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)

Stopping Drinking Milk Especially If You Have a Leaky Gut

It seems that drinking cow milk is bad especially when you have a leaky gut. 

The BCM7 (a 7 amino-acids peptide)  is the peptides that you will get from drinking cow milk.

Adverse Health Effects from Drinking Cow Milk

Biological role of BCM7 still remains unclear.  But there is strong evidence that these peptides may modulate gastrointestinal, immune and nervous systems. 

• Researchers concluded that consumption of cow milk containing BCM7 may induce inflammatory response in gut by activating Th2 pathway.
• Thus BCM7 are considered to be factors involved in etiology and exacerbation of symptoms in food allergy and atopic dermatitis, diabetes, schizophrenia, postpartum psychoses, sudden infant death syndrome, apparent life-threatening event, and autism.

Avoid Yogurt Too

Note that taking yogurt actually is worse than drinking milk.  cCGP (or cow caseinoglycopeptide) in the diagram shows that concentrations of cCGP in the blood after milk or yogurt ingestion.

My findings are mainly based on below video which mainly links cow milk to Autism.   In addition to above mentioned adverse health effects.  Drinking milk was also linked to as the risk factor of Prostate Cancer.

References

1. Does A2 Milk Carry Less Autism Risk?
2. Chabance B, Marteau P, Rambaud JC, Migliore-Samour D, Boynard M, Perrotin P, Guillet R, Jollès P, Fiat AM. Casein peptide release and passage to the blood in humans during digestion of milk or yogurt. Biochimie. 1998 Feb;80(2):155-65. 
3. The establishment of cow's milk protein allergy in infants is related with a deficit of regulatory T cells (Treg) and vitamin D

Could Pre-existing Immunities the Explanation of Taiwan's Mystery

Figure 1.  Number of new infections (08/17/2021; Source: Nikkei Asia)

Taiwan has seen extremely low cases and – more importantly – low death rates in the current COVID-19 pandemic.  On 11/07/2020, there is an article titled:^[1]

The Mystery Of Taiwan

published on the ZeroHedge website.  Here is the question asked in that article:

We are still left with a mystery. Taiwan did not lock down. It did not widely test. And yet it had the lowest death rate per million of any populous country in the world. It experienced 0.3 deaths per million and ranks 189th in the world.

As much as public health authorities in the West want to consider policy as a decisive factor in the success or failure of pandemic response, the Taiwanese case might have nothing at all to do with the public policy response.  

If public policy response is not the real explanation, then what is it?  Could it be pre-existing immunities?

Figure 2. Taipei 101 (right)

Pre-existing Immunity

An article published on Nature, it states that pre-existing immunity to common-cold coronaviruses or to other antigens could be another possible determinant of COVID-19 disease severity.  Here are the summary of the evidences presented in that article:^[2]

• T cell reactivity to SARS-CoV-2 has been detected in unexposed individuals.
• Presumably due to cross-reactive immunity to common-cold coronaviruses^[3] or to other antigens, as has been shown for other virus-specific T cells.^[4]
• A study found SARS-CoV-1 reactive T cells in patients who were infected with SARS 17 years ago.^[5]
• T cell reactivity is found in unexposed individuals and has been linked to prior exposures to common-cold coronaviruses.^[6]
•  IgG that is specific to SARS-CoV-2 spike protein has been found in unexposed individuals
• Particularly in children and young adults, and some of these had neutralizing activity against SARS-CoV-2, indicating a potentially protective effect against severe COVID-19.^[7]  
• However, another study also identified such antibodies but found no evidence for a protective effect against COVID-19.^[8] 
• Cross-reactive antibodies are also more frequently found in serum samples collected in sub-Saharan Africa prior to the COVID-19 pandemic.^[9] 
• This provides a possible explanation for the surprisingly low number of severe COVID-19 cases seen on this continent.

Conclusion

The real explanation of Taiwan's mystery could deal with innate immunities from other vaccines or virus exposures.  

