The Complete Genome of a Novel Typical Species Thiocapsa bogorovii and Analysis of Its Central Metabolic Pathways.

The purple sulfur bacterium Thiocapsa roseopersicina BBS is interesting from both fundamental and practical points of view. It possesses a thermostable HydSL hydrogenase, which is involved in the reaction of reversible hydrogen activation and a unique reaction of sulfur reduction to hydrogen sulfide. It is a very promising enzyme for enzymatic hydrogenase electrodes. There are speculations that HydSL hydrogenase of purple bacteria is closely related to sulfur metabolism, but confirmation is required. For that, the full genome sequence is necessary. Here, we sequenced and assembled the complete genome of this bacterium. The analysis of the obtained whole genome, through an integrative approach that comprised estimating the Average Nucleotide Identity (ANI) and digital DNA-DNA hybridization (DDH) parameters, allowed for validation of the systematic position of T. roseopersicina as T. bogorovii BBS. For the first time, we have assembled the whole genome of this typical strain of a new bacterial species and carried out its functional description against another purple sulfur bacterium: Allochromatium vinosum DSM 180T. We refined the automatic annotation of the whole genome of the bacteria T. bogorovii BBS and localized the genomic positions of several studied genes, including those involved in sulfur metabolism and genes encoding the enzymes required for the TCA and glyoxylate cycles and other central metabolic pathways. Eleven additional genes coding proteins involved in pigment biosynthesis was found.

Myeloid cell deficiency of the inflammatory transcription factor Stat4 protects long-term synaptic plasticity from the effects of a high-fat, high-cholesterol diet.

Neuroinflammation is associated with neurodegenerative diseases, including Alzheimer's and Parkinson's. The cytokine interleukin-12 activates signal transducer and activator of transcription 4 (Stat4), and consumption of a high-fat, high-cholesterol diet (HFD-C) and Stat4 activity are associated with inflammation, atherosclerosis, and a diabetic metabolic phenotype. In studies of in vitro hippocampal slices from control Stat4fl/flLdlr-/- mice fed a HFD-C diabetogenic diet, we show that Schaffer collateral-CA1 synapses exhibited larger reductions in activity-dependent, long-term potentiation (LTP) of synaptic transmission, compared to mice fed a standard diet. Glucose tolerance and insulin sensitivity shifts produced by HFD-C diet were reduced in Stat4ΔLysMLdlr-/- mice compared to Stat4fl/flLdlr-/- controls. Stat4ΔLysMLdlr-/- mice, which lack Stat4 under control of the LysMCre promoter, were resistant to HFD-C induced impairments in LTP. In contrast, Schaffer collateral-CA1 synapses in Stat4ΔLysMLdlr-/- mice fed the HFD-C diet showed larger LTP than control Stat4fl/flLdlr-/- mice. Expression of a number of neuroinflammatory and synaptic plasticity genes was reduced by HFD-C diet in control mice, and less affected by HFD-C diet in Stat4ΔLysMLdlr-/- mice. These data suggest that suppression of Stat4 activation may protect against effects of Western diet on cognition, type 2 diabetes, and reduce risk of Alzheimer's disease and other neurodegenerative disorders associated with neuroinflammation.

Neutrophil-specific STAT4 deficiency attenuates atherosclerotic burden and improves plaque stability via reduction in neutrophil activation and recruitment into aortas of Ldlr-/- mice.

