaemias, adult B-cell acute lymphoblastic leukaemias (B ALL) and in childhood and adult pre-B ALL. In this study, the expression of Ikaros isoforms in 49 infant and childhood leukaemia patients was analysed by reverse transcription polymerase chain reaction and Western blot analysis. We found overexpression of the DN Ikaros  6 (Ik6) isoform in a subset of leukaemia patients harbouring t(4;11) translocations. To further study the consequences of Ik6 overexpression in B ALL, we inducibly expressed Ik6 in BaF3 cells and found that Ik6 overexpression delayed cell death after interleukin-3 withdrawal, suggesting that overexpression of Ik6 found in t(4;11) B cells could contribute to leukaemogenesis by preventing the apoptosis of cells in an environment with reduced survival factors. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (SNPs) of inflammatory cytokine genes were examined in 84 adult Japanese patients with chronic immune thrombocytopenic purpura (ITP) and 56 race-matched healthy controls. The SNPs examined were within the genes encoding tumour necrosis factor (TNF)- α (−238 G/A and −308 G/A), TNF- β (+252 G/A), and interleukin (IL)-1 β (−511 C/T and +3953 T/C). Of these SNPs, the frequency of the TNF- β (+252) G/G phenotype was significantly higher in ITP patients than in healthy controls (21% vs. 7%, P = 0·04, odds ratio = 3·6, 95% confidence interval 1·1–11·1), while no significant association was detected for the other SNPs. The distribution of the TNF- β (+252) phenotype was not associated with human leucocyte antigen class II alleles or the therapeutic response in ITP patients. The frequency of circulating anti-glycoprotein IIb/IIIa antibody-producing B cells was significantly higher in ITP patients with the TNF- β (+252) G/G phenotype than in those with the G/A or A/A phenotype (11·9 ± 4·9 vs. 6·8 ± 4·9 and 3·7 ± 2·8 per 105 peripheral blood mononuclear cells; P = 0·02 and P < 0·001, respectively). These findings suggest that the SNP located at TNF- β (+252) contributes to susceptibility to chronic ITP by controlling the autoreactive B-cell responses to platelet membrane glycoproteins. [ABSTRACT FROM AUTHOR]

The treatment results of indolent lymphoid malignancies in Chinese are poorly reported. The efficacy of FND (fludarabine 25 mg/m2/d, ×3; mitoxantrone 10 mg/m2/d, ×1; dexamethasone 20 mg/d, ×5; monthly cycles, ×6) in 95 Chinese patients with indolent B-cell malignancies (at diagnosis: 55, relapse/refractory disease: 40) and nine Chinese patients with T-cell large granular lymphocyte leukaemia (T-LGL leukaemia) (at diagnosis: two, refractory disease: seven) was evaluated. For B-cell malignancies, the complete response (CR), partial response (PR) and overall response (OR) rates were 50·5%, 18% and 68·5% respectively. Better results were obtained for primary versus relapse/refractory disease (CR: 60% vs. 37·5%, P = 0·03; OR: 84% vs. 47·5%, P < 0·001; median progression-free survival (PFS): 44 months vs. 22 months; 2-year PFS: 66% vs. 47%, P = 0·039; overall survival (OS): not reached vs. 32%; 2-year OS: 92% vs. 58%, P < 0·001). Responsive patients (CR/PR) had a better median PFS (44 months vs. 5 months, P < 0·001) and OS (67 months vs. 13 months, P < 0·001) than unresponsive patients. For T-LGL leukaemia, the CR and molecular-remission rates were 56% and 67% (median follow-up: 23 months). FND is an active regimen for the treatment of indolent B- and T-cell malignancies in Chinese patients, with results comparable with Western patients with similar indolent lymphomas. [ABSTRACT FROM AUTHOR]

Multiple mechanisms exist by which tumour cells can escape CD95-mediated apoptosis. Previous studies by our laboratory have shown that primary B cells from non-Hodgkin's Lymphoma (B-NHL) were resistant to CD95-induced cell death. In the current study, we have analysed the mechanisms underlying CD95 resistance in primary human lymphoma B cells. We report that FADD (FAS-associated death domain protein) and caspase-8 were constitutively expressed in lymphoma B cells and that the CD95 pathway was blocked upstream to caspase-8 activation. However, caspase-8 was processed and functional after treatment with staurosporine (STS). We found that the expression levels of FLICE (FADD-like interleukin-1 beta-converting enzyme)-Inhibitory Protein (c-FLIP) and Bcl-2-related proteins were heterogeneous in B-NHL cells and were not related to CD95 resistance. Finally, we report the absence of a CD95-induced signalling complex [death-inducing signalling complex (DISC)] in lymphoma B cells, with no FADD and caspase-8 recruitment to CD95 receptor. In contrast, DISC formation was observed in CD95-resistant non-tumoural (NT) B cells. Therefore, we propose that the absence of DISC formation in primary lymphoma B cells may contribute to protect these cells from CD95-induced apoptosis. [ABSTRACT FROM AUTHOR]

In patients with neoplastic meningitis (NM), the rapid institution of intrathecal therapy may ameliorate the course of disease, indicating that a timely diagnosis is clinically relevant. As immunocytology (IC) of cerebrospinal fluid and magnetic resonance imaging (MRI), as diagnostic methods, have potential pitfalls, the present study assessed the results of both methods, to determine the predictive capability of the initial evaluations with respect to the risk that the patient would develop NM during the course of their disease. A total of 166 individuals with B-cell non-Hodgkin's lymphoma (B-NHL; n = 95), B-acute lymphocytic leukaemia (ALL; n = 18), acute myeloid leukaemia ( n = 27) or solid tumours ( n = 26), with at least one definitive IC and MRI result within 3 weeks, were evaluated at a median follow-up of 29·5 months (range 6–53 months). IC and MRI results reached the highest concordance (98%) in B-NHL patients and were most discordant in ALL patients (43%). In haematological malignancies, IC displayed considerable sensitivity, ranging from 89% to 95%, while MRI had very low sensitivity. Conversely, MRI showed high sensitivity (100%) and specificity (92%) in solid tumours. We conclude that IC is of particular value in the diagnosis of NM due to haematological malignancies while MRI is superior to IC in the diagnosis of NM due to solid tumours. [ABSTRACT FROM AUTHOR]

