Disrupted Peyer's patch microanatomy in COVID-19 including germinal centre atrophy independent of local virus

Confirmed SARS-coronavirus-2 infection with gastrointestinal symptoms and changes in microbiota associated with coronavirus disease 2019 (COVID-19) severity have been previously reported, but the disease impact on the architecture and cellularity of ileal Peyers patches (PP) remains unknown. Here we analysed post-mortem tissues from throughout the gastrointestinal (GI) tract of patients who died with COVID-19. When virus was detected by PCR in the GI tract, immunohistochemistry identified virus in epithelium and lamina propria macrophages, but not in lymphoid tissues. Immunohistochemistry and imaging mass cytometry (IMC) analysis of ileal PP revealed depletion of germinal centres (GC), disruption of B cell/T cell zonation and decreased potential B and T cell interaction and lower nuclear density in COVID-19 patients. This occurred independent of the local viral levels. The changes in PP demonstrate that the ability to mount an intestinal immune response is compromised in severe COVID-19, which could contribute to observed dysbiosis.

Follicular cholecystitis with cholelithiasis – A diagnostic pitfall

Follicular Cholecystitis (FC) is an extremely rare subtype of Chronic Cholecystitis (CC). It is characterized by hyperplastic lymphoid follicles along with prominent germinal centers. It constitutes about 2% of routine cholecystectomies. In this article, we report a case of FC in a 69 years lady. She had abdominal pain, clinically diagnosed as Calculus cholecystitis and managed by laparoscopic cholecystectomy. Grossly, thickening of the gall bladder wall was noted. Histopathological examination revealed gall bladder wall infiltrated by dense lymphoid infiltrate forming lymphoid follicles with prominent germinal centres. Hence, we rendered a diagnosis of FC. The purpose of presenting this case is to make pathologists aware about this entity. One should not mistake this lesion for lymphoma. A careful histopathological examination is diagnostic and Immunohistochemistry may be helpful in difficult cases.Follicular Cholecystitis is extremely rare variant of Chronic cholecystitis. It is characterized by at least 3 Lymphoid Follicles per cm of Gall Bladder tissue with inflammatory infiltrate composed almost exclusively of scattered well-formed Lymphoid Follicles. Pathologist must be familiar with this entity to avoid misdiagnosis of lymphoma.

Low dose prime and delayed boost can improve COVID-19 vaccine efficacies by increasing B cell selection stringency in germinal centres

The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal centre (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.

Comparitive Study of Human Lymph Nodes

All the lymph nodes observed were typically bean shaped irrespective of their age or sex. The cervical lymph nodes were the largest of all the four groups in size. The mean maximum short axis axial diameter was 7.19mm (Range 5.67mm - 8.12mm). The mesentericl lymph nodes were the smallest of all the four groups in size. The mean maximum short axis axial diameter was 3.89mm (Range 2.7mm -6.lmm). The lymph nodes showed well defined deep cortical regions often containing large lymphoblasts and prominent endothelial cells in small blood vessels. The thickness of the deep cortex was however reduced when compared to its foetal counterpart. The mean thickness of the deep cortical region was 423 microns. To reconfirm the age related involution of the paracortical region, the mesenteric lymph nodes were observed. In sharp· distinction, axillary lymph nodes showed fewer germinal centres which were relatively smaller in size.Mean actual diameter of the germinal centre was77 microns also had had fewer and smaller germinal centres. Mean actual diameter of the germinal centre was 68 microns.

Germinal Centre Shutdown

Germinal Centres (GCs) are transient structures in secondary lymphoid organs, where affinity maturation of B cells takes place following an infection. While GCs are responsible for protective antibody responses, dysregulated GC reactions are associated with autoimmune disease and B cell lymphoma. Typically, ‘normal’ GCs persist for a limited period of time and eventually undergo shutdown. In this review, we focus on an important but unanswered question – what causes the natural termination of the GC reaction? In murine experiments, lack of antigen, absence or constitutive T cell help leads to premature termination of the GC reaction. Consequently, our present understanding is limited to the idea that GCs are terminated due to a decrease in antigen access or changes in the nature of T cell help. However, there is no direct evidence on which biological signals are primarily responsible for natural termination of GCs and a mechanistic understanding is clearly lacking. We discuss the present understanding of the GC shutdown, from factors impacting GC dynamics to changes in cellular interactions/dynamics during the GC lifetime. We also address potential missing links and remaining questions in GC biology, to facilitate further studies to promote a better understanding of GC shutdown in infection and immune dysregulation.

Coordinated changes in glycosylation regulate the germinal centre through CD22

Germinal centres (GC) are sites of B-cell expansion and selection, which are essential for antibody affinity maturation. Compared to naive follicular B-cells, GC B-cells have several notable changes in their cell surface glycans. While these changes are routinely used to identify the GC, functional roles for these changes have yet to be ascribed. Detection of GCs by the antibody GL7 reflects a reduction in the glycan ligands for CD22, which is an inhibitory co-receptor of the B-cell receptor (BCR). To test a functional role for downregulated CD22 ligands in the GC, we generated a mouse model that maintains CD22 ligands on GC B-cells. With this model, we demonstrate that glycan remodeling is crucial for proper GC B-cell response, including plasma cell output and affinity maturation of antibodies. The defect we observe in this model is dependent on CD22, highlighting that coordinated downregulation of CD22 ligands on B cells plays a critical function in the GC. Collectively, our study uncovers a crucial role for glycan remodeling and CD22 in B-cell fitness in the GC.