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ZusammenfassungEs wird ein Patient vorgestellt, der im Alter von 9 Jahren eine polyartikuläre Arthritis entwickelte, die auf eine Therapie mit Methotrexat zunächst ansprach. Aufgrund deutlicher Transaminasenerhöhungen wurde die Methotrexat-Therapie nach 4 Monaten beendet und Etanercept gegeben. Darunter entwickelte der Patient eine Pneumonitis und es kam es zur Entwicklung eines systemischen Lupus erythematodes, der nach Absetzen des Etanercept wieder verschwand. Wir vermuteten dann eine Mischkollagenose und therapierten mit Steroiden und Mycophenolat-Mofetil sowie später mit Tocilizumab. Im Verlauf kam es zur Entwicklung einer Kalzinose und erst auswärts nach Nachweis von MDA-5-Antikörpern zur Diagnose eines dermatopulmonalen Syndroms und einer weitgehend amyopathischen juvenilen Dermatomyositis. Unter einer Therapie mit Cyclosporin A persistieren Bewegungseinschränkungen an der Schulter, ansonsten ist der Patient weitgehend beschwerdefrei, treibt Sport und wird von Erwachsenenrheumatologen weiter betreut.

Primare Immundefekte sind seltene angeborene Erkrankungen, die lange Zeit vor allem durch eine erhohte Infektanfalligkeit und das Auftreten schwerer und opportunistischer Infektionen charakterisiert waren. In den letzten Jahren wurden aber zunehmend primare Immundefekte identifiziert, bei denen die Immundysregulation im Vordergrund steht und die durch Autoimmunitat und Autoinflammation gekennzeichnet sind. Chronische Arthritiden und andere rheumatologische Symptome konnen dabei nicht nur als Komplikation der Immundefekte auftreten, sondern auch eines der charakteristischen Krankheits-definierenden Symptome darstellen. Gerade im Kindes- und Jugendalter kann die rheumatologische Manifestation zudem als erstes klinisches Symptom des zugrunde liegenden Immundefekts auftreten. Daher ist in der Kinder- und Jugendrheumatologie ein grundlegendes Wissen uber primare Immundefekte unabdingbar. Im folgenden Ubersichtsartikel soll ein Uberblick uber primare Immundefekte, die mit rheumatologischen Symptomen einhergehen konnen, gegeben werden. Ein besonderer Fokus liegt dabei auf kurzlich charakterisierten neuen Immundefekten, bei denen die Autoimmunitat haufig im Vordergrund steht. Primary immunodeficiencies are rare diseases generally characterized by increased susceptibility to infections. In contrast to this definition, over the last years several primary immunodeficiency syndromes were identified that mainly present with immune dysregulation, namely autoimmunity and autoinflammation, as major manifestations. In some cases, chronic arthritis and other rheumatological phenomena might be the most important symptom in these immunodeficiencies. Especially in children and teenagers, rheumatological symptoms can also be the first and, at time of diagnosis, only symptom of the underlying immune dysregulation. Therefore, pediatric rheumatologists should provide a basic knowledge about primary immunodeficiencies. This review comprises recent updates on primary immunodeficiencies with immune dysregulation and rheumatological manifestations.

Comprehensive studies investigated the role of T-cells in asthma which led to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B-cells to this chronic inflammatory disease. In this study we investigated the contribution of various B-cell populations to specific clinical features in asthma.In the All Age Asthma Cohort (ALLIANCE), a subgroup of 154 adult asthma patients and 28 healthy controls were included for B-cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B-cells using association studies and multivariate linear models.Patients with severe asthma showed decreased immature B-cell populations while memory B-cells were significantly increased compared with both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of IgAWith this study we demonstrate for the first time a significant association of increased IgA

Eine Gruppe der Universitätsklinik Münster unter Beteiligung mehrerer Mitglieder unserer Gesellschaft für Kinder- und Jugendrheumatologie analysiert im Detail das Zytokinmuster beim Zytokinsturm-Syndrom im Rahmen von COVID-19. Insbesondere geht es dabei um die Identifizierung charakteristischer Unterschiede zwischen dem Zytokinsturm bei SARS-CoV-2-Infektion einerseits und einem Makrophagenaktivierungssyndrom (MAS) oder der sekundären hämophagozytischen Lymphohistiozytose (HLH).

