FcRH4
Overview
FcRH4 (Fc Receptor-Like 4; also FCRL4, IRTA1) is an ITIM-containing Fc receptor homolog expressed on a subset of human memory B cells. It can exert powerful inhibitory effects on BCR signalling. Critically, FcRH4 expression distinguishes tissue-resident (tonsillar/mucosal) CD27⁻ memory B cells from circulating peripheral blood CD27⁻ (double-negative) memory B cells — a distinction with practical implications for flow cytometry panel design.
FcRH4 is closely related to FcRH5 (FCRL5), which has emerged in more recent literature as a marker of atypical/T-bet⁺ B cells in acute infections including malaria, SARS-CoV-2, and potentially dengue.
Key Points from Literature
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PBL DN B cells (IgD⁻CD27⁻) in both healthy subjects and SLE patients are uniformly FcRH4⁻; FcRH4 expression is absent from all peripheral blood B cell subsets (see Wei2007 - DN Memory B Cells in SLE, n=29 healthy + n=36 SLE cross-sectional).
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In tonsil, FcRH4 is expressed in a fraction of CD27⁻ cells (whether IgD⁺ or isotype-switched), and in a subset of Bm5 CD27⁻ cells. Tonsillar DN B cells thus contain both FcRH4⁺ and FcRH4⁻ fractions (see Wei2007 - DN Memory B Cells in SLE).
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This FcRH4 expression pattern was first described by Ehrhardt et al. (2005, J Exp Med) as marking a “distinctive tissue-based population of memory B cells” — cited in Wei2007 - DN Memory B Cells in SLE as the comparator population.
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The absence of FcRH4 on PBL DN cells distinguishes Wei et al.’s circulating DN population from the Ehrhardt tissue-resident population; the recirculating FcRH4⁻ DN cells are proposed to be the biologically relevant population in peripheral blood studies (see Wei2007 - DN Memory B Cells in SLE).
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FCRL4⁻ on SLE DN2 cells — a key distinguishing feature: DN2 B cells (IgD⁻CD27⁻CXCR5⁻CD21⁻CD11c⁺) in SLE are FCRL4⁻ but FCRL5⁺. This FCRL4⁻/FCRL5⁺ pattern sharply distinguishes DN2 cells from HIV-associated exhausted CD21⁻ memory B cells, which are FCRL4⁺. The FCRL4⁻ status of DN2 cells also indicates that they retain intact BCR signalling capacity (FCRL4 is an ITIM-bearing inhibitory receptor), consistent with their functional role as active pre-plasmablasts rather than anergic/exhausted cells (see Jenks2018 - DN2 B Cells and EF Pathway in SLE, flow cytometry on SLE + HCD cohorts).
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Note on FcRH5/FCRL5: FcRH5 (a related family member) has emerged as a marker of atypical B cells in malaria and COVID-19 literature. The FCRL4⁻/FCRL5⁺ pattern in SLE DN2 cells is now the most precisely defined phenotype within this receptor family for extrafollicular effector B cells. See FCRL5 for full characterisation.
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Historical origin of the “atypical memory” label: The initial proposal for a separate AtB memory compartment stemmed from the identification of blood CD27⁻ CD21lo B cells in HIV patients with phenotypic features similar to FcRH4⁺ tissue-based memory cells (Ehrhardt et al. 2005). The extension of the FcRH4⁺ tissue-based label to circulating CD27⁻ cells is now recognised as misleading, since circulating DN cells are uniformly FcRH4⁻ (see Sanz2025 - Human Atypical B Cells Overview, review).
Contradictions & Debates
None documented in current wiki sources.
Related Pages
Double-Negative B Cell, DN2 B Cell, FCRL5, CD27, Memory B Cell, Extrafollicular Response