Shorter answer

Already by 6 months of age, gut microflora polysaccharides stimulate antibodies capable of binding ABO blood group antigens (1). In particular, anti-histo blood group B antibodies can bind gut microflora (2) while the environmental trigger for anti-histo blood group A still remains undefined (3).

Thus, rather than indicative of defense, Cross-reactivity – Wikipedia as in structural similarity between microbial and histo-blood group antigens explains antibodies against the latter. The 20th century human invention of blood transfusion simply uncovers the scope of such cross-reactivity (4).

A dynamic snapshot of a person’s immunological history, circulating antibodies embody the immunological imprint of past antigenic encounters. However, which antigens specifically induce such circulating antibodies? Grouped under the umbrella term, Natural antibodies – Wikipedia, they’re found in circulation even in absence of explicit infection. In actuality, the term simply signifies unknown antigenic targets triggered such antibodies. Until recently, explicitly looking for such antigens was akin to looking for the proverbial needle in a haystack.

Now though Systems biology – Wikipedia approaches that combine high-throughput computational and Omics – Wikipedia techniques are beginning to trace out the broad overlaps in structure within the universe of antigens, overlaps that antibodies and other receptors of the Adaptive immune system – Wikipedia already so brilliantly glom onto when they bind their antigenic targets so specifically.

Such studies reveal how a contradiction of terms, specificity married to redundancy, could even come to be such a hallmark feature of the adaptive immune system receptors. For example, one study (5) suggests a universal architecture for the human anti-carbohydrate antibody repertoire, universal implying capacity to bind structurally similar Moiety (chemistry) – Wikipedia across living organisms, be they microbes or mammals.

Back in the mid-20th century, Arthur Mourant – Wikipedia proposed that modern-day geographic ABO distributions are the consequence of past epidemics (6). Though severely understudied, research spanning decades has in fact uncovered several examples of antibodies that cross-react on microbial and histo-blood group antigens.

  • Exposure to bacterial antigens stimulates anti-histo blood group antigen antibody titers (7), suggesting the two, bacterial and blood group antigens, are antigenically related.
  • As far back as 1971, researchers discovered that blood group O and A volunteers fed E.coli O86 had spike in anti-blood group B antibody titers (1), clearly indicating antigenic similarity between E.coli O86 and blood group B antigens.
  • Histo-blood group and viral antigen similarities have been reported for SARS Coronavirus – Wikipedia (Severe acute respiratory syndrome – Wikipedia) (8) and Crimean–Congo hemorrhagic fever – Wikipedia virus (9).

Such cross-reactivity can co-exist with immunological tolerance to one’s own histo-blood group antigens since sources of antibodies, the B cell – Wikipedia with receptors capable of binding them would get deleted through the process of developmentally dictated tolerance.

Longer Answer With Some Examples Of Antibodies Cross-Reactive to Histo-Blood Groups & Microbial Antigens

Table below from 10 lists some linkages between disease-causing/associated microbial agents and blood groups.


O blood group is associated with resistance to severe malaria (11). As well, high percentage of O blood group individuals in malaria-endemic regions suggests selective advantage of having this blood group (12). Malaria seems to have exerted selective pressure in blood group distribution (13).


Anti-Vibrio cholerae antibody response induced by cholera vaccines was lower in blood group O compared to A individuals (14, 15). Epidemiological studies have found O blood group correlates with cholera disease severity (16, 17) fueling the speculation cholera selection pressure may account for the extremely low and high prevalence of histo-blood groups O and B, respectively, among people living in the Gangetic Delta (18, 19).

FUT2 – Wikipedia Lewis Blood Group Antigen: Rotavirus & Norovirus

Rotavirus infectivity appears to be highly dependent on histo-blood groups (7). Non-B and FUT2 – Wikipedia secretor blood groups tend to be more susceptible to norovirus and rotavirus infection-associated gastroenteritis (13, 20, 21). In a test of norovirus vaccine candidates, anti-histo blood group antibody titers in placebo group individuals positively correlated with protection while vaccinees with higher pre-challenge anti-histo blood group antibody titers had lower frequency of severe disease (22). OTOH, FUT2 – Wikipedia secretor phenotype is associated with influenza, respiratory syncytial virus, echovirus (23).


