Search

Abstract Bone marrow plasma cells (BMPC) are the correlate of humoral immunity, consistently releasing antibodies into the bloodstream. It remains unclear if BMPC reflect different activation environments or maturation of their precursors. Here we define human BMPC heterogeneity and track the recruitment of antibody-secreting cells (ASC) from SARS-CoV-2 vaccine immune reactions to the bone marrow (BM). Trajectories based on single-cell transcriptomes and repertoires of peripheral and BM ASC reveal sequential colonisation of BMPC compartments. In activated B cells, IL-21 suppresses CD19 expression, indicating that CD19low-BMPC are derived from follicular, while CD19high-BMPC originate from extrafollicular immune reactions. In primary immune reactions, both CD19low- and CD19high-BMPC compartments are populated. In secondary immune reactions, most BMPC are recruited to CD19high-BMPC compartments, reflecting their origin from extrafollicular reactivations of memory B cells. A pattern also observable in vaccinated-convalescent individuals and upon diphtheria/tetanus/pertussis recall-vaccination. Thus, BMPC diversity reflects the evolution of a given humoral immune response.

BackgroundAlcohol-associated liver disease (ALD) is an important cause of morbidity and mortality worldwide. The intestinal microbiota is involved in the development and progression of ALD; however, little is known about commensal fungi therein.MethodsWe studied the dynamic changes of the intestinal fungal microbiome, or mycobiome, in 66 patients with alcohol use disorder (AUD) and after 2 weeks of alcohol abstinence using internal transcribed spacer 2 (ITS2) amplicon sequencing of fecal samples.ResultsPatients with AUD had significantly increased abundance of the genera Candida, Debaryomyces, Pichia, Kluyveromyces, and Issatchenkia, and of the species Candida albicans and Candida zeylanoides compared with control subjects. Significantly improved liver health markers caspase-cleaved and intact cytokeratin 18 (CK18-M65) levels and controlled attenuation parameter (CAP) in AUD patients after 2 weeks of alcohol abstinence were associated with significantly lower abundance of the genera Candida, Malassezia, Pichia, Kluyveromyces, Issatchenkia, and the species C. albicans and C. zeylanoides. This was mirrored by significantly higher specific anti-C. albicans immunoglobulin G (IgG) and M (IgM) serum levels in AUD patients in relation to control participants, and significantly decreased anti-C. albicans IgG levels in AUD subjects after 2 weeks of abstinence. The intestinal abundance of the genus Malassezia was significantly higher in AUD subjects with progressive liver disease compared with non-progressive liver disease.ConclusionIn conclusion, improved liver health in AUD patients after alcohol abstinence was associated with lower intestinal abundances of Candida and Malassezia, and lower serum anti-C. albicans IgG levels. Intestinal fungi might serve as a therapeutic target to improve the outcome of patients in ALD.

The intestinal tract is densely populated by microbiota consisting of various commensal microorganisms that are instrumental for the healthy state of the living organism. Such commensals generate various molecules that can be recognized by the Toll-like receptors of the immune system leading to the inflammation marked by strong upregulation of various proinflammatory cytokines, such as TNF, IL-6, and IL-1β. To prevent excessive inflammation, a single layer of constantly renewing, highly proliferating epithelial cells (IEC) provides proper segregation of such microorganisms from the body cavities. There are various triggers which facilitate the disturbance of the epithelial barrier which often leads to inflammation. However, the nature and duration of the stress may determine the state of the epithelial cells and their responses to cytokines. Here we discuss the role of the microbiota-TLR-cytokine axis in the maintenance of the epithelial tissue integrity. In particular, we highlight discrepancies in the function of TLR and cytokines in IEC barrier during acute or chronic inflammation and we suggest that intervention strategies should be applied based on the type of inflammation.