Background and aims: Neutrophils drive atheroprogression and directly contribute to plaque instability. We recently identified signal transducer and activator of transcription 4 (STAT4) as a critical component for bacterial host defense in neutrophils. The STAT4-dependent functions of neutrophils in atherogenesis are unknown. Therefore, we investigated a contributory role of STAT4 in neutrophils during advanced atherosclerosis. Methods: We generated myeloid-specific Stat4ΔLysMLdlr-/-, neutrophil-specific Stat4ΔS100A8Ldlr-/-, and control Stat4fl/flLdlr-/- mice. All groups were fed a high-fat/cholesterol diet (HFD-C) for 28 weeks to establish advanced atherosclerosis. Aortic root plaque burden and stability were assessed histologically by Movat pentachrome staining. Nanostring gene expression analysis was performed on isolated blood neutrophils. Flow cytometry was utilized to analyze hematopoiesis and blood neutrophil activation. In vivo homing of neutrophils to atherosclerotic plaques was performed by adoptively transferring prelabeled Stat4ΔLysMLdlr-/- and Stat4fl/flLdlr-/- bone marrow cells into aged atherosclerotic Apoe-/- mice and detected by flow cytometry. Results: STAT4 deficiency in both myeloid-specific and neutrophil-specific mice provided similar reductions in aortic root plaque burden and improvements in plaque stability via reduction in necrotic core size, improved fibrous cap area, and increased vascular smooth muscle cell content within the fibrous cap. Myeloid-specific STAT4 deficiency resulted in decreased circulating neutrophils via reduced production of granulocyte-monocyte progenitors in the bone marrow. Neutrophil activation was dampened in HFD-C fed Stat4ΔLysMLdlr-/- mice via reduced mitochondrial superoxide production, attenuated surface expression of degranulation marker CD63, and reduced frequency of neutrophil-platelet aggregates. Myeloid-specific STAT4 deficiency diminished expression of chemokine receptors CCR1 and CCR2 and impaired in vivo neutrophil trafficking to atherosclerotic aorta. Conclusions: Our work indicates a pro-atherogenic role for STAT4-dependent neutrophil activation and how it contributes to multiple factors of plaque instability during advanced atherosclerosis in mice.

Neutrophil-specific STAT4 deficiency attenuates atherosclerotic burden and improves plaque stability via reduction in neutrophil activation and recruitment into aortas of Ldlr -/- mice.

Background and Aims: Neutrophils drive atheroprogression and directly contribute to plaque instability. We recently identified signal transducer and activator of transcription 4 (STAT4) as a critical component for bacterial host defense in neutrophils. The STAT4-dependent functions of neutrophils in atherogenesis are unknown. Therefore, we investigated a contributory role of STAT4 in neutrophils during advanced atherosclerosis. Methods: We generated myeloid-specific Stat4 ΔLysM Ldlr -/- , neutrophil-specific Stat4 ΔS100A8 Ldlr -/- , and control Stat4 fl/fl Ldlr -/- mice. All groups were fed a high-fat/cholesterol diet (HFD-C) for 28 weeks to establish advanced atherosclerosis. Aortic root plaque burden and stability were assessed histologically by Movat Pentachrome staining. Nanostring gene expression analysis was performed on isolated blood neutrophils. Flow cytometry was utilized to analyze hematopoiesis and blood neutrophil activation. In vivo homing of neutrophils to atherosclerotic plaques was performed by adoptively transferring prelabeled Stat4 ΔLysM Ldlr -/- and Stat4 fl/fl Ldlr -/- bone marrow cells into aged atherosclerotic Apoe -/- mice and detected by flow cytometry. Results: STAT4 deficiency in both myeloid-specific and neutrophil-specific mice provided similar reductions in aortic root plaque burden and improvements in plaque stability via reduction in necrotic core size, improved fibrous cap area, and increased vascular smooth muscle cell content within the fibrous cap. Myeloid-specific STAT4 deficiency resulted in decreased circulating neutrophils via reduced production of granulocyte-monocyte progenitors in the bone marrow. Neutrophil activation was dampened in Stat4 ΔLysM Ldlr -/- mice via reduced mitochondrial superoxide production, attenuated surface expression of degranulation marker CD63, and reduced frequency of neutrophil-platelet aggregates. Myeloid-specific STAT4 deficiency diminished expression of chemokine receptors CCR1 and CCR2 and impaired in vivo neutrophil trafficking to atherosclerotic aorta. Conclusions: Our work indicates a pro-atherogenic role for STAT4-dependent neutrophil activation and how it contributes to multiple factors of plaque instability during advanced atherosclerosis in mice.

The AAV-PCSK9 murine model of atherosclerosis and metabolic dysfunction.