Das PAPA-Syndrom, eine Kombination bestehend aus pyogener steriler Arthritis, Pyoderma gangraenosum und Akne, ist eine autosomal-dominant vererbbare Erkrankung, die durch eine Mutation im PSTPIP1(„proline-serine-threonine phosphatase interacting protein 1“)-Gen auf dem fur das Prolin-Serin-Threonin-Phosphatase-interagierende Protein 1 kodierenden Chromosom 15 verursacht wird. Eine Verbindung mit Morbus Crohn (MC), Autoimmunerkrankungen der Leber und dem PAPA-Syndrom wurde in der Literatur bisher noch nicht beschrieben. In dieser Arbeit untersuchten wir intensiv eine Familie mit 3 betroffenen Mitgliedern (Mutter und 2 Kinder), diagnostizierten ein PAPA-Syndrom neu sowie zusatzlich intestinale und hepatobiliare autoimmune Symptome. Wir fuhrten eine tiefe Phanotypisierung sowie dermatologische, radiologische, rheumatologische, gastroenterologische, histologische und genetische Analysen bei den 3 Betroffenen dieser Familie durch. Bei allen 3 Familienmitgliedern konnte ein PAPA-Syndrom mit einer krankheitsverursachenden Mutation c.688G > A (p.Ala230Thr) im PSTPIP1-Gen nachgewiesen werden. Der jungere Sohn hatte zusatzlich einen Morbus Crohn, die Mutter eine Colitis ulcerosa (CU) und ein Overlap-Syndrom zwischen Autoimmunhepatitis (AIH) und primar sklerosierender Cholangitis (PSC) entwickelt. Bei allen 3 Betroffenen konnte keine Mutation im NOD2(„nucleotide binding oligomerization domain containing protein 2“)-Gen nachwiesen werden. Die Assoziation von PAPA-Syndrom mit einem Morbus Crohn und Autoimmunerkrankungen der Leber konnte eine Symptomerweiterung des PAPA-Syndroms, also ahnliche pathogenetische Mechanismen dieser Symptome, oder sogar ein neues Syndrom darstellen. Zukunftig sollten Patienten mit PAPA-Syndrom sorgfaltig auf intestinale und hepatobiliare Erkrankungen untersucht werden.

Die Klassifikation der juvenilen idiopathischen Arthritis (JIA) steht derzeit im Fokus vieler Diskussionen. In dem Übersichtsartikel stellt ein internationales Autor*innenteam aus den USA, Großbritannien, Kanada und Italien unter der Seniorautorenschaft von Alberto Martini die derzeit verwendete ILAR-Klassifikation einer möglichen zukünftigen Klassifikation basierend auf biologischen Charakteristika gegenüber.

Background Asthma is a widespread, multifactorial chronic airway disease. The influence of regulatory B cells on airway hyperreactivity (AHR) and remodeling in asthma is poorly understood. Objective Our aim was to analyze the role of B cells in a house dust mite (HDM)-based murine asthma model. Methods The influence of B cells on lung function, tissue remodeling, and the immune response were analyzed by using wild-type and B-cell–deficient (μMT) mice and transfer of IL-10–proficient and IL-10–deficient B cells to μMT mice. Results After HDM-sensitization, both wild-type and μMT mice developed AHR, but the AHR was significantly stronger in μMT mice, as confirmed by 2 independent techniques: invasive lung function measurement in vivo and examination of precision-cut lung slices ex vivo. Moreover, airway remodeling was significantly increased in allergic μMT mice, as shown by enhanced collagen deposition in the airways, whereas the numbers of FoxP3+ and FoxP3– IL-10–secreting regulatory T cells were reduced. Adoptive transfer of IL-10–proficient but not IL-10–deficient B cells into μMT mice before HDM-sensitization attenuated AHR and lung remodeling. In contrast, FoxP3+ regulatory T cells were equally upregulated by transfer of IL-10–proficient and IL-10–deficient B cells. Conclusion Our data in a murine asthma model illustrate a central role of regulatory B cells in the control of lung function and airway remodeling and may support future concepts for B-cell–targeted prevention and treatment strategies for allergic asthma.

