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IgG4 subclass antibodies represent the rarest subclass of IgG antibodies, comprising only 3-5% of antibodies circulating in the bloodstream. These antibodies possess unique structural features, notably their ability to undergo a process known as fragment-antigen binding (Fab)-arm exchange, wherein they exchange half-molecules with other IgG4 antibodies. Functionally, IgG4 antibodies primarily block and exert immunomodulatory effects, particularly in the context of IgE isotype-mediated hypersensitivity reactions. In the context of disease, IgG4 antibodies are prominently observed in various autoimmune diseases combined under the term IgG4 autoimmune diseases (IgG4-AID). These diseases include myasthenia gravis (MG) with autoantibodies against muscle-specific tyrosine kinase (MuSK), nodo-paranodopathies with autoantibodies against paranodal and nodal proteins, pemphigus vulgaris and foliaceus with antibodies against desmoglein and encephalitis with antibodies against LGI1/CASPR2. Additionally, IgG4 antibodies are a prominent feature in the rare entity of IgG4 related disease (IgG4-RD). Intriguingly, both IgG4-AID and IgG4-RD demonstrate a remarkable responsiveness to anti-CD20-mediated B cell depletion therapy (BCDT), suggesting shared underlying immunopathologies. This review aims to provide a comprehensive exploration of B cells, antibody subclasses, and their general properties before examining the distinctive characteristics of IgG4 subclass antibodies in the context of health, IgG4-AID and IgG4-RD. Furthermore, we will examine potential therapeutic strategies for these conditions, with a special focus on leveraging insights gained from anti-CD20-mediated BCDT. Through this analysis, we aim to enhance our understanding of the pathogenesis of IgG4-mediated diseases and identify promising possibilities for targeted therapeutic intervention.

Stroke is a leading cause of death and long-term disability. Pigs have been considered an ideal large animal model in biomedicine; however, the complex vascular anatomy has posed challenges for stroke research. Nonetheless, we have previously overcome these limitations and demonstrated the feasibility of endovascularly inducing stroke in pigs. Here, we study to further mimic clinical situation by achieving recanalization, which has not been previously accomplished. A stroke was induced in eight juvenile male domestic pigs. In anaestethised animals catheter was placed in the ascending pharyngeal artery near the rete mirabile (RM) under X-ray guidance. The animals were then transferred to an MRI scanner. Gadolinium-based contrast agent (GBCA) was infused at various speeds until transcatheter cerebral perfusion was visible on MRI. Subsequently, a mixture of thrombin and GBCA was infused, and the retention of contrast on MRI scans proved successful induction of thrombosis. Subsequent DWI and PWI MR images confirmed the successful induction of stroke. Two hours after ischemia, we intra-arterially infused rtPA (20 mg) and confirmed recanalization of the thrombosed vessels using MRI. One month later the stroke was confirmed through follow-up MRI scans and post-mortem histological and immunohistochemical analyses. We successfully induced stroke with an average lesion size based on ADC at 8.18 ± 4.98 cm , ranging from 3.27 to 17.33 cm . After recanalization, the severely hypoperfused area (Tmax>6) was only 1.168 ± 0.223 cm . Subsequent histological analysis revealed neuronal loss within the lesion, the formation of astrocytic scar tissue, and elevated levels of activated microglia. Our study demonstrates the successful recanalization of cerebral vasculature in porcine model of ischemic stroke. It makes the model highly relevant to the current clinical workflow and offers an attractive avenue for studying novel diagnostics, therapeutics and further exploration of the underlying pathomechanisms. The feasibility of continuous MR imaging throughout the entire procedure facilitates the achievement of the aforementioned goals more readily.

Stroke is the second leading cause of death and disability worldwide. Current treatments, such as pharmacological thrombolysis or mechanical thrombectomy, reopen occluded arteries but do not protect against ischemia‐induced damage that occurs before reperfusion or neuronal damage induced by ischemia/reperfusion. It has been shown that disrupting the conversion of glyoxal to glycolic acid (GA) results in a decreased tolerance to anhydrobiosis in Caenorhabditis elegans dauer larva and that GA itself can rescue this phenotype. During the process of desiccation/rehydration, a metabolic stop/start similar to the one observed during ischemia/reperfusion occurs. In this study, the protective effect of GA is tested in different ischemia models, i.e., in commonly used stroke models in mice and swine. The results show that GA, given during reperfusion, strongly protects against ischemic damage and improves functional outcome. Evidence that GA exerts its effect by counteracting the glutamate‐dependent increase in intracellular calcium during excitotoxicity is provided. These results suggest that GA treatment has the potential to reduce mortality and disability in stroke patients. In this paper, it is shown how the survival strategy of the worm Caenorhabditis elegans against desiccation, namely, producing glycolic acid at high concentrations, can be used to protect against stroke in mammals. Glycolic acid mitigates the deleterious effects of ischemia/reperfusion by decreasing the glutamate‐dependent abnormal calcium influx to the cells, leading to reduced lesion sizes in mice and swine.