Even though about 680 people in Taiwan were infected with SARS in 2003, the study shows a possibility that enduring T cells could influence the effect SARS-CoV-2 has on people with certain preexisting immunities. A different study found that there were strong differences in mortalities between Asia, the Middle East, Latin America, and Western countries, suggesting that genetic factors may also play a role in these disparities.

But, the above conclusion is just speculation without further proofs and scientific researches.

 

References

1. The Mystery Of Taiwan
2. Immune determinants of COVID-19 disease presentation and severity
3. Grifoni, A. et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 181, 1489–1501 (2020).
4. Su, L. F., Kidd, B. A., Han, A., Kotzin, J. J. & Davis, M. M. Virus-specific CD4+ memory-phenotype T cells are abundant in unexposed adults. Immunity 38, 373–83 (2013)
5. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls
6. Mateus, J. et al. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science 370, 89–94 (2020).
7. Ng, K. W. et al. Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. Science 370, eabe1107 (2020).
8. Anderson, E. M. et al. Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection.
9. Tso, F. Y. et al. High prevalence of pre-existing serological cross-reactivity against SARS-CoV-2 in sub-Sahara Africa. Int. J. Infect. Dis. 102, 577–583 (2020).
10. BBC Discovery — Covid origins: The science

Vitamin D3 — A Promising Candidate for Prevention and Treatment of COVID-19

Figure 1.  I-MASK+ (Prophylaxis & Early Outpatient Treatment Protocol for Covid-19)

In Figure 1, it shows the prophylaxis protocol proposed by FLCCC Alliance.^[1] And, the below items on the proposed list:

• Vitamin D3
• Vitamin C
• Quercetin
• Zinc
• Melatonin

are added as immune boosters for fighting Covid-19 virus.

In this article, we will discuss why Vitamin D3 could be a promising candidate for prevention and treatment of COVID-19.

Vitamin D3 — A promising treatment option for COVID-19

Vitamin D is not actually a vitamin. By definition, a vitamin is a substance that is essential to human health but cannot be produced by the body. Vitamin D is essential to the metabolism of calcium and phosphorous in the body. However it is also produced by our bodies when we are exposed to UVB rays of the sun.

Based on multiple recent studies, vitamin D3 is believed to be a promising candidate for prevention and treatment of Covid-19:^[2]

• A French experimental study
• At a nursing home with 66 people suggested that taking regular vitamin D supplements was “associated with less severe Covid-19 and a better survival rate”. 
• A study of 200 people in South Korea 
• The study suggested that vitamin D deficiency could “decrease the immune defenses against Covid-19 and cause progression to severe disease”. 
• Preliminary research by Queen Elizabeth Hospital foundation trust and the University of East Anglia 
• The research found a correlation between European countries with low vitamin D levels and coronavirus infection rates. 
• Broadly, countries closer to the equator have been less affected by Covid-19 than those further away from it, though Brazil and India are notable exceptions. 
• A study at Singapore General Hospital
• The study found that treating patients with a combination of vitamin D, magnesium and vitamin B12 was associated with a “significant reduction” in the worst outcomes.
• A Spanish study
• The study conducted in early September, that came close to incontrovertibly proving low vitamin D levels have a pivotal role in causing increased death rates. 
• There, 50 patients with Covid-19 were given a high dose of vitamin D, while another 26 patients did not receive the nutrient. Half of patients who weren’t given vitamin D had to be placed in intensive care, and two later died. Only one patient who received vitamin D required ICU admission, and they were later released with no further complications.

Conclusion

In April of 2020, dozens of doctors wrote to the British Medical Journal describing the correction of vitamin D deficiencies as “a safe, simple step” that “convincingly holds out a potential, significant, feasible Covid-19 mitigation remedy”.

Finally, as stated in my companion article:^[3]

Important Health Benefits of Vitamin D

there are many other health benefits of supplementing with vitamin D.

 

References

1. FLCCC Alliance (Front Line Covid-19 Critical Care Alliance)
2. Does vitamin D combat Covid?
3. Important Health Benefits of Vitamin D
4. Can Vitamin D Help With Covid-19 Coronavirus? Here Is The Science