Anti-histo blood group antibodies could even function to neutralize viruses such as HIV, albeit in a blood group-specific manner. For example, an anti-blood group A monoclonal antibody could neutralize HIV viruses isolated from peripheral blood lymphocytes from blood group A donors but not B or O donors (24, 25).


The biomedical literature is pockmarked with sporadic reports of various vaccines triggering increase in anti-histo blood group antibodies, pneumoccocal vaccine (26) and tetanus and diphtheria toxoids (27) being cases in point. Again antigenic similarity explains the data. Streptococcus pneumoniae‘s polysaccharide capsule and pig stomach pepsin used back then to produce toxoids, both contain an A-like substance (28).

Lifestyle & Diet Influence Anti-Histo Blood Group Antibodies

Some volunteers who took probiotic supplements developed high anti-histo blood group B antibody titers (28). Turned out some bacterial strains in these supplements had antigenic similarity to histo-blood group B antigens.

Children who are fed intravenously for a long time have low to practically non-existent ABO antibodies, especially anti-B (29). Being essentially ‘sterile’, such nutrition alters and reduces gut microflora suggesting major source of triggers for anti-histo blood group antibodies are gut microflora. Interesting then that mean ABO titers have declined dramatically among those on present-day diet of processed, ‘pasteurized’ food compared to historical controls (30).


1. Springer, G. F. “Blood-Group and Forssman Antigenic Determinants Shared between Microbes and Mammalian Cells1.” Progress in Allergy Vol. 15. Karger Publishers, 1971. 9-77.

2. Galili, U., et al. “Interaction between human natural anti-alpha-galactosyl immunoglobulin G and bacteria of the human flora.” Infection and immunity 56.7 (1988): 1730-1737. https://www.ncbi.nlm.nih.gov/pmc…

3. Branch, Donald R. “Anti‐A and anti‐B: what are they and where do they come from?.” Transfusion 55.S2 (2015): S74-S79. https://www.researchgate.net/pro…

4. Blackwell, C. Caroline, et al. “Blood group phenotypes and infectious diseases.” Susceptibility to infectious diseases: the importance of host genetics 4 (2004).

5. Schneider, Christoph, et al. “The human IgG anti-carbohydrate repertoire exhibits a universal architecture and contains specificity for microbial attachment sites.” Science translational medicine 7.269 (2015): 269ra1-269ra1. https://www.ncbi.nlm.nih.gov/pmc…

6. Mourant, Arthur Ernest. “The Distribution of the Human Blood Groups.” The Distribution of the Human Blood Groups. (1954).

7. Cooling, Laura. “Blood groups in infection and host susceptibility.” Clinical microbiology reviews 28.3 (2015): 801-870. Blood Groups in Infection and Host Susceptibility

8. Guillon, Patrice, et al. “Inhibition of the interaction between the SARS-CoV spike protein and its cellular receptor by anti-histo-blood group antibodies.” Glycobiology 18.12 (2008): 1085-1093. https://www.researchgate.net/pro…

9. Güven, Ahmet Sami, et al. “Value of ABO blood group in predicting the severity of children with Crimean-Congo hemorrhagic fever.” International journal of clinical and experimental medicine 7.2 (2014): 416. https://www.ncbi.nlm.nih.gov/pmc…

10. Dotz, Viktoria, and Manfred Wuhrer. “Histo-blood group glycans in the context of personalized medicine.” Biochimica et Biophysica Acta (BBA)-General Subjects 1860.8 (2016): 1596-1607. https://www.researchgate.net/pro…

11. Timmann, Christian, et al. “Genome-wide association study indicates two novel resistance loci for severe malaria.” Nature 489.7416 (2012): 443-446.