Allergic asthma is a widespread chronic inflammatory disease of the airways. The role of different B cell subsets in developing asthma and respiratory tolerance is not well known. Especially regulatory B (Breg) cells are proposed to be important in asthma regulation. Using wild-type (WT) and B cell-deficient (μMT) mice we investigated how B cells are affected by induction of allergic airway inflammation and respiratory tolerance and whether they are necessary to develop these conditions. WT mice with an asthma-like phenotype, characterized by increased airway hyper reactivity, eosinophilic airway inflammation, mucus hypersecretion and elevated Th2 cytokines, exhibited increased MHCII and CD23 expression on follicular mature B cells in lung, bronchial lymph nodes (bLN) and spleen, which contributed to allergen-specific T cell proliferation in vitro. Germinal center B cell numbers were elevated and associated with increased production of allergen-specific immunoglobulins especially in bLN. In contrast, respiratory tolerance clearly attenuated these B cell alterations and directly enhanced marginal zone precursor B cells, which induced regulatory T cells in vitro. However, μMT mice developed asthma-like and tolerized phenotypes like WT mice. Our data indicate that although B cell subsets are affected by asthma-like and respiratory tolerant phenotypes, B cells are not required for tolerance induction.

Asthma is a widespread chronic multifactorial disease of the airways which is often triggered by the perennial allergen house dust mite (HDM). Next to regulatory T cells (Tregs), IL10 producing regulatory B cells are crucial to substantially counteract inflammatory responses. However, their regulatory impact in asthma is inadequately known so far. To better understand the regulatory influence of B cells in allergic asthma, we employed a HDM-based experimental asthma model using wildtype (WT) and B cell deficient (µMT) mice. Compared to WT counterparts, HDM-sensitized µMT mice developed a significantly increased airway hyperreactivity (AHR), a cardinal feature of asthma, measured by invasive lung function. This observation was confirmed by independent precision cut lung slices (PCLS) technique, demonstrating stronger bronchoconstriction of explanted lung tissue slices of allergic µMT mice after methacholine provocation. Furthermore, allergic µMT mice displayed diminished levels of Tregs and Th2 cytokines, especially IL10, as determined by flow cytometry and immunoassays. Adoptive transfer of naive WT B cells followed by HDM-sensitization substantially attenuated AHR in µMT mice and boosted IL10 production and Treg expansion. To test the impact of IL10, B cells from IL10 deficient (IL10-/-) mice were transferred, but failed to improve lung function of allergic µMT mice. Furthermore, transfer of WT and IL10-/- B cells provoked comparable amounts of IL10 and Tregs. Taken together, our data indicate that B cells are critical in HDM-induced AHR, and that IL10 competent B cells may be central in regulating AHR in allergic airway inflammation.

The PAPA syndrome, an acronym for pyogenic sterile arthritis, pyoderma gangraenosum and acne, is an autosomal dominant hereditary disease which is caused by a mutation in the PSTPIP1 ("proline-serine-threonine phosphatase interacting protein 1") gene located on chromosome 15 and encodes the proline-serine-threonine phosphatase-interacting protein 1. An association with Crohn's disease (CD), autoimmune diseases of the liver and PAPA syndrome has not yet been reported in the literature.To thoroughly investigate a family with three affected members (mother and 2 children) with newly diagnosed PAPA syndrome and intestinal and hepatobiliary symptoms.We performed an in-depth phenotyping, dermatologic, radiologic, rheumatologic, gastroenterologic, histologic and genetic analysis in this family.All three family members could be newly diagnosed as suffering from PAPA syndrome and carried the known disease-causing mutation c.688G A (p.Ala230Thr) in the PSTPIP1 gene. The younger son suffered from CD in addition to PAPA syndrome. The mother additionally suffered from ulcerative colitis (UC) and an overlap syndrome between autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). A mutation in in the NOD2 ("nucleotide binding oligomerization domain containing protein 2") gene could not be detected in any of the three persons affected.We extended the symptoms of PAPA syndrome to CD and autoimmune liver disease. These different disease entities might share a similar pathogenetic mechanism or even represent a new syndrome. This can be clarified in the future by screening patients with PAPA syndrome for intestinal and also hepatobiliary diseases.

The increased susceptibility to infections of neonates is caused by an immaturity of the immune system as a result of both qualitative and quantitative differences between neonatal and adult immune cells. With respect to B cells, neonatal antibody responses are known to be decreased. Accountable for this is an altered composition of the neonatal B cell compartment towards more immature B cells. However, it remains unclear whether the functionality of individual neonatal B cell subsets is altered as well. In the current study we therefore compared phenotypical and functional characteristics of corresponding neonatal and adult B cell subpopulations. No phenotypic differences could be identified with the exception of higher IgM expression in neonatal B cells. Functional analysis revealed differences in proliferation, survival, and B cell receptor signaling. Most importantly, neonatal B cells showed severely impaired class-switch recombination (CSR) to IgG and IgA. This was associated with increased expression of miR-181b in neonatal B cells. Deficiency of miR-181b resulted in increased CSR. With this, our results highlight intrinsic differences that contribute to weaker B cell antibody responses in newborns.

