Role of antibodies and the cells that synthesize them, B cell, in protection against TB is a really important yet woefully neglected question. Is it even true Antibody has no protective role against TB (Tuberculosis)? The problem is a 100+ year old dogma that antibodies don’t protect against TB disease has held sway since the early 20th century. This created a scientific culture in TB research that rendered the idea of a protective role for antibodies against TB disease scientifically unpopular and stymied a rational, rigorous and systematic effort to explore their role in TB disease and resistance. How did this dogma get established and why does it dominate so? We need to dip a bit into history to understand that.
How The Outdated And Likely Wrong Dogma That Antibody Is Unprotective Against TB Disease Got Established
In the late 19th and early 20th centuries, efforts to treat TB disease using antibodies proved inconclusive. In those early days of microbiology ‘Serum Therapy’ (Antiserum) was the practical approach to assess whether or not antibody could be protective against a microbial disease. This entailed taking serum from an animal infected with a microbe and injecting it into a healthy one, and then challenging it with that same microbe. The liquid portion of blood after it clots, serum contains circulating antibodies, and serum therapy was found to prevent disease by microbes such as Streptococcus pneumoniae (causes pneumococcal pneumonia) and Neisseria meningitidis (causes meningitis).
Experiments also showed serum therapy worked with ‘immune’ but not ‘non-immune’ serum, i.e., only from serum obtained from animals injected with the specific microbes. Immune serum was thus functionally different from non-immune, meaning infection had induced some circulating component(s) with the capacity to prevent the same infection in uninfected, i.e., naive, animals. In the case of humans, immune serum was typically obtained from a convalescent, i.e., someone who’d successfully recovered from a natural infection. Serum therapy exists even today in the form of rabies immunoglobulin injected in people believed to have been bitten by a rabid animal.
Did serum therapy work against TB Disease? Short answer, no. According to an extremely detailed and thorough 1998 review by Aharona Glatman-Freedman and Arturo Casadevall, several attempts to successfully use serum therapy against TB disease in cow, donkey, horse and sheep were published between 1895 to 1934 (1).
Upshot? Unlike for microbes such as S. pneumoniae and N. meningitidis where serum therapy clearly worked, results were scatter-shot and all over the place with TB disease. With no consensus to support it, serum therapy thus fast faded from the TB scene. Science culture also played its role in this demise. After all, science doesn’t happen in a vacuum and ideas that dominate over time tend to ensue from individuals who dominate the field in their time. In those days the likes of Albert Calmette, Edward Livingston Trudeau dominated the TB field and they strongly believed that cells, i.e., Cell-mediated immunity, rather than antibodies, i.e., Humoral immunity, were important in controlling chronic TB disease, a situation they explicitly contrasted with acute S. pneumoniae and N. meningitidis diseases.
Let’s remember that back in those days little was known about the immune system. But given the human wont to classify, even back then cells could be easily differentiated from body fluids. Thus, even with the limited technology of those days, humoral, i.e., fluid-based, immunity was separable from cellular, i.e., cell-based, immunity. Common understanding is that humoral immunity means antibodies. Of course, this terminology was established long before T and B cells were discovered and long before the latter were identified as the source of antibodies. Separating humoral from cellular immunity, this absurd terminology representing truly outdated ideas persists even into our times, absurd because the former, humoral, is a product of the latter, cellular, specifically B cells.
Thus, dominated by early 20th century ideas of the kinds of immune responses deemed effective or ineffective against it, TB and immune system research proceeded to develop on parallel paths. As B and T cell were discovered in the 1950s to 1970s, and work continued apace to understand how they developed and functioned, this information was incorporated into the TB field on top of the pre-existing dogma that antibodies played no protective role against TB.
The choice to separate immune responses effective against TB disease from those effective against bacteria like S. pneumoniae and N. meningitidis also became premised on the distinction that TB disease’s causative agent, Mycobacterium tuberculosis (MTB), is an intracellular bacterium while the latter are extracellular. And of course, by then the idea that antibodies could be effective against entities residing inside cells had quickly become heresy.
Thus, as others took over the reins of TB research in the mid to late 20th century, the dogma persisted, with primacy accorded not to B cells and antibodies but rather to the phagocyte, Macrophage, the cell considered to be the primary site of MTB infection and growth, and to the T helper cell, the cell that should engage and guide these infected cells to exterminate their cargo of ingested mycobacteria. Succeeding generations of TB researchers continued disproportionately mining these same well-trod furrows while neglecting other aspects of the immune system, especially B cells and antibodies.
