Understanding the Basics of Memory B Cells—The Antibody Factory

B cells generate humoral immunity by secreting immunoglobulins (Igs; aka antibodies, Abs) that are specifically selected for high-affinity binding to foreign substances. By 5 or so days after infection or immunization, specific Abs can be detected in serum in the form of IgM heavy chains.^[26] 

Over the next three weeks, Ab levels increase and shift to IgG and IgA heavy chains as antibody affinity increases because of ongoing somatic mutation, reducing the levels of Abs needed for protection. 

Most IgA Abs are delivered to mucosal surfaces, while IgG Abs typically function in blood, lymph, and tissues. Specific Ab-producing cells persist from weeks to a lifetime depending on the nature of the immunogen.

Abs protect against viral infections in many ways:^[26] 

The simplest and typically most effective mechanism is to bind to virion surface proteins and prevent virus attachment to host cells or viral penetration to the cytosol. The relevant target protein for SARS-CoV-2 and other CoVs is the spike glycoprotein, which attaches virions to ACE2 receptors on host cells. Such Ab-mediated “neutralization” is the only adaptive immune mechanism to provide truly sterilizing immunity: i.e., zero virus infection of host cells. 

The Ig N terminus, known as the Fc domain, functions as a bridge to innate immune effector functions. These include binding to Fc receptors on natural killer cells or macrophages, which, respectively, can kill infected cells displaying bound anti-viral Abs or phagocytose and destroy Ab-decorated virions. Fc also can interact with complement proteins to lyse cells expressing viral surface proteins or enhance the potency of Abs bound to the virion surface.

 

Immune Memory

Immune memory (or immunological memory), from either primary infection or immunization, is the source of protective immunity from a subsequent infection.^[3-5] Thus, COVID-19 vaccine development is closely tied to the topic of immunological memory.^[6,7]

A thorough understanding of immune memory to SARS-CoV-2 requires evaluation of its various components, including:^[2]

• B cells (aka B lymphocytes)
• CD8+ T cells (aka killer T-cells or cytotoxic T cells)
• CD4+ T cells (i.e., T helper cells)

as these different cell types may have immune memory kinetics relatively independent of each other. In this article, we will discuss memory B cell in more details.

Figure 1.  Selenium supplementation boosts T_FH cells in mice and humans (Source: [24])

Memory B Cell

The humoral immune response to infection or vaccination results in two major outcomes: 

1. Production of Antibodies by antibody secreting cells (ASC), which can provide rapid protective immunity
2. Generation of long-lived memory B cells capable of mounting recall responses

If circulating antibodies fail to confer protection to a future exposure, memory B cells drive the recall response by producing new antibodies through formation of new ASC or re-initiating germinal center reactions to generate new high-affinity B cell clones through additional rounds of somatic hypermutation.

In the context of acute SARS CoV2 infection, immunological memory in the form of antibodies and memory B cells has been shown to be durable for over 8 months post-symptom onset.^[19-21] 

However, the magnitude of the memory B cell response induced by vaccination was lower in older individuals, revealing an age-dependence to mRNA vaccine-induced B cell memory.^[18] 

Figure 2.  Clonal expansion is the process by which daughter cells arise from a parent cell. During B cell clonal expansion, many copies of that B cell are produced that share affinity with and specificity of the same antigen.

How B Cells Adapt?

Viruses or bacteria evolve.  But, our immune system also evolve and adapt through antigen-driven selection.  Here we will discuss how B cells evolve and become more selective to a certain antigen.

In our body, antibody factories (i.e., B cells) were created randomly before we were born.  Each B cell only manufacture a single type of antibodies and the scripts of making such antibodies are encoded in the DNA of B cell. 

Normally, our body makes rare mistakes or none when copying DNA.  But B-cells are an exception to that rule: the DNA for the antibody gets copied with an error rate up to 1 million times higher than normal.^[14,15]

Here is how B cells adapt

When a new virus, say SARS-CoV-2, circulates in our body and causes damage, our body fires up the immune system—at this moment, there are still no antibodies specifically targeted to SARS-CoV-2. However, due to the large amount of random antibody designs created earlier, there is a chance that one will stick to the virus.

At beginning, it's could be a weak binding between this antibody and the virus. When a B cell senses that it is “occupied”, it will initiate the command: CLONE AND MUTATE.

The “occupied B-cell” now clones itself.  But, the offspring could be different from the original. Maybe the antibody works a little bit better now, but more often it will be worse.

If the new antibody is an improvement, this copy will have a greater chance of binding to a SARS-CoV-2 again. After activation, this improved B cell now repeat the process: DIVIDE AND MUTATE. And proliferate rapidly upon exposure.

In this way, within a few days to weeks B-cells evolve and adapt, which becomes a factory for antibodies that fit the virus better. And only those well-functioned B-cells will continue to be cloned.  Viola, a new army of effective antibodies could be produced.

