Human Fc Receptor-like 3 Inhibits Regulatory T Cell Function and Binds Secretory IgA

Agarwal, Stuti; Kraus, Zachary J.; Dement-Brown, Jessica; Alabi, Oyeleye; Starost, Kyle A.; Tolnay, Máté

doi:10.1016/j.celrep.2019.12.099

Cited by 35 publications

(38 citation statements)

References 43 publications

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“…Recognition of J chain-linked IgA as natural ligand for FCRL4 will also permit studies using this reagent to investigate potential activating or inhibitory function of FCRL4 upon ligand binding. In this context, it is interesting that a recent study on FCRL3 determined that this FCRL family member recognized mucosal sIgA, but not serum IgA, and that engagement of FCRL3 inhibited regulatory T cell function and promoted a proinflammatory Th17-like phenotype (32). Structural analysis of FCRL4 and FCRL3 in complex with their respective IgA ligands will resolve the molecular basis for the opposing IgA-binding characteristics.…”

Section: Discussionmentioning

confidence: 99%

FCRL4 Is an Fc Receptor for Systemic IgA, but Not Mucosal Secretory IgA

Liu

Goroshko

Leung

et al. 2020

The Journal of Immunology

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Fc receptor–like (FCRL) 4 is an immunoregulatory receptor expressed on a subpopulation of human memory B cells of mucosa-associated lymphoid tissue. Fc receptor function of FCRL4 was demonstrated by binding of IgA to FCRL4 following heat aggregation of the Ig. In this study, we demonstrate that FCRL4 recognizes J chain–linked systemic IgA in the absence of heat aggregation. We further demonstrate that mucosal secretory IgA is not recognized by FCRL4 and that systemic IgA binding can be competitively inhibited by recombinant secretory component protein. Finally, we provide evidence that primary FCRL4-bearing human memory B cells are constitutively bound to IgA. Our study provides a mechanism for the negative regulatory activity of FCRL4 on AgR-mediated B cell activation.

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Section: Discussionmentioning

confidence: 99%

FCRL4 Is an Fc Receptor for Systemic IgA, but Not Mucosal Secretory IgA

Liu

Goroshko

Leung

et al. 2020

The Journal of Immunology

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“…Whether this altered mode of binding may account for the different immune responses elicited by monomeric IgA and SIgA remains to be investigated 40 . Recently, human Fc receptor-like 3 (FCRL3) has been identified as a SIgA-specific receptor 41 . It is likely that the J-chain and SC are involved in the interaction between SIgA and FCRL3, thereby contributing to the signaling function of SIgA.…”

Section: Discussionmentioning

confidence: 99%

Structural insights into secretory immunoglobulin A and its interaction with a pneumococcal adhesin

Wang

et al. 2020

Preprint

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AbstractSecretory Immunoglobulin A (SIgA) is the most abundant antibody at the mucosal surface. SIgA possesses two additional subunits besides IgA: the joining chain (J-chain) and secretory component (SC). SC is the ectodomain of the polymeric immunoglobulin receptor (pIgR), which functions to transport IgA to the mucosa. The underlying mechanism of how the J-chain and pIgR/SC facilitates the assembly and secretion of SIgA remains to be understood. During the infection of Streptococcus pneumoniae, a pneumococcal adhesin SpsA hijacks SIgA and unliganded pIgR/SC to evade host defense and gain entry to human cells. How SpsA specifically targets SIgA and pIgR/SC also remains unclear. Here we report a cryo-electron microscopy structure of the Fc region of human IgA1 (Fcα) in complex with J-chain and SC (Fcα-J-SC), which reveals the organization principle of SIgA. We also present the structure of Fcα-J-SC in complex with SpsA, which uncovers the specific interaction between SpsA and human pIgR/SC. These results advance the molecular understanding of SIgA and shed light on the pathogenesis of S. pneumoniae.

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“…Surface expression of FCRL3, an immunoglobulin receptor, on B cells has been associated with increased risk for several autoimmune diseases, including systemic lupus erythematosus, autoimmune thyroid disease, Graves’ disease and rheumatoid arthritis 32 – 39 , though incongruously, the same allele (which is in high LD with the risk allele of the rs6681271 variant) associated with increased FCRL3 expression and risk for these diseases was found to be associated with protection from MS 40 , 41 , and the association with SLE was not present in African-American, Korean or European-American groups 36 , 42 – 44 . Nevertheless, FCRL3 stimulation via secretory IgA has recently been shown to promote a pro-inflammatory phenotype, in part by inhibiting the suppressive effects of regulatory T cells 45 , as previously shown 46 , and the risk allele of the rs6681271 variant has been shown to increase FCRL3 expression 39 , 47 , consistent with an increased MS risk (assuming the increased expression promotes increased total FCRL3 stimulation on regulatory T cells). Similarly, expression of its homolog FCRL1 was higher in patients with MS 48 .…”

Section: Discussionmentioning

confidence: 70%

Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans

Nakatsuka

Patterson

Patsopoulos

et al. 2020

Sci Rep

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Epidemiological studies have suggested differences in the rate of multiple sclerosis (MS) in individuals of European ancestry compared to African ancestry, motivating genetic scans to identify variants that could contribute to such patterns. In a whole-genome scan in 899 African-American cases and 1155 African-American controls, we confirm that African-Americans who inherit segments of the genome of European ancestry at a chromosome 1 locus are at increased risk for MS [logarithm of odds (LOD) = 9.8], although the signal weakens when adding an additional 406 cases, reflecting heterogeneity in the two sets of cases [logarithm of odds (LOD) = 2.7]. The association in the 899 individuals can be fully explained by two variants previously associated with MS in European ancestry individuals. These variants tag a MS susceptibility haplotype associated with decreased CD58 gene expression (odds ratio of 1.37; frequency of 84% in Europeans and 22% in West Africans for the tagging variant) as well as another haplotype near the FCRL3 gene (odds ratio of 1.07; frequency of 49% in Europeans and 8% in West Africans). Controlling for all other genetic and environmental factors, the two variants predict a 1.44-fold higher rate of MS in European-Americans compared to African-Americans.

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Human Fc Receptor-like 3 Inhibits Regulatory T Cell Function and Binds Secretory IgA

Cited by 35 publications

References 43 publications

FCRL4 Is an Fc Receptor for Systemic IgA, but Not Mucosal Secretory IgA

FCRL4 Is an Fc Receptor for Systemic IgA, but Not Mucosal Secretory IgA

Structural insights into secretory immunoglobulin A and its interaction with a pneumococcal adhesin

Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans

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