Novel N-glycosylation sites are introduced by somatic mutation into the V genes of the majority of follicular lymphomas. Sites are positively selected and rare in normal memory B cells, indicating a potential role in tumour survival in the germinal centre (GC). The incidence of c. 40% in diffuse large B-cell lymphomas (DLBCL) parallels the known heterogenity of the disease. Immunodeficiency-related non-Hodgkin's lymphomas (NHL) include post-transplant lymphoproliferative disorders (PTLD) and acquired immunodeficiency syndrome-related NHL (AIDS-NHL). Most PTLD derive from B cells that carry mutated VH genes and that have completed the GC reaction. All AIDS-NHL carry mutated VH genes and variable features of GC or post-GC cells. To determine if N-glycosylation is a feature of immunodeficiency-related lymphomas, we analysed the VH genes of 19 PTLD and 36 AIDS-NHL. Novel sites were rare in PTLD (4/19), similar to memory B cells ( P = 0·15). AIDS-NHL, including DLBCL and Burkitt's lymphomas (BL), showed heterogeneity with 16 of 36 (44%) having novel sites. The findings indicate no selection of N-glycosylation sites in PTLD, consistent with post-GC features. The variable incidence of N-glycosylation sites in AIDS-NHL mirrors that in DLBCL and sporadic BL of immunocompetent hosts, supporting the known heterogeneity of these disorders, and possibly pointing to distinct routes of tumour development. [ABSTRACT FROM AUTHOR]

Dysregulation of fibroblast growth factor receptor 3 ( FGFR3) by the translocation t(4;14)(p16;q32) occurs in 15% of multiple myeloma (MM) patients and confers a growth and survival advantage to malignant plasma cells. As FGFR3 is a molecular target, we assessed the therapeutic potential of the FGFR-specific tyrosine kinase inhibitors SU5402 and SU10991 in MM. SU5402 inhibited FGFR3 phosphorylation in vitro and in murine MM tumour models. B cells dependent on FGFR3 for survival were specifically sensitive to SU5402. A panel of 11 human myeloma cell lines was studied, five bearing the t(4;14) translocation. The KMS11 human myeloma cell line, which expresses constitutively active mutant FGFR3, displayed an 85% decrease in S-phase cells, a 95% increase in G0/G1 cells, and 4·5-fold increase in apoptotic cells after 72 h treatment with 10 μmol/l SU5402. Activated extracellular signal-regulated kinases  1 and 2 and signal transducer and activator of transcription 3 were rapidly down-regulated after SU5402 treatment. In human myeloma cell lines expressing wild-type FGFR3 the stimulating effect of aFGF ligand was abrogated by SU5402 treatment. Myeloma cells lacking the t(4;14) or with the t(4;14) and a secondary RAS mutation did not respond to therapy. These findings support the development of clinical trials of early intervention with FGFR3 inhibitors in t(4;14) myeloma. [ABSTRACT FROM AUTHOR]

We have investigated whether intracellular signal transduction molecules can be used as immunohistological markers of normal and neoplastic human leucocytes in routine tissue sections. We obtained selective labelling of white cells for eight such molecules (the ‘linker’ molecules SLP-76 and BLNK, the Src family kinases Lyn, Fyn, Syk and Hck, and the phospholipases PLC- γ1 and PLC- γ2). Antibodies to SLP-76 and PLC- γ1 selectively labelled T cells, and antibodies to BLNK, Lyn, Fyn, Syk and PLC- γ2 labelled B cells (although Fyn immunostaining was restricted to mantle zone B cells). Antibodies to the Syk and Hck kinases labelled probable thymocyte precursors at the periphery of the thymic cortex. In addition to lymphoid cells, several other leucocyte types were immunostained (e.g. SLP-76, Lyn, Syk and Hck were found in megakaryocytes, myeloid cells and/or macrophages, and PLC- γ2 was detected in arterial endothelium). SLP-76 and PLC- γ1 were found in most T-cell lymphomas studied, and some B-cell lymphomas were also positive for PLC- γ1 (e.g. diffuse large cell and Burkitt's lymphoma). The five B cell-associated markers were found in most B-cell non-Hodgkin's lymphomas, although some diffuse large B-cell lymphomas were negative (e.g. for Lyn) and anti-Fyn tended not to stain small B-cell neoplasms. The observation that a range of leucocyte signalling molecules can be detected in routine biopsies offers new possibilities for studying normal and neoplastic human white cells in diagnostic tissue samples. [ABSTRACT FROM AUTHOR]

Primary intraocular lymphoma (PIOL) is a rare presentation of lymphoma that is particularly difficult to recognize. In our institution, 36 cases of PIOL were diagnosed between March 1997 and July 2002. The recognition of lymphoma cells by cytology with or without immunophenotyping on slides generated a strong suspicion of the diagnosis in 34 of 36 cases. The diagnosis was confirmed by measurement of interleukin-10 (IL-10) in the vitreous humour or aqueous humour; high levels were observed in 35 of 36 cases, all were of B-cell origin. As expected, the only case with T-cell lymphoma had a very low level of IL-10. Furthermore, IL-10 levels excluded this diagnosis in two cases that were incorrectly suspected of PIOL after cytological examination. Finally, detection of clonality by polymerase chain reaction techniques, performed in 29 cases, represented a helpful tool in diagnosing PIOL as this approach definitively confirmed the diagnosis of B- or T-cell lymphoma in 17 cases. [ABSTRACT FROM AUTHOR]

B-cell chronic lymphocytic leukaemia (B-CLL) is a neoplastic disorder characterized by defective apoptosis, cell accumulation in G0/G1, and high expression of BCL2 oncogene. Intracellular cyclic adenosine monophosphate (cAMP) accumulation increases the chemosensitivity of B-CLL cells in vitro and in vivo. In the present study, we investigated the effects of β2-adrenergic compounds, well known cAMP-inducing drugs, on the in vitro survival of leukaemia cells. In contrast to the short-acting β2-mimetic (β2Mim) salbutamol, a consistent pro-apoptotic effect was observed with the long-acting β2Mim salmeterol and formoterol. Normal B cells isolated from control donors were totally resistant to the above molecules. These compounds also increased chlorambucil- and fludarabine-induced death of B-CLL cells. Blockade of β-adrenergic receptor signalling or cAMP did not alter B-CLL apoptosis with β2 Mimagents. Leukaemia cell apoptosis by β2Mim correlated with an increase in calcium influx, decreased bcl-2 protein and mRNA levels, increase in BAX gene expression and a marked rise in BCL2/BAX mRNA ratios. Interleukin-4, a cytokine that increases bcl-2 expression in B-CLL cells, rescued leukaemia cell from apoptosis with β2Mim. These data show that long-acting β2-adrenergic agents promote apoptotic leukaemia cell death through an adrenoreceptor- and cAMP-independent, Ca2+-dependent mechanism. [ABSTRACT FROM AUTHOR]