Another reality of science culture is that ideas that counter the dominating dogma are less likely to be funded and thus less likely to be studied. This is not to say that role of antibodies in TB stopped being studied. Just that focus of such studies became primarily technical as in efforts to develop serologic tests for TB disease diagnosis while B cell and antibody’s roles in helping establish or prevent TB disease remained a sparse and niche field that continued to yield contradictory results.
Some Data From More Recent Human Studies Support Roles For B Cells And Antibodies In Protection Against TB Disease
- Patients with TB disease among a Mexican Totonaca Indian population had better outcome if they had circulating anti-TB antibodies directed against the specific MTB antigen, Ag85 (2).
- Serum samples from healthy volunteers given two intradermal BCG vaccinations 2 months apart contained specific anti-MTB antibodies that demonstrated two critical protective features (3)
- Enhanced the ability of neutrophils and monocytes/macrophages to inhibit MTB’s growth within them.
- Enhanced proliferation of interferon-gamma secretion by MTB-specific CD4 and CD8 T cells. Interferon gamma is considered to be a critical cytokine for instructing infected macrophages and other phagocytes to turn on the biochemical machinery capable of killing intracellular mycobacteria.
Basis For Reconsidering Protective Roles For B Cells And Antibodies Against TB Disease
The absurdly reductionist view that an intracellular MTB is beyond the reach of antibodies overlooks the many pathways by which antibodies could still modify outcomes of such infections, ranging from engaging Fc receptor on the infected cell’s surface to Opsonin to Complement system activation, not to mention the many ways B cells could hep effect protection (see figures below from 4, 5 for some additional details). Such antibody-MTB engagement could
- Enhance MTB’s uptake by Phagocyte in a manner that enhances their killing.
- Enhance the capacity of MTB-specific T cells to secrete Cytokine capable of helping infected macrophages and other phagocytes turn on the biochemical machinery capable of killing intracellular mycobacteria they ingested.
Another research avenue grievously overlooked in TB-antibody research is the role of anti-MTB antibodies present in locations other than blood. TB is an airborne infection acquired through inhalation of MTB-laden aerosol droplets expelled by a person with active TB disease. It thus enters the body through the airways and indeed lung tissue is its primary target. Thus, the first cell types and pertinently, immune cell types it encounters are associated with respiratory mucosal membranes, i.e., Mucosal immunology. In that regard, one of the most neglected aspects in TB research is the potential role of mucosa-associated Immunoglobulin A antibodies in protecting against TB, a major oversight since the vast bulk of TB-antibody studies such as they are focus on circulating, i.e., blood-associated, anti-TB antibodies.
1. Glatman-Freedman, Aharona, and Arturo Casadevall. “Serum Therapy for Tuberculosis Revisited: Reappraisal of the Role of Antibody-Mediated Immunity againstMycobacterium tuberculosis.” Clinical Microbiology Reviews 11.3 (1998): 514-532. Reappraisal of the Role of Antibody-Mediated Immunity againstMycobacterium tuberculosis
2. Sanchez-Rodriguez, C., et al. “An IgG antibody response to the antigen 85 complex is associated with good outcome in Mexican Totonaca Indians with pulmonary tuberculosis.” The International Journal of Tuberculosis and Lung Disease 6.8 (2002): 706-712. http://www.ingentaconnect.com/co…
3. De Valliere, S., et al. “Enhancement of innate and cell-mediated immunity by antimycobacterial antibodies.” Infection and immunity 73.10 (2005): 6711-6720. Enhancement of Innate and Cell-Mediated Immunity by Antimycobacterial Antibodies
4. Rao, Martin, et al. “B in TB: B Cells as Mediators of Clinically Relevant Immune Responses in Tuberculosis.” Clinical Infectious Diseases 61.suppl 3 (2015): S225-S234. B Cells as Mediators of Clinically Relevant Immune Responses in Tuberculosis
5. Achkar, Jacqueline M., John Chan, and Arturo Casadevall. “B cells and antibodies in the defense against Mycobacterium tuberculosis infection.” Immunological reviews 264.1 (2015): 167-181. B cells and Antibodies in the Defense against Mycobacterium tuberculosis infection