Table 3.

Factors affecting the number of EBV infected memory B cells recognizing fungal antigens.

Factor	Mechanism	Expected effects
BCR of naive B cell	EBV virions infect resting naive B cells that have a “random” BCR. This “random” BCR is biased toward either fungal or bacterial antigens, and will thus bias affinity maturation	Variations in V(D)J genes and recombination during production of naive B cells in the bone marrow may be genetically biased toward either bacterial or fungal antigens, respectively reducing or increasing multiple sclerosis (MS) risk
Naive CD4+ T cell antigen recognition	Affinity maturation requires naive CD4+ T cells to clonally expand and become CD4+ (follicular helper) T cells. This requires dendritic cell presentation of antigens through HLA-D molecules, which will be biased toward antigens best recognized by naive CD4+ T cells	Variations in V(D)J genes and recombination during production of naive CD4+ T cells in the thymus may be genetically biased toward either bacterial or fungal antigens, respectively reducing or increasing MS risk. HLA-D molecules which efficiently present bacterial antigens should reduce MS risk, whereas HLA-D molecules which efficiently present fungal antigens should increase MS risk
CD4+ (follicular helper) T cell antigen recognition	Affinity maturation requires CD4+ (follicular helper) T cell recognition of a portion of the antigen endocytosed by the B cell through its BCR and presented through HLA-D molecules. During affinity maturation, competitive selection of somatically hypermutated B cells recognizing either bacterial or fungal antigens will be biased toward the antigen type best recognized by CD4+ (follicular helper) T cells
Relative concentration of commensal microbe antigens in lymph node where EBV-positive naive B cells mature	The ratio of bacterial to fungal antigens in lymph nodes where EBV infected naive B cells mature will skew affinity maturation toward the more abundant antigen type due to improved receptor-ligand kinetics	A reduction of commensal bacteria (e.g. Lactobacillus) or an increase in commensal fungi (e.g. Candida) would increase MS risk. For example, antibacterial/antifungal drugs will dramatically increase and then decrease antigens in lymph nodes, due to the massive initial die-off of targeted microbes, followed by a suppression of the targeted microbial population
Total number of EBV infected B cells	CD8+ (cytotoxic) T cell control of the EBV infected B cell population determines how often a naive B cell matures into a memory B cell while EBV infected	Lower EBV loads result in fewer chances of producing a memory B cell which recognizes a “forbidden” antigen present in the central nervous system, in turn reducing MS risk. Individuals with strong CD8+ (cytotoxic) T cell control of EBV would be at lower MS risk. Interventions to lower the general B cell population (e.g. anti-CD20 drugs) or the EBV infected B cell population (e.g. using adoptive immunotherapy) would both be expected to reduce MS risk

Commensal microbes collocated with Epstein-Barr virus (EBV) virions (e.g., in the mouth and genitals) provide an ideal antigenic target to complete EBV’s lifecycle, and are likely recognized by the B cell receptor (BCR) of EBV infected memory B cells. Bacteria are normally the dominant commensal microbe type in both sites, so EBV infected memory B cells would mostly target bacterial antigens. However, if sufficient fungal antigens are also present during affinity maturation, some EBV infected memory B cells’ BCRs may converge onto fungal rather than bacterial antigens. Note that an EBV-positive B cell that recognizes a “forbidden” antigen cannot do much harm immediately after leaving the germinal center: as long as a B cell remains EBV infected, CD8+ (cytotoxic) T cell control will prevent it from secreting antibodies or clonally expanding. Only after a few dozen divisions is the memory B cell expected to lose EBV episomes, and the associated CD8+ (cytotoxic) T cell control.