Transverse Myelitis und Retrobulbarneuritis bei einer jugendlichen Patientin mit systemischem Lupus erythematodes

Introduction Primary immunodeficiency disorders (PIDs) are a heterogeneous group of more than 200 rare diseases. Timely diagnosis is of uttermost importance. Therefore, we aimed to develop a diagnostic questionnaire with computerized pattern-recognition in order to support physicians to identify suspicious patient histories. Materials and methods Standardized interviews were conducted with guardians of children with PID. The questionnaire based on parental observations was developed using Colaizzis’ framework for content analysis. Answers from 64 PID patients and 62 controls were analyzed by data mining methods in order to make a diagnostic prediction. Performance was evaluated by k-fold stratified cross-validation. Results The diagnostic support tool achieved a diagnostic sensitivity of up to 98%. The analysis of 12 interviews revealed 26 main phenomena observed by parents in the pre-diagnostic period. The questions were systematically phrased and selected resulting in a 36-item questionnaire. This was answered by 126 patients with or without PID to evaluate prediction. Item analysis revealed significant questions. Discussion Our approach proved suitable for recognizing patterns and thus differentiates between observations of PID patients and control groups. These findings provide the basis for developing a tool supporting physicians to consider a PID with a questionnaire. These data support the notion that patient’s experience is a cornerstone in the diagnostic process.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children younger than 16 years of age, and is characterized by joint inflammation of longer than 6 weeks' duration that cannot be explained by other causes, most importantly, systemic autoimmunity, infection, or trauma. Several factors are thought to contribute to the pathogenesis of JIA, including genetic, environmental, and immunologic factors. With respect to the immune system, different cell types of the innate and adaptive immune system, as well as various chemokines and inflammatory cytokines, are involved in the pathogenesis of JIA (1–6). The frequent detection of autoantibodies, most importantly antinuclear antibodies (ANAs) in JIA and anti–cyclic citrullinated peptide antibodies in rheumatoid arthritis (RA), indicates that a disturbed B cell tolerance contributes to the pathogenesis of these diseases. This view is further supported by the effectiveness of therapeutic B cell depletion in several autoimmune disorders (7–9). Previously, it has been shown that defects in both central and peripheral B cell tolerance can result in increased numbers of autoreactive B cells in RA patients, thus promoting the development of the disease (10). Depending on the severity of the disease, treatment of JIA comprises the administration of nonsteroidal antiinflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs, most importantly methotrexate (MTX) and biologic agents, including tumor necrosis factor α (TNFα) inhibition using etanercept (11). MTX has long been used as a cytostatic drug to treat malignancies. More recently, although its mechanism of action is mostly unknown, low-dose MTX has been shown to be an effective antiinflammatory drug in managing the progression of autoimmune diseases such as RA and JIA (12). Etanercept is a soluble TNFα inhibitor and is efficiently used for the treatment of polyarticular RA and JIA (13,14). TNFα is a pleiotropic proinflammatory cytokine secreted by different cell types and has effects on both innate and adaptive immune cells (15). It has been found to play an important role in the development and progression of several autoimmune diseases (16–18). Because both B cells and TNFα are important in the pathogenesis of RA and JIA, we aimed to determine how current treatment strategies influence B cells. In the present study, we therefore investigated the effect of MTX and etanercept on the B cell compartment in patients with JIA.

Background Allergic asthma is a chronic lung disease resulting from inappropriate immune responses to environmental antigens. Early tolerance induction is an attractive approach for primary prevention of asthma. Objective We analyzed the mechanisms of perinatal tolerance induction to allergens, with particular focus on the role of B cells in preconception and early intrauterine immune priming. Methods Wild-type (WT) and B cell–deficient mice received ovalbumin (OVA) intranasally before mating. Their offspring were analyzed in a murine model of allergic airway inflammation. Results Although antigen application before conception protected WT progeny from allergy, it aggravated allergic airway inflammation in B cell–deficient offspring. B-cell transfer restored protection, demonstrating the crucial role of B cells in perinatal tolerance induction. Effective diaplacentar allergen transfer was detectable in pregnant WT mice but not in pregnant B-cell knockout dams, and antigen concentrations in WT amniotic fluid (AF) were higher than in IgG-free AF of B cell–deficient dams. Application of OVA/IgG immune complexes during pregnancy boosted OVA uptake by fetal dendritic cells (DCs). Fetal DCs in human subjects and mice expressed strikingly higher levels of Fcγ receptors compared with DCs from adults and were highly efficient in taking up OVA/IgG immune complexes. Moreover, murine fetal DCs effectively primed antigen-specific forkhead box P3 + regulatory T cells after in vitro coincubation with OVA/IgG-containing AF. Conclusion Our data support a decisive role for B cells and immunoglobulins during in utero tolerance priming. These findings improve the understanding of perinatal immunity and might support the development of effective primary prevention strategies for allergy and asthma in the future.