Aims: Mouse models with genetic modifications are required to investigate atherogenesis and associated metabolic syndrome. Adeno-associated virus-8 (AAV8)-mediated overexpression of PCSK9 (AAV8-PCSK9) induces hyperlipidaemia and promotes atherosclerosis in C57BL/6 mice. We aimed to assess whether AAV8-PCSK9-injected C57BL/6 mice fed high-fat diet with added cholesterol (HFD-C) would serve as a model of combined metabolic syndrome and atherosclerosis. Methods and results: C57BL/6 mice received i.v. injection of AAV-PCSK9 and sex- and age-matched Ldlr-/- and C57BL/6 control mice were placed on HFD-C or chow diet for 20 weeks (B6-PCSK9-HFD-C, Ldlr-/- HFD-C, B6-HFD-C, and B6-Chow, respectively). High-fat diet with added cholesterol feeding led to insulin resistance and impaired glucose clearance in B6-PCSK9-HFD-C mice compared with B6-Chow controls. This decrease in metabolic health in B6-PCSK9-HFD-C mice as well as the development of atherosclerosis was similar to Ldlr-/- HFD-C mice. Importantly, HFD-C feeding induced pancreatic islet hyperplasia in B6-PCSK9-HFD-C and B6-HFD-C compared with B6-Chow controls. In line with alterations in the metabolic phenotype, there was an increase in the number of pro-inflammatory Ly6Chigh/med monocytes within the adipose tissues of B6-PCSK9-HFD-C and B6-HFD-C compared with B6-Chow controls. Conclusion: High-fat diet with added cholesterol-fed AAV-PCSK9-injected C57BL/6 mice can serve as a useful model of integrated metabolic syndrome and atherosclerosis that does not require genetic manipulations.

Immune Response at the Crossroads of Atherosclerosis and Alzheimer's Disease.

Alzheimer's disease (AD) and cardiovascular disease (CVD) are pathologies that are characterized by common signatures of vascular dysfunction and chronic inflammation that are accelerated with aging. Importantly, epidemiological studies report an independent interaction between AD and CVD and data suggest that chronic inflammation in CVD may accelerate AD development. Atherosclerosis affects most large to medium sized arteries including those supplying the cerebral circulation. Vascular dysfunction caused by atherosclerosis results in blood brain barrier breakdown, inflammation, an impaired clearance of amyloid-beta (Aß), and finally ends with neurovascular dysfunction. Numerous data indicate that innate and adaptive immune responses shape atherogenesis and increasing evidence suggests an implication of the immune response in AD progression. Currently, mechanisms by which these two diseases are interconnected with each other are not well-defined. In this review, we discuss the recent advances in our understanding of the intertwined role of the immune response in atherosclerosis and AD and the implications of these findings for human health.

Atherosclerosis and multi-organ-associated pathologies.

Atherosclerosis is a chronic inflammatory disease of the vascular system that is characterized by the deposition of modified lipoproteins, accumulation of immune cells, and formation of fibrous tissue within the vessel wall. The disease occurs in vessels throughout the body and affects the functions of almost all organs including the lymphoid system, bone marrow, heart, brain, pancreas, adipose tissue, liver, kidneys, and gastrointestinal tract. Atherosclerosis and associated factors influence these tissues via the modulation of local vascular functions, induction of cholesterol-associated pathologies, and regulation of local immune responses. In this review, we discuss how atherosclerosis interferers with functions of different organs via several common pathways and how the disturbance of immunity in atherosclerosis can result in disease-provoking dysfunctions in multiple tissues. Our growing appreciation of the implication of atherosclerosis and associated microenvironmental conditions in the multi-organ pathology promises to influence our understanding of CVD-associated disease pathologies and to provide new therapeutic opportunities.

A Factor H-Fc fusion protein increases complement-mediated opsonophagocytosis and killing of community associated methicillin-resistant Staphylococcus aureus.

Staphylococcus aureus employs a multitude of immune-evasive tactics to circumvent host defenses including the complement system, a component of innate immunity central to controlling bacterial infections. With antibiotic resistance becoming increasingly common, there is a dire need for novel therapies. Previously, we have shown that S. aureus binds the complement regulator factor H (FH) via surface protein SdrE to inhibit complement. To address the need for novel therapeutics and take advantage of the FH:SdrE interaction, we examined the effect of a fusion protein comprised of the SdrE-interacting domain of FH coupled with IgG Fc on complement-mediated opsonophagocytosis and bacterial killing of community associated methicillin-resistant S. aureus. S. aureus bound significantly more FH-Fc compared to Fc-control proteins and FH-Fc competed with serum FH for S. aureus binding. FH-Fc treatment increased C3-fragment opsonization of S. aureus for both C3b and iC3b, and boosted generation of the anaphylatoxin C5a. In 5 and 10% serum, FH-Fc treatment significantly increased S. aureus killing by polymorphonuclear cells. This anti-staphylococcal effect was evident in 75% (3/4) of clinical isolates tested. This study demonstrates that FH-Fc fusion proteins have the potential to mitigate the protective effects of bound serum FH rendering S. aureus more vulnerable to the host immune system. Thus, we report the promise of virulence-factor-targeted fusion-proteins as an avenue for prospective anti-staphylococcal therapeutic development.