Pneumonia is the most frequent severe medical complication after stroke. An overactivation of the cholinergic signaling after stroke contributes to immunosuppression and the development of spontaneous pneumonia caused by Gram-negative pathogens. The α7 nicotinic acetylcholine receptor (α7nAChR) has already been identified as an important mediator of the anti-inflammatory pathway after stroke. However, whether the α2, α5 and α9/10 nAChR expressed in the lung also play a role in suppression of pulmonary innate immunity after stroke is unknown. In the present study, we investigate the impact of various nAChRs on aspiration-induced pneumonia after stroke. Therefore, α2, α5, α7 and α9/10 nAChR knockout (KO) mice and wild type (WT) littermates were infected with Streptococcus pneumoniae (S. pneumoniae) three days after middle cerebral artery occlusion (MCAo). One day after infection pathogen clearance, cellularity in lung and spleen, cytokine secretion in bronchoalveolar lavage (BAL) and alveolar-capillary barrier were investigated. Here, we found that deficiency of various nAChRs does not contribute to an enhanced clearance of a Gram-positive pathogen causing post-stroke pneumonia in mice. In conclusion, these findings suggest that a single nAChR is not sufficient to mediate the impaired pulmonary defense against S. pneumoniae after experimental stroke.

Alzheimer’s disease and small vessel ischemic disease frequently co-exist in the aging brain. However, pathogenic links between these 2 disorders are yet to be identified. Therefore we used Taqman genotyping, exome and RNA sequencing to investigate Alzheimer’s disease known pathogenic variants and pathways: APOE ε4 allele, APP-Aβ metabolism and late-onset Alzheimer’s disease main genome-wide association loci ( APOE , BIN1 , CD33 , MS4A6A , CD2AP , PICALM , CLU , CR1 , EPHA1 , ABCA7) in 96 early-onset small vessel ischemic disease Caucasian patients and 368 elderly neuropathologically proven controls (HEX database) and in a mouse model of cerebral hypoperfusion. Only a minority of patients (29%) carried APOE ε4 allele. We did not detect any pathogenic mutation in APP , PSEN1 and PSEN2 and report a burden of truncating mutations in APP-Aß degradation genes. The single-variant association test identified 3 common variants with a likely protective effect on small vessel ischemic disease (0.54>OR > 0.32, adj. p-value <0.05) ( EPHA1 p.M900V and p.V160A and CD33 p.A14V). Moreover, 5/17 APP-Aß catabolism genes were significantly upregulated (LogFC > 1, adj. p-val<0.05) together with Apoe , Ms4a cluster and Cd33 during brain hypoperfusion and their overexpression correlated with the ischemic lesion size. Finally, the detection of Aβ oligomers in the hypoperfused hippocampus supported the link between brain ischemia and Alzheimer’s disease pathology.

Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies.

Background: Adult hippocampal neurogenesis is altered after cerebral ischemia. Although stroke increases newborn neuron production, many cells show aberrant morphology and positioning that may impair integration and contribute to cognitive decline. It remains unclear whether these alterations are conserved across focal ischemia paradigms. We aimed to define shared and model-specific features of hippocampal neurogenesis across stroke models. Methods: We performed a multi-center, multimodel analysis within the STROKE-IMPaCT consortium using permanent and transient middle cerebral artery occlusion (MCAO): distal MCAO by ligation or cauterization under normoxia (dMCAO) or hypoxia (dMCAO+Hypoxia), and filament-based tMCAO. Adult C57BL/6J mouse brains were collected 3 days, 7 days, or 2 months after ischemia, sham, or naive conditions. Hippocampal proliferation (Ki67) and neuroblast density (DCX) were quantified, and newborn neuron maturation assessed by high-resolution analyses of dendritic architecture and somatodendritic polarity. Analyses were blinded. Results: Across all models, ischemia induced a robust bilateral increase in hippocampal proliferation, highest at 3 days and still elevated at 7 days, returning to baseline by 2 months. Neuroblast density similarly increased at 7 days, particularly ipsilaterally, but normalized by 2 months. Despite recovery in cell number, long-term analysis revealed reduced apical dendrite length and more neurons with aberrant features including ectopic localization, multipolar or inverted polarity, and abnormal lateral growth. These abnormalities were consistent across sites and within each model. Conclusions: Ischemia induces an early, transient increase in hippocampal neurogenesis across diverse stroke paradigms, but newborn neurons consistently display maladaptive morphological features. Aberrant hippocampal neurogenesis is therefore a robust hallmark of post-stroke pathology, independent of ischemia type or surgical approach. These findings support the concept that impaired neuronal integration may contribute to chronic post-stroke cognitive decline and highlight the need to consider the quality, not only the quantity, of newborn neurons in therapeutic strategies.Competing Interest StatementThe authors have declared no competing interest.

