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Assuming illness refers to infection, first, could one know for certain that an infection didn’t induce antibody production? Typically, we look for infection-specific antibodies in blood. However, absence of infection-specific antibodies in blood doesn’t mean their absence per se since they may be abundant as infection-specific IgA antibodies in saliva or other mucosal secretions. Such site-specific antibodies are missed if only blood’s examined for infection-specific antibodies.

Second, antibodies are sometimes, not always, necessary to control infections. However, it’s far from easy, even practically impossible to experimentally determine whether antibody is both necessary and sufficient to control a particular human infection. Why? Because this requires several experimental interventions, namely,

  • Selective inhibition/deletion of particular genes necessary for B cell development, activation, memory formation and antibody production.
  • Experimental infection of such mutated individuals with a particular infectious disease agent.
  • Comparison of disease outcome in such experimentally mutated subjects with healthy, unmutated ones.
  • Lack of infection control only in the former, not the latter, would be proof positive of essential, non-redundant role of antibodies in control of that particular infection.

Obviously such interventions are impossible in human but very much possible in an experimental animal model such as the mouse which is one of the reasons it became the most common experimental animal model for human infectious disease.

Since such interventions are impossible in human, how could we ascertain when antibodies are absolutely necessary against an infection? Through nature because nature can and does perform such experiments in the form of non-lethal mutations that enable fetal development and birth but which nevertheless selectively impair B cell function, particularly antibody production. What do such examples teach us about antibody necessity and relevance?

In 1952, Ogden C. Burton reported the case of an 8-year old boy who repeatedly developed pneumococcal sepsis and had complete absence of circulating antibodies, i.e., agammaglobulinemia (1). Subsequent research showed the cause of this particular agammaglobulinemia to be X-linked agammaglobulinemia (XLA). Similar combination of specific recurrent infections and complete absence of circulating antibodies but this time in an adult was reported in 1953 (2), the cause here being Common variable immunodeficiency (CVID). While XLA mainly affects males with symptoms showing up in childhood and entails little/no circulating B cells, CVID affects males and females equally with adult patients typically having ~normal B cells. Both XLA and CVID, however, suffer from recurrent infections, typically involving encapsulated bacteria such as Haemophilus infuenzae and Streptococcus pneumoniae. Subsequently a wide variety of B cell mutations causing selective antibody deficiency have been identified, all having the common feature of being highly susceptible to infections with Polysaccharide encapsulated bacteria (3, 4). This obviously means antibodies are critical in controlling such infections.

Since recurrent infections with encapsulated bacteria are hallmark features for individuals with a wide range of impairments in B cells and antibodies, it’s reasonable to assume antibodies are critical in controlling such infections in a non-redundant manner, i.e., in a manner that can’t be compensated by other components of the immune system. Why is this so? These bacteria typically infect a local site close to where they gain entry into the body, i.e., portal of entry, say the respiratory tract. As long as they stay localized in such local tissues, fallout of infection is minimal and easily contained. However, if these bacteria gain access to circulation and spread to other sites such as brain, they can cause much more serious infections leading to death. Antibodies specific for antigens of these bacteria can bind such bacteria and prevent their systemic, i.e., blood, spread. Why can’t other components of the immune system take over the function of stopping systemic spread of encapsulated bacteria in absence of antibodies? Capsule of such encapsulated bacteria are  typically complex polysaccharides. T cells, the other major component of the immune system, can’t bind carbohydrates. Thus, in absence of antibodies, such bacteria aren’t effectively controlled. This is why inducing effective and robust antibody production is the basis of vaccines against these bacteria, and the reason such vaccines have been highly effective in controlling encapsulated bacterial infections.

Logical corollary for antibodies being effective only sometimes, not always, involves examples where antibodies are counter-productive. Tuberculosis (TB) is an example where this is the case. While exact role of antibodies in TB infection control is still unclear, high circulating anti-TB antibodies are usually associated with TB disease and not its control. Thus, plenty of antibodies are useful only as long as they effectively contain the infection and this isn’t always the case.

Third, often an infection can be effectively contained by other types of immune responses. For example, when CD4 helper T cells are appropriately activated, they exercise control over monocytes and macrophages, correctly instructing them in effective TB control. Similarly, in viral infections, often CD8 cytotoxic killer cells rather than B cells and antibodies are critical for effective control. This is even clearer in patients with B cell deficiencies.

  • In a small study of 12 XLA- and 23 age-matched healthy controls vaccinated with the seasonal flu virus, the DC (dendritic cell) and CD4 and CD8 T cell responses of flu-vaccinated XLA patients were comparable to those of healthy controls (5).
  • Another group also reported normal CD4 T cell responses to pandemic flu vaccine in other B cell deficient patients (6).

Thus, whether or not infections induce antibodies isn’t the relevant question. Rather, issue is whether antibodies are effective in infection control and whether or not such antibody-mediated infection control is redundant. When B cell and antibody roles are redundant, other components of the immune system can still manage to control infection in their absence. However, when they aren’t, as in the case of encapsulated bacteria as an example, situation can be dangerous, life-threatening and even lethal, as it often is for individuals with selective immunodeficiencies in B cells and antibodies.


1. Bruton, Ogden C. “Agammaglobulinemia.” Pediatrics 9.6 (1952): 722-728.

2. Janeway, Ch A., L. Apt, and D. Gitlin. “Agammaglobulinemia.” Transactions of the Association of American Physicians 66 (1953): 200.

3. Conley, Mary Ellen, et al. “Primary B cell immunodeficiencies: comparisons and contrasts.” Annual review of immunology 27 (2009): 199-227. http://download.bioon.com.cn/upl…

4. Conley, Mary Ellen. “Genetics of hypogammaglobulinemia: what do we really know?.” Current opinion in immunology 21.5 (2009): 466-471. http://www.ncbi.nlm.nih.gov/pmc/…

5. Liu, Yinping, et al. “Dendritic and T cell response to influenza is normal in the patients with X-linked agammaglobulinemia.” Journal of clinical immunology 32.3 (2012): 421-429. http://download.springer.com/sta…

6. Pedersen, G., et al. “Pandemic Influenza Vaccination Elicits Influenza‐Specific CD4+ Th1‐cell Responses in Hypogammaglobulinaemic Patients: Four case reports.” Scandinavian journal of immunology 74.2 (2011): 210-218. http://onlinelibrary.wiley.com/d…