Despite a successful outcome of the anti-D prophylaxis programme, alloimmunization still occurs. The aim of this study was to estimate the frequency of Rh-specific B lymphocytes in the peripheral blood of nine Rh-alloimmunized individuals at different time intervals after parturition. The donors’ B lymphocytes were transformed with Epstein–Barr virus (EBV) and cultured at different cell densities over a feeder of human fetal fibroblasts. Culture supernatants were screened for human immunoglobulin by enzyme-linked immunosorbent assay (ELISA) and for anti-Rh antibody by using a direct haemagglutination technique. The percentage of CD19+ B lymphocytes in peripheral blood was determined by flow cytometry, and the frequency of Rh-specific B lymphocytes was estimated by limiting-dilution assay (LDA). The frequency of Rh-specific B lymphocytes varied from 1 : 150 to 1 : 27 850 in different donors. There was a decrease in this frequency and level of anti-Rh antibody with increase in time interval between bleeding and last exposure to the antigen. Furthermore, a positive correlation was observed between the titre of Rh-specific antibody and frequency of Rh-specific B cells in each of three subjects bled at multiple time-points postdelivery. The magnitude of the specific antibody response to Rh antigens varies greatly in Rh-alloimmunized women, which partly reflects the difference in frequency of specific B cells in these individuals. [ABSTRACT FROM AUTHOR]

Summary. The available data on rituximab in combination with chemotherapy confirm that the addition of an independently active biological agent to full-dose standard chemotherapy results in higher rates of complete response, lower rates of relapse, prolonged survival, little additional toxicity and no compromise of the dose intensity of standard chemotherapy regardless of age and risk group. Given the strength of these data, the British Committee for Standards in Haematology believes that rituximab should be available for prescription by UK haematologists and oncologists according to its licensed indication in patients with diffuse large B-cell lymphoma until further data are available to confirm or refute these results. We consider that the use of rituximab with chemotherapy in aggressive lymphoma is cost-effective and that failure to support its introduction will be strongly in conflict with professional and patient opinion. [ABSTRACT FROM AUTHOR]

Summary: A subset of individuals with 'primary' or 'idiopathic' immune thrombocytopenia (ITP) who fail to respond to conventional first‐ and second‐line agents or who lose responsiveness are considered to have 'refractory' disease (rITP), placing them at increased risk of bleeding and complications of intensive treatment. However, the criteria used to define the refractory state vary among studies, which complicates research and clinical investigation. Moreover, it is unclear whether rITP is simply 'more severe' ITP, or if there are specific pathogenic pathways that are more likely to result in refractory disease, and whether the presence or development of rITP can be established or anticipated based on these differences. This paper reviews potential biological features that may be associated with rITP, including genetic and epigenetic risk factors, dysregulation of T cells and cytokine networks, antibody affinity and specificity, activation of complement, impaired platelet production and alterations in platelet viability and clearance. These findings indicate the need for longitudinal studies using novel clinically available methodologies to identify and monitor pathogenic T cells, platelet antibodies and other clues to the development of refractory disease. [ABSTRACT FROM AUTHOR]

Summary: Since its first description by Evans in 1951, this syndrome has been linked to chronic immune thrombocytopenia with the concurrent or delayed onset of autoimmune haemolytic anaemia or neutropenia. For decades, the evolution of Evans syndrome (ES) has carried a poor prognosis and often resulted in chronic steroid exposure, multiple immune suppressing medications directed against T or B lymphocytes, and splenectomy. This paper presents a new view of ES based on recent advances in genomics which begin to classify patients based on their underlying molecular variants in previously described primary immune disorders. This has opened up new avenues of targeted therapy or bone marrow transplant at rather than broad long‐term immune suppression or splenectomy. Importantly, recent studies of the full lifespan of ES suggest that at least 80% of those paediatric patients will progress to various clinical or biological immunopathological manifestations with age despite the resolution of their cytopenias. Those patients merit long‐term follow‐up and monitoring in dedicated transition programs to improve outcome at the adult age. [ABSTRACT FROM AUTHOR]

This work investigates the existence and asymptotic behavior of solutions to a nonlocal dispersal in‐host viral model with humoral immunity. The model features both spatial movement of virus and humoral immunity response to the virus. This paper gives the principal eigenvalue (H0$\mathcal {H}_0$) of the nonlocal dispersal problem, and it is verified to be a critical value that determines the infection dynamics. The uninfected equilibrium is unique and stable for H0≤0$\mathcal {H}_0\le 0$. For H0>0$\mathcal {H}_0>0$, the equilibrium is not stable, and infected with/without B cells response equilibrium emerges. This paper also establishes the dynamics of infected equilibria. Numerical simulations are carried out to demonstrate the analytical results of this study. [ABSTRACT FROM AUTHOR]

