Background: The granulocyte-macrophage colony-stimulating factor (GM-CSF) (or CSF-2) is involved in myeloid cell growth and differentiation, and, possibly, a major mediator of inflammation in body tissues. The role of GM-CSF in the activation of microglia (CNS resident macrophages) and the consequent impacts on neuronal survival, excitability, and synaptic transmission are widely unknown, however. Here, we focused on electrical neuronal network rhythms in the gamma frequency band (30–70 Hz). Gamma oscillations are fundamental to higher brain functions, such as perception, attention, and memory, and they are exquisitely sensitive to metabolic and oxidative stress.Methods: We explored the effects of chronic GM-CSF exposure (72 h) on microglia in male rat organotypic hippocampal slice cultures (in situ), i.e., postnatal cortex tissue lacking leukocyte invasion (adaptive immunity). We applied extracellular electrophysiological recordings of local field potential, immunohistochemistry, design-based stereology, biochemical analysis, and pharmacological ablation of microglia.Results: GM-CSF triggered substantial proliferation of microglia (microgliosis). By contrast, the release of proinflammatory cytokines (IL-6, TNF-α) and nitric oxide, the hippocampal cytoarchitecture as well as the morphology of parvalbumin-positive inhibitory interneurons were unaffected. Notably, GM-CSF induced concentration-dependent, long-lasting disturbances of gamma oscillations, such as slowing (beta frequency band) and neural burst firing (hyperexcitability), which were not mimicked by the T lymphocyte cytokine IL-17. These disturbances were attenuated by depletion of the microglial cell population with liposome-encapsulated clodronate. In contrast to priming with the cytokine IFN-γ (type II interferon), GM-CSF did not cause inflammatory neurodegeneration when paired with the TLR4 ligand LPS.Conclusions: GM-CSF has a unique role in the activation of microglia, including the potential to induce neuronal network dysfunction. These immunomodulatory properties might contribute to cognitive impairment and/or epileptic seizure development in disease featuring elevated GM-CSF levels, blood-brain barrier leakage, and/or T cell infiltration.

Background: Bullous pemphigoid (BP), the by far most frequent autoimmune blistering skin disease (AIBD), is immunopathologically characterized by autoantibodies against the two hemidesmosomal proteins BP180 (collagen type XVII) and BP230 (BPAG1 or dystonin). Several comorbidities and potentially disease‐inducing medication have been described in BP, yet a systematic analysis of these clinically relevant findings and autoantibody reactivities has not been performed.Objective: To determine associations of autoantibody reactivities with comorbidities and concomitant medication.Methods: In this prospective multicenter study, 499 patients diagnosed with BP in 16 European referral centers were included. The relation between anti‐BP180 NC16A and anti‐BP230 IgG ELISA values at the time of diagnosis as well as comorbidities and concomitant medication collected by a standardized form were analysed.Results: An association between higher serum anti‐BP180 reactivity and neuropsychiatric but not atopic and metabolic disorders was observed as well as with the use of insulin or antipsychotics but not with dipeptidyl peptidase‐4 (DPP4) inhibitors, inhibitors of platelet aggregation and L‐thyroxine. The use of DPP4 inhibitors was associated with less anti‐BP180 and anti‐BP230 reactivity compared with BP patients without these drugs. This finding was even more pronounced when compared with diabetic BP patients without DPP4 inhibitors. Associations between anti‐BP180 and anti‐BP230 reactivities were also found in patients using insulin and antipsychotics, respectively, compared with patients without this medication, but not for the use of inhibitors of platelet aggregation, and L‐thyroxine.Conclusion: Taken together, these data imply a relation between autoantibody reactivities at the time of diagnosis and both neuropsychiatric comorbidities as well as distinct concomitant medication suggesting a link between the pathological immune mechanisms and clinical conditions that precede the clinically overt AIBD.

Summary: Background and Objectives: Pemphigoid diseases are primarily mediated by IgG or IgA autoantibodies against the cutaneous basement membrane zone (BMZ). Although recent observations suggest the existence of exclusively IgM‐mediated pemphigoid disease, a larger study is lacking. Patients and Methods: This prospective multicenter study included ten patients with exclusive IgM deposition along the BMZ by direct immunofluorescence (IF). Circulating IgM was detected by indirect IF and immunoblotting with recombinant BP180. Results: The cohort, four females and six males with a median age of 77 years, presented predominantly with prurigo‐like lesions without blisters and mucosal involvement. Sera from nine patients demonstrated linear IgM labeling the blister roof of human salt‐split skin by indirect IF. Four patients yielded IgM reactivity against BP180, but none against BP230. In none of the controls (n = 100), anti‐BMZ IgM was seen by direct IF. 1/30 and 3/60 controls with or without pruritic non‐pemphigoid diseases revealed serum IgM reactivity against the BMZ, respectively. Conclusions: IgM pemphigoid is characterized by exclusive tissue‐bound anti‐BMZ IgM, serum anti‐BMZ IgM reactivity with BP180 as main target antigen, a predominantly non‐bullous clinical phenotype, absence of mucosal involvement, and a rather mild disease course. Our findings indicate that IgM pemphigoid may represent a distinct entity.