Complete Genome Assembly of Yersinia pestis subsp. pestis bv. Medievalis SCPM-O-B-6530, a Proline-Dependent Strain Isolated from the Central-Caucasian High-Mountain Plague Focus in Kabardino-Balkar Republic (Russia).

We report the complete genome assembly of Yersinia pestis subsp. pestis bv. Medievalis SCPM-O-B-6530, a strain belonging to the most ancient phylogenetic group (group 2.MED0) of Y. pestis subsp. pestis bv. Medievalis. This proline-dependent strain, carrying an additional plasmid (pCKF), was isolated from the Central-Caucasian high-mountain plague focus in Kabardino-Balkar Republic, Russia.

Draft Genome Sequences of Six Yersinia kristensenii Strains.

Yersinia kristensenii is one of the Yersinia enterocolitica-like bacterial species, which are considered nonpathogenic to humans. In this work, we reported the draft genome sequences of six Yersinia kristensenii strains. These draft genomes will help to better characterize Yersinia kristensenii at the genomic level.

Role of neutrophils in type 2 diabetes and associated atherosclerosis.

The development of cardiovascular diseases associated with Type-2 diabetes remains one of the most challenging public health burdens in the developed world. Early onset of metabolic deficiencies, namely dysregulated glucose homeostasis, peripheral insulin resistance, and impaired insulin production are accompanied by both innate and adaptive immune responses that culminate in a state of chronic, low-grade inflammation. Neutrophils are a critical component of the innate immune system which offer frontline defense against pathogens through a variety of potent effector functions. Recent data indicate an essential role of neutrophils in various disease processes that contribute to the development of Type-2 diabetes and atherosclerosis. In this brief review, we aim to distill the most relevant clinical and pre-clinical literature that investigates the role of neutrophils as an important mediator for the Type-2 diabetes/atherosclerosis connection.

Estimation of the probability of daily fluctuations of incidence of COVID-19 according to official data.

When studying the dynamics of morbidity and mortality, one should not limit ourselves to analyzing general trends. Interesting information can be obtained from the analysis of deviations in morbidity and mortality from the general dynamics. Comparison of the cases of morbidity or death for adjacent time intervals allows us to find out whether the changes in conditions were for short periods of time and whether the cases of morbidity or death were independent. The article consists of two parts: Study of the probability distribution (CDF) of the difference between two independent observations of the Poisson distribution; Application of the results to analyze the morbidity and mortality trends by day for the new coronavirus infection. For the distribution function of the module of difference between two independent observations of the Poisson distribution, an analytical expression has been obtained that allows to get an exact solution. A program has been created, whose software can be downloaded at http://1mgmu.com/nau/DeltaPoisson/DeltaPoisson.zip. An approximate solution that does not require complex calculations has also been obtained, which can be used for an average of more than 20. If real difference is greater than expected, it may be in the following cases: morbidity or mortality varies considerably during the day. That could happen, for example, if the registered number of morbidity on Saturday and Sunday is less than on weekdays due to the management model of the health system, or if the cases are not independent; for example, due to the active identification of infected people among those who have come into contact with the patient. If the difference is less than expected, it may be due to external limiting factors, such as a shortage of test systems for making a diagnosis, a limited number of pathologists to determine the cause of death, and so on. In the analysis of the actual data for COVID-19 it was found that for Poland and Russia, excluding Moscow, the difference in the number of cases and deaths is greater than expected, while for Moscow-less than expected. This may be due to the information policy-the effort to somehow reassure Moscow's population, which in the spring of 2020 had a high incidence rate of the new coronavirus infection.

STAT4 is expressed in neutrophils and promotes antimicrobial immunity.