Background: Prediction of post-stroke outcome using the degree of subacute deficit or magnetic resonance imaging metrics is well studied in humans. While mice are the most commonly used animals in pre-clinical stroke research, systematic analysis of outcome predictors is lacking. Methods: Data from a total of 13 studies that included 45 minutes of middle cerebral artery occlusion on 148 mice were pooled. Motor function was measured using a modified protocol for the staircase test of skilled reaching. Phases of subacute and residual deficit were defined. Magnetic resonance images of stroke lesions were co-registered on the Allen Mouse Brain Atlas to characterize stroke topology. Different random forest prediction models that either used motor-functional deficit or imaging parameters were generated for the subacute and residual deficits. Results: We detected both a subacute and residual motor-functional deficit after stroke in mice. Different functional severity grades and recovery trajectories could be observed. We found that lesion volume is the best predictor of subacute deficit. The residual deficit can be predicted most accurately by the degree of the subacute deficit. When using imaging parameters for the prediction of the residual deficit, including information about the lesion topology increases prediction accuracy. A subset of anatomical regions within the ischemic lesion have an outstanding impact on the prediction of long-term outcome. Prediction accuracy depends on the degree of functional impairment. Conclusions: For the first time, we identified and characterized predictors of post-stroke outcome in a large cohort of mice and found strong concordance with clinical data. In the future, using outcome prediction can improve the design of pre-clinical studies and guide intervention decisions. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://doi.org/10.5281/zenodo.6534690

Stroke is the second leading cause of death and disability worldwide. Current treatments, such as pharmacological thrombolysis or mechanical thrombectomy, re-open occluded arteries but do not protect against ischemia-induced damage that has already occurred before reperfusion or ischemia/reperfusion-induced neuronal damage. It has been shown that disrupting the conversion of glyoxal to glycolic acid (GA) results in a decreased tolerance to anhydrobiosis in C. elegans dauer larva, while GA itself can rescue this phenotype. During the process of desiccation/rehydration, a metabolic stop/start similar to the one observed during ischemia/reperfusion occurs. In this study, we tested the protective effect of GA in different ischemia models, including commonly used stroke models in mice and swine. Our results show that GA, given during reperfusion, strongly protects against ischemic damage and improves the functional outcome. We provide evidence that GA exerts its effect by counteracting the glutamate-dependent increase in intracellular calcium during excitotoxicity. These results suggest that GA treatment has the potential to reduce the mortality and disability caused by stroke in patients. Competing Interest Statement FP-M has a patent pending on the use of glycolic acid in ischemia. DG, PW, and MJ are co-owners of Ti-com, which performed swine experiments. All other authors declare no competing interests. Footnotes * New title, re-wrote the text after adding experiments in swine.

Reduced brain levels of docosahexaenoic acid (C22:6n-3), a neurotrophic and neuroprotective fatty acid, may contribute to cognitive decline in Alzheimer's disease. Here, we investigated whether the liver enzyme system that provides docosahexaenoic acid to the brain is dysfunctional in this disease. Docosahexaenoic acid levels were reduced in temporal cortex, mid-frontal cortex and cerebellum of subjects with Alzheimer's disease, compared to control subjects (P  =  0.007). Mini Mental State Examination (MMSE) scores positively correlated with docosahexaenoic/α-linolenic ratios in temporal cortex (P =  0.005) and mid-frontal cortex (P  =  0.018), but not cerebellum. Similarly, liver docosahexaenoic acid content was lower in Alzheimer's disease patients than control subjects (P  =  0.011). Liver docosahexaenoic/α-linolenic ratios correlated positively with MMSE scores (r  =  0.78; P<0.0001), and negatively with global deterioration scale grades (P  =  0.013). Docosahexaenoic acid precursors, including tetracosahexaenoic acid (C24:6n-3), were elevated in liver of Alzheimer's disease patients (P  =  0.041), whereas expression of peroxisomal d-bifunctional protein, which catalyzes the conversion of tetracosahexaenoic acid into docosahexaenoic acid, was reduced (P  = 0.048). Other genes involved in docosahexaenoic acid metabolism were not affected. The results indicate that a deficit in d-bifunctional protein activity impairs docosahexaenoic acid biosynthesis in liver of Alzheimer's disease patients, lessening the flux of this neuroprotective fatty acid to the brain.