. 2022 Oct 31;11(11):e1418. doi: 10.1002/cti2.1418

Table 2.

Major subpopulations of human circulating memory B cells, highlighting important functional characteristics, proposed mechanisms of involvement in the immunopathogenesis of multiple sclerosis and known effects of MS therapies on them

	Marginal zone B cells	CD11c⁺/T‐bet⁺ MBCs	Conventional MBCs
Distinguishing and important immunophenotypes	CD19⁺, CD20⁺, CD27⁺, IgD^low, IgM^hi	CD19⁺, CD20⁺, CD27^+/−, IgD⁻, CXCR3⁺, CD11c⁺	CD19⁺, CD20⁺, CD27⁺, IgD⁻
Subpopulations	MZB1 and MZB2	IgG⁺, IgA⁺, (IgM‐only)	IgM‐only, IgG⁺, IgA⁺
Primary functions	Initiating B‐cell and antibody responses (‘first responders’) Long‐term Bcell memory	Controlling infections in concert with effector T cells (mainly established for viruses and Plasmodium sp.)	Preventing infections through memory responses that produce plasmablasts and long‐lived plasma cells and antibodies
Important functional characteristics	Microbe recognition by low‐affinity BCRs and various pathogen recognition molecules APC function for CD4⁺ T cells via HLA molecules MBZ2 cells express HLA‐DBR1 and exhibit antiviral characteristics	Microbe recognition by BCRs and TLR7/9 Probable APCs for T cells, involving CD11c/CD18 Antibody responses skewed towards IgG3, enhancing cDC activation and antigen presentation to CD8⁺ T cells	Microbe recognition by high affinity BCRs Production of antibodies with high affinity for antigens and functional diversity of Fc regions through immunoglobulin isotype switching of B cells
Proposed involvement in the immunopathogenesis of MS	Initiate a B‐cell response against EBV proteins, such as EBNA‐1, in GALT that is cross‐reactive with autoantigens, such as GlialCAM Possibly activate ‘autoproliferative’ CD4⁺ T cells, as well as pathogenic B cells in CSF	EBNA‐1/GlialCAM‐specific IgG⁺ cells: Differentiate from MZB2 cells, under the influence of IFN‐γ from CD4⁺ T cells, and migrate to the CNS facilitated by CXCR3 expression Induce a cytotoxic CD8⁺ T‐cell response against glial cells and/or myelin in the CNS by acting as APCs and/or eliciting antibody‐dependent activation of cDCs Possibly produce BAFF in CNS IgA⁺ cells possibly produce IgA anti‐EBV that interferes with IgG antibodies.	EBV‐infected cells possibly produce BAFF in CNS IgA⁺ cells possibly produce IgA anti‐EBV that interferes with IgG antibodies.
Demonstrated effect of MS therapies ¹ , ¹⁶⁰ , ¹⁶¹ , ¹⁶²	Depletion by anti‐CD52 (ATB), anti‐CD20 (OLB), IFN‐β and Cladribine ^a	Inhibition of adhesion to receptors in CNS by anti‐α4‐integrin (NLB) Depletion by MS therapies? ^b	Inhibition of adhesion to receptors in CNS and possibly GALT by anti‐α4‐integrin (NLB) Depletion by anti‐CD52 (ATB) anti‐CD20 (OLB), IFN‐β, DMF, GTA, Cladribine and Fingolimod

ATB, alemtuzumab; DMF, dimethyl fumarate; GTA, glatiramer acetate; NLB, natalizumab; OLB, ocrelizumab.

^{^a}

Based on data for ‘unswitched’ CD27⁺ B cells.

^{^b}

Insufficient information on depletion of this subpopulation by MS therapies but probable that anti‐CD20 (OLB), at least, does this.