Antigen-driven selection of virgin and memory B cells 

A review article^[15] has summarized the evidence indicating that far more B cells are produced in adult bone marrow than are required to maintain B cell numbers in the periphery. 

It is shown that most if not all these newly-formed B cells have the potential to become mature peripheral B cells. However, to do this they need to receive an appropriate signal in secondary lymphoid organs. Cells failing to receive such a signal die after a brief period. 

Two separate situations have been identified which result in recruitment of newly-formed virgin B cells into the peripheral B-cell pool: Following activation by antigen.

These B-cells then remain active for as long as necessary.  But ,over time they could fall into the sleep mode.  However, they are ready to fight the next infection quickly should it come back. This becomes our long-term immunity.

Figure 3.  Anamnestic Response. 

Figure 4.  Secondary response vs primary response

Primary Response vs Secondary Response

After the primary exposure to an antigen, there is an inductive period of generally several days to a week when no measurable antibodies are detected in the serum. This is the period when the antigen is being exposed to immunocompetent cells, being processed by APCs, clonal selection and clonal expansion are taking place, and B-lymphocytes are differentiating into plasma cells and B-memory cells. Because of the memory cells, however, a second exposure to the same antigen results in more antibodies being made faster for a longer period of time, as shown in the secondary response (see Figure 3&4).

If you're interested in this topic, you can read a good article below for more information:

Anamnestic (Memory) Response

Video 1.  B cell boot camp with Gabriel Victora (YouTube link)

References

1. Human T Cell Memory: A Dynamic View
2. Immunological memory to SARS-CoV-2 assessed for greater than six months after infection
3. W. A. Orenstein, R. Ahmed, Simply put: Vaccination saves lives. Proc National Acad Sci. 114, 4031–4033 (2017).
4. P. Piot, H. J. Larson, K. L. O’Brien, J. N’kengasong, E. Ng, S. Sow, B. Kampmann, Immunization: vital progress, unfinished agenda. Nature. 575, 119–129 (2019).
5. S. Plotkin, W. Orenstein, P. Offit, Plotkin’s vaccines, 7th edition (Elsevier, 2018), Elsevier.
6. D. S. Stephens, M. J. McElrath, COVID-19 and the Path to Immunity. Jama. 324 (2020), doi:10.1001/jama.2020.16656.
7. F. Krammer, SARS-CoV-2 vaccines in development. Nature, 1–16 (2020).
8. S. M. Kissler, C. Tedijanto, E. Goldstein, Y. H. Grad, M. Lipsitch, Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science. 368, 860–868 (2020).
9. C. M. Saad-Roy, C. E. Wagner, R. E. Baker, S. E. Morris, J. Farrar, A. L. Graham, S. A. Levin, M. J. Mina, C. J. E. Metcalf, B. T. Grenfell, Immune life history, vaccination, and the dynamics of SARS-CoV-2 over the next 5 years. Science, eabd7343 (2020).
10. R. S. Akondy, M. Fitch, S. Edupuganti, S. Yang, H. T. Kissick, K. W. Li, B. A. Youngblood, H. A. Abdelsamed, D. J. McGuire, K. W. Cohen, G. Alexe, S. Nagar, M. M. McCausland, S. Gupta, P. Tata, W. N. Haining, M. J. McElrath, D. Zhang, B. Hu, W. J. Greenleaf, J. J. Goronzy, M. J. Mulligan, M. Hellerstein, R. Ahmed, Origin and differentiation of human memory CD8 T cells after vaccination. Nature. 552, 362–367 (2017).
11. Vaccine bootcamp (nice animation)
12. Immunological Memory — The Source of Protective Immunity from a Subsequent Infection
13. Researchers discover how cells remember infections decades later
14. The mutation patterns in B-cell immunoglobulin receptors reflect the influence of selection acting at multiple time-scales
15. Antigen-driven selection of virgin and memory B cells
16. Our amazing immune system
17. B cells responses and cytokine production are regulated by their immune microenvironment
18. Longitudinal Analysis Reveals Distinct Antibody and Memory B Cell Responses in SARS-CoV2 Naive and Recovered Individuals Following mRNA Vaccination
19. Dan, J. M. et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science (80-. ). 371, eabf4063 (2021).
20. Rodda, L. B. et al. Functional SARS-CoV-2-Specific Immune Memory Persists after Mild COVID559 19. Cell 184, 169-183.e17 (2021).
21. Ellebedy, A. et al. SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans.  Research square (2020)
22. Hybrid Immunity
23. Immunological Memory — The Source of Protective Immunity from a Subsequent Infection
24. Selenium saves ferroptotic TFH cells to fortify the germinal center
25. T cells in Human Disease 
26. Antigenic drift: Understanding COVID-19 (good)