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Summary The co-stimulatory molecule CD137 (4-1BB) plays a crucial role in the development and persistence of asthma, characterized by eosinophilic airway inflammation, mucus hypersecretion, airway hyperreactivity, increased T helper type 2 (Th2) cytokine production and serum immunoglobulin (Ig)E levels. We have shown previously that application of an agonistic CD137 monoclonal antibody (mAb) prevented and even reversed an already established asthma phenotype. In the current study we investigated whether deficiency of the CD137/CD137L pathway affects the development of allergic airway inflammation or the opposite immune reaction of respiratory tolerance. CD137−/− and wild-type (WT) mice were sensitized and challenged with the model allergen ovalbumin (OVA) and analysed for the presence of allergic disease parameters (allergy protocol). Some animals were tolerized by mucosal application of OVA prior to transferring the animals to the allergy protocol to analyse the effect of CD137 loss on tolerance induction (tolerance protocol). Eosinophilic airway inflammation, mucus hypersecretion, Th2 cytokine production and elevated allergen-specific serum IgE levels were increased equally in CD137−/− and WT mice. Induction of tolerance resulted in comparable protection from the development of an allergic phenotype in both mouse strains. In addition, no significant differences could be identified in CD4+, CD8+ and forkhead box protein 3 (FoxP3+) regulatory T cells, supporting the conclusion that CD137−/− mice show equal Th2-mediated immune responses compared to WT mice. Taken together, CD137−/− mice and WT mice develop the same phenotype in a murine model of Th2-mediated allergic airway inflammation and respiratory tolerance.

The splenic B cell compartment is comprised of two major, functionally distinct, mature B cell subsets, i.e., follicular mature (FM) and marginal zone (MZ) B cells. Whereas MZ B cells exhibit a robust proliferative response following stimulation with the TLR4 ligand LPS, FM B cells display markedly delayed and reduced levels of proliferation to the identical stimulus. The current study was designed to identify a potential mechanism(s) accounting for this differential responsiveness. In contrast to the delay in cell cycle entry, FM and MZ B cells exhibited nearly identical LPS-driven alterations in the expression level of cell surface activation markers. Furthermore, both the NF-κB and mTOR signaling cascades were similarly activated by LPS stimulation in FM vs MZ B cells, while inducible activation of ERK and AKT were nearly absent in both subsets. MZ B cells, however, exhibited higher basal levels of phospho-AKT and pS6, consistent with a preactivated status. Importantly, both basal and LPS activation-induced c-myc expression was markedly reduced in FM vs MZ B cells and enforced c-myc expression fully restored the defective proliferative response in FM B cells. These data support a model wherein TLR responses in FM B cells are tightly regulated by limiting c-myc levels, thereby providing an important checkpoint to control nonspecific FM B cell activation in the absence of cognate Ag.

Imatinib is a receptor tyrosine kinase inhibitor that blocks the activity of c-Abl, c-Kit, and PDGF receptors. We tested the protective effects of imatinib in thymic stromal lymphopoietin transgenic mice, a model of cryoglobulinemia and associated membranoproliferative glomerulonephritis (MPGN), in which some glomerular manifestations likely result from PDGF receptor activation. Surprising, administration of imatinib beginning at weaning suppressed production of cryoglobulin, attenuating both the renal injury and systemic features of cryoglobulinemia. Flow cytometry suggested that inhibition of B cell development in the bone marrow likely caused the reduction in cryoglobulin production. In addition, administration of imatinib to thymic stromal lymphopoietin transgenic mice with established MPGN also diminished cryoglobulin production and reversed the renal and systemic lesions. These data suggest that treatment with imatinib may be a novel therapeutic approach for cryoglobulinemia and MPGN in humans.

