CD22
B-cell receptor CD22 precursor (B-lymphocyte cell adhesion molecule) (BL-CAM) (Sialic acid-binding Ig-like lectin 2) (Siglec-2) (T-cell surface antigen Leu-14) (CD22 antigen) [SIGLEC2]
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Microglia are brain macrophages that mediate neuroinflammation and contribute to and protect against neurodegeneration. The terminal sugar residue of all glycoproteins and glycolipids on the surface of mammalian cells is normally sialic acid, and addition of this negatively charged residue is known as "sialylation," whereas removal by sialidases is known as "desialylation." High sialylation of the neuronal cell surface inhibits microglial phagocytosis of such neurons, via: (i) activating sialic acid receptors (Siglecs) on microglia that inhibit phagocytosis and (ii) inhibiting binding of opsonins C1q, C3, and galectin-3. Microglial sialylation inhibits inflammatory activation of microglia via: (i) activating Siglec receptors CD22 and CD33 on microglia that inhibit phagocytosis and (ii) inhibiting Toll-like receptor 4 (TLR4), complement receptor 3 (CR3), and other microglial receptors. When activated, microglia release a sialidase activity that desialylates both microglia and neurons, activating the microglia and rendering the neurons susceptible to phagocytosis. Activated microglia also release galectin-3 (Gal-3), which: (i) further activates microglia via binding to TLR4 and TREM2, (ii) binds to desialylated neurons opsonizing them for phagocytosis via Mer tyrosine kinase, and (iii) promotes Aβ aggregation and toxicity [i]in vivo[/i]. Gal-3 and desialylation may increase in a variety of brain pathologies. Thus, Gal-3 and sialidases are potential treatment targets to prevent neuroinflammation and neurodegeneration.
Keywords
- aging
- desialylation
- galectin-3
- microglia
- neurodegeneration
- phagocytosis
- sialic acid
Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR-Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-β oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.
MeSH Terms
- Aging
- Animals
- Brain
- CRISPR-Associated Protein 9
- CRISPR-Cas Systems
- Cognition
- Female
- Homeostasis
- Male
- Mice
- Mice, Inbred C57BL
- Microglia
- N-Acetylneuraminic Acid
- Phagocytosis
- Sequence Analysis, RNA
- Sialic Acid Binding Ig-like Lectin 2
The aim of this study was to determine age-related changes in the mRNA expression of four clusters of differentiation (CD: e.g. CD5, CD21, CD22 and CD23) in lymphocytes of calves. Blood samples were collected from 10 Holstein heifers on day 2, 22 and 56 of life and used for lymphocyte isolation. Subsequently, the mRNA was isolated from lymphocytes and the relative expression of CD5, CD21, CD22 and CD23 was investigated using quantitative real-time PCR with GAPDH as a reference gene. CD5, CD21 and CD23 mRNA expression increased linearly (p ≤ 0.04) with calf age, whereas CD22 mRNA expression did not change in the investigated period (p > 0.05). Age related changes in CD5, CD21 and CD23 mRNA expression suggest their importance in the process of lymphocyte maturation in calves.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- Cattle
- Female
- Gene Expression Regulation, Developmental
- RNA, Messenger
Keywords
- clusters of differentiation
- immune system development
- lymphocyte maturation
- marker
Siglec-G, a member of the sialic acid-binding Ig-like lectin (Siglec) family, is expressed on B cell and dendritic cell surfaces. It acts as an inhibitory coreceptor and modulates B cell activation, especially on B1 cells, as Siglec-G-deficient mice show mainly a B1 cell-restricted phenotype resulting in increased B1 cell numbers. Although higher B1 cell numbers are discussed to be associated with autoimmunity, loss of Siglec-G does not result in autoimmune disease in BALB/c mice. However, there is evidence from Siglec-G × CD22 double-deficient mice and Siglec-G(-/-) mice on an autoimmune-prone MRL/lpr background that Siglec-G is important to maintain tolerance in B cells. In this study, we analyzed the role of Siglec-G in induction and maintenance of B cell tolerance on C57BL/6 background and in the FcγRIIb-deficient background. We find that aging Siglec-G-deficient and Siglec-G × FcγRIIb double-deficient mice develop an autoimmune phenotype with elevated autoantibody levels and mild glomerulonephritis. Aging Siglec-G-deficient mice have elevated numbers of plasma cells and germinal center B cells, as well as a higher number of activated CD4 T cells, which likely all contribute to autoantibody production. Additional loss of the inhibitory receptor FcγRIIb in Siglec-G(-/-) mice does not result in exacerbation of disease. These results indicate that Siglec-G is important to maintain tolerance in B cells and prevent autoimmunity.