Epigallocatechin‐3‐gallate (EGCG) is a major bioactive compound in tea polyphenol extract. After ingestion, EGCG reaches the intestine and may commence anti‐inflammation in the intestinal organ. Thus, in this paper, the anti‐inflammatory effect of EGCG was studied using lipopolysaccharide (LPS)‐induced inflammation in RAW 264.7 cells. LPS induction instigated morphological deformation extensively which was normalized by EGCG. In LPS‐induced macrophage cells, EGCG was found to lower cellular nitric oxide (32% of LPS group) and intercellular ROS level (45.4% of LPS group). It also suppressed the expression of IL‐1β (LPS 132.6 ± 14.6, EGCG 10.67 ± 3.65), IL‐6 (LPS 2994.44 ± 178.5, EGCG 408.33 ± 52.34), TNF‐α (LPS 27.11 ± 2.84, EGCG 1.22 ± 0.03), and iNOS (LPS 40.45 ± 11.17, EGCG 10.24 ± 0.89). The GO function analysis identified that these differential genes involved 24 biological processes, 18 molecular functions, and 19 cellular component‐related processes. KEGG pathway enrichment analysis revealed that LPS significantly affects NF‐κB, TNF, and TLR signaling pathways. Western blotting revealed that EGCG diminished P‐IκB/IκB ratio by 75% and p‐p65/p65 by 50% compared to the LPS group. Finally, Arg‐1 and CD‐206 mRNA expression were determined by RT‐PCR, which was consistent with the RNA‐Seq result. These findings indicate that EGCG exerts an anti‐inflammatory effect by reducing NO and ROS production, suppressing TLR4 protein expression, and inhibiting IκB and p65 phosphorylation. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a global health problem with increasing prevalence and association with an enormous medical and socioeconomic burden. New recognition of immune cells such as type 2 innate lymphocytes (ILC2s), T helper (Th2) 2 cells, follicular helper T cells, follicular regulatory T cells, regulatory T cells, B cells, dendritic cells, and epithelial cells in AR pathogenesis has been updated in this review paper. An in‐depth understanding of the mechanisms underlying AR will aid the identification of biomarkers associated with disease and ultimately provide valuable parameters critical to guide personalized targeted therapy. As the only etiological treatment option for AR, allergen‐specific immunotherapy (AIT) has attracted increasing attention, with evidence for effectiveness of AIT recently demonstrated in several randomized controlled trials and long‐term real‐life studies. The exploration of biologics as therapeutic options has only involved anti‐IgE and anti‐type 2 inflammatory agents; however, the cost‐effectiveness of these agents remains to be elucidated precisely. In the midst of the currently on‐going COVID‐19 pandemic, a global life‐threatening disease, although some studies have indicated that AR is not a risk factor for severity and mortality of COVID‐19, this needs to be confirmed in multi‐centre, real‐life studies of AR patients from different parts of the world. [ABSTRACT FROM AUTHOR]

CD38 is a multifunctional receptor and enzyme present on the surface of B lymphocytes, which can induce B lymphocytes proliferation and apoptosis by crosslinking related cytokines to affect the function of B cells, thus affecting immune regulation in humans and promoting tumorigenesis. The level of CD38 expression in B cells has become an important factor in the clinical diagnosis, treatment, and prognosis of malignant tumors and other related diseases. Therefore, studying the relationship between CD38 expression on the surface of B cells and the occurrence of the disease is of great significance for elucidating its association with disease pathogenesis and the clinical targeted therapy. In this paper, we review the effects of CD38 on B‐cell activation, proliferation, and differentiation, and elaborate the functional role and mechanism of CD38 expression on B cells. We also summarize the relationship between the level of CD38 expression on the surface of B cells and the diagnosis, treatment, and prognosis of various diseases, as well as the potential use of targeted CD38 treatment for related diseases. This will provide an important theoretical basis for the scientific research and clinical diagnosis and treatment of B‐cell‐related diseases. [ABSTRACT FROM AUTHOR]

IgE, the key molecule in atopy has been shown to bind two receptors, FcεRI, the high‐affinity receptor, and FcεRII (CD23), binding IgE with lower affinity. Whereas cross‐linking of IgE on FcεRI expressed by mast cells and basophils triggers the allergic reaction, binding of IgE to CD23 on B cells plays an important role in both IgE regulation and presentation. Furthermore, IgE‐immune complexes (IgE‐ICs) bound by B cells enhance antibody and T cell responses in mice and humans. However, the mechanisms that regulate the targeting of the two receptors and the respective function of the two pathways in inflammation or homeostasis are still a matter of debate. Here, we focus on CD23 and discuss several mechanisms related to IgE binding, as well as the impact of the IgE/antigen‐binding on different immune cells expressing CD23. One recent paper has shown that free IgE preferentially binds to FcεRI whereas IgE‐ICs are preferentially captured by CD23. Binding of IgE‐ICs to CD23 on B cells can, on one hand, regulate serum IgE and prevent effector cell activation and on the other hand facilitate antigen presentation by delivering the antigen to dendritic cells. These data argue for a multifunctional role of CD23 for modulating IgE serum levels and immune responses. [ABSTRACT FROM AUTHOR]

NF‐κB (nuclear factor kappa light chain enhancer of activated B cells) signaling pathway is involved in the occurrence and development of various kinds of inflammation, including rheumatoid arthritis (RA). In this paper, the relationship between the activation or inhibition of NF‐κB and the pathogenesis of RA is discussed. It is found that activated NF‐κB operates a dual‐aspect effect which can either promote or suppress inflammation. When NF‐κB is inhibited, the symptoms of RA are significantly improved. The specific role of NF‐κB is closely related to its upstream stimulator and downstream activator. Therefore, we review the research on NF‐κB in RA over the past 20 years in order to have a clearer understanding of its mechanism. [ABSTRACT FROM AUTHOR]

The maintenance of inner integrity of an organism is founded on the proper performance of two immunity branches, innate and adaptive immune responses. Recently, it became apparent that subset of splenic B cells named marginal zone B cells (MZB cells) exhibits unique developmental and functional features that bridge these two immunity branches. Strategically positioned at the site where blood and lymph are filtered, MZB cells represent a population of sentinels that rapidly proliferate and differentiate into IgM plasmablast cells when encountered with blood‐borne, thymus‐independent (TI) Ags. Moreover, MZB cells have intrinsic capability to induce potent CD4+ helper T cell response and cytokine production upon stimulation with soluble antigens. Due to their ability to overcome a time gap prior the establishment of the full adaptive response towards pathogens, MZB cells connect and direct innate and adaptive immunity. An additional interesting characteristic of MZB cells is capacity to function as regulatory cells in autoimmune processes. MZB cells may also contribute to the control of autoimmunity via the induction of tolerance by apoptotic cells. Importantly, in the clear association with inflammation and autoimmunity, MZB cells may transform into MALT lymphoma, representing a concurrence point for the infection, immunity and malignancy. This paper presents an insight into the complex biology of marginal zone B cells and their role in intertwining and directing innate and adaptive immune processes at the physiological and pathological level. [ABSTRACT FROM AUTHOR]