To more precisely identify the B-cell phenotype in Wiskott-Aldrich syndrome (WAS), we used 3 distinct murine in vivo models to define the cell intrinsic requirements for WAS protein (WASp) in central versus peripheral B-cell development. Whereas WASp is dispensable for early bone marrow B-cell development, WASp deficiency results in a marked reduction in each of the major mature peripheral B-cell subsets, exerting the greatest impact on marginal zone and B1a B cells. Using in vivo bromodeoxyuridine labeling and in vitro functional assays, we show that these deficits reflect altered peripheral homeostasis, partially resulting from an impairment in integrin function, rather than a developmental defect. Consistent with these observations, we also show that: (1) WASp expression levels increase with cell maturity, peaking in those subsets exhibiting the greatest sensitivity to WASp deficiency; (2) WASp+ murine B cells exhibit a marked selective advantage beginning at the late transitional B-cell stage; and (3) a similar in vivo selective advantage is manifest by mature WASp+ human B cells. Together, our data provide a better understanding of the clinical phenotype of WAS and suggest that gene therapy might be a useful approach to rescue altered B-cell homeostasis in this disease.

B cells play a central role in the pathogenesis of multiple autoimmune diseases and the recognition of the importance of B cells in these disorders has grown dramatically in association with the remarkable success of B cell depletion as a treatment for autoimmunity. The precise mechanisms that promote alterations in B cell tolerance remain incompletely defined. There is increasing evidence, however, that TLRs play a major role in these events. Stimulation of B cells via the TLR pathway not only leads to an increase in antibody production but also promotes additional changes including cytokine production and up-regulation of activation markers increasing the effectiveness of B cells as APCs. Understanding the role of TLRs in systemic autoimmunity will not only provide insight into the disease pathogenesis but may also lead to the development of novel therapies. This article gives an overview of TLR signaling in B cells and the possible involvement of such signals in autoimmune diseases.

We have characterized a distinct, late transitional B cell subset, CD21int transitional 2 (T2) B cells. In contrast to early transitional B cells, CD21int T2 B cells exhibit augmented responses to a range of potential microenvironmental stimuli. Adoptive transfer studies demonstrate that this subset is an immediate precursor of both follicular mature and marginal zone (MZ) B cells. In vivo, a large percentage of CD21int T2 B cells has entered the cell cycle, and the cycling subpopulation exhibits further augmentation in mitogenic responses and B cell-activating factor of the TNF family (BAFF) receptor expression. Consistent with these features, CD21int T2 cells exhibit preferential responses to BAFF-facilitated homeostatic signals in vivo. In addition, we demonstrate that M167 B cell receptor (BCR) idiotypic-specific B cells are first selected within the cycling CD21int T2 population, ultimately leading to preferential enrichment of these cells within the MZ B cell compartment. These data, in association with the coordinate role for BAFF and microenvironmental cues in determining the mature BCR repertoire, imply that this subset functions as a unique selection point in peripheral B cell development.

Protective immunity against T cell independent (TI) antigens such as Streptococcus pneumoniae is characterized by antibody production of B cells induced by the combined activation of T cell independent type 1 and type 2 antigens in the absence of direct T cell help. In mice, the main players in TI immune responses have been well defined as marginal zone (MZ) B cells and B-1 cells. However, the existence of human equivalents to these B cell subsets and the nature of the human B cell compartment involved in the immune reaction remain elusive. We therefore analyzed the effect of a TI antigen on the B cell compartment through immunization of healthy individuals with the pneumococcal polysaccharide (PnPS)-based vaccine Pneumovax®23, and subsequent characterization of B cell subpopulations. Our data demonstrates a transient decrease of transitional and naive B cells, with a concomitant increase of IgA+ but not IgM+ or IgG+ memory B cells and a predominant generation of PnPS-specific IgA+ producing plasma cells. No alterations could be detected in T cells, or proposed human B-1 and MZ B cell equivalents. Consistent with the idea of a TI immune response, antigen-specific memory responses could not be observed. Finally, BAFF, which is supposed to drive class switching to IgA, was unexpectedly found to be decreased in serum in response to Pneumovax®23. Our results demonstrate that a characteristic TI response induced by Pneumovax®23 is associated with distinct phenotypical and functional changes within the B cell compartment. Those modulations occur in the absence of any modulations of T cells and without the development of a specific memory response.

