Flow Cytometry Reveals that Fasting Impairs Humoral Immune Memory by Depleting Plasma Cells via β-Hydroxybutyrate-FAQs

1. Do different modes of intermittent fasting (such as ADF and prolonged fasting) have differential effects on humoral immunity?

There is no significant qualitative difference; the core mechanism of action is consistent. Both the alternate-day fasting (ADF) and prolonged fasting (three days per week) models used in the study significantly reduced serum-specific antibody concentrations and depleted bone marrow long-lived plasma cells (LLPCs), with no significant difference in the degree of impairment to humoral immune memory between the two. Furthermore, the 16:8 time-restricted feeding regimen produced similar effects. This indicates that regardless of the specific intermittent fasting pattern, as long as it triggers a metabolic shift leading to elevated ketone bodies (specifically β-hydroxybutyrate), it will impair humoral immune memory. The differences lie only in the implementation, not the underlying mechanism.

2. Does the fasting-induced impairment of humoral immunity affect the number and function of memory B cells?

No, it does not. The study found that fasting specifically targets and depletes plasma cells, particularly long-lived plasma cells in the bone marrow. It has no significant effect on memory B cells (MBCs), another crucial component of humoral immune memory. Specifically, the numbers of antigen-specific memory B cells in the spleen and bone marrow remained unchanged after fasting, and their ability to respond to secondary immunization (antigen boost) was unaffected. This suggests that the impairment of humoral immunity by fasting is specific to plasma cells and does not affect the homeostasis and function of memory B cells.

3. Besides β-hydroxybutyrate, do other ketone bodies (such as acetoacetate) also lead to plasma cell depletion?

No, only β-hydroxybutyrate has this effect. During fasting, two main ketone bodies are produced: β-hydroxybutyrate (BHB) and acetoacetate (AcAc). However, the research confirmed that only BHB significantly reduces bone marrow plasma cell numbers and decreases serum antibody levels. Validation through both in vitro and in vivo experiments showed that treatment with acetoacetate (AcAc) resulted in no significant changes in plasma cell counts or antibody concentrations. This demonstrates that the impairment of humoral immunity by ketone bodies is specific, with BHB being the key molecule mediating fasting-induced plasma cell depletion.

4. Does fasting indirectly cause plasma cell depletion by affecting the bone marrow microenvironment?

No, it does not. The study analyzed the impact of fasting, a ketogenic diet, and BHB treatment on the bone marrow microenvironment. It found that none of these interventions altered the numbers of other cell types in the bone marrow (such as T cells, eosinophils, monocytes, etc.) nor affected the expression of key niche factors within the bone marrow microenvironment (such as CXCL12, Tnfsf13, and TNFα). This indicates that the depleting effect of fasting on plasma cells is a direct effect on the plasma cells themselves, rather than being indirectly mediated by disrupting the bone marrow microenvironment.

5. Does fasting affect the generation of plasma cells or their ability to home to the bone marrow?

Fasting does not affect the generation of plasma cells. Neither intermittent fasting nor BHB treatment altered the number of antigen-specific plasmablasts or plasma cells generated in the spleen, nor did it affect the survival of newly generated plasma cells.

It also does not affect the bone marrow homing ability of plasma cells. Cell transfer experiments confirmed that the capacity of plasma cells to migrate to and colonize the bone marrow was unimpaired after fasting treatment. This indicates that fasting specifically damages the maintenance of long-lived plasma cells already resident in the bone marrow, without affecting the processes of plasma cell generation or homing.