This paper formulates a virus dynamics model with impairment of B‐cell functions. The model incorporates two modes of viral transmission: cell‐free and cell‐to‐cell. The cell‐free and cell‐cell incidence rates are modeled by general functions. The model incorporates both, latently and actively, infected cells as well as three distributed time delays. Nonnegativity and boundedness properties of the solutions are proven to show the well‐posedness of the model. The model admits two equilibria that are determined by the basic reproduction number R0. The global stability of each equilibrium is proven by utilizing Lyapunov function and LaSalle's invariance principle. The theoretical results are illustrated by numerical simulations. The effect of impairment of B‐cell functions and time delays on the virus dynamics are studied. We have shown that if the functions of B‐cell is impaired, then the concentration of viruses is increased in the plasma. Moreover, we have observed that increasing the time delay will suppress the viral replication. [ABSTRACT FROM AUTHOR]

This paper studies an (n+4)‐dimensional nonlinear virus dynamics model that characterizes the interactions of the viruses, susceptible host cells, n‐stages of infected cells, B cells and cytotoxic T lymphocyte (CTL) cells. Both viral and cellular infections have been incorporated into the model. The infected‐susceptible and virus‐susceptible infection rates as well as the generation and removal rates of all compartments are described by general nonlinear functions. Five threshold parameters are computed, which insure the existence of the equilibria of the model under consideration. A set of conditions on the general functions has been established, which is sufficient to investigate the global dynamics of the model. The global asymptotic stability of all equilibria is proven by utilizing Lyapunov function and LaSalle's invariance principle. The theoretical results are illustrated by numerical simulations of the model with specific forms of the general functions. [ABSTRACT FROM AUTHOR]

Aim: A significant proportion of patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are either steroid dependent or steroid resistant, requiring long‐term calcineurin inhibitors (CNI) use. Rituximab has more favourable safety profile. The present study was undertaken to evaluate the efficacy and safety of rituximab in CNI‐dependent patients. Methods: This was a prospective observational study conducted from July 2014 to February 2018. Steroid‐dependent nephrotic syndrome or steroid‐resistant nephrotic syndrome (biopsy proven MCD/FSGS), who were CNI dependent were enrolled. Mean age at enrolment was 22.77 ± 7.45 years. All patients received rituximab at a dose of 375 mg/m2 at entry in the study. CD‐19 levels were monitored monthly and patients having CD‐19 levels >5/μL and/or > 1% received additional low‐dose (100 mg) of rituximab. Results: A total of 24 patients were followed up for 12 months. At the end of 6 and 12 months, 87.5% and 79.16% of the patients achieved remission, respectively. Eight (33.33%) patients developed relapse. The mean dose of rituximab in the first year was 791 mg. The average cost of rituximab in the first year was 487.17$. Rituximab was well‐tolerated, with mild infusion reactions, respiratory tract infection and oral candidiasis in 5 (20.83%), 5 (20.83%) and 1 (4.17%) patient, respectively. Conclusions: CD‐19 targeted rituximab is a safe and cost‐effective agent in remission maintenance in adults with CNI dependent. Over three‐fourths of the patients with CNI‐dependent podocytopathy maintain clinical remission with CD‐19 targeted rituximab therapy. SUMMARY AT A GLANCE: This paper shows that rituximab, a monoclonal antibody‐based therapy that depletes CD‐19 and CD‐20‐positive B cells, may be an alternative approach to maintain remission in calcineurin‐inhibitor dependent podocytopathies. [ABSTRACT FROM AUTHOR]

Lymphomatoid granulomatosis (LYG) is an angiocentric and angiodestructive lymphoproliferative disease which can involve multiple organs of the body and is most common in the lungs. Its pathological features are proliferation of large atypical B‐cells related to Epstein–Barr virus, T‐cell infiltration and tissue necrosis. This disease is rare, and LYG which uniquely involves the central nervous system (CNS) is extremely rare. In this paper, we report a case of isolated lymphomatoid granulomatosis of the CNS (iCNS‐LYG) diagnosed by histological biopsy and we review the clinical features of all similar cases reported in the past 46 years. A total of 49 cases of iCNS‐LYG have been reported to date. The clinical, imaging and pathological features of iCNS‐LYG are discussed in combination with a literature review. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a disease with high prevalence all over the world and therefore needs to be thoroughly investigated and treated accordingly. The mechanisms underlying the pathology and treatment of AR have been widely studied, but many aspects remain unclear and warrant further investigations. This review presents an overview of recently published papers highlighting the risk factors, mechanisms, and treatment of AR. Additionally, recent studies discussing the role of single nucleotide polymorphism, DNA methylation, regulatory B cells, group 2 innate lymphoid cells, immunotherapy, and biologics in AR are also covered. [ABSTRACT FROM AUTHOR]

Summary: Background: Thyroid eye disease (TED) is an autoimmune inflammatory disease that can be disfiguring and potentially sight threatening. Suppression of inflammation in active disease can reduce the risk of visual loss and limit long‐term sequelae. Current management involves inflammation suppression using glucocorticoids. The aim of this study was to evaluate the efficacy of early disease intervention with targeted immunomodulatory therapy to alter disease course. This paper reports the efficacy of low‐dose rituximab in reducing clinical activity in TED in a small population. Methods: A retrospective audit of consecutive patients with active TED managed primarily with a 100 mg rituximab infusion. Further glucocorticoid or steroid‐sparing agents were prescribed if clinically indicated. Clinical activity score, VISA overall severity score and Oxford Quality of Life score were recorded at each visit as well as TSH receptor antibody levels (TRAb), B cell subsets and adverse reactions. Results: Twelve patients had mean follow‐up of 6.3 months. Clinical activity scores significantly decreased (mean score 5.08 to 1.58; P < 0.001), VISA overall severity scores reduced by 50% from 12 to 6, P < 0.001 and the mean cumulative dose of IV methylprednisolone was 2.3 g. 100 mg rituximab induced significant CD19+ B cell depletion (n = 8, P < 0.001). There was no significant reduction in serum TRAb (n = 8, P = 0.06). A transient infusion‐related rash was the only adverse effect, n = 4. QoL scores did not differ markedly before and after treatment. Conclusion: Low‐dose rituximab is an efficacious, well‐tolerated and safe treatment for active TED; reducing disease activity and allowing reduced administration of systemic steroid. [ABSTRACT FROM AUTHOR]