Signal transducer and activator of transcription 4 (STAT4) is expressed in hematopoietic cells and plays a key role in the differentiation of T helper 1 cells. Although STAT4 is required for immunity to intracellular pathogens, the T cell-independent protective mechanisms of STAT4 are not clearly defined. In this report, we demonstrate that STAT4-deficient mice were acutely sensitive to methicillin-resistant Staphylococcus aureus (MRSA) infection. We show that STAT4 was expressed in neutrophils and activated by IL-12 via a JAK2-dependent pathway. We demonstrate that STAT4 was required for multiple neutrophil functions, including IL-12-induced ROS production, chemotaxis, and production of the neutrophil extracellular traps. Importantly, myeloid-specific and neutrophil-specific deletion of STAT4 resulted in enhanced susceptibility to MRSA, demonstrating the key role of STAT4 in the in vivo function of these cells. Thus, these studies identify STAT4 as an essential regulator of neutrophil functions and a component of innate immune responses in vivo.

Functional Role of B Cells in Atherosclerosis.

Atherosclerosis is a lipid-driven inflammatory disease of blood vessels, and both innate and adaptive immune responses are involved in its development. The impact of B cells on atherosclerosis has been demonstrated in numerous studies and B cells have been found in close proximity to atherosclerotic plaques in humans and mice. B cells exert both atheroprotective and pro-atherogenic functions, which have been associated with their B cell subset attribution. While B1 cells and marginal zone B cells are considered to protect against atherosclerosis, follicular B cells and innate response activator B cells have been shown to promote atherosclerosis. In this review, we shed light on the role of B cells from a different, functional perspective and focus on the three major B cell functions: antibody production, antigen presentation/T cell interaction, and the release of cytokines. All of these functions have the potential to affect atherosclerosis by multiple ways and are dependent on the cellular milieu and the activation status of the B cell. Moreover, we discuss B cell receptor signaling and the mechanism of B cell activation under atherosclerosis-prone conditions. By summarizing current knowledge of B cells in and beyond atherosclerosis, we are pointing out open questions and enabling new perspectives.

Meta-Analysis of Leukocyte Diversity in Atherosclerotic Mouse Aortas.

The diverse leukocyte infiltrate in atherosclerotic mouse aortas was recently analyzed in 9 single-cell RNA sequencing and 2 mass cytometry studies. In a comprehensive meta-analysis, we confirm 4 known macrophage subsets-resident, inflammatory, interferon-inducible cell, and Trem2 (triggering receptor expressed on myeloid cells-2) foamy macrophages-and identify a new macrophage subset resembling cavity macrophages. We also find that monocytes, neutrophils, dendritic cells, natural killer cells, innate lymphoid cells-2, and CD (cluster of differentiation)-8 T cells form prominent and separate immune cell populations in atherosclerotic aortas. Many CD4 T cells express IL (interleukin)-17 and the chemokine receptor CXCR (C-X-C chemokine receptor)-6. A small number of regulatory T cells and T helper 1 cells is also identified. Immature and naive T cells are present in both healthy and atherosclerotic aortas. Our meta-analysis overcomes limitations of individual studies that, because of their experimental approach, over- or underrepresent certain cell populations. Mass cytometry studies demonstrate that cell surface phenotype provides valuable information beyond the cell transcriptomes. The present analysis helps resolve some long-standing controversies in the field. First, Trem2+ foamy macrophages are not proinflammatory but interferon-inducible cell and inflammatory macrophages are. Second, about half of all foam cells are smooth muscle cell-derived, retaining smooth muscle cell transcripts rather than transdifferentiating to macrophages. Third, Pf4, which had been considered specific for platelets and megakaryocytes, is also prominently expressed in the main population of resident vascular macrophages. Fourth, a new type of resident macrophage shares transcripts with cavity macrophages. Finally, the discovery of a prominent innate lymphoid cell-2 cluster links the single-cell RNA sequencing work to recent flow cytometry data suggesting a strong atheroprotective role of innate lymphoid cells-2. This resolves apparent discrepancies regarding the role of T helper 2 cells in atherosclerosis based on studies that predated the discovery of innate lymphoid cells-2 cells.

Characterization of Islet Leukocyte Populations in Human and Murine Islets by Flow Cytometry.