Pemphigoid diseases (PD) are autoimmune blistering disorders in which alterations of the skin and gut microbiota have been reported, yet how microbial variation relates to disease severity remains unclear. Using a bullous pemphigoid-like mouse model, we compared genetically identical C57BL/6J mice from two breeding facilities that differed in their baseline microbiota. Mice from Charles River developed markedly milder disease than in-house-bred animals. Co-housing partially homogenized their gut microbiota, shifting in-house mice asymmetrically toward the Charles River community, coinciding with reduced disease severity in co-housed in-house mice. The skin microbiota showed more modest and less consistent shifts, potentially reflecting its lower biomass and higher technical noise. Lower gut microbial diversity and enrichment of pro-inflammatory taxa like Turicimonas muris and Muribaculum intestinale were linked to more severe disease, whereas taxa such as Lactobacillus intestinalis and Parabacteroides distasonis correlated with protection. A gut taxon belonging to Scatocola was identified as a candidate negative predictor of disease severity in correlation and machine-learning analyses. Together, these findings support an association between natural variation in the gut microbiota and autoimmune skin inflammation and identify candidate microbial taxa that warrant further functional validation.

Zusammenfassung: Hintergrund und Zielsetzung: Die Pemphigoid‐Erkrankungen werden primär durch IgG‐ oder IgA‐Autoantikörper gegen die kutane Basalmembranzone (BMZ) vermittelt. Obwohl rezente Arbeiten auf die Existenz einer ausschließlich IgM‐vermittelten Pemphigoid‐Erkrankung hindeuten, fehlt bislang eine umfassendere Untersuchung. Patienten und Methodik: In dieser prospektiven multizentrischen Studie wurden zehn Patienten mit ausschließlich IgM‐Ablagerungen entlang der BMZ in der direkten Immunfluoreszenz (IF) eingeschlossen. Zirkulierende IgM‐Autoantikörper wurden mittels indirekter IF und Immunoblot mit rekombinantem BP180 nachgewiesen. Ergebnisse: Die Kohorte umfasste vier Frauen und sechs Männer mit einem medianen Alter von 77 Jahren, die überwiegend Prurigo‐artige Hautveränderungen ohne Blasenbildung und Schleimhautbeteiligung aufwiesen. In der indirekten IF auf NaCl‐separierter humaner Spalthaut zeigten die Seren von neun Patienten lineare IgM‐Ablagerungen am Dach der artifiziellen Blase. Bei vier Patienten konnte eine IgM‐Reaktivität gegen BP180 nachgewiesen werden, bei keinem jedoch gegen BP230. Bei keinem der Kontrollpatienten (n   =   100) wurden IgM‐Ablagerungen an der BMZ in der direkten IF beobachtet. Eine IgM‐Reaktivität gegen die BMZ im Serum wurde bei 1 von 30 Kontrollpatienten mit chronischem Pruritus beziehungsweise bei 3 von 60 Kontrollpatienten ohne chronischen Pruritus nachgewiesen. Schlussfolgerungen: Das IgM‐Pemphigoid ist durch gewebsgebundene, exklusive IgM‐Autoantikörper gegen die BMZ, serologische IgM‐Reaktivität mit BP180 als primärem Zielantigen, überwiegend nichtbullösen klinischen Phänotyp, fehlende Schleimhautbeteiligung und eher milden Krankheitsverlauf gekennzeichnet. Unsere Ergebnisse deuten darauf hin, dass das IgM‐Pemphigoid eine eigenständige Entität darstellen könnte.

Autoimmune blistering diseases (AIBD) involve autoantibodies targeting proteins in the epidermal/epithelial desmosome (pemphigus) or basement membrane zone (pemphigoid). Despite widespread antigen distribution, lesions exhibit a scattered involvement pattern. This study maps the frequency/severity of AIBD lesions in various body parts and investigates whether differential antigen expression contributes to specific predilection sites. We analyzed affected sites presenting blisters/erosions, erythematous/urticarial lesions, and mucosal lesions in bullous pemphigoid (BP-cohort 1, n=65; BP-cohort 2, n=119), pemphigus vulgaris (PV, n=67), and pemphigus foliaceus (PF, n=20) patients. To assess antigen expression, we conducted indirect immunofluorescence (IF) staining of 11 AIBD antigens from 13 anatomical sites of 10 body donors without AIBD. In BP, blisters/erosions and erythematous/urticarial lesions predominantly affected arms and legs, while PV/PF patients exhibited frequent involvement of buccal mucosa and back, respectively. IF staining identified significant regional differences in BP180, BP230, and integrin β4 expression, although these variations did not correlate with a higher lesion frequency/severity. Other antigens showed consistent expression across all regions. Our findings suggest that predilection sites for BP and PV/PF are largely unaffected by regional variations in antigen expression but may be influenced by factors like microbiota, mechanical stress, sunlight exposure, local immunity, or genetics.