Allergic asthma is a widespread chronic inflammatory disease of the airways. Research has mainly focused on T cells, while the role of B cells in this disease is largely unknown. B cells produce immunoglobulins, cytokines and act as antigen presenting cells. Regulatory B cells are proposed to be be crucial in the regulation of asthma pathogenesis. To better understand the role of B cells in asthma and respiratory tolerance, we analyzed the B cell compartment in wildtype (WT) and B cell deficient (µMT) mice in a model of ovalbumin (OVA)-induced asthma and respiratory tolerance. Allergic WT mice showed increased AHR, lung eosinophilia, pulmonary inflammation, mucus hyperproduction and secretion of Th2 cytokines analyzed by invasive lung function, bronchoalveolar lavage fluid cell differentials, histochemistry and ELISA, respectively. As compared to control group, asthmatic mice displayed elevated numbers of regulatory marginal zone precursor B cells in the spleen, which were determined by flow cytometry. Moreover, we found significant higher numbers of germinal center B cells in spleen and bronchial lymph nodes (bLN) and OVA-specific antibody secreting cells especially in local niches, which were detected by ELISPOT. In addition, OVA-treated mice exhibited increased expression of MHCII and the low affinity IgE receptor CD23 on follicular mature B cells in lung, bLN and spleen. Induction of respiratory tolerance prevented all of these alterations on the B compartment. Nevertheless, µMT mice also developed allergic responses and respiratory tolerance in an extent similar to WT mice. Our data indicate that B cell subsets are affected but not essential in development of allergic asthma and respiratory tolerance.

Immunoglobulin A (IgA) is the most abundantly produced immunoglobulin found primarily on mucosal surfaces. The generation of IgA and its involvement in mucosal immune responses have been intensely studied over the past years. IgA can be generated in T cell-dependent and T cell-independent pathways, and it has an important impact on maintaining homeostasis within the mucosal immune system. There is good evidence that B-1 cells contribute substantially to the production of mucosal IgA and thus play an important role in regulating commensal microbiota. However, whether B-1 cells produce antigen-specific or only nonspecific IgA remains to be determined. This review will discuss what is currently known about IgA production by B-1 cells and the functional relevance of B-1 cell-derived IgA both in vitro and in vivo.

Synovial fibroblasts were infected with Yersinia enterocolitica or Salmonella enterica serovar Enteritidis and analyzed by electron microscopy and fluorescence in situ hybridization. Intracellular bacterial replication was followed by degradation leading to “ghosts” possessing lipopolysaccharides but not DNA. However, single bacteria survived for more than 2 weeks. Therefore, transient intra-articular infection might be the missing link between initial intestinal infection and late synovial inflammation in the pathogenesis of reactive arthritis.

BACKGROUND Intestinal and diffuse adenocarcinomas of the stomach differ in phenotypic properties, morphology, and growth behavior. Apoptosis (programmed cell death) is induced via specific cell-surface receptors (SC-1, Fas/APO-1/CD95) and coregulated by intracellular molecules (bcl-2, p53, etc.); the success of apoptotic processes is dependent on the expression of these signals. Differences in the expression of specific apoptosis receptors and intracellular-related signals might help to explain the molecular pathogenesis of these two types of stomach adenocarcinoma. METHODS Immunohistochemical studies were performed on frozen sections of tumor tissue using human monoclonal antibody SC-1 and murine monoclonal antibodies Fas and p53, followed by peroxidase-coupled second antibodies. To determine binding of SC-1 and Fas antibodies to stomach carcinoma cells on the molecular level, Western blot analysis was performed with cell extract preparations from stomach carcinoma cells. To investigate functional apoptotic activity, MTT assays were performed with SC-1 and Fas antibodies on stomach carcinoma cells. RESULTS On frozen sections intestinal type stomach carcinoma cells demonstrate little or no expression of SC-1 and Fas receptors (4 of 17 and 1 of 17, respectively). Diffuse type stomach carcinoma cells show just the opposite: greater than 50% express SC-1 and Fas at a high level (15 of 30 and 22 of 30, respectively). Normal stomach mucosa is negative with both antibodies. Expression of p53 is positively correlated with intestinal type carcinomas (11 of 17) but not with diffuse type (5 of 30). In functional studies (MTT assay) the SC-1 and Fas antibodies react with stomach carcinoma by inducing apoptosis and inhibiting growth. On Western blot analysis of extracts from stomach carcinoma cells, SC-1 detects a protein of 50 kilodalton (kD) and Fas proteins of approximately 30, 45, and 60 kD. CONCLUSIONS These data indicate that gastric carcinoma cells of the intestinal and diffuse type differ in their expression of the apoptotic receptors SC-1 and Fas and the tumor suppressor gene product p53. These new data on phenotypic differences support the hypothesis that these two types of stomach carcinoma do not only differ in morphology, growth pattern, and risk factors but also in genetic pathways. Cancer 1997; 79:433-40. © 1997 American Cancer Society.