An increasing body of evidence indicates that a local islet immune response is not only limited to type 1 diabetes, but also is associated with islet dysfunction in type 2 diabetes. Recently, the presence of pancreatic CD68+ macrophages within islet tissues was demonstrated by RT-PCR and immunohistochemical methods. However, the precise profile and activation status of intraislet leukocytes, which are present in both murine and human islets, are poorly defined. Here, we describe a detailed flow cytometry protocol designed to analyze both human and murine islets for intraislet leukocytes and leukocyte subsets. This approach permits the simultaneous identification of multiple intraislet leukocyte subsets, as well as their activation statuses. The use of flow cytometry-based approaches will advance the field of islet biology and help to identify unique changes in the immune cell composition that accompanies pathological islet inflammation and dysfunction in type 2 diabetes.

ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells.

L-selectin on T-cells is best known as an adhesion molecule that supports recruitment of blood-borne naïve and central memory cells into lymph nodes. Proteolytic shedding of the ectodomain is thought to redirect activated T-cells from lymph nodes to sites of infection. However, we have shown that activated T-cells re-express L-selectin before lymph node egress and use L-selectin to locate to virus-infected tissues. Therefore, we considered other roles for L-selectin proteolysis during T cell activation. In this study, we used T cells expressing cleavable or non-cleavable L-selectin and determined the impact of L-selectin proteolysis on T cell activation in virus-infected mice. We confirm an essential and non-redundant role for ADAM17 in TCR-induced proteolysis of L-selectin in mouse and human T cells and show that L-selectin cleavage does not regulate T cell activation measured by CD69 or TCR internalisation. Following virus infection of mice, L-selectin proteolysis promoted early clonal expansion of cytotoxic T cells resulting in an 8-fold increase over T cells unable to cleave L-selectin. T cells unable to cleave L-selectin showed delayed proliferation in vitro which correlated with lower CD25 expression. Based on these results, we propose that ADAM17-dependent proteolysis of L-selectin should be considered a regulator of T-cell activation at sites of immune activity.

Vowel Formant Dispersion Reflects Severity of Apraxia of Speech.

BACKGROUND: Apraxia of Speech (AOS) has been associated with deviations in consonantal voice-onset-time (VOT), but studies of vowel acoustics have yielded conflicting results. However, a speech motor planning disorder that is not bound by phonological categories is expected to affect vowel as well as consonant articulations. AIMS: We measured consonant VOTs and vowel formants produced by a large sample of stroke survivors, and assessed to what extent these variables and their dispersion are predictive of AOS presence and severity, based on a scale that uses clinical observations to rate gradient presence of AOS, aphasia, and dysarthria. METHODS & PROCEDURES: Picture-description samples were collected from 53 stroke survivors, including unimpaired speakers (12) and speakers with primarily aphasia (19), aphasia with AOS (12), primarily AOS (2), aphasia with dysarthria (2), and aphasia with AOS and dysarthria (6). The first three formants were extracted from vowel tokens bearing main stress in open-class words, as well as VOTs for voiced and voiceless stops. Vowel space was estimated as reflected in the formant centralization ratio. Stepwise Linear Discriminant Analyses were used to predict group membership, and ordinal regression to predict AOS severity, based on the absolute values of these variables, as well as the standard deviations of formants and VOTs within speakers. OUTCOMES AND RESULTS: Presence and severity of AOS were most consistently predicted by the dispersion of F1, F2, and voiced-stop VOT. These phonetic-acoustic measures do not correlate with aphasia severity. CONCLUSIONS: These results confirm that the AOS affects articulation across-the-board and does not selectively spare vowel production.

Insights Into the Molecular Mechanisms of T Follicular Helper-Mediated Immunity and Pathology.

T follicular helper (Tfh) cells play key role in providing help to B cells during germinal center (GC) reactions. Generation of protective antibodies against various infections is an important aspect of Tfh-mediated immune responses and the dysregulation of Tfh cell responses has been implicated in various autoimmune disorders, inflammation, and malignancy. Thus, their differentiation and maintenance must be closely regulated to ensure appropriate help to B cells. The generation and function of Tfh cells is regulated by multiple checkpoints including their early priming stage in T zones and throughout the effector stage of differentiation in GCs. Signaling pathways activated downstream of cytokine and costimulatory receptors as well as consequent activation of subset-specific transcriptional factors are essential steps for Tfh cell generation. Thus, understanding the mechanisms underlying Tfh cell-mediated immunity and pathology will bring into spotlight potential targets for novel therapies. In this review, we discuss the recent findings related to the molecular mechanisms of Tfh cell differentiation and their role in normal immune responses and antibody-mediated diseases.