Abstract: Probabilistic modeling is fundamental to the statistical analysis of complex data. In addition to forming a coherent description of the data‐generating process, probabilistic models enable parameter inference about given datasets. This procedure is well developed in the Bayesian perspective, in which one infers probability distributions describing to what extent various possible parameters agree with the data. In this paper, we motivate and review probabilistic modeling for adaptive immune receptor repertoire data then describe progress and prospects for future work, from germline haplotyping to adaptive immune system deployment across tissues. The relevant quantities in immune sequence analysis include not only continuous parameters such as gene use frequency but also discrete objects such as B‐cell clusters and lineages. Throughout this review, we unravel the many opportunities for probabilistic modeling in adaptive immune receptor analysis, including settings for which the Bayesian approach holds substantial promise (especially if one is optimistic about new computational methods). From our perspective, the greatest prospects for progress in probabilistic modeling for repertoires concern ancestral sequence estimation for B‐cell receptor lineages, including uncertainty from germline genotype, rearrangement, and lineage development. [ABSTRACT FROM AUTHOR]

Lists research papers related to immunology to be published in the journal. "T Cells Homeostasis in Mice Exposed to Airborne Xenobiotics," by Nadzieja Drela, Justyna Bien, and Ewa Kozlowska; "B Cell Reconstruction by Transplantation of B220+ CD117+ B-lymphoid Progenitors Into Irradiated Mice," by Susumu Kawaguchi; "TGF-β1 Increases CXCR4 Expression, SDF-1alpha-stimulated Signaling and HIV-1 Entry in Human Monocyte-derived Macrophages," by Jeffrey Harrison.

As the amount of biomedical information available in the literature continues to increase, databases that aggregate this information continue to grow in importance and scope. The population of databases can occur either through fully automated text mining approaches or through manual curation by human subject experts. We here report our experiences in populating the National Institute of Allergy and Infectious Diseases sponsored Immune Epitope Database and Analysis Resource ( IEDB, http://iedb.org), which was created in 2003, and as of 2012 captures the epitope information from approximately 99% of all papers published to date that describe immune epitopes (with the exception of cancer and HIV data). This was achieved using a hybrid model based on automated document categorization and extensive human expert involvement. This task required automated scanning of over 22 million PubMed abstracts followed by classification and curation of over 13 000 references, including over 7000 infectious disease-related manuscripts, over 1000 allergy-related manuscripts, roughly 4000 related to autoimmunity, and 1000 transplant/alloantigen-related manuscripts. The IEDB curation involves an unprecedented level of detail, capturing for each paper the actual experiments performed for each different epitope structure. Key to enabling this process was the extensive use of ontologies to ensure rigorous and consistent data representation as well as interoperability with other bioinformatics resources, including the Protein Data Bank, Chemical Entities of Biological Interest, and the NIAID Bioinformatics Resource Centers. A growing fraction of the IEDB data derives from direct submissions by research groups engaged in epitope discovery, and is being facilitated by the implementation of novel data submission tools. The present explosion of information contained in biological databases demands effective query and display capabilities to optimize the user experience. Accordingly, the development of original ways to query the database, on the basis of ontologically driven hierarchical trees, and display of epitope data in aggregate in a biologically intuitive yet rigorous fashion is now at the forefront of the IEDB efforts. We also highlight advances made in the realm of epitope analysis and predictive tools available in the IEDB. [ABSTRACT FROM AUTHOR]

B cells have an important pathogenic role in the development of type 1 diabetes in the non-obese diabetic ( NOD) mouse. We have previously reported that NOD mice display an increased percentage of TACIhigh-expressing B cells compared with C57 BL/6 mice and this trait is linked to chromosomes 1 and 8. In this paper the genetic association of the transmembrane activator, calcium modulator and cyclophilin ligand interactor ( TACI) trait was confirmed using double congenic NOD. B6C1/Idd22 mice. TACI ligation by a proliferation-inducing ligand ( APRIL) has been shown to influence plasma cell differentiation, immunoglobulin production and isotype switch. Hence, the functional consequence of the up-regulation of TACI on NOD B cells was analysed both in vitro and in vivo. NOD B cells stimulated with APRIL showed an enhanced plasma cell differentiation and class switch to IgG and IgA compared with B cells from C57 BL/6 mice. Moreover, flow cytometry analyses revealed that germinal centre B cells in NOD failed to down-regulate TACI. Availability of the TACI ligand B-cell activating factor ( BAFF) has been shown to be a limiting factor in the germinal centre reaction. In line with this, upon immunization with 4-hydroxy-3-nitrophenylacetyl hapten-conjugated hen egg lysozyme, NOD mice produced higher titres of low-affinity antibodies compared with C57 BL/6 mice. This observation was supported by the detection of increased levels of BAFF in NOD germinal centres after immunization compared with C57 BL/6 by immunofluorescence. Our results support the hypothesis that increased TACI expression on NOD B cells contributes to the pathogenesis of type 1 diabetes in the NOD mouse. [ABSTRACT FROM AUTHOR]

Background: Primary cutaneous B-cell lymphomas (PCBCL) are cutaneous non-Hodgkin lymphomas and can be classified clinically and by prognosis. The aim of this paper is to perform a review of standard and new treatments. Method: This paper provides a literature review of the different treatments of PCBCL. Results: Surgery and radiotherapy remain the standard therapies in isolated cutaneous lesions. Systemic or intralesional interferon (IFN)-α may be an alternative in PCBCL with diffuse cutaneous lesions. In aggressive forms with poor prognosis, polychemotherapy is the first line of treatment although rituximab and radioimmunotherapy are evolving therapeutic options. Conclusion: In the majority of cases, the treatment of CBCL is straightforward. In aggressive forms, new therapies and biologic therapies may be of real interest. [ABSTRACT FROM AUTHOR]

The article presents a list of forthcoming books about immunology. These include "IL-5 Target Genes Involved in B Cell Terminal Maturation," by Keisuke Horikawa and K. Takatsu, "The Riddle of the Dual Expression of IgM and IgD," by Roland Geisberger, Marinus Lamers and Gernot Achatz, and "Anti-Idiotype Antibody Induced Cellular Immunity in Mice Transgenic for Human Carcinoembryonic Antigen," by Asim Saha, Sunil Chaterjee, Kenneth Foon and Malaya Chatterjee.