Summary In 2009, a federally funded clinical and research consortium (PID–NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies (PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency (CVID), the most prevalent PID.

Costimulatory molecules like ICOS are crucial in mediating T cell differentiation and function after allergen contact and thereby strongly affect the immunologic decision between tolerance or allergy development. In this study, we show in two independent approaches that interruption of the ICOS signaling pathway by application of a blocking anti-ICOSL mAb in wild-type (WT) mice and in ICOS−/− mice inhibited respiratory tolerance development leading to eosinophilic airway inflammation, mucus hypersecretion, and Th2 cytokine production in response to OVA sensitization. Respiratory Ag application almost doubled the number of CD4+Foxp3+ regulatory T cells (Tregs) in the lung of WT mice with 77% of lung-derived Tregs expressing ICOS. In contrast, in ICOS−/− mice the number of CD4+CD25+Foxp3+ Tregs did not increase after respiratory Ag application, and ICOS−/− Tregs produced significantly lower amounts of IL-10 than those of WT Tregs. Most importantly, in contrast to WT Tregs, ICOS−/− Tregs did not convey protection when transferred to “asthmatic” recipients demonstrating a strongly impaired Treg function in the absence of ICOS signaling. Our findings demonstrate a crucial role of ICOS for the generation and suppressive function of Tregs conveying respiratory tolerance and support the importance of ICOS as a target for primary prevention strategies.

Unlike other immune cells, B cells express both an antigen-specific B cell receptor (BCR) and Toll-like receptors (TLRs). Dual BCR and TLR engagement can fine-tune functional B cell responses, directly linking cell-intrinsic innate and adaptive immune programmes. Although most data regarding B cell-specific functions of the TLR signalling pathway have been obtained in mice, the discovery of patients with a deficiency in this pathway has recently provided an insight into human B cell responses. Here, we highlight the importance of the integration of signalling pathways downstream of BCRs and TLRs in modulating B cell function, focusing when possible on B cell-intrinsic roles.

The PTPN22 genetic variant 1858T, encoding Lyp620W, is associated with multiple autoimmune disorders for which the production of autoantibodies is a common feature, suggesting a loss of B cell tolerance. Lyp620W results in blunted BCR signaling in memory B cells. Because BCR signal strength is tightly coupled to central and peripheral tolerance, we examined whether Lyp620W impacts peripheral B cell homeostasis in healthy individuals heterozygous for the PTPN221858T variant. We found that these subjects display alterations in the composition of the B cell pool that include specific expansion of the transitional and anergic IgD+IgM−CD27− B cell subsets. The PTPN22 1858T variant was further associated with significantly diminished BCR signaling and a resistance to apoptosis in both transitional and naive B cells. Strikingly, parallel changes in both BCR signaling and composition of B cell compartment were observed in type 1 diabetic subjects, irrespective of PTPN22 genotype, revealing a novel immune phenotype and likely shared mechanisms leading to a loss of B cell tolerance. Our combined findings suggest that Lyp620W-mediated effects, due in part to the altered BCR signaling threshold, contribute to breakdown of peripheral tolerance and the entry of autoreactive B cells into the naive B cell compartment.

In a manner dependent on CD4 T cell help and Toll-like receptor signals, B cells lacking WASp induce autoantibody production and autoimmune disease in mice., Patients with the immunodeficiency Wiskott-Aldrich syndrome (WAS) frequently develop systemic autoimmunity. Here, we demonstrate that mutation of the WAS gene results in B cells that are hyperresponsive to B cell receptor and Toll-like receptor (TLR) signals in vitro, thereby promoting a B cell–intrinsic break in tolerance. Whereas this defect leads to autoantibody production in WAS protein–deficient (WASp−/−) mice without overt disease, chimeric mice in which only the B cell lineage lacks WASp exhibit severe autoimmunity characterized by spontaneous germinal center formation, class-switched autoantibodies, renal histopathology, and early mortality. Both T cell help and B cell–intrinsic TLR engagement play important roles in promoting disease in this model, as depletion with anti-CD4 antibodies or generation of chimeric mice with B cells deficient in both WASp and MyD88 prevented development of autoimmune disease. These data highlight the potentially harmful role for cell-intrinsic loss of B cell tolerance in the setting of normal T cell function, and may explain why WAS patients with mixed chimerism after stem cell transplantation often develop severe humoral autoimmunity.