MeSH Terms
- Aging
- Animals
- Autoantibodies
- Autoimmunity
- B-Lymphocytes
- CD4-Positive T-Lymphocytes
- Crosses, Genetic
- Female
- Gene Expression
- Germinal Center
- Glomerulonephritis
- Immune Tolerance
- Lectins
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred MRL lpr
- Mice, Knockout
- Receptors, Antigen, B-Cell
- Receptors, IgG
- Sialic Acid Binding Immunoglobulin-like Lectins
Immunosenescence is characterized by the impairment of humoral immunity with changes in the memory/naive B cell compartment. In particular we have previously reported the percentage increase of a Memory IgD(-)CD27(-) (Double Negative, DN) B cell population in aged people. In this study, we have further characterized DN B cells with the aim to better understand their contribution to immunosenescence. As DN B cells show a poor ability to proliferate in vitro, we have evaluated the expression of the inhibitory receptors CD307d and CD22 on these cells from young and old individuals. In addition we have evaluated the ability to activate DN B cells by the simultaneous use of innate (CpG) and adaptive (α-Ig/CD40) ligands. Our data demonstrate that the refractoriness to proliferate of DN B cells does not depend on the expression of inhibitory receptors, but it is due to the kind of stimulation. Indeed, when DN B cells are stimulated engaging both BCR and TLR9, they become able to proliferate and reactivate the telomerase enzyme. In the present study, we have also compared the telomerase activity in a group of people genetically advantaged for longevity as centenarian offspring (CO) and in a group of moderate-severe Alzheimer's disease (AD) patients, who represent a model of unsuccessful aging. Our study suggests that telomerase reactivation of DN B cells, as well as their number and ability in activating, depend essentially by the biological age of the subjects studied, so the evaluation of DN B cells might allow to gain insight to healthy and unsuccessful aging.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Alzheimer Disease
- Antigens, Surface
- B-Lymphocyte Subsets
- Cellular Senescence
- Humans
- Immunologic Memory
- Immunophenotyping
- Lymphocyte Activation
- Middle Aged
- Phenotype
- Receptors, Antigen, B-Cell
- Severity of Illness Index
- Telomerase
- Young Adult
Keywords
- Aging
- Alzheimer
- B lymphocytes
- Centenarian offspring
- Inflammation
- Telomerase
Prescapular, femoral, mesenteric, mediastinal and splenic lymph nodes from nine camels of one to 12 years of age were studied. There were no obvious structural differences between these different lymph nodes or between the ages. The lymph nodes were surrounded by a capsule formed of two layers, an outer thicker layer of connective tissue and an inner thinner layer mainly of smooth muscles. Trabeculae extended from the inner layer of the capsule dividing the parenchyma characteristically into incomplete lobules. Subcapsular and trabecular lymphatic sinuses were supported by a reticular fiber network. The parenchyma was uniquely different from that of other species, as it was arranged in the form of lymphoid follicles and interfollicular lymphoid tissue. The lymphoid follicles of CD22 positive lymphocytes were supported by a reticular fiber network. This fine network of α-smooth muscle actin positive cells enclosed the lymphoid follicles. The interfollicular tissue was mainly made up of diffusely distributed CD3 positive lymphocytes. MHC class II: DR was expressed by most lymphocytes of the follicles and interfollicular tissue. Lymphatic sinuses and high endothelial venules were found in the interfollicular zone. The lymphatic sinuses were lined by discontinuous endothelial cells. The wall of the high endothelial venules was infiltrated by several lymphocytes and enclosed in a layer of α-smooth muscle actin positive cells. Acid phosphatase positive cells were evenly distributed in the interfollicular zone. A few cells were localized in the lymph follicles. Alkaline phosphatase was observed in the endothelium of the lymphatic sinuses and in the lymphoid follicles.
MeSH Terms
- Aging
- Animals
- Camelus
- Coloring Agents
- Immunohistochemistry
- Lymph Nodes
- Lymphocytes
- Lymphoid Tissue
- Male
- Microscopy, Electron, Transmission
The aims of this flow cytometry study were to quantify B lymphoid precursors known as hématogones across age and clinical conditions and to study the immunophenotypic profile of these benign immature B cells. A total of 406 consecutive marrow specimens were analyzed for hématogones using 4-color flow cytometry during a 19 month period (60% males and 40% females). The age range was 3 months to 89 years. Hématogones were present in 80% of the specimens. Morphologic analysis of the smears from each patient showed small numbers of hématogones (<13% of total cellularity). The B cell population was defined by CD19 CD45 bright positivity, coexpression of other B lineage markers: CD20, CD22, CD10, CD29, CD38 and CD58 in addition to HLA-DR and CD34. In our study we found a significant decline in hématogones with increasing age but a broad range was found at all ages. Marrow from some adults contained relatively high numbers. Diagnosis in these patients included cytopenias, infections, and neoplastic diseases. Distinction of hématogones is critical for disease management particularly after therapy of paediatric B acute lymphoblastic leukaemia to monitor for minimal residual disease.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigens, CD
- Child
- Child, Preschool
- Female
- Flow Cytometry
- Humans
- Immunophenotyping
- Infant
- Male
- Middle Aged
- Precursor Cells, B-Lymphoid
- Prospective Studies
- Young Adult
The neonatal immune system responds to a restricted range of antigens, producing largely IgM antibody of low affinity. Comparison of the components of the B-cell antigen receptor complex shows significantly elevated membrane levels of IgM in neonatal B cells, compared with adult cells. CD79, which acts as the signal transducer for membrane immunoglobulin, is elevated in parallel with IgM, while IgD is elevated to a lesser degree. CD19, CD21, CD22 and CD81, which are all involved in transmitting activation signals when immunoglobulin is engaged, are not elevated. CD32, which is involved in negative regulation of activation, is present at reduced levels on cord B cells. The elevation of B-cell membrane IgM persists during infancy. Neonatal B cells respond in vitro to interleukin-4 (IL-4) by further elevation of membrane IgM levels. The elevated level of membrane IgM may make neonatal B cells easier to trigger by low concentrations of antigen, but in vitro activation and immunoglobulin modulation experiments did not show significant differences between cord and adult B-cell responses to anti-IgM.
MeSH Terms
- Adult
- Aging
- B-Lymphocyte Subsets
- B-Lymphocytes
- CD5 Antigens
- Cell Culture Techniques
- Fetal Blood
- Humans
- Immunoglobulin M
- Immunologic Capping
- Infant, Newborn
- Interleukin-4
- Receptors, Antigen, B-Cell