In the preceding paper a population of lymphoid cells was identified which (1) were derived from germinal centres in the appendix, (2) were localized in follicular structures elsewhere, and (3) could perform as antibody-forming cell precursors. The present paper presents evidence (1) that germinal centres in the spleen and lymph nodes perform the same function as germinal centres in the appendix, and (2) that germinal centres are dependent upon a stream of cells derived from the bone marrow. A new hypothesis is put forward regarding the origin and cellular kinetics of the B-cell system in mammals. It is proposed that germinal centres throughout the body function as an essentially antigen-dependent amplification system for the B-cell population of lymphocytes. Implications of this hypothesis are discussed. [ABSTRACT FROM AUTHOR]

Vitamin D seems to be implicated in the pathophysiology of autoimmune disorders as a natural immune modulator. Beneficial effects of vitamin D have been associated with different cells of the immune system; however, thus far, B cells seem to be somewhat neglected. In this paper, we describe the possible direct effects of vitamin D on B cells, with a focus on antibody production and the more recently identified regulatory B (Breg) cells. B cells upregulate the vitamin D receptor (VDR) upon activation. Furthermore, due to regulated expression of the metabolizing enzymes CYP27B1 and CYP24A1, B cells have the potential to control the local availability of active vitamin D. B cells, therefore, may participate in vitamin D-mediated immune homeostasis, including plasma cell generation. Whether or not other B cell subsets, such as Breg cells, are equally responsive to vitamin D remains to be established. [ABSTRACT FROM AUTHOR]

Vitamin D seems to be implicated in the pathophysiology of autoimmune disorders as a natural immune modulator. Beneficial effects of vitamin D have been associated with different cells of the immune system; however, thus far, B cells seem to be somewhat neglected. In this paper, we describe the possible direct effects of vitamin D on B cells, with a focus on antibody production and the more recently identified regulatory B (Breg) cells. B cells upregulate the vitamin D receptor (VDR) upon activation. Furthermore, due to regulated expression of the metabolizing enzymes CYP27B1 and CYP24A1, B cells have the potential to control the local availability of active vitamin D. B cells, therefore, may participate in vitamin D-mediated immune homeostasis, including plasma cell generation. Whether or not other B cell subsets, such as Breg cells, are equally responsive to vitamin D remains to be established. [ABSTRACT FROM AUTHOR]

In 1998, the landmark paper describing the isolation and culture of human embryonic stem cells (ESCs) was published. Since that time, the main goal of many diabetes researchers has been to derive β cells from ESCs as a renewable cell-based therapy for the treatment of patients with diabetes. In working toward this goal, numerous protocols that attempt to recapitulate normal pancreatic development have been published that result in the formation of pancreatic cell types from human pluripotent cells. This review examines stem cell differentiation methods and places them within the context of pancreatic development. We additionally compare strategies that are currently being used to generate pancreatic cell types and contrast them with approaches that have been used to generate functional cell types in different lineages. In doing this, we aim to identify how new approaches might be used to improve yield and functionality of in vitro-derived pancreatic β cells as an eventual cell-based therapy for type 1 diabetes. [ABSTRACT FROM AUTHOR]

Any discussion of the regulation of effector class must include feedback control on the magnitude of the response. The induced effector activities are biodestructive and ridding. They are, in and of themselves, unspecific with respect to self and nonself. Consequently all responses include some level of innocent bystander pathology. The regulation of magnitude is essential to keeping this level of pathology at an evolutionarily acceptable level. This is my postulated role of suppressor T-cells, more popularly referred to as Treg. In order to perform this function they must be somatically selected to be anti-nonself like all other T/B-cells. If correct, any role that they might play in determining normal tolerance is excluded. As the commentary of Ellestad illustrates, their function to regulate autoimmunity is the consensus view today and, therefore, this competing concept and my analysis of suggested papers should invite a wide ranging debate. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Petukhova et al. (2011) B- and T-cell memory elicited by a seasonal live attenuated reassortant influenza vaccine: assessment of local antibody avidity and virus-specific memory T-cells using trogocytosis-based method. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750-2659.2011.00279.x. Purpose The main purpose of vaccination is to generate immunological memory providing enhanced immune responses against infectious pathogens. The standard and most commonly used assay for influenza vaccine immunogenicity evaluation is a hemagglutination inhibition assay (HAI). It is clear now that HAI assay is unable to properly assess the proven protective immunity elicited by live attenuated influenza vaccines (LAIV). New methods need to be developed for more accurate LAIV immunogenicity assessment and prediction of vaccine efficacy among target populations. Objective Randomized placebo-controlled study of memory B- and T-cell responses to intranasal LAIV in young adults. Methods A total of 56 healthy young adults 18-20 years old received seasonal monovalent LAIV. Mucosal memory B-cell responses were measured by IgA avidity assessment in nasal swabs. CD4 memory T cells in peripheral blood were examined by the expression of CD45RO marker and in functional test by the ability of virus-specific T cells to maintain the trogocytosis with antigen-loaded target cells. Results Intranasal LAIV immunization enhances mucosal IgA avidity even without reliable increases in antibody titers. At the day 21 after vaccination, up to 40% of subjects demonstrated significant increases in both total and virus-specific CD4 memory T cells that were observed regardless of seroconversion rate measured by HAI assay. Conclusion The data suggest that immunogenicity of LAIV vaccines should be evaluated on the mucosal and cellular immunity basis. The assays applied could be used to support influenza clinical trials through preliminary screening of volunteers and subsequent measurement of anti-influenza in immunity. [ABSTRACT FROM AUTHOR]

B cells have been shown to function as tolerogenic antigen presenting cells (APCs) both in vivo and in vitro. We have taken advantage of this property, as well as the ability of IgG carriers to be potent ‘schleppers’ for tolerogenic entities, to develop a gene therapy approach to induce unresponsiveness in a number of systems, including the elimination of haemophilia inhibitors. Thus, peptide-IgG constructs have been engineered into retroviral vectors to create ‘transgenic’ B cells for tolerance applications. In this paper, we discuss our gene therapy approach mediated by B cells (as well as bone marrow cells) for tolerance acquisition in various mouse models for autoimmune disease and haemophilia A. The mechanisms that are the underpinning of this effort and role of regulatory T cells are discussed herein. Our results indicate that gene therapy strategies can successfully reduce the incidence and or onset of autoimmune diseases and prevent/reverse inhibitor formation in haemophilia A mice. Based on recent success with a model for tolerance with human T cell clones in vitro, plans for future application in patients are discussed. [ABSTRACT FROM AUTHOR]

The ability of B cells to negatively regulate cellular immune responses and inflammation has only recently been described. Hallmark papers from a number of distinguished laboratories have identified phenotypically diverse B-cell subsets with regulatory functions during distinct autoimmune diseases, including IL-10-producing B cells, CD5+ B-1a cells, CD1d+ marginal zone B cells, and transitional-2-marginal zone precursor B cells. Most recently, a numerically rare and phenotypically unique CD1dhiCD5+CD19hi subset of regulatory B cells has been identified in the spleens of both normal and autoimmune mice. CD1dhiCD5+ B cells with the capacity to produce IL-10 have been named B10 cells as they produce IL-10 exclusively and are the predominant B-cell source of IL-10. Remarkably, B10 cells are potent negative regulators of inflammation and autoimmunity in mouse models of disease in vivo. Herein, our current understanding of B10-cell development and function is reviewed in the context of previous studies that have identified and characterized regulatory B cells, emerging evidence for B10-cell regulation of tumor immunity, and the likelihood that B10 cells exist in humans. [ABSTRACT FROM AUTHOR]

There are two major forms of diabetes: type 1 and type 2. However, monogenic diabetes, associated with severe β-cell dysfunction or with severe resistance to insulin action, is diagnosed with increasing frequency by genetic testing. The list of such forms of diabetes includes MODY, mitochondrial diabetes, permanent neonatal diabetes (PNDM) and transient neonatal diabetes, familial lipodystrophies and some others. These rare forms constitute probably at least a few per cent of all diabetes cases seen in diabetic clinics. The identification of the molecular background of specific forms of diabetes gives new insight into the underlying aetiology. This knowledge helps to optimize treatment in specific clinical situations. The proper differential diagnosis also helps to predict the progress of diabetes in affected individuals and defines the prognosis in the family. For example, in patients with MODY2 because of glucokinase mutations who have very mild diabetes characterized by modest fasting, hyperglycaemia diet is frequently sufficient. Some other forms of monogenic diabetes associated with impaired function of the β-cell, such as MODY3 and PNDM linked to mutations in Kir6.2 and SUR1 genes, can be successfully managed by sulphonylurea agents. Although the examples of pharmacogenetics seem to be less spectacular in rare syndromes of insulin resistance, those patients can also benefit from genetic testing. In this paper, the aetiology of some monogenic diabetes forms is reviewed together with the clinical aspects of management of the affected individuals. [ABSTRACT FROM AUTHOR]

In this paper, we describe a new model of immune network based on biological immune response network. We propose an immunity like multiple-valued network with apoptosis mechanism. The model is based on the interaction between B cells and T cells and the biological apoptosis mechanism in the human body. With the mechanism, a naturally immune system can be reproduced. The model is also applied to pattern recognition. It becomes possible with a conventional model to restrict the category increase of memory patterns. © 2007 Wiley Periodicals, Inc. Electr Eng Jpn, 162(3): 51– 57, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.20320 [ABSTRACT FROM AUTHOR]

The pathogenesis of B-cell lymphoproliferative disorders in general and B-cell chronic lymphocytic leukaemia in particular appears to involve dysfunctional regulation of humoral and cellular immunity with the subsequent development of genetic aberrations in B cells. In theory, either component may arise de novo or may be influenced by environmental exposures including infectious agents, antigens, genotoxic chemicals, or radiation. As an intermediary within the exposure-disease continuum, monoclonal B-cell lymphocytosis may be a helpful biomarker for teasing out these various contributions to risk. This article introduces a series of papers that resulted from an International Workshop held in May 2007 entitled ‘Monoclonal B-cell Lymphocytosis and Chronic Lymphocytic Leukemia: Environmental and Genetic Risk Factors’. Research efforts, such as those described in this issue, should lead to improved interventions, more predictive biomarkers, more effective treatments, and a greater appreciation of how the immune system functions over the entire human lifespan. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is represents the most common chronic inflammatory joint disease and is still a major medical challenge because of unsolved issues related to the etiologic and pathogenetic questions. Intensive research has been conducted over the last years that focused on the inappropriate activation of the immune system: although T cells have long been deemed to play a central role in the origin and propagation of joint inflammation, data accumulated so far have widened this perspective recognizing the contribution of other cells, as well as the major histocompatibility complex class II proteins and a composite set of costimulatory signals responsible for the production of proinflammatory cytokines and other soluble mediators implicated in tissue destruction typical of the disease. This paper will provide an insight into the immune system in RA, dissecting cellular and humoral aspects both in serum and in synovium of patients. [ABSTRACT FROM AUTHOR]

Background: CD23 expression in normal B lymphocytes is limited to autoreactive B cells, naïve B cells and mature B cells manifesting an activated phenotype. As a marker of hematologic dyscrasia/malignancy, expression of CD23 is associated with small lymphocytic lymphoma/chronic lymphocytic leukemia. An absence of CD23 expression within small lymphocytes is typically seen in marginal zone lymphoma and mantle cell lymphoma. Positive CD23 expression amidst neoplastic cells in primary cutaneous B-cell lymphoma is not a reported phenomenon. Methods: This paper reports nine patients with cutaneous B-cell lymphoma manifesting CD23 expression. Results: In seven of the nine cases CD23 expression was observed in the setting of recurrent disease, being present in both large and small lymphocytes. CD23 expression paralleled staining for CD40 in all but one case. Conclusions: A potential mechanism of CD23 upregulation may involve the anti-apoptotic nuclear kappa beta CD40–CD40 ligand pathway. Neoplastic B cells manifesting CD23 expression could have a survival advantage, predisposing to recurrent disease and or oncogenic events permissive to disease progression. [ABSTRACT FROM AUTHOR]