12. Anstee, David J. “The relationship between blood groups and disease.” Blood 115.23 (2010): 4635-4643. https://www.researchgate.net/pro…

13. Tirumalai Kamala’s answer to What are the similarities of people having the same blood group?

14. Clemens, John D., et al. “ABO blood groups and cholera: new observations on specificity of risk and modification of vaccine efficacy.” The Journal of infectious diseases 159.4 (1989): 770-773.

15. Qadri, Firdausi, et al. “Peru-15, a live attenuated oral cholera vaccine, is safe and immunogenic in Bangladeshi toddlers and infants.” Vaccine 25.2 (2007): 231-238. https://www.researchgate.net/pro…

16. Barua, D., and A. S. Paguio. “ABO blood groups and cholera.” Annals of human biology 4.5 (1977): 489-492.

17. Glass, Roger I., et al. “Predisposition for cholera of individuals with o blood group possible evolutionary significance.” American journal of epidemiology 121.6 (1985): 791-796.

18. Harris, Jason B., and Regina C. LaRocque. “Cholera and ABO Blood Group: Understanding an Ancient Association.” The American Journal of Tropical Medicine and Hygiene 95.2 (2016): 263-264. https://pdfs.semanticscholar.org…

19. Kuhlmann, F. Matthew, et al. “Blood group O–dependent cellular responses to cholera toxin: parallel clinical and epidemiological links to severe cholera.” The American journal of tropical medicine and hygiene (2016): 16-0161.

20. Tirumalai Kamala’s answer to Why do my American friends get sick by norovirus every Thanksgiving, but I’ve never seen a Russian citizen gotten sick by norovirus in her homeland?

21. Payne, Daniel C., et al. “Epidemiologic association between FUT2 secretor status and severe rotavirus gastroenteritis in children in the United States.” JAMA pediatrics 169.11 (2015): 1040-1045. <i>FUT2</i> Secretor Status and Severe Rotavirus Gastroenteritis

22. Atmar, Robert L., et al. “Serological correlates of protection against a GII. 4 norovirus.” Clinical and Vaccine Immunology 22.8 (2015): 923-929. https://www.researchgate.net/pro…

23. Raza, M. W., et al. “Association between secretor status and respiratory viral illness.” Bmj 303.6806 (1991): 815-818. http://pubmedcentralcanada.ca/pm…

24. Arendrup, Maiken, et al. “Antibody to histo-blood group A antigen neutralizes HIV produced by lymphocytes from blood group A donors but not from blood group B or O donors.” Aids 5.4 (1991): 441-444.

25. Rother, Russell P., et al. “A novel mechanism of retrovirus inactivation in human serum mediated by anti-alpha-galactosyl natural antibody.” Journal of Experimental Medicine 182.5 (1995): 1345-1355. http://europepmc.org/backend/ptp…

26. Boyer, Kenneth M., et al. “Antibody response to group B streptococcus type III and AB blood group antigens induced by pneumococcal vaccine.” The Journal of pediatrics 98.3 (1981): 374-378.

27. Elliott, G. B. “Transiently dangerous universal blood donor.” Canadian Medical Association journal 70.5 (1954): 571. https://www.ncbi.nlm.nih.gov/pmc…

28. Daniel‐Johnson, Jennifer, et al. “Probiotic‐associated high‐titer anti‐B in a group A platelet donor as a cause of severe hemolytic transfusion reactions.” Transfusion 49.9 (2009): 1845-1849. https://www.ncbi.nlm.nih.gov/pmc…

29. Cooling, L. W., et al. “Abo Typing Discrepancies in Children Requiring Long-term Nutritional Support.” Transfusion 47 (2007): 9A-10A.

30. Mazda, T., et al. “Differences in ABO antibody levels among blood donors: a comparison between past and present Japanese, Laotian, and Thai populations.” Immunohematology/American Red Cross 